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Ivi annual report 2003 2004
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Vaccines, Children and a Better World
The International Vaccine Institute is founded on the belief that the health of children in developing countries can be
dramatically improved by the development, introduction, and use of new and improved vaccines, and that these vaccines
should be developed through a dynamic interaction among the scientific community, public health organizations, and
industry.
Created by the United Nations Development Programme (UNDP), the IVI began formal operations in October 1997
under an independent Board of Trustees. Its programs receive support from international organizations; from private
and public research institutions; and from national governments around the world. The Republic of Korea contributes
to the IVI’s operating budget and hosts the IVI at its state-of-the-art headquarters in Seoul. The IVI’s network of
partnerships and collaborations extends from the World Health Organization (WHO) to leading research laboratories
in the industrialized world and the foremost disease prevention research centers in the developing world. IVI
programs are operating in countries in Asia and Africa and range from field epidemiological and clinical studies to
vaccine development and technology transfer to qualified local vaccine producers.
International Vaccine Institute in Brief
Prof. Samuel Katz, Chairman of the Board of Trustees, with President Roh Moo-hyun
TABLE OF CONTENTS
Letter from the Director 1
Division of Translational ResearchIntroduction 5
Diseases of the Most Impoverished: Typhoid Program 7
Diseases of the Most Impoverished: Cholera Program 11
Diseases of the Most Impoverished: Shigellosis Program 15
Diseases of the Most Impoverished: Existing Data Collection Program 18
Pediatric Dengue Vaccine Initiative 20
Japanese Encephalitis Program 23
Respiratory Encapsulated Bacteria Program: Haemophilus influenzae type b (Hib) Disease 26
Respiratory Encapsulated Bacteria Program: Pneumococcal Disease 29
Rotavirus Diarrhea Program 31
Vaccine Safety Program 34
Division of Laboratory SciencesIntroduction 39
Vaccine Development and Process Research 41
Mucosal Immunology 43
Cellular Immunology 45
Humoral Immunology 47
Molecular Microbiology 50
Technology Transfer Program 52
Building SuccessTraining and Capacity Building 55
IVI Scientific Publications 57
Administration and Finance 61
Organizational Chart 63
Financial Statements 64
Donors to the IVI and the Korea Support Committee 76
International Collaborators 77
Board of Trustees 79
Dear Colleagues,I am pleased to share with you the International Vaccine
Institute’s annual report for 2003-2004, a period of both rapid
growth and change.
Professor Barry Bloom, the Chairman of the Founding Board
of Trustees for the Institute, completed his second term as Chair
in 2003, the maximum number of terms allowed by the IVI
Constitution. The Board elected as its new Chairman Professor
Samuel Katz, Chairman Emeritus of the Department of
Pediatrics at Duke University. Fortunately for the IVI, Professor
Bloom has agreed to stay on the Board as Chairman Emeritus.
In its July 2004 meeting, the Board voted to expand its
membership to include five new seats for representatives of
member countries, and also voted to name Doctor Nay Htun, the
United Nations Development Programme (UNDP) representative
on the Board, as the Chairman of the Institute Support Council
(ISC). Doctor Htun has exciting plans for the ISC, which has the
important mandate of increasing international awareness of the
IVI and its programs and accelerating institutional development.
For the past five years, the IVI has focused its research efforts
on translational research to provide an evidence base for the
rational introduction of new vaccines into programs for the poor
in developing countries. The main priorities of these research
programs, which have been implemented in 12 countries in Asia
and Africa, have been work on vaccines against enteric
infections; vaccines against encapsulated bacteria that cause
invasive infections, such as meningitis and pneumonia; and
vaccines against the mosquito borne Flavivirus infections,
Japanese encephalitis and dengue fever. The programs have
also addressed methods for creating population-based
computerized databases that link vaccination histories to severe
disease outcomes in developing countries, allowing detection
and evaluation of rare but potentially serious adverse vaccine-
related events.
In 2003 the IVI was awarded a US$ 55 million grant by the Bill
& Melinda Gates Foundation for the Pediatric Dengue Vaccine
Initiative (PDVI), a program of research, also funded by the
Rockefeller Foundation, to accelerate the rational introduction of
new vaccines against dengue fever for children in developing
countries. This is the second major grant to the IVI from the Bill &
Melinda Gates Foundation; the first, a grant of US$ 40 million,
was awarded in 2000 to support the Diseases of the Most
Impoverished (DOMI) Program, a program of research and
technical assistance to accelerate the rational introduction of new
vaccines against cholera, typhoid fever, and shigellosis into
public-health programs for the poor in developing countries.
During the past year the IVI has also received large grants from
the Korean International Cooperation Agency (KOICA) for
research that will accelerate the rational introduction of vaccines
against Japanese encephalitis and from the UBS Optimus
Foundation for research into vaccines against paratyphoid fever.
The IVI’s translational research agenda includes clinical trials of
experimental vaccine candidates in developing countries and of
Letter from the Director
1
IVI Director Dr. John Clemens visits a slum in Karachi prior to a trial of a vaccine against typhoid fever.
established vaccines that are not being used in developing
countries, providing the information policymakers need in order
to make rational decisions about vaccine introduction. This
information includes: assessments of the disease burden and its
financial costs; evaluations of the logistical and programmatic
feasibility of introducing new vaccines and of the impact on
disease to be expected of newly introduced vaccines; economic
studies of the cost-effectiveness of vaccine use; behavioral
studies of the public demand and willingness to pay for new
vaccines; and policy analyses of program options and channels
for vaccine introduction and of options for the financial
sustainability of vaccine programs. Recently, IVI scientists and
collaborators in the DOMI Program have begun an ambitious
project to synthesize the diverse epidemiological, clinical,
economic, and behavioral findings of these studies in order to
facilitate decision-making by policymakers at the national level
on the use of vaccines against the diseases targeted by DOMI.
A sample of the other activities of the IVI’stranslational research
programs during the past year, all conducted with local
collaborators, and many done in collaboration with international
groups, include the following:
A study in Mozambique found that recombinant B subunit,
killed whole-cell (rBS-WC) oral cholera vaccine was highly
protective in a population with a high seroprevalence of HIV
infection.
A study in Bangladesh demonstrated that the BS-WC oral
cholera vaccine conferred substantial herd immunity to non-
vaccinated neighbors living in neighborhoods with high levels
of vaccine coverage.
A study in Vietnam demonstrated that a locally developed and
produced, oral killed whole-cell vaccine against cholera
conferred protection for at least three years after immunization.
Coordinated, population-based studies of the shigellosis
disease burden in nearly 500,000 persons residing in
Bangladesh, China, Indonesia, Pakistan, Thailand, and
Vietnam revealed a much greater diversity of epidemiologically
prevalent Shigella species and serotypes than was previously
thought. This observation will have major implications for the
design of new-generation Shigella vaccines because vaccine-
induced protection is thought to be species- and serotype-
specific.
Work in China and Indonesia developed and validated a new
serological method for detecting culture-negative typhoid fever,
which can be used in evaluations of typhoid vaccines.
Large-scale demonstration projects of Vi polysaccharide
vaccine against typhoid fever were launched in approximately
150,000 subjects in China, Indonesia, Pakistan, and Vietnam.
A field site for the study of enteric vaccines was established in
a population of approximately 60,000 persons in the urban
slums of Kolkata, India. A large-scale effectiveness trial of Vi
vaccine against typhoid fever is due to begin in this site in
November 2004.
Studies of rotavirus diarrhea, completed in children in China
and Korea, demonstrated that although the G1-4 serotypes,
conventionally considered to be most prevalent, account for
most cases in China, the G9 serotype is responsible for an
important fraction of cases in Korea.
Population-based studies in China and Vietnam revealed an
unexpectedly high incidence of intussusception in infants, a
finding that indicates that detecting intussusception as a side-
effect of newer generation rotavirus vaccines may be more
difficult in these settings.
Population-based research in Bali, Indonesia, demonstrated an
incidence of Japanese encephalitis that is among the highest in
the world, contradicting the prevailing wisdom that Japanese
encephalitis is not a major problem in Indonesia and
suggesting that vaccination against Japanese encephalitis
needs to be considered for Indonesia.
An innovative, population-based computerized database,
linking vaccination histories to severe disease outcomes in Nha
Trang, Vietnam, was successfully established. It demonstrated
that a mass immunization of Vietnamese children and
adolescents against measles was not associated with
2
Letter from the Director
Dr. John D. Clemens, Director of the IVI
significant side-effects.
Technical assistance and training has continued to be a major
component of the IVI’sprograms. The Institute has continued to
participate in the Global Training Network of the WHO. The IVI’s
Annual International Course on Vaccinology, including basic
science, clinical, epidemiology, and policy topics, given in each of
the past four years with support from the Bill & Melinda Gates
Foundation, GlaxoSmithKline, the Rockefeller Foundation, and
Sartorius, expanded in 2004. In addition, during the past year, in
collaboration with GlaxoSmithKline, the IVI offered its first
courses on Good Clinical Practices for clinical trials to public-
health professionals in developing countries. With support from
the Bill & Melinda Gates Foundation and AusAID, the IVI
provided technical assistance to vaccine producers and national
regulatory authorities in China, India, Indonesia, Pakistan, and
Vietnam. Finally, in 2004, IVI scientific staff offered a Masters-
level course in vaccinology for students at the Seoul National
University School of Public Health. Several IVI scientists hold
adjunct professor appointments at Seoul National University, and
a Masters-level degree in vaccinology to be offered by Seoul
National University and supervised by the IVI is an important goal
for the future.
A watershed event in the IVI’s history was the completion in
mid-2003 of the new IVI headquarters building, located on the
campus of Seoul National University and generously provided by
the Republic of Korea. The building has 18,000 square meters of
floor space, including state-of-the-art laboratories, offices,
meeting areas, animal facilities, and a vaccine pilot production
plant. Under the leadership of Doctor Aldo Tagliabue, Deputy
Director for Laboratory Sciences, a Laboratory Science Division
is under development in the headquarters building. The Division
already consists of laboratories devoted to immunology,
molecular microbiology, and vaccine development. The Division
has been energized by the return to the IVI of talented young
Korean scientists sent by the IVI for two-year post-doctoral
fellowships at outstanding vaccinology laboratories at
Gothenburg University, Harvard University, Institut Pasteur, the
University of Alabama, and the University of Maryland. Although
the IVI laboratories are still in the process of being equipped, IVI
scientists have already embarked upon several important
research programs, including research on the basis of antigen
presentation in mucosal immunity; the evaluation of human
serological and cellular immune responses to infections and
vaccines; the genetic profiles of human bacterial pathogens;
improved manufacturing processes for killed, oral cholera
vaccine; and development of a subunit vaccine against Shigella.
With the completion of the IVI headquarters building and the
launch of the IVI’s Laboratory Sciences Division, the stage is
now set for the realization of the dream of the IVI’s founders: a
center devoted to vaccine science for developing countries, with
activities spanning the entire vaccine continuum, from vaccine
discovery, to vaccine production, to vaccine evaluation, to
vaccine introduction. We look forward to working with the global
public-health community in this important endeavor.
Sincerely,
John Clemens
3
Dr. John Clemens with President Roh and First Lady Ms. Kwon Yang-suk at IVI headquarters in Seoul
Introduction
Diseases of the Most Impoverished: Typhoid Program
Diseases of the Most Impoverished: Cholera Program
Diseases of the Most Impoverished: Shigellosis Program
Diseases of the Most Impoverished: Existing Data Collection Program
Pediatric Dengue Vaccine Initiative
Japanese Encephalitis Program
Respiratory Encapsulated Bacteria Program: Haemophilus influenzae type b (Hib) Disease
Respiratory Encapsulated Bacteria Program: Pneumococcal Disease
Rotavirus Diarrhea Program
Vaccine Safety Program
Division of Translational Research
Overcoming Hurdles to New Vaccine Introduction
Much has been written about the scientific challenges of
vaccine discovery and about strategies to improve the process of
discovering new vaccine candidates. There are many institutions
around the world, ranging from industrial corporations to
academic laboratories, attempting to overcome these challenges.
As well, the financial hurdles and administrative obstacles that
impede the movement of new vaccines into developing countries
are well known. Less well appreciated is the fact that, even for
exciting new vaccine candidates that have been discovered, there
are other, formidable scientific challenges that can impede their
introduction into public-health programs in developing countries.
These scientific challenges are of three types. Firstly, a
vaccine candidate may languish on the laboratory shelf without
an opportunity to be tested in humans. This developmental
impasse is most notorious for orphan vaccines, targeted to
diseases that are of little or no interest to populations in
industrialized countries and that have limited potential profitability
for vaccine producers. Examples of such vaccines include those
directed against leishmaniasis, hookwarm, and schistosomiasis.
Because such diseases primarily affect developing countries and
because affluent travelers to developing countries do not have a
particularly high risk of contracting these diseases, there is little
economic incentive for vaccine producers to undertake
expensive clinical development programs for these vaccines.
Secondly, even for vaccines that are of interest to populations
in both industrialized and less-developed countries alike, there
may be interest in and funding for human studies, but only in
industrialized countries, where the most profitable markets are
located. Indeed, conducting clinical development in developing
countries in parallel with clinical development in industrialized
countries risks delays in licensure in the latter, with major
potential losses of income. This creates a problem for developing
countries, because the results of studies done in populations in
industrialized countries do not always predict the performance of
5
IVI senior scientist Dr. Lorenz von Seidlein visits a DOMI field site in North Jakarta,Indonesia, in January 2003.
Vaccines for children in developing countries face significant obstacles.
Introduction
a vaccine in developing country populations. Such has been the
case for early generation vaccines against rotavirus, which were
highly protective in children in industrialized countries but poorly
protective in developing countries. Too often in the past, studies
of such vaccines have been done in developing countries many
years after licensure in industrialized countries, creating
unacceptable delays in the introduction of the vaccine into
developing countries.
Thirdly, even if a vaccine has been shown to be safe and
protective in developing countries in Phase III trials, in which the
vaccine is given to large groups of people, policymakers may still
have uncertainties about whether an adequate case can be
made for introducing the vaccine into public-health programs in
their countries. This is because the evidence provided by pre-
licensure evaluations, even those done in developing countries,
typically fails to address many of the practical questions about
implementing a new vaccine in real-life programs. The
insufficiency of this downstream evidence constitutes the third
scientific hurdle.
Overcoming these three hurdles requires three types of
translational research. The first scientific hurdle requires that initial
human studies (Phase I) of promising vaccine candidates be
conducted. The second scientific hurdle requires clinical trials in
settings in developing countries, ideally conducted in parallel with
evaluations in industrialized countries. And the third scientific
hurdle requires, for vaccines that have proven safe and effective in
Phase Ⅲtrials in the developing world, a constellation of
epidemiological, clinical, economic, behavioral, and policy
evidence sufficient to inform judgments about whether the
introduction of a new vaccine into public-health programs in a
developing country is rational, feasible, acceptable, and affordable.
The IVI has established a major downstream program of
translational research and technical assistance that addresses
these three challenges in order to accelerate the rational
introduction of new-generation vaccines against enteric and
invasive bacterial infections of children, as well as against
Japanese encephalitis and dengue fever, into programs for the
poor in countries affected by these diseases. These programs
are currently being conducted in Bangladesh, Cambodia, China,
Egypt, India, Indonesia, Mozambique, Pakistan, the Philippines,
the Republic of Korea, Thailand, and Vietnam. Details on the IVI’s
translational research activities for each of these diseases are
given in the sections that follow.
6
Introduction
BackgroundTyphoid fever is a major cause of morbidity with an estimated
global prevalence of between 16 million and 33 million cases and
500,000 to 700,000 deaths per year. Typhoid fever is both a
water-borne and food-borne gastrointestinal infection with an
annual incidence rate approaching one percent of the population
in some endemic areas. The disease typically lasts several weeks
and can lead to serious complications, including gastrointestinal
hemorrhage, perforation of the gut, and shock. Multidrug-resistant
Salmonella typhi has spread into many parts of the world, limiting
the ability to treat the disease with available antibiotics.
In the absence, in many less-developed countries, of near-
term programs to assure safe water and better sanitary
conditions, efforts have also been directed towards primary
prevention through vaccination. The widely available heat-
inactivated, phenol-preserved whole-cell typhoid vaccine, which
provides approximately 65% protection, has limited usefulness
because of the adverse reactions it evokes. However, two
licensed new-generation typhoid vaccines promise protection
without significant side effects: the live, attenuated oral vaccine
Ty21a and the injectable subunit Vi polysaccharide vaccine. Both
Vi and Ty21a vaccines have been shown to be safe.
There are several advantages of Vi over Ty21a for use in
developing countries. First, the protective efficacy of Vi has been
fairly consistent in all field trials, ranging from 64% to 77%, while
the efficacy of Ty21a has varied widely from one geographic
area to another, from as high as 95% to as low as 53%.
Secondly, Vi immunization consists of a single-dose regime,
while Ty21a requires at least three precisely timed doses.
Furthermore, Ty21a is heat-labile and requires storage in a strict
cold-chain, while Vi vaccine has much less strict cold-chain
requirements. Finally, Vi, unlike Ty21a, has not in the past been
protected by patent rights, making technology transfer to local
producers easier and the vaccine less costly to produce. In fact,
the technology for producing Vi has already been transferred to
local producers in Vietnam and China. For all these reasons, Vi
vaccine is considered by most public-health experts to be the
licensed new-generation typhoid vaccine that is best suited for
public-health programs in developing countries. The DOMI
Typhoid Program is consequently targeting Vi vaccine for
accelerated rational introduction into public-health programs.
Although Vi vaccine is particularly appropriate for vaccinating
specific target populations such as school-age children or
adolescents, it also has several limitations inherent to all
polysaccharide vaccines that would make improved vaccines
more attractive for use in routine infant immunization programs.
Firstly, the protective efficacy of Vi vaccine is not complete.
Secondly, like most polysaccharide vaccines, Vi vaccine does
not induce protective levels of antibodies in infants nor does a
booster response of Vi elicit memory responses. Finally, it is not
known whether the protective efficacy of Vi exceeds three years,
so that current recommendations for its use include periodic re-
vaccination.
7
Women get together to participate in a DOMI Typhoid project in Karachi, Pakistan.
Diseases of the Most Impoverished: Typhoid Program
An affordable vaccine that can provide long-term protection in
children and adults, that can induce immunological memory, and
that can be administered at the same time as other routine infant
vaccinations could be readily taken up by programs for the poor
in typhoid endemic countries and could dramatically reduce the
burden of this disease. Therefore, the DOMI program has, since
its inception, also sought to collaborate with public and private
institutions in the development and clinical evaluation of new
promising candidate vaccines.
Progress in 2003-2004Disease burden studies were launched at the inception of the
program alongside the implementation of Vi vaccine
demonstration projects, targeting more than 250,000 people.
Several disease burden evaluations were completed during
2003-2004 in: Hechi city (Guangxi, China); Sultanabad, Hijrat,
and Bilal colonies (Karachi, Pakistan); Hue city (Central
Vietnam); Kolkata (India); North Jakarta (Indonesia); and Dhaka
(Bangladesh). Annual typhoid fever incidence rates of blood-
culture-proven disease in these sites have varied from from 0.1
case per thousand per year in Hechi to 3 cases per thousand per
year in Karachi. The DOMI typhoid fever disease burden studies
have revealed various patterns of typhoid fever. The majority of
cases occur in school-aged children in Eastern Asia; in contrast,
a younger age spectrum in South Asia, particularly in urban
areas, is observed. This suggests that whereas school-based
immunization may be rational for Eastern Asian countries, in
South Asia both school-based and infant immunizations may be
warranted.
These DOMI typhoid fever disease burden studies have also
revealed two unexpected findings. Salmonella enterica serovar
Paratyphi A (S. paratyphi A) is emerging as a major pathogen in
some parts of Asia. In China, it is now much more common than
Salmonella enterica serovar Typhi (S. typhi) and its incidence is
approaching that of S. typhi in Pakistan. Since 1999, S.
paratyphi A has become 1.5 times more prevalent than S. typhi
in Hechi (China) and from 3 to 24 times more prevalent in the
entire Guangxi province. Additionally, in this province, most
enteric fever outbreaks have been caused by S. paratyphi A.
These results challenge the conventional view that more than
80% of enteric fever cases are caused by S. typhi. If this trend
continues, strong consideration will have to be given to
developing bivalent (S. typhi-paratyphi A) enteric fever vaccines
for Asia. In 2003, the UBS Optimus Foundation awarded the IVI
a US$ 714,000 three-year grant to generate the multidisciplinary
evidence needed to inform policymakers in the Chinese province
of Guangxi (population of approximately 50 million) on whether
introducing new vaccines against S. paratyphi A is necessary
and can be accomplished in a sustainable fashion.
Another noteworthy finding is that DOMI serology-based
typhoid fever studies indicate that blood-culture based typhoid
fever may greatly underestimate the real incidence. A new
analytical use of traditional (Widal) and newer generation
serology-based detection methods (Tubex and Typhidot-M) in
culture-negative febrile patients, which diagnoses culture-
negative typhoid cases with 100% specificity, has demonstrated
that the disease burden of culture-negative typhoid fever in these
Asian countries is high. The real burden of typhoid may therefore
be two or three times that revealed by blood-culture methods.
8
Diseases of the Most Impoverished: Typhoid Program
The objectives of the DOMI Typhoid Program are:
To generate and disseminate the evidence needed by policymakers to rationally introduce existing, licensed, new-
generation Vi vaccine. This evidence derives from measuring the disease burden; assessing vaccine efficacy and
effectiveness; evaluating vaccine demand, cost-effectiveness, and acceptability; and analyzing policy strategies for vaccine
introduction.
To assure an adequate and cost-competitive supply of Vi vaccines by assisting the transfer of production technologies to
qualified producers in Asia and by providing training in vaccine production and regulation.
To ensure that the pipeline of newer generation experimental vaccines against typhoid is exploited by accelerating the
development of new candidates and evaluating these vaccines in endemic settings.
To help develop consensus at the national, regional, and international levels on the use of vaccines against typhoid fever.
This important finding has major implications for accurately
estimating the true disease burden and provides a stronger
reason for introducing typhoid fever vaccines.
Data on re-injection safety, effectiveness, and duration of
protection are pivotal to tailoring future Vi vaccination programs.
DOMI has generated policy-relevant data on the safety of Vi re-
injections. In collaboration with the Jiangsu Center for Disease
Control (CDC) in China, a randomized placebo-controlled
double-blinded trial of 998 school children was conducted in
Suzhou city, Jiangsu province, China. Though a statistically
significantly higher incidence of local pain was reported in the Vi
re-injection group, compared to the placebo group and primary Vi
injection group, all of the reported symptoms were restricted to
mild grade reactions. No difference in the frequency of systemic
adverse events was detected. Also a locally produced and
routinely administered Vi vaccine in China was 70% protective
when evaluated in the course of a typhoid fever outbreak in a
middle school (Guangxi). The program has generated evidence
on the duration of Vi polysaccharide protection. A six-year follow-
up of a population that participated in two placebo-controlled,
randomized trials of locally produced Vi vaccine in Guangxi and
Jiangsu, China, indicated that Vi protects for at least three years
after inoculation.
Preliminary cost-of-illness data for typhoid fever indicate a high
economic burden, costing approximately US$ 100 per episode to
a family earning on average US$ 50 per month in a Delhi slum.
More than half of these costs correspond to out-of-pocket
expenses and the rest is borne by the public-health system.
Furthermore the annual expected costs of typhoid fever illness
are approximately US$ 8 for each child 2-5 years old in the
community; these total costs in pre-school children were higher
than for any other age group, especially the institutional costs.
The high disease burden and several-fold higher non-patient
costs of typhoid fever in preschool children compared to older
children and adults imply that attention should also be given to
developing preventive interventions that are efficacious in young
children. These are the first estimates of the costs of illness for
typhoid in a specific community in India, and among the most
detailed estimates available for any developing country, and
should facilitate cost-benefit analyses of various preventive
strategies, including mass and selective immunization.
Other important parallel activities of the program are capacity-
building and facilitating technology transfer for the production of
vaccines by qualified local producers in Asia. Regarding the
former, local scientific staff have received periodic training in
several areas: Good Clinical Practice (GCP) guidelines,
laboratory detection methods, and database management.
Fellowship programs have been launched and project monitoring
teams have been formed among local scientific staff coordinated
by IVI. Technology transfer of Vi polysaccharide production to
BioFarma (Indonesia), Shantha Biotechnics (India), and Amson
(Pakistan) is currently being facilitated by the DOMI program.
Furthermore, the IVI together with local investigators has
launched large Vi effectiveness trials in: Hechi city, China (April
2003); three slums in Karachi, Pakistan (August 2003 and
August 2004); Hue, Vietnam (December 2003); and North
Jakarta, Indonesia (February 2004). These trials have been
performed in accordance with the principles of Good Clinical
Practice. Over 200,000 individuals have been immunized;
typhoid fever surveillance is underway and final results will be
available after two years of follow-up. Each trial administered the
vaccine via the routine public-health system, albeit with different
target age groups and venues, and each trial found that large-
scale administration of Vi vaccine is feasible and acceptable.
Finally, during 2003 the IVI successfully reached an
agreement with Microscience (U.K.) to clinically evaluate its
single-dose, genetically attenuated, live oral typhoid vaccine.This
candidate is the most advanced of any live oral vaccine and is
already in a Phase II outpatient trial in the U.S. Furthermore, the
IVI, together with the National Institute of Child Health & Human
Development (NICHD/NIH), has launched a program of research
and development for Vi conjugate vaccine that includes
laboratory-scale development at IVI laboratories, technology
transfer to qualified manufacturers, large-scale production,
clinical evaluation, and licensure in the countries of manufacture.
Future ActivitiesA mass vaccination campaign with Vi vaccine will be launched
in Kolkata (Nov 2004) targeting 60,000 people. Furthermore,
analysis will be completed of a case-control study conducted in
Jiangsu province in collaboration with the Jiangsu CDC in order
to generate data on the effectiveness of Vi vaccine in another
province in China (besides that reported in Guangxi).
During the year 2004 and beyond, the DOMI Typhoid Program
will conduct a safety and immunogenicity study of a bivalent
vaccine (Meningococcal A and Vi polysaccharide) in Guangxi,
China. It is also anticipated that the DOMI Typhoid Program will
conduct Phase II studies of the Microscience live oral attenuated
typhoid vaccine in Vietnam, while simultaneously setting up a
field site for a Phase III study in that country.
9
10
Diseases of the Most Impoverished: Typhoid Program
In the next few years, the DOMI Typhoid Program and the
Division of Laboratory Sciences will work jointly to ensure the
following:
development of a serum bank at the IVI from the samples
originating in the DOMI typhoid fever study sites;
standardization and optimization of typhoid fever serologic
rapid diagnostic assays;
standardization and validation of an ELISA (enzyme-linked
immunosorbent assay) to measure anti-Vi antibodies; and
research on other molecular markers in relation to vaccine
protection in large efficacy trials.
Finally, the DOMI Typhoid Program increasingly will focus on
synthesizing the results of its multidisciplinary studies into
coherent investment cases that comprehensively analyze the
impact, cost, and cost-effectiveness of different Vi vaccination
programs, and communicating these to local policy makers.
Three countries, Indonesia, Vietnam, and Pakistan, will be the
focus of the first three investment cases for Vi immunization.
These investment cases will be based on a rigorous analysis of
the data emerging from the country-level epidemiological studies
on disease burden, antibiotic resistance, and risk factors;
economic studies on the costs of illness of typhoid fever, on Vi
vaccine delivery costs, and on the public’s willingness to pay for
vaccine; sociobehavioral analyses on public perceptions of the
importance of typhoid fever and the need for vaccinating against
it; demonstration studies on the practical feasibility, acceptability,
and impact of Vi vaccination programs; and policy analyses of
channels for vaccine introduction and financing mechanisms.
IVI Associate Director Dr. Luis Jodar discusses investment cases for the accelerated introduction at the country level of Vi vaccines.
BackgroundCholera remains a serious public-health problem worldwide. In
2002, a total of 142,311 cases and 4,564 deaths were reported
to the WHO from 52 countries, primarily in Africa, Asia, and Latin
America. The true figures are likely much higher due to under-
reporting. Besides the high mortality and morbidity figures,
cholera outbreaks cause economic and social disruption as well.
Providing safe water and food, establishing adequate sanitation,
and implementing personal and community hygiene constitute
the main public-health interventions against cholera. These
measures cannot be implemented fully in the near future in most
cholera-endemic areas. A safe, effective, and affordable vaccine
would be a useful tool for cholera prevention and control.
Considerable progress has been made during the last decade
in the development of new-generation oral vaccines against
cholera. A monovalent (anti-O1) killed, oral cholera vaccine
consisting of inactivated whole cells of V. cholerae supplemented
with a purified recombinant-DNA derived B-subunit of the cholera
toxin (rBS-WC) was developed by Professor Jan Holmgren at
the University of Gothenburg in Sweden. The vaccine was
licensed by the Swedish Bacteriologic Laboratories (SBL) in
several industrialized countries and is used mainly by Western
travelers. Unfortunately, the vaccine is still expensive for public-
health use in developing countries. Starting in the mid-1980s,
following technology transfer from Sweden, Vietnamese
scientists at the National Institute of Hygiene and Epidemiology
(NIHE) in Hanoi developed and produced a killed, oral cholera
vaccine that contains killed whole cells but lacks the toxin B
subunit. The vaccine has undergone field trials in Vietnam and is
locally licensed and used in the country’s public-health
programs. The DOMI Cholera Program demonstrated in head-
to-head immunogenicity trials in Vietnam that the Vietnamese-
produced vaccine, which is considerably less expensive to
produce, was as safe and protective as the SBL vaccine.
The Vietnamese killed, oral cholera vaccine, although safe and
affordable, is only moderately effective (60-70%) after two doses.
For these reasons, investigators have been developing several
new-generation, live-attenuated oral cholera vaccines that could
be administered in single-dose regimens. The first such vaccine
candidate to be tested extensively, CVD 103-HgR, was
developed at the Center for Vaccine Development (CVD) of the
University of Maryland. When a single-dose regimen of this
vaccine was tested in a large-scale, randomized, placebo-
controlled field trial that enrolled more than 67,000 children and
adults in Jakarta, Indonesia, no statistically significant protective
efficacy was shown against the cholera cases identified during 4
years of follow-up. Other live-oral vaccines requiring only single-
dose regimens were also developed at Harvard University.
Especially promising results were obtained with the O1
serogroup candidate, Peru-15. This candidate, which is now
produced by AVANT Immunotherapeutics, has been found to be
safe and highly immunogenic when administered as a single
dose (108 cfu) to North American volunteers.
11
IVI researcher Mr. Mahesh Puri visits an IVI cholera study site in Beira, Mozambique, during the rainy season, when diarrheal diseases reach a peak.
Diseases of the Most Impoverished: Cholera Program
The DOMI Cholera Program has generated data to inform the
introduction of both the internationally and locally-produced killed,
oral cholera vaccines; developed collaborations with producers,
providing technical assistance and facilitating technology transfer
in order to create an ample and cost-competitive vaccine supply;
sponsored clinical trials of Peru-15 in Bangladesh; and
conducted advocacy activities.
Progress in 2003-2004By mid-2003, a prospective, population-based cholera
surveillance study in an urban slum site in North Jakarta,
Indonesia, was completed. The surveillance in North Jakarta is
part of a combined study of the disease burden of cholera,
typhoid fever, and shigellosis, conducted in collaboration with the
National Institute of Health Research and Development and the
Naval Medical Research Unit 2 (NAMRU-2) in Indonesia. The
incidence of detected cholera was highest at 4 cases per
thousand per year in children less than one year of age (Figure
1). The overall incidence of detected diarrhea due to V. cholerae
O1 was 0.5 per thousand per year. V. cholerae O139 was not
detected during the surveillance period.
By early 2004, the first year of a prospective population-based
cholera surveillance study was completed in an urban slum site
in Kolkata, India. Cholera surveillance in Kolkata is part of a
combined study of the cholera and typhoid disease burdens,
which is being conducted in preparation for vaccine trials of
killed, oral cholera vaccine and Vi typhoid vaccine at the same
study site. Similar to the Jakarta data, the disease burden of
cholera was highest among those less than one year of age at
15 cases per thousand person-years and gradually decreased
among the older age groups (Figure 2). The overall incidence
12
Diseases of the Most Impoverished: Cholera Program
The goals of the DOMI Cholera Program are:
To provide the data and analyses necessary for the rational targeting and implementation of vaccines against cholera in
endemic areas.
To facilitate the introduction, in a rational fashion, of killed, oral cholera vaccine into the public-health programs in cholera-
endemic countries in Asia.
To provide pre-licensure clinical evidence of the safety and immunogenicity of at least one experimental cholera vaccine in
a cholera-endemic setting in Asia.
To enhance the global production capacity of killed, oral cholera vaccine by working with international producers, facilitating
technology transfer for local production of the vaccine to qualified producers in Asia, and providing training to improve local
production and regulation of the vaccine.
Figure 1. Annual incidence of V. cholerae by age group in North Jakarta, August2001 to July 2003.
The Cholera Treatment Centre is crowded with patients during the cholera seasonin Beira, Mozambique.
rate of detected diarrhea due to V. cholerae O1 was 2 cases per
thousand person-years. V. cholerae O139 was not detected
during the surveillance period. In May 2003, a cholera outbreak
occurred in Hue city, Vietnam, and its surrounding districts. An
outbreak investigation was conducted that revealed 115
clinically-suspected and laboratory-confirmed cholera cases in
Hue (Figure 3). Interestingly, Hue city was also the site of
cholera vaccination demonstration projects in 1998 and 2000.
Two doses of the Vietnamese killed, oral whole-cell cholera
vaccine were administered during a mass immunization in 13
communities in Hue city from March to April 1998. The second
mass immunization of the remaining 12 communities was
conducted in August 2000. These immunization campaigns
targeted residents one year and older and excluded pregnant
women. A case-control study linking previous vaccination with
cholera was conducted in 2003. It was found that vaccination in
1998 or 2000 was associated with a protection of about 50%.
No protective effectiveness was observed against non-cholera
diarrhea. A feasibility study of the use of an oral cholera vaccine
in Beira, Mozambique, was undertaken in collaboration with the
Mozambique Ministry of Health, the WHO, and Medicins Sans
Frontieres/Epicentre. Mass vaccination with the internationally
13
Stagnant, unclean water and unhygienic conditions are common causes of the DOMI diseases.
Figure 2. Annual incidence rate of cholera by age group in Kolkata, India, May2003 to April 2004.
Figure 3. Outbreak curve of the 115 clinically-diagnosed and culture-confirmedcholera cases by week, Hue city, Vietnam, May to September 2003.
′
licensed rBS-WC, killed, oral cholera vaccine took place from
December 2003 to January 2004. A major outbreak of cholera
occurred in Beira from January 12 to May 26, 2004. A case-
control study found that receipt of one or more doses of the rBS-
WC vaccine was associated with a 76% protection against
cholera severe enough for the patient to have sought care. No
protective effectiveness was observed against non-cholera
diarrhea.
In collaboration with the International Centre for Diarrhoeal
Disease Research, Bangladesh (ICDDR,B), DOMI is conducting
Phase II trials in Bangladeshi adults and children of the Peru-15
live oral vaccine, developed at Harvard Medical School and
produced by AVANT Immunotherapeutics in the U.S. The trials
of safety, immunogenicity, fecal excretion, and genetic stability
of Peru-15 have been completed in adults and toddlers, and
studies in infants are ongoing.
Transfer of the technology for producing the killed, oral WC
cholera vaccine from the National Institute of Hygiene and
Epidemiology (NIHE) in Hanoi, Vietnam, to BioFarma of
Indonesia has been completed and is ongoing for Shantha
Biotechnics in India. For details see the Technology Transfer
section.
Future ActivitiesDOMI has shown that the oral, killed whole-cell cholera
vaccines are safe, effective, feasible to administer, and
affordable (at least for locally-produced vaccine).
An inexpensive, locally produced oral, killed whole-cell cholera
vaccine will achieve widespread international use only after
licensure by a WHO pre-qualified producer. DOMI is working
towards this goal through a technology transfer to Shantha
Biotechnics in India and a large Phase III efficacy trial in Kolkata.
Accelerated, rational introduction of both the internationally and
locally-produced killed oral vaccines will require continued
advocacy at international, regional, and national levels. Policies
for cholera vaccination in endemic areas and for the control of
outbreaks need to be developed.
Aware of the shortcomings of the killed, oral cholera vaccine,
the DOMI Cholera Program is also providing Phase II evidence
of the Peru-15 live oral cholera vaccine in Bangladesh. This new-
generation vaccine is envisioned to be given in a single dose,
with potentially better and longer-lasting protection. The results
so far have shown the vaccine to be safe and immunogenic.
Ultimate deployment of this single dose vaccine in developing
countries will require a large Phase III trial.
14
Diseases of the Most Impoverished: Cholera Program
BackgroundShigellosis causes considerable morbidity and mortality
worldwide. Before the establishment of the DOMI program, there
was very limited information available regarding the country-
specific disease burden of Shigella and the regional distribution
of Shigella species and serotypes that cause shigellosis. As no
vaccine against shigellosis is licensed outside China, these data
are crucial to informing decisions on Shigella research and in
budgeting for the development of future Shigella vaccines.
Results from DOMI policymaker surveys in six Asian countries
done in 2000 showed a high demand for a safe, affordable, and
effective Shigella vaccine, enthusiasm for including such a
vaccine in routine infant immunization programs, and a
corresponding willingness to pay for such a vaccine with public-
and private-sector resources.
While the ultimate goal of shigellosis research is the
development of a safe and protective vaccine candidate, the
DOMI program decided to undertake, even at a relatively early
stage of vaccine development, a translational research agenda
to answer key policy questions about the ultimate deployment of
potential new Shigella vaccines in public-health practice. As it did
for cholera and typhoid, this translational research agenda
included not only epidemiological studies but also: analyses of
the economic consequences of vaccine introduction;
assessments of the perceived importance of the target disease,
the usefulness of current, non-vaccine control measures, and the
need for vaccination against shigellosis; and policy research to
assess potential channels for vaccine introduction, as well as
feasible, transparent, and sustainable mechanisms for financing
the purchase and delivery of the new vaccine.
To assess the magnitude of the Shigella problem, in 2001 the
DOMI Shigellosis Program launched prospective, population-
based disease burden studies in six Asian countries using
standardized epidemiological and laboratory methods. To
increase the sensitivity of the surveillance studies, heath-care
utilization surveys were conducted in each study site to estimate
the number of people likely to be missed by surveillance.
Furthermore, highly sensitive, experimental diagnostic methods
were used to estimate the proportion of infections missed
through the use of traditional microbiological methods.
Embedded in the surveillance studies were social science
studies that allowed the measurement of social perceptions of
the disease and the economic impact of laboratory-confirmed
Shigella cases.
Although at the time of the program’s inception there were
several promising approaches to vaccine development, except
for the Lanzhou FS vaccine, which is not licensed outside of
China, there was no licensed vaccine available to protect
individuals against shigellosis. The major technological platforms
for modern Shigella vaccines included oral live attenuated and
parenteral subunit vaccines. An early DOMI study of a live oral
attenuated SC602 S. flexneri 2a vaccine in Bangladesh showed
poor colonization and immunogenicity in young children (in
15
A child receives rehydration therapy at the International Centre for Diarrhoeal Disease Research, Bangladesh, a collaborating institution in the DOMI program.
Diseases of the Most Impoverished: Shigellosis Program
contrast to very promising results in North American adults).
These findings indicate that live oral Shigella vaccines face
substantial challenges for inducing good immune responses in
Shigella-endemic populations where there may be subgroups
that have high levels of preexisting natural immunity. Additionally,
conjugate vaccines against Shigella looked promising in one
proof-of-principle human efficiency study, but DOMI found no
major manufacturers interested in producing these vaccines, in
part because of the complexity and expense of detoxifying the
lipopolysaccharide (LPS) prior to conjugation and, in part,
because of the limited market in industrialized countries. Thus,
DOMI included in its agenda the development and, if warranted,
the ultimate technology transfer to local producers of a promising
subunit vaccine technology (ribosomal) that is potentially
inexpensive to produce and capable of eliciting T-cell dependent
immune responses in animals, analogous to those elicited by
conjugate vaccines. Details on the development of this vaccine
by the IVI are described in the Laboratory Sciences section.
Progress in 2003-2004By the end of 2003 and the first half of 2004, prospective
population-based two-year disease burden studies of shigellosis
were completed for the six selected study sites, namely:
Zhengding, China; North Jakarta, Indonesia; Kaengkhoi District,
Thailand; Dhaka, Bangladesh; Karachi, Pakistan; and Hue,
Vietnam. In total, 568,000 individuals were under surveillance. In
these study sites 62,867 episodes of diarrhea were detected,
2,944 (5%) of which were shigellosis. Preliminary estimates
indicate very high incidence rates of treated shigellosis in
children under five years of age in China (52 cases per thousand
children per year) and Bangladesh (48 cases per thousand
children per year) (Figure 1).
The incidence of treated shigellosis was observed to be high
not only in children under five years old, but also in the elderly,
resulting in a bimodal disease distribution. Furthermore, to get a
better understanding of the disease burden caused by Shigella in
Nha Trang, Vietnam, real-time TaqMan polymerase chain
reaction (PCR) tests were used to detect Shigella-associated
DNA in fecal specimens. The data from real-time TaqMan PCR
amplification indicated that the culture-proven prevalence of
Shigella among diarrheal patients (3%) may severely
underestimate the true prevalence of shigellosis among treated
episodes of diarrhea, which could be as high as 35%. Following
the example of the study in Vietnam, stool specimens from
Saraburi, Thailand, were evaluated in a similar fashion with
similar observed results. Further studies making use of real-time
TaqMan PCR are planned in the remaining study sites.
Considerable heterogeneity of Shigella species and serotypes
was observed between sites. In five sites S. flexneri was the most
16
Diseases of the Most Impoverished: Shigellosis Program
The objectives of the DOMI Shigellosis Program are:
To measure the disease burden for shigellosis in six Asian sentinel sites, supplementing prospective data with a systematic
collection of existing data.
To explore the perceptions of at-risk communities and health care providers towards shigellosis and a potential shigellosis
vaccine.
To estimate the economic implications of introducing a vaccine against shigellosis.
To accelerate the development of a shigellosis vaccine.
A child with shigellosis receives care in Bangladesh.
frequently isolated Shigella species. In Thailand the large majority
(80%) of shigellosis cases was caused by S. sonnei and
interestingly, in Bangladesh, more than 30% of isolated Shigella
belonged to S. boydii species, which is not commonly observed
either in developed or developing countries (Figure 2). In addition,
DOMI studies detected significant differences in distributions of S.
flexneri serotypes and subtypes between sites (Figure 3).
Since immunity against Shigella is thought to be species- and
serotype-specific, a vaccine against Shigella will need to
comprise a broad “cocktail” of antigens from different Shigella
organisms to have an important epidemiological impact. It is
conceivable that tailor-made vaccines against prevalent Shigella
strains could be developed for certain endemic regions.
Finally, complementing the epidemiological data to enable
rational decisions about introducing new Shigella vaccines, cost-
of-illness studies were completed for Zhengding, China; North
17
Figure 1. Incidence rates of culture-proven shigellosis in six Asiancountries.
Figure 2. Relative distribution ofShigella species in the six DOMIsites in Asia.
Figure 3. Distribution of S. flexneriserotypes in five DOMI sites.
Jakarta, Indonesia; Kaengkhoi district, Thailand; and are in
progress for Dhaka, Bangladesh; Karachi, Pakistan; and Hue,
Vietnam. Surveys collecting socio-behavioral data to ascertain
perceptions both in the community and among health-care
providers about the importance of Shigella and the need for
vaccinating have been completed in Dhaka, Zhengding, North
Jakarta, Karachi, Kaengkhoi district, and Nha Trang.
Future ActivitiesThe collection of epidemiologic disease burden data has been
completed. Analysis of the data is in progress. In-house
development of a ribosomal candidate vaccine against S. flexneri
2a is ongoing (for details see the Vaccine Development and
Process Research section). Clinical evaluation of other vaccine
candidates is under discussion.
BackgroundRecent interviews with policymakers conducted in the DOMI
program highlighted the need for accurate disease burden data
on cholera, shigellosis, and typhoid fever. The DOMI program
has developed a new activity to systematically collect
epidemiological data on diarrhea, cholera, shigellosis, typhoid
fever, and enteric fever between 1991 and 2000 from three
sources: government statistics, representative hospital and
laboratory data, and published and unpublished literature, both
local and international.
The data has been collected for six DOMI participating
countries: Pakistan, India, Thailand, Vietnam, China, and
Indonesia. As a part of this study, the DOMI team has also
developed the Existing Data Collection (EDC) web site
(http://220.93.120.132:10002/main/main.asp). This web site
allows investigators to review materials related to the EDC study,
such as background, methods, data, and preliminary results.
This newly developed tool will be essential in enabling
collaborating economists to appreciate the economic impact of
the target diseases.
Examples of past findings from the Existing Data Collection
Program include recently completed work in China, where
considerable differences were revealed in the distribution of
dysentery between seven regions. High rates were reported from
the North-West (Xingjiang) and South (Guangxi) but not from the
eastern regions (Hebei, Jiangsu). A systematic review of
government data on diarrhea, dysentery, typhoid fever, and
cholera in Indonesia during the decade from 1991 to 2000
revealed a striking increase in the annual incidence of enteric
infections following the onset of the Asian economic crisis in 1997.
This finding may be due to the close correlation between water-
and food-borne gastrointestinal diseases, on the one hand, and
water supply and environmental sanitation, on the other, which is
in turn closely related to national economic well-being.
Progress in 2003-2004In the years 2003 and 2004 special attention has been placed
on the meta-analysis of the data compiled for typhoid fever in
18
The IVI's Existing Data Collection Program is designed to create a database of governmental data, research literature, and hospital records for the DOMI diseases.
Diseases of the Most Impoverished: Existing Data Collection Program
IVI staff in Mozambique conduct a household survey.
Vietnam, Indonesia, and Pakistan as part of the development of
investment cases for the accelerated introduction of Vi typhoid
vaccines in these countries (for details see the DOMI Typhoid
Program). For example, the data used to calculate average
incidence rates in Vietnam originates from routine government
data¹on enteric fever (1991-2003) and the population-based
surveillance study on typhoid fever in Hue city conducted in 2001
by the DOMI program, after accounting for a test sensitivity
multiplier.²
The results of the triangulation of the data suggest that there is
under-reporting of the annual incidences for all provinces in
Vietnam.
Future ActivitiesThe Existing Data Collection Program is an ongoing activity.
New data are continually collected and added to the database
from which a variety of investigators extract relevant information.
19
The goals of the DOMI Existing Data Collection Program are:
To determine the incidence of treated episodes of cholera, shigellosis, and typhoid fever.
To determine the mortality due to shigellosis, cholera, and typhoid fever.
To determine the age-specific incidence and mortality of treated episodes of cholera, shigellosis, and typhoid fever.
To determine the number or fraction of cases requiring hospital admission and the number or fraction of cases treated as
outpatients.
To determine the antibiotic-resistance profiles of the causative organisms.
To determine the distribution of V. cholerae by serogroup, biotype, and serotype, and of Shigella by species and serotype.
¹Statistics on Infectious Diseases 1991-2003. National Institute of Hygiene and Epidemiology, Ministry of Health, Hanoi, Vietnam.
²Crump, J.A. et al. (2003). Estimating the Incidence of Typhoid Fever and Other Febrile Illnesses in Developing Countries. Emerging Infectious Diseases 9(5): 539-544.
BackgroundVaccines against dengue are urgently needed; they offer a
realistic and near-term solution for controling the twentieth- and
twenty-first-century dengue pandemic. Since World War II, the
four dengue viruses, of the genus Flavivirus, have spread
geographically to virtually all tropical countries as a result of
trends in life-style and demographics, such as the population
explosion, growing urbanization, and global mass transportation.
Dengue can be acquired two or more times, and the disease
may be more severe in individuals who, prior to infection, already
have dengue antibodies acquired either passively or actively
from a previous dengue infection. Late in the course of this
enhanced illness, there is the sudden onset of increased capillary
permeability, varying amounts of bleeding, and hypovolemic
shock. Fortunately, modern intensive-care treatment can be life-
saving but, untreated, fatality rates in both adults and children
can be as high as 33%. Each year there are tens of millions of
cases of dengue fever, and several hundred thousand persons
are hospitalized for dengue hemorrhagic fever or dengue shock
syndrome (DHF/DSS). Dengue infections can result in life-long
immunity. Related viruses, yellow fever and Japanese
encephalitis, are successfully prevented by live attenuated
vaccines.
Existing technologies have resulted in a number of robust, live
attenuated dengue vaccine candidates, and several with
commercial pharmaceutical sponsors are in Phase I or II human
testing. One or more of these candidates may be eligible for
Phase III trials in the near future. In December 2001, a meeting
of international medical scientists held in Ho Chi Minh City,
Vietnam, and sponsored by the Rockefeller Foundation and the
IVI, recommended a ten-year plan of action. To accelerate the
introduction of safe and effective dengue vaccines, a new
alliance was formed in mid-2002, the Pediatric Dengue Vaccine
Initiative (PDVI). Governance is provided by the PDVI Board of
Councillors and the IVI Board of Trustees. The PDVI has
received support from the Rockefeller Foundation, and in June
2003, the IVI was awarded a US$ 55 million five-year grant by
the Bill & Melinda Gates Foundation.
Progress in 2003-2004
Establishment of the PDVI
The PDVI Board of Councillors (chaired by Professor Duane
Gubler of the University of Hawaii) met in Geneva, Switzerland,
in April 2003, by conference call in June, and in Washington,
D.C., in November. Doctor Scott Halstead served as Interim
Director until June 2004, when Doctor Harold Margolis was
appointed Director of the PDVI. The Board of Councillors
approved the submission of a grant renewal proposal to the
Rockefeller Foundation, as well as a new grant proposal to the
Bill & Melinda Gates Foundation, and a portfolio of activities with
a budget for 2003.
20
A child with dengue hemorrhagic fever in Ca Mau Provincial Hospital, Ca Mau, Vietnam in 2002
Pediatric Dengue Vaccine Initiative
The PDVI sponsored two scientific meetings in 2003. In April,
the Antibody Protection Against Viral Infection meeting at the
World Health Organization, Geneva, Switzerland, attracted 50
participants. In June, at the University of Vienna, Vienna, Austria,
70 participants attended Dengue Virus: Molecular Basis of Cell
Entry and Pathogenesis.
Disease Burden Studies
To prepare budgets for the purchase of newly introduced
vaccines, governments of dengue-endemic countries need to
estimate the cost burden imposed by nationwide mosquito
control programs and by the deaths, hospitalized and non-
hospitalized illnesses, and loss of work by patients or family
members as a result of the illness. A request for proposal (RFP)
was placed in international journals in August 2003 to find an
institution to manage this program component. Proposals were
received in September and a grant made in October to the
Schneider Institute for Health Policy at the Heller School for
Social Policy and Welfare, Brandeis University, Waltham,
Massachusetts. To date, disease burden studies in El Salvador,
Nicaragua, Panama, Venezuela, Brazil, Cambodia, and Laos
have been received. A consultant visited four Asian countries,
finding a high level of concern regarding the impact of dengue
illness and interest in the purchase and distribution of dengue
vaccines. This report was published.¹
Field Sites
PDVI studies of prospective population cohorts in hyperendemic
countries have dual goals. Initially, they will supply data and
research materials relevant to the outcome of dengue infections:
severe, mild, or inapparent. The clinical, epidemiological, and
laboratory management of these population cohorts will also train
and prepare teams to design and manage Phase III vaccine
efficacy trials. In August 2003, a Scientific Advisory Group was
appointed (chaired by Doctor David Vaughn, Walter Reed Army
Institute of Research), and an RFP was written and advertised in
21
The goal of the Pediatric Dengue Vaccine Initiative is to accelerate the development and introduction ofaffordable dengue vaccines for children in endemic countries. The initiative has four components:
To measure the disease burden of dengue illness in affected countries.
To create two or more new dengue field sites in preparation for Phase III vaccine clinical trials.
To carry out targeted research to achieve safe and effective long term vaccine-induced protection against severe dengue
disease.
To negotiate and form vaccine development partnerships to achieve products designed for and affordable to dengue-
endemic countries.
A child suffering from dengue fever in Kamphong Cham Hospital, Kamphong Cham, Cambodia.
international journals. PDVI seeks to establish or maintain a
study cohort to measure Flavivirus infection and dengue disease
rates in a population at risk for primary and secondary (which will
include tertiary or quaternary) dengue virus infections. It is
planned that these sites will be made available for Phase III trials
of candidate dengue vaccines. As a secondary objective,
organized and funded by the PDVI under a separate initiative,
the cohort study will produce pedigreed clinical samples to
support laboratory-based research on dengue. In response to
the RFP, 22 letters of intent were received by November 15,
2003. These were reviewed and four applicants invited to provide
a full proposal, with a submission date of May 2004.
Vaccine Safety Studies
The goal of this component is to lessen vaccine-related risks
by developing an in vitro test for vaccine recipients that
correlates with protective immunity. It is intended that such a test
will facilitate the design of schedules for administering vaccines
and booster doses that will achieve the desired protective
response. The PDVI is seeking proposals in the following areas:
dengue virus structure; viral and cell receptors and entry
mechanisms; identification of dengue neutralizing, protective,
and enhancing antibodies; and animal models to study natural
and vaccine protection. The RFP was published in international
journals resulting in 78 letters of intent received by November
2003. Twenty-nine candidate investigators were invited to submit
full proposals, and 13 were approved and funded.
Future ActivitiesIn 2004 and 2005 it is expected that new proposals will be
solicited for disease burden studies. Grants will be awarded for
the management of a total of at least three prospective cohort
studies in dengue-endemic areas and, following the
recommendations of a peer-review committee, for ten or more
targeted research proposals. Field site managers and targeted
research investigators will share information at annual meetings
and through an interactive website. At the first meeting, held in
June 2004, efforts were made to standardize reagents, viral
strains, and laboratory methods among PDVI investigators.
22
Pediatric Dengue Vaccine Initiative
¹DeRoeck, D. et al. (2003). Vaccine 22: 121-9.
BackgroundJapanese encephalitis (JE) is a greatly neglected disease of
Asia, affecting virtually all countries of the continent. JE is a viral
infection, transmitted by mosquitoes in mostly rural areas
inhabited by Asia’s poorest populations. Approximately 35,000
cases are reported to the WHO annually. Well over 99% of all
cases of JE reported globally occur in Asia. Because of this
geographical localization to Asia and because JE tends to target
Asia’s poorest people, JE has not attracted the interest or
support of the global vaccine research and development
community. Nor have vaccines against JE been of great interest
to commercial producers.
Korea, Japan, and Taiwan have effectively controlled JE with
vaccines, which are the most effective public-health tools to
protect populations at risk. Despite the success in these three
countries, other countries afflicted with JE have been slow to
pursue the use of vaccines, in part due to an inadequate
appreciation of the actual JE disease burden, as well as of the
cost-effectiveness of vaccinating. In addition, commercially
available vaccines against JE, although protective, are not ideal
due to their side-effects and expense. Similarly, the SA 14-14-2
vaccine developed and used in China, although protective and
apparently safe, has so far failed to gain international acceptance
due to its production in primary cell cultures that are not known to
be free of contaminating infectious agents that might themselves
pose health risks to vaccine recipients. Moreover, local
production of JE vaccines, in both China and Vietnam, occurs
under manufacturing conditions still in need of international
recognition.
Newer generation, potentially safer, but as yet unlicensed
vaccines have been developed against JE. A particularly
attractive vaccine candidate is the so-called “chimeric vaccine”,
in which genes from the JE virus are inserted into the genome of
the existing licensed vaccine strain 17D against yellow fever.
Unfortunately, however, because JE is an “orphan disease”with
little commercial interest, funds have not been available in the
past to conduct the necessary trials of these newer generation
vaccines in humans to determine whether or not they should be
introduced into public-health practice.
The Japanese Encephalitis Program at the IVI was
established in 2001 with the support of the Children’s Vaccine
Program at the Program for Appropriate Technology in Health
(PATH) and the Korean International Cooperation Agency
(KOICA) to conduct a comprehensive set of activities to develop
investment cases for JE vaccine introduction into selected
countries of Asia. The aim is to generate and disseminate the
evidence needed by policymakers for rationally introducing JE
vaccines. This evidence derives from measuring the disease
burden; assessing vaccine effectiveness in public-health
programs; estimating vaccine demand and the cost-effectiveness
of vaccination; and analyzing determinants of and obstacles to
the implementation of JE immunization in public-health
programs.
23
Dr. Liu Wei, an IVI scientist, works with an Indonesian collaborator.
Japanese Encephalitis Program
Progress in 2003-2004
A prospective field assessment of the JE disease burden has
been finalized in Bali, Indonesia. A high annual incidence of
approximately 10 cases per 100,000 children under 12 years of
age was found during surveillance from July 2001 to December
2003. To put this figure into perspective, it is of the same order of
magnitude as the incidence in endemic areas of Thailand,
Japan, Korea, and China before vaccine programs were
launched in these countries. Historically, Asian countries near the
Equator Indonesia, Malaysia, and the Philippines have been
considered to be at low risk for JE. The IVI’s findings challenge
this conventional wisdom and call for more studies of the disease
burden in these countries.
An innovative, controlled and blinded cohort study of the long-
term neurobehavioral sequelae of JE among children
hospitalized for JE in Shanghai, China, has also been completed.
This study revealed a high rate of major neurologic deficits in
survivors 6 to 26 years after acute meningoencephalitic illnesses.
Of the post-JE patients, 22% had objective neurologic deficits
compared with 3% in non-JE encephalitis patients. Moreover,
28% of post-JE patients had subnormal IQs compared to 2% in
non-JE encephalitis patients.
A computerized decision analysis model was developed by IVI
scientists to assess the cost-effectiveness of JE vaccine
introduction for China. This analysis, which used empiric data on
JE incidence and costs from Shanghai, showed clearly that the
two JE vaccines currently in use in China (P3 and SA 14-14-2)
are saving costs for the health-care system in that city.
Compared to the outcome of no JE immunization program, a
program using the P3 vaccine would prevent 420 JE cases and
105 deaths and would save 6,456 Disability Adjusted Life Years
(DALYs) per 100,000 persons. The use of the SA 14-14-2
vaccine would prevent 427 cases and 107 deaths and would
save 6,556 DALYs per 100,000 persons. In Vietnam, the same
methodology was used to estimate the cost-effectiveness of a JE
immunization program that used a locally produced, mouse-brain
derived, inactivated JE vaccine and was delivered either through
the Expanded Program on Immunization (EPI) or by charging a
user’s fee. Compared to a strategy of no vaccinations, the EPI
delivery of the inactivated vaccine to 100,000 persons would
prevent 117 JE cases, 12 deaths, and 1,076 DALYs lost; the
costs of treating acute JE cases would be reduced from US$
29,971 to US$ 4,945. In comparison, modeling a vaccination
strategy with a user’s fee attached shows that 84 JE cases and
771 DALYs would be averted. The net cost of each JE case
avoided was US$ 1,332, and US$ 144 for each DALY averted.
Cost-effectiveness analyses, in cooperation with the Thai
Ministry of Health, are in progress in Thailand.
Finally, the JE program has finished surveys of policymakers
about their perceptions of the importance of JE in their countries,
the need for introducing JE immunization, and determinants of
obstacles to implementing JE immunization in public-health
programs in China and Vietnam. Similar analyses are ongoing in
Thailand, where JE vaccines are being used in the EPI.
24
Japanese Encephalitis Program
The goals of the Japanese Encephalitis Program are:
To generate and disseminate the evidence needed by policymakers to rationally introduce existing, licensed, new-
generation JE vaccine in developing countries of Asia through measurements of disease burden; assessment of vaccine
effectiveness; evaluation of vaccine demand, cost-effectiveness, and acceptability; and analysis of policy strategies for
vaccine introduction.
To assure an adequate and cost-competitive vaccine supply of JE vaccines by the provision of training in vaccine
production and regulation to qualified local producers in Asia.
To ensure that the pipeline of newer generation experimental vaccines against JE is exploited by evaluating these vaccines
in endemic settings.
To help develop consensus at the national, regional, and international levels on the use of JE vaccines.
Future ActivitiesIn the next few years, the IVI expects to complete the
development of investment cases for the rational, accelerated
introduction of JE vaccines in several countries in Asia.
In Indonesia, after the successful completion of the
population-based surveillance study in Bali, local and central
health authorities have requested further studies to address the
feasibility, acceptability, and effectiveness of vaccine
introduction; analysis of the economic consequences of JE
illness; and the cost-effectiveness and policy determinants of
introducing the vaccine. Furthermore, in order to determine the
disease burden of JE in non-Hindu areas (the Bali study
described above was conducted in Hindu populations), the JE
vaccine program will be launching a series of hospital-based
studies in Muslim regions.
In Vietnam, a prospective hospital-based surveillance study
in a northern Vietnamese province linked with economic and
socio-behavioral analyses will be launched. As epidemiological
data becomes available, a large demonstration project will be
conducted using the mouse-brain derived, inactivated JE vaccine
produced by the local Vietnamese manufacturer VaBiotech. It is
hoped that these multidisciplinary studies will provide
Vietnamese policymakers with the analytic framework and data
needed to evaluate its current JE immunization program as well
as to expand it in the most efficient way.
Finally, the Japanese Encephalitis Program will be launching a
multidisciplinary research program in Cambodia. The program
will start with hospital-based surveillance studies and will follow-
up with economic and vaccine demonstration studies if the
epidemiological data justify such interventions.
25
BackgroundGlobally, invasive bacterial disease due to Haemophilus
influenzae type b (Hib) accounts for three to four hundred
thousand deaths and 2.2 million cases annually. While
hospitalizations and deaths are often the most frequently
considered Hib-associated outcomes, neurologic sequelae
following Hib meningitis may occur in 20% to 30% of children
with Hib meningitis. The majority of this disease burden may
occur in populations in developing countries. Hib conjugate
vaccines have been shown to be safe and effective and have
dramatically reduced the incidence of Hib disease when
introduced into routine infant immunization programs. However,
Hib conjugate vaccines have not yet been introduced in many
developing countries in Asia and around the world. A number of
factors may account for this relatively slow integration of safe and
highly effective Hib vaccines, including limitations in
immunization program infrastructure, the cost of vaccines, and a
dearth of Hib disease burden data. In 1997, a number of
countries gathered at an international conference in Bali,
Indonesia, to review and discuss the existing data on Hib
disease. Many countries documented the presence of Hib as a
cause of meningitis, pneumonia, and bloodstream infections,
including life-threatening sepsis. Hib was also identified as the
most common bacterial etiology of these invasive disease
manifestations. At this meeting, it was concluded that while
important data, largely from hospital-based studies, was
available in Asian countries, there was little data that allowed
population-based disease burden estimates. At that time, it was
felt that studies providing population-based data would allow
national agencies to directly and accurately estimate the true
incidence of Hib disease and Hib-associated mortality. In 1997,
few countries in Asia had credible laboratory-based data on Hib
incidence or mortality from which they could begin to estimate
their national disease burdens.
To determine the incidence of invasive Hib disease in selected
countries in Asia, the IVI, together with a group of collaborating
scientists, launched population-based surveillance studies for Hib
meningitis in field sites in Jeonbuk province, South Korea; Hanoi
city, Vietnam; and Nanning city and Wuming and Yongning
counties, China. These field sites were well-known to local
investigators and were chosen because of the high level of
cooperation that could be achieved with local doctors and the
demographic stability of their populations. In Jeonbuk province,
South Korea, from September 1999 to December 2001, 2,176
children were evaluated for possible meningitis, 605 had
26
Prof. Jung Soo Kim (right) of Chonbuk National University Hospital, Korea, reviews digital images of childhood pneumonia for a joint study by the Korean Society forPediatric Infectious Diseases and the IVI in 2003.
Haemophilus influenzae type b (Hib) Disease
Respiratory Encapsulated Bacteria Program
cerebrospinal fluid (CSF) abnormalities indicating suspected
bacterial meningitis but no pathogen identified; six patients had
probable Hib meningitis and eight had confirmed Hib meningitis.
Annual incidence of suspected bacterial meningitis in children
under five years old was 258.4 cases per 100,000 children, and for
probable or confirmed Hib meningitis the incidence was 6.0 cases
per 100,000. Suspected bacterial meningitis incidence was high,
but proven invasive Hib meningitis incidence was low.
Nonetheless, Hib was the leading cause of bacterial meningitis,
although bacterial pathogens were identified in only 4% of
abnormal CSF samples. This may have reflected a truly low
incidence, presumptive antibiotic treatment, or partial Hib
immunization of the population. In Hanoi, Vietnam, from March
2000 through March 2002, among 580 children enrolled in active
surveillance, 254 (44%) had suspected bacterial meningitis, 167
(29%) had probable bacterial meningitis, and 23 (4%) had
culture-confirmed or probable Hib meningitis. Hib meningitis
annual incidence was 12.2 cases per 100,000 in children less
than 60 months in age and 25.7 cases per 100,000 among
children less than 24 months of age. Passive surveillance in
children referred from outside Hanoi identified additional Hib (95),
pneumococcal (23) and meningococcal (5) meningitis cases and
two cases of pneumococcal sepsis. These data suggest that
invasive bacterial meningitis due to Hib and other pathogens is a
major source of morbidity and mortality in Vietnamese children.
In Nanning city, China, and adjacent counties the population-
based study started in 2001 and finished at the end of 2003.
Progress in 2003-2004In Nanning city and Wuming and Yongning counties, China, from
January 2001 through December 2003, 1,192 patients were
evaluated and 287 (24.1%) had suspected bacterial meningitis, 144
(12.1%) had probable bacterial meningitis, and 5 (0.4%) had CSF
27
The objectives of the Hib Disease Program are:
To generate and disseminate the evidence needed by policymakers for the rational introduction of licensed, new-
generation Hib conjugate vaccines. This evidence derives from measuring the disease burden; assessing vaccine
effectiveness; evaluating vaccine demand, cost-effectiveness, and acceptability; and analyzing policy strategies for vaccine
introduction.
To develop consensus at the national level on the use of Hib conjugate vaccines.
A bedside examination of a child with severe diarrheal illness at the Beijing Friendship Hospital, Beijing, China (Credit: Dr. Fang Zhao Yin).
28
Respiratory Encapsulated Bacteria Program
laboratory-confirmed Hib meningitis. Among children aged less
than five years, the annual incidence of suspected bacterial
meningitis was 101.3 cases per 100,000 and the annual incidence
of probable bacterial meningitis was 50.9 cases per 100,000. The
annual Hib meningitis incidence rate was 1.8 cases per 100,000 in
children less than five years old, 3.4 among children aged less than
two years, and 6.9 cases per 100,000 among young infants aged 7
to 11 months. The low rates of laboratory-confirmed Hib meningitis
found in this study suggest the possibility that Hib infections are
unusual in Chinese children compared with other countries or that
one or more factors currently limit laboratory-based detection of Hib
infections. The high rate of probable bacterial meningitis and the
apparent injudicious use of antimicrobials in the field-site population
suggest that additional studies to evaluate Hib vaccine
effectiveness and the attributable fraction of meningitis or
pneumonia due to Hib may be necessary to establish appropriate
Hib immunization policies for infants in China.
These three epidemiological studies done in South Korea,
Vietnam, and China were also unique because they were some of
the first epidemiologic studies on invasive bacterial diseases that
included methods for testing spinal fluid by polymerase chain
reaction (PCR). This testing was incorporated because there was
some information from Asia suggesting that antibiotic administration
to children before coming to the hospital was very common. This
meant that cultures done on spinal fluid or blood might be negative
due to the use of antibiotics. Latex agglutination testing (LAT) was
also used to evaluate spinal fluid specimens that were abnormal (by
biochemical or cytologic tests) but were culture-negative.
Future ActivitiesThe IVI is planning a research agenda that could substantially
contribute to the accelerated introduction of Hib conjugate
vaccines in the region, if funds become available. This research
agenda includes implementing studies of vaccine effectiveness,
cost of illness, cost-effectiveness, and long-term sequelae in
several Asian countries.
The Study Investigative Team for Rotavirus Diarrhea at Ma-An-Shan Hospital, Ma-An-Shan, China (Credit: Dr. Wang Bei).
BackgroundStreptococcus pneumoniae causes high morbidity and
mortality, even in regions where antibiotics are readily available.
It is the single most common cause of community-acquired
bacterial pneumonia, and has become the most common cause
of meningitis in many regions. Pneumococcal disease is
estimated to kill one to two million children under the age of five
each year in developing countries, accounting for up to 20% to
25% of all deaths in this age group. The problem of
pneumococcal disease is being further exacerbated by the rate
at which this organism is acquiring resistance to multiple classes
of antibiotics and the rapid global spread of highly resistant
clones. In developed countries this is necessitating the use of
newer, more expensive alternative antimicrobials, but this option
is not available in the developing world.
A 7-valent pneumococcal conjugate vaccine has recently been
licensed for use in children, is effective against invasive disease,
and provides some protection against nasal carriage and otitis
media. Unfortunately, however, it protects against only 50% to
70% of invasive pneumococcal infections in many developing
countries. Alarmingly, trials of the conjugate vaccine have shown
that although carriage of serotypes targeted by the vaccine was
reduced, the vacated niche was promptly occupied by non-
vaccine serotypes. Thus, the introduction of such vaccines may
simply alter the serotype distribution of pneumococcal disease
rather than reducing its overall impact. In addition, the high cost
of the vaccine is prohibitive for use in developing countries. Other
conjugate vaccines covering 11 serotypes are currently under
development. In collaboration with the Pneumococcal Vaccine
Accelerated Development and Introduction Program (Pneumo
ADIP) at Johns Hopkins University and other partners, and in
order to help answer key policy questions about the ultimate
deployment of pneumococcal vaccines in public-health practice,
the IVI aims to conduct epidemiologic studies in Asia that
measure the actual disease burden of pneumococcus.
Progress in 2003-2004A network consisting of 13 hospitals and departments of
pediatrics in South Korea has been organized to describe
disease patterns in children who are hospitalized with
pneumonia. This study is designed to identify hospitals in which
future prospective disease burden studies can be done in South
Korea. Geographically, the study covers all of South Korea and
includes hospitals where members of the Korean Society of
Pediatric Infectious Diseases (KSPID) are working. IVI scientists
29
Respiratory Encapsulated Bacteria Program
A laboratory scientist working on pneumococcal disease research in Vietnam
Pneumococcal Disease
have visited each hospital to review preliminary results of the
data collected at each individual hospital. Results are now being
prepared for review by members of KSPID and will be published
at the end of 2004 or early 2005.
Future ActivitiesIn collaboration with Pneumo ADIP and vaccine
manufacturers, the IVI will develop and conduct hospital-based
studies to estimate patterns of pneumococcal pneumonia in
children aged less than five years in Vietnam. These studies
will build on existing infrastructure, collaborations, and expertise
among clinicians, laboratorians, and epidemiologists with
experience in conducting population-based surveillance for Hib
disease. In Vietnam, a provisional field site in Nha Trang
province has been identified for a pilot study to ensure that
appropriate screening procedures are in place to identify children
with invasive pneumococcal disease. The first phase of the study
in Vietnam will be conducted over an 8- to 12-month period.
30
The objectives of the Pneumococcal Disease Program are:
To generate and disseminate the evidence needed by policymakers for the rational introduction of new-generation
pneumococcal vaccines through the evaluation of disease burden, vaccine effectiveness, cost of illness, public demand,
and the cost-effectiveness, feasibility, and acceptability of vaccination.
To ensure that the pipeline of newer generation experimental vaccines against pneumococcal disease is exploited and to
evaluate these vaccines in endemic settings in developing countries.
Respiratory Encapsulated Bacteria Program
A health worker prepares to immunize students against typhoid fever in Hue,Vietnam, in November 2003.
BackgroundRotavirus is the most common cause of severe diarrhea in
infants and children less than five years old. Rotavirus also kills
an estimated 440,000 children each year, and in Asia, many of
these deaths occur among the poorest children where access to
health care is limited. A new rotavirus vaccine has been licensed
in Mexico and the Dominican Republic and is likely to be
licensed within the next year in several other countries. As
licensure moves forward, a number of countries have initiated
studies to estimate the local disease burden. These studies are
focused on identifying children with severe diarrhea who require
rehydration therapy.
Rotavirus diarrhea has been identified in every country where
children have been tested. However, few systematic studies
have been conducted in Asia, and in particular, studies in China
have been limited either by the testing methods used or are
applicable only to areas where surveillance was conducted.
Previous studies in South Korea were also limited as they were
based at selected hospitals and conducted surveillance over a
limited period, typically either one rotavirus season (i.e., four to
five months), or were conducted only in hospitals in Seoul. In
both China and South Korea, policymakers now need credible
estimates of the disease burden of rotavirus in order to decide
whether to introduce current and future vaccines. In China and
South Korea, the IVI has launched prospective hospital-based
surveillance for rotavirus diarrhea among children aged less than
five years, as well as studies to characterize G and P types of
rotavirus isolates using genotyping methods (reverse
transcription-PCR).
Intussusception is an acute obstructive process that occurs
rarely in segments of the small intestine in infants and young
children. During the past five years, intussusception gained
increased recognition when, after an oral, live, attenuated rhesus
reassortant tetravalent rotavirus vaccine was introduced in the
United States, intussusception cases were observed in infants
after receiving doses of the vaccine. The IVI has launched
retrospective intussusception studies among children aged less
than five years to determine intussusception patterns in Vietnam
and South Korea. From January 2000 through December 2002,
282 children (168 in Korea; 114 in Vietnam) were diagnosed with
intussusception. In both Korea and Vietnam, 80% of diagnosed
children were aged less than 24 months. In Korea, one
intussusception-associated death was found but none were
found in Vietnam. The mean annual incidence of intussusception
in Korea (43.5 cases per 100,000 for children aged less than five
years) was similar to that in Vietnam (39.3 cases per 100,000).
While clinical patterns of intussusception and diagnostic
approaches varied between Korea and Vietnam, incidence rates
were similar.
31
IVI scientists Dr. Paul Kilgore (third from left) and Dr. Nyambat Batmunkh (second from left) visit Jeongeup Health Center, South Korea, with Prof. Jung-soo Kim (third fromright) of Chunbuk National University Hospital prior to the launch of a rotavirus disease burden study in August 2002.
Rotavirus Diarrhea Program
Progress in 2003-2004In China, from August 2001 through July 2003, prospective
hospital-based surveillance for rotavirus diarrhea among children
aged less than five years was conducted in six sentinel hospitals
using standardized methods for clinical screening, data
collection, and laboratory testing. Rotavirus strains collected from
these children were characterized to describe G and P types
circulating during the study. Among 3,260 children screened for
rotavirus, 1,590 (49%) were positive by antigen detection assay,
and 95% of all the rotavirus episodes reported occurred in the
first two years of life. Among 454 strains typed, the most
common strain (20%) was G3[P8] while 4% contained the G9
serotype. Ongoing efforts are now underway to define more
precisely the burden of rotavirus in urban and rural populations,
as well as the proportion that may be due to unusual or emerging
human rotavirus strains.
In Jeongeub province, South Korea, from July 2002 through
June 2003, a total of 1,920 patients were evaluated for rotavirus
diarrhea, representing one out of every four children in the study
population aged less than five years. Among the 1,080 children
with diarrhea, 200 (18.5%) fecal specimens were rotavirus
positive 175 children visited outpatient clinics and 25 children
were hospitalized. By extrapolating the proportion of rotavirus-
positive patients to all children with diarrhea in the surveillance
system, it was calculated that 356 children suffered from
rotavirus diarrhea in Jeongeub province (311 and 45 clinic visits
and hospitalizations, respectively). Genotyping of rotavirus
strains showed 41% were G9P[8] and 25% were G1P[8]. The
incidence rate for all rotavirus-diarrhea outcomes was 45.9 cases
per thousand in children under five years old. The annual
incidence rate for rotavirus hospitalizations was 5.8 cases per
thousand.
To determine the distribution of rotavirus genotypes in children
throughout South Korea, rotavirus-positive specimens were
collected from July 2002 through June 2003 in eight hospitals of
the Korean Rotavirus Strain Surveillance Network and
genotyped by reverse transcription-PCR. The globally
32
The goals of the Rotavirus Diarrhea Program are:
To generate and disseminate the evidence needed by policymakers to rationally introduce new-generation rotavirus
vaccines. This evidence derives from measuring the disease burden; assessing vaccine effectiveness; evaluating the cost
of illness; assessing the public demand for and the cost-effectiveness, feasibility, and acceptability of vaccination; and
analyzing policy strategies for vaccine introduction.
To ensure that the pipeline of newer generation rotavirus vaccines is exploited by clinically evaluating these vaccines in
developing countries.
Rotavirus Diarrhea Program
IVI senior scientist Dr. Zhi-yi Xu and Dr. Zhao-ying Fang inspect evaluations ofdiarrheal specimens at the National Center for Disease Control in Beijing, China.
Dr. Zhi-yi Xu and Dr. Zhao-ying Fang visit a diarrheal disease clinic in the BeijingFriendship Hospital in Beijing, China.
uncommon G4P[6] type was most prevalent (27%), the newly
emerging strain G9P[8] accounted for 11% of strains, and
globally common genotypes constituted only 55% of the strains
characterized. Ninety percent of G4P[6] strains were detected in
specimens from neonates. Common genotypes were responsible
for a rotavirus epidemic that began in January and ended in May
2003, but G4P[6] strains showed an early peak from August
through October 2002 and were detected throughout the
remaining study period. G4P[6] strains were most commonly
identified in large urban centers, but they were absent from two
rural centers. The newly emerging G9P[8] strain represented a
relatively greater proportion of strains from a central region
hospital and two hospitals in southern South Korea. The
identification of novel rotavirus genotypes in this laboratory-
based surveillance underscores the public-health importance of
continued strain surveillance among children for whom
vaccination against rotavirus might be considered.
Future ActivitiesIn collaboration with national leaders, pediatricians, and
national public-health leaders in four Asian countries (Cambodia,
Laos, Mongolia, and Sri Lanka) and supported by the rotavirus
ADIP at PATH, the IVI will conduct a multi-country hospital-
based rotavirus surveillance study that will estimate the
proportion of diarrheal hospitalizations among children under five
years of age who have laboratory-confirmed rotavirus diarrhea
over a 24-month period. Clinical and epidemiologic data will be
combined with characterization data for the strains of rotavirus to
provide a current picture of rotavirus epidemiology in each
country. The WHO Collaborating Centre for Research in Human
Rotavirus will assist countries in characterizing rotavirus strains
by G and P types.
33
BackgroundThe success of vaccines in preventing diseases has created a
sense of complacency about these diseases among the public,
leading to an underestimation of the value of ongoing vaccination
for disease control, and an overemphasis on potential vaccine
side-effects. Allegations about putative severe vaccine side-
effects emerge almost daily in the lay press, reducing public
confidence in vaccines. Recent examples include allegations that
measles vaccine causes autism and inflammatory bowel disease
and that hepatitis B vaccine causes multiple sclerosis. At times
these allegations have led to a reduced public acceptance of
vaccination, with the result that old diseases have re-emerged in
major epidemics, as has been illustrated with pertussis in both
Sweden and the United Kingdom, and more recently with
measles in the United Kingdom. While many of these allegations
about vaccine safety have come from the industrialized world,
progressively, they are emerging in the developing world as well.
To maintain credibility, it has been essential for the public-
health community to evaluate in a timely fashion and with
scientific studies concerns about potential vaccine side-effects.
Because it is usually necessary to address the concerns with
controlled studies in human populations, most of these scientific
studies employ epidemiological methods. However, it can take
years to organize and conduct such epidemiological studies.
Because of the need for much more rapid epidemiological
analyses, several countries in the industrialized world, including
the United States and the United Kingdom, have created large,
computerized, population databases that contain linked
information on all vaccines received and all illnesses occurring in
defined populations of children. With such a database, one can
immediately address a concern as to whether “vaccine X causes
disease Y”by comparing the rates of disease Y in children who
received vaccine X versus those who did not. Because the data
is computerized in a continuously updated database, the analysis
can be done very rapidly and cheaply. Moreover, because the
databases are continuously updated and are large, the analyses
can address safety concerns in current populations of children
and can evaluate very rare, but serious potential side-effects.
With the exception of one pilot project in Vietnam, large, linked
computerized databases for evaluating concerns about vaccine
safety do not exist in the developing world. Yet concerns about
potentially serious vaccine side-effects are beginning to emerge
in developing countries and could threaten vaccination programs
for vulnerable children in these settings. A recent example was a
publication in the British Medical Journal that reported that DTP
(diptheria, tetanus, pertussis) vaccine elevates the overall risk of
death in infants and children in Guinea Bissau. If this association,
which was not substantiated in replication studies, had resulted
in the withdrawal of DTP vaccine, the rebound in deadly cases of
whooping cough could have been disastrous. Clearly, large-
linked databases, similar to those in the industrialized world,
34
Vaccine Safety Program
IVI scientist Dr. Mohammad Ali and IVI fellow Dr. Vu Dinh Thiem train community workers on vaccine safety at the Khanh Hoa Health Service office in Nha Trang, Vietnam,in August 2002.
need to be developed in the developing world.
To date, there has been relatively little experience in
establishing large, linked databases for evaluating vaccine safety
concerns in developing countries. Creating such systems in
developing countries will entail several challenges not
encountered in industrialized settings: poor recording of
vaccination histories, limited clinical facilities for making accurate
diagnoses in patients who present themselves for care, lack of
standardized systems for coding such diagnoses, and limited
capabilities in creating computerized databases.
The IVI has created a large, linked database for a semi-rural
province in central Vietnam to allow the systematic collection and
analysis of adverse events potentially related to vaccinations.
The design overcomes several problems inherent in databases
of medical events and vaccinations in developing countries.
Medical identification cards with permanent, unique identification
(ID) numbers were distributed. Assigning a permanent ID
number to each resident avoided the ambiguities of ID numbers
based on addresses. Medical records of all admissions were
coded according to the International Classification of Diseases
(ICD-10) and transcribed into a computer system. Project staff
checked records on vaccinations and hospital admissions
35
The objectives of the Vaccine Safety Program are:
To develop model, large, linked databases for use in scientific evaluations of vaccine safety concerns in selected
developing countries in the Asia-Pacific region.
To validate the accuracy of these databases.
To demonstrate the use of these databases in evaluating the safety of routine childhood vaccines in each of the settings for
the model databases.
A child getting vaccinated in Karachi, Pakistan
through regular household visits. Data describing vaccinations
and medical events were linked to the data collected by the
project staff in a computer system.
Progress in 2003-2004During the study period, September 2002 to July 2003, a total
of 107,022 immunizations of children in a catchment area in Nha
Trang, Vietnam, an area with a population of about 350,000,
were recorded. Five vaccines, BCG, DTP, oral polio (OPV),
hepatitis B, and measles were provided free of charge by the
national immunization program. Target population sizes and
vaccine coverage are shown in Table 1.
The number of medical events recorded in the target
population was 32,527. The majority of the medical events,
22,005 (68%), were recorded in the Nha Trang provincial
hospital; 7,918 (24%) were recorded in Ninh Hoa hospital; and
the remaining 2,604 events were recorded in six polyclinics.
Overall, the study detected nine cases of intussusception
resulting in an intussusception rate among children five years old
or younger of 3.2 per 10,000 per year. Seven (77%) of the
intussusception cases were male and all but two of the patients
were below one year of age (the mean age was eight months).
The study recorded 20 episodes of convulsions, six of which
were in children under two years of age. None of the convulsions
were detected within 30 days of vaccination. A patient’s distance
from the hospital had some effect on health-care utilization.
Individuals living near the two hospitals had higher rates of
reported medical events compared to individuals living further
away from the hospitals.
A mass measles vaccination campaign was conducted in the
study area in March and April of 2003. The aim of the campaign
was to provide a measles vaccination to children between nine
months and ten years of age, regardless of their previous history
of measles vaccination. Children already vaccinated against
measles received a booster dose. Parents and guardians of
eligible children residing within the catchment area were invited
to participate in the campaign. There were 61,856 children
between nine months and ten years of age registered in the
vaccine safety datalink and eligible for a measles vaccination.
The study documented vaccinations of 53,267 children resulting
in an estimated 86% coverage. The mean age of the children
participating in the campaign was six years. There were 337
medical events reported during the 60 days before the
vaccination, and 355 medical events were registered following
the vaccination. Incidence rate ratios for the ten most frequent
presentations are shown in Table 2. No cases of syncope, local
reactions, allergic reactions, or encephalopathy were detected.
There was no statistically significant difference in the incidence
rates of medical events detected by the datalink before and after
the mass measles vaccination.
Between September 2002 and September 2003 the study
36
Immunization Target population % Coverage
BCG
DTP1
DTP2
DTP3
OPV1
OPV2
OPV3
HepB1
HepB2
HepB3
Measles 1
Measles vaccination campaign
4,568
4,485
4,240
3,926
4,505
4,276
4,021
4,568
4,469
4,013
2,095
61,856
94.2
93.7
92.8
87.7
94.1
93.7
89.1
78.3
75.6
67.5
91.2
86.1
Vaccine Safety Program
Table 1. Target population and coverage with BCG vaccine; diphtheria, tetanus,pertussis vaccine (DTP); oral polio vaccine (OPV); hepatitis B vaccine; andmeasles vaccine in Nha Trang, Vietnam, in 2002-2003.
Presentation
Acute respiratory infection
Gastroenteritis
Pneumonia
Tonsillitis
Pharyngitis
Asthma
Skin infection
Dengue
Lymphadenitis
Convulsions
During 60 days
before vaccination
n=53,267
63
59
22
14
10
9
5
3
4
1
During 60 days
after vaccination
n=53,267
69
45
34
16
10
8
8
4
3
3
Rate ratio
adjusted
for age
1.18
0.86
1.66
1.12
1.00
0.87
1.63
1.31
0.80
3.21
95% confidence
interval
0.84 to 1.65
0.58 to 1.26
0.97 to 2.84
0.55 to 2.30
0.41 to 2.40
0.34 to 2.27
0.53 to 5.00
0.29 to 5.85
0.18 to 3.57
0.33 to 30.90
Table 2. The ten most frequently observed medical events following the measles vaccination campaign in in Khanh Hoa province, Vietnam.
detected 33 deaths in children under 15 years of age. The mean
age of the 33 children was 6.2 years. None of the children had a
vaccination within 30 days of their death. The presumptive cause
of death was reported for seven children, three of whom died of
pneumonia and one child each died of gastroenteritis, congenital
heart disease, hydrocephalus, and leukemia.
The detection of operational problems was an essential part of
the study. Medical ID (MID) cards were distributed to all 67,129
households in the study area to facilitate the retrieval of the ID
number of any patient presenting him of herself to health-care
providers. However, in 99% of visits to participating health-care
providers, the parents or guardians failed to bring the MID card.
Repeated attempts by political leaders and representatives of the
public health-care system to encourage the population to bring
the MID card when requesting medical services did not improve
compliance. In the absence of an MID card, a computer-based
ID search program was used to identify patients. This computer-
based system was able to identify 4,548 children (73%) out of
6,272 children presenting for care in the target age group. A
second problem detected was the large discrepancy between
the number of visits to health-care providers reported by the
health-care system and the number of visits reported during
quarterly household visits. Health-care providers recorded 5,707
visits, but during the quarterly validation visits to households, only
2,062 visits to health-care providers were reported. Household
visits therefore proved to be expensive but insensitive in
identifying these visits.
Future ActivitiesThe successful creation of this database in Vietnam, and the
lessons learned from this pilot project, provide a platform for
exporting the system to other developing countries. In the
future, the IVI expects to create and validate model large,
linked, computerized databases in several developing countries
in the Asia-Pacific region.
37
Introduction
Vaccine Development and Process Research
Mucosal Immunology
Cellular Immunology
Humoral Immunology
Molecular Microbiology
Technology Transfer Program
Division of Laboratory Sciences
Vaccines at a Turning PointVaccines and vaccination are at a turning point. The
development of new vaccines and the accelerated introduction of
existing vaccines face several challenges.
First, the rapid development and introduction of new vaccines
for populations in developing countries needs a cost-competitive
and sustainable supply of these vaccines. Although vaccination
has been demonstrated to be the most effective way to prevent
infectious diseases, its major public-health impact has been
restricted essentially to the control of a limited number of human
diseases, including smallpox, poliomyelitis, tetanus, diphtheria,
pertussis, and measles. An inequity in access to existing and
newly licensed vaccines has increased over the past two
decades as new vaccines have become available at prices that
most low-income countries cannot afford. Until recently, many of
the poorest countries lacked the capacity to deliver existing
vaccines, let alone add newer, more expensive ones such as the
hepatitis B vaccines and Haemophilus influenzae type b (Hib) or
pneumococcal conjugate vaccines. From the first introduction of
these vaccines in Europe or the U.S., it can take a decade or
more for their adoption in a limited number of developing
countries. For diseases primarily affecting developing-country
populations, prospects that vaccines could be introduced into
public-health programs are limited. The high cost to vaccine
companies of vaccine development or of building additional
production facilities to increase capacity, as well as the high
“opportunity”costs of failing to pursue more profitable projects,
all act as powerful deterrents for these companies. Additional
vaccine development and the establishment of a sustainable
cost-competitive supply of vaccines for the “orphan diseases”of
the poor may therefore also require a number of highly qualified
producers in developing countries that can: (1) acquire the
technology to produce them; (2) produce enough number of
doses at affordable costs; and (3) be appropriately trained in
production, quality control, and regulatory processes.
There is a dearth of institutions with the capacity to transfer
technology to local producers and/or provide continuous assistance in
process research, physicochemical characterization, and quality
control/quality assurance. The IVI, with its new research
laboratories occupying 211,713 square feet of floor space, aims
to become such an institution. The IVI has established a
laboratory dedicated to process research under strictly controlled
Good Laboratory Practices (GLP) conditions for the production of
clinical lots of selected vaccines and for training staff from
producers in selected developing countries who will be ultimately
responsible for large scale manufacturing. The laboratories are
being equipped with modern physicochemical methods that
allow biological products to be characterized with a high degree
of precision. In addition, the IVI is establishing a laboratory for
humoral immunology that will conduct a range of serological
assays to measure the impact of candidate vaccines in
experimental animals and humans. These assays need to be
validated and to be robust and reproducible, thus this laboratory
will also be devoted to the standardization and validation of these
assays. In the area of technology transfer, the IVI has provided
39
Dr. Aldo Tagliabue, Deputy Director for Laboratory Sciences, and Mr. Rodney Carbis, IVI Senior Scientist, at an IVI laboratory.
Introduction
assistance to vaccine producers in China, Indonesia, India,
Vietnam, and Pakistan. This assistance has focused on
upgrading the production quality of existing vaccines, as well as
the transfer of technologies for the production of newer
generation vaccines. These programs take advantage of the IVI’s
international network of vaccine developers and producers,
which serve as sources of new technologies, as well as of the
IVI’s in-house expertise in providing the hands-on assistance
necessary for a successful technology transfer. Specific activities
carried out by the laboratories for Vaccine Development and
Process Research, Humoral Immunology, and the Technology
Transfer Program are described in this section.
A second major challenge is posed by the rapid expansion of
immunization programs worldwide. To cope with it, the
development of safer and more effective immunization delivery
systems are becoming increasingly important. So far, with few
exceptions, most vaccines are administered as part of routine
childhood immunization programs. Today, over 100 million
children are immunized every year throughout the world. It is
estimated that 1.2 billion vaccine injections are performed every
year, and the number of antigens routinely administered is
increasing rapidly. The fact that many vaccines are administered
parenterally necessitates the presence of a health-care
professional to perform the injection. At the same time, it is
anticipated that the majority of new vaccines that will be available
in the next few years will be injectable and the number of
immunization injections could increase to some 3.5 billion a year.
Worryingly, unsafe injection practices may be spreading
diseases such as hepatitis B and C, and HIV. Allegations of
adverse vaccine-related effects that are not rapidly and
effectively evaluated and dealt with can undermine confidence in
a vaccine, and ultimately, have dramatic consequences for
immunization coverage and disease incidence. Immunization via
the oral route offers obvious advantages. Only a few vaccines,
such as those against polio, cholera, and typhoid fever, are
licensed for oral administration. However, diverse antigen
delivery systems are now being developed for the administration
of non-living and living vaccine antigens to mucosal surfaces and
protective vaccine antigens are even being expressed in
transgenic plants, which would then be administered as edible
vaccines. The IVI has established a laboratory of Mucosal
Immunology for the research and development of vaccines that
can be administered via the mucosal surfaces. Specific activities
launched by this laboratory are also described in this section. At
the same time, recent advances in microbial genetics and
immunology have opened the way towards a revolution in
“Vaccinology”. Based on an improved understanding of
microbial pathogenesis and of host defense mechanisms, new
vaccine strategies are now emerging against pathogens for
which conventional vaccine approaches have not worked. To
fully participate in this ongoing revolution, the IVI is establishing
laboratories of Cellular Immunology and Molecular Microbiology.
Research projects being undertaken in these laboratories are
also described in this section.
Finally, a third major immediate public-health threat for the
world in general and the Asia Pacific region in particular is the
emergence of new deadly diseases whose spread will not be
halted by national boundaries. More than thirty new diseases
have emerged or been identified for the first time in the last three
decades, most notoriously HIV/AIDS which now affects around
40 million people. The need for strengthened surveillance, early
identification, and monitoring of emerging infectious diseases in
the Asia Pacific region has been especially heightened by the
recent emergence of bird flu and Severe Acute Respiratory
Syndrome (SARS). The economic and political impact of these
epidemics has been enormous for the countries affected. More
worrying, a virulent new strain of influenza, for example, could
spread much more rapidly than SARS, which is not especially
contagious in comparison to other respiratory diseases, with
even more dramatic consequences. Recent developments in the
fields of molecular epidemiology and population genetics offer
new possibilities for the early identification of hypervirulent
isolates that have been responsible for epidemics across the
world. The IVI wishes to become a major player in the prevention
of potential epidemics of pathogenic infectious diseases through
the establishment of a state-of-the-art laboratory of molecular
epidemiology within its Molecular Microbiology department.
These programs are further described in this section.
The work of the Division of Laboratory Sciences began in early
2004, with orders of equipment, the establishment of safety and
other procedures, and the recruitment of staff. Although research
in this division has barely started, the work in the division is
already taking place. While the laboratory program at the IVI has
been designed to complement and synergize with the IVI’s
already well-established epidemiological and field research
programs, it has also been conceived to participate in the
advances in vaccinology that will contribute to the panel of
clinically available vaccines in the next twenty years.
Introduction
40
BackgroundAs mentioned in the report on the DOMI Shigellosis Program,
existing conjugate and live attenuated Shigella vaccine
candidates have been either difficult to produce on a large scale
or have rendered disappointing results when tested in Shigella
endemic areas. In order to help overcome these obstacles, as its
first in-house vaccine development project, the IVI has initiated
the manufacture of a Shigella vaccine prototype.
This vaccine is based on an old technology developed by
Levenson et al. in the 1970s. The technology is based on
attaching the Shigella O antigen to bacterial ribosomes. The
association of the antigen with the ribosome converts it from T-
cell independent to T-cell dependent, and the ribosome also acts
as an adjuvant that amplifies the immune response to the O
antigen. The vaccine produced by Levenson et al. was shown to
be immunogenic and protective in animal models. Ribosomal
vaccine development was halted, however, due to contamination
with lipopolysaccharide (LPS), which results in excessive
pyrogenicity. In 2000, a new approach was jointly conceived by
the IVI, Institut Pasteur, and the Walter Reed Army Institute of
Research (WRAIR) to reduce the LPS content of this vaccine.
Shigella mutant (msbB) seed strains expressing low LPS activity
were constructed at Institut Pasteur. WRAIR was responsible for
process development (including pyrogenicity tests in animals) for
clinical-grade batches of this vaccine for human testing.
Unfortunately, a shift in WRAIR’sdevelopment portfolio resulted
in the ribosomal vaccine project being abandoned. In 2003, the
IVI has taken on the challenge of a Shigella ribosomal vaccine as
the first developmental project for its new laboratories.
Progress in 2003-2004During the end of 2003 and first half of 2004, fermentation and
optimization of the growth of S. flexneri 2a and S. sonnei strains
were performed at a three-litre scale. Very high cell yields on semi-
defined media (without the addition of any animal components)
were achieved with both strains. Furthermore, downstream
processing to develop the vaccine at a laboratory scale was
launched. A cell disruption procedure has been developed and
shown to be efficient at the laboratory scale, using equipment that
is scalable to production size. A methodology for separating cell
debris from ribosomes has been tested and a methodology for
removing LPS has been developed and validated. Currently only
wild strains have been used in feasibility studies, but as a parallel
strategy the S. flexneri 2a msbB mutant will also be examined as
a candidate vaccine seed strain. A crude ribosomal preparation
has been made to demonstrate feasibility, and characterization of
this and future preparations will follow. Finally, an enzyme-linked
immunosorbent assay (ELISA) is being developed for quantifying
the antigen for in-process and final lot testing. The ELISA uses
polyclonal antiserum against purified LPS of S. flexneri 2a and S.
sonnei obtained from rabbits.
41
Mr. Hyun Jang of the IVI tests laboratory equipment.
Vaccine Development and Process Research
Future Activities
Future activities are directed at optimizing the manufacturing
process, initially at the laboratory scale, then once consistency is
established, on a pilot scale, and finally for full-scale production.
Assays will be developed to monitor and control the manufacturing
process and ensure the final lot meets all the required specifications.
Control testing and final lot requirements will be agreed to, and
perhaps developed with, the appropriate national regulatory
authorities. The vaccine will be tested for safety and immunogenicity
in appropriate animal models at the IVI. Large-scale manufacturing
will be performed under appropriate Good Manufacturing Practices
(GMP) guidelines in order to produce clinical lots for testing in Phase I
and Phase II trials. After the successful completion of all clinical trials
and the demonstration of manufacturing consistency, the technology
will be transferred to selected vaccine producers willing to
manufacture the vaccine at affordable prices for developing countries.
Ultimately this technology could become a platform technology for the
development of vaccines against a wide range of pathogens of great
public-health importance.
The goals of the Vaccine Development and Process Research Program for its Shigella ribosomal vaccineproject are:
To develop a manufacturing process for a Shigella ribosomal vaccine that can be scaled up and easily produced by
vaccine manufacturers in developing countries.
To develop a manufacturing process that specifically addresses the removal of endotoxins.
To demonstrate consistency of manufacture on a laboratory scale.
With the assistance of partner vaccine producers, to scale up the process to pilot (100 litres) and eventually production
scale (1,000 litres).
To produce vaccine lots and validate production facilities.
To develop assays for in-process control and final lot release.
To perform clinical trials with vaccine lots used in validation studies.
To transfer the vaccine technology, including the training of quality control and production staff, to partner vaccine
producers.
Vaccine Development and Process Research
42
BackgroundAs an alternative to the parenteral administration of vaccines,
mucosal vaccination offers obvious safety advantages since it
eliminates the risks of blood-borne infections due to unsterile
needles. Mucosally administered vaccines are generally more
readily accepted than injectable vaccines, and as the current
global polio eradication initiative is demonstrating, offer large
logistic advantages for immunization programs.
Mucosal cells, whether of the digestive, respiratory, or
reproductive systems, are constantly exposed to antigens of
microbial, environmental, or food origin and require an effective
defense system. The mucosal immune system covers over 400
square meters of tissue in humans and the cellular mass far
exceeds the total lymphoid cells found in the bone marrow,
thymus, spleen, and lymph nodes combined. Immune cells
stimulated at one mucosal surface induce local as well as
systemic protection, thus providing the potential for vaccines to
be used for a broad spectrum of infectious diseases.
The successful experience with the oral, trivalent attenuated
Sabin polio virus vaccine, which is the driving force in the global
polio eradication effort, triggered research to develop and license
other mucosal vaccines. Examples include Ty21a, a live oral
typhoid vaccine, CVD 103-HgR, a live oral cholera vaccine, and
whole-cell based killed oral cholera vaccines, as well as nasal
formulations of influenza vaccine. Furthermore, aerosolized
administration of measles vaccine has attracted interest as a
technology for accelerating measles control and elimination
efforts worldwide. The Mucosal Immunology Laboratory was
established to expand on these successes through the research
and development of mucosal vaccines that target infectious
diseases of great public-health importance.
Transcutaneous immunization (TCI) will be the second major
area of research for the Mucosal Immunology Laboratory. TCI,
the simple introduction of antigens to the host using a topical
application to intact skin, may have profound implications for
immunization programs, both for their safety and effectiveness.
From the point of view of safety, TCI is a simple, needle-free
vaccine delivery system with the potential to eliminate the risks
associated with injection devices. The feasibility of TCI is based
on the skin’s role as a potent immunologic site. Hydrating the
skin allows the vaccine to penetrate to the Langerhans cells,
potent antigen-presenting cells found in the superficial layers of
skin. Langerhans cells are abundant in the skin, present in 25%
of the surface area, and are highly phagocytic, eliciting co-
stimulatory molecules and cytokines. Pre-clinical studies have
shown that TCI is able to induce priming and secondary humoral
immune responses, without signs of local or systemic toxicity.
Progress in 2003-2004The first six months of 2004 have been dedicated to setting up
the Mucosal Immunology Laboratory with the equipment, animal
facility, and assays necessary to initiate mucosal immunology
studies. These include:
43
Mucosal Immunology
Dr. Mi-na Kweon, Chief of Mucosal Immunology, working at an IVI laboratory.
Warm and cold rooms, carbon dioxide incubators, balances,
freeze dry apparatus, glassware preparations, autoclave,
ELISA and ELISPOT readers, FACS, an automated Flow
Cytometry Sorter, Confocal Laser Scanning Microscope, and
a real-time PCR system.
An animal facility equipped with one hundred cages and water
bottles for mice.
A method to purify dendritic cells from the spleen and large
intestine. This method will be used to characterize mucosal
dendritic cells after rectal vaccination and rectal inflammation.
A method for studying transcutaneous immunization and
purification of Langerhans cells. This method is now being
used to measure immune responses in mice immunized with
tetanus toxoid antigen together with cholera toxin as a
mucosal adjuvant through the skin.
Future ActivitiesRoles of Dendritic Cells in the Mucosal Immune System
The Mucosal Immunology Laboratory will focus its research
on determining the roles of mucosal dendritic cells in the
development of intestinal inflammation, infection, and allergic
reactions. Dendritic cells are antigen presenting cells that are
likely to be pivotal in the balance between a person’s tolerance
and active immunity to food antigens, pathogenic organisms,
and commensal microorganisms. Specific goals of the laboratory
are to clarify (1) the distinct features of the colonic dendritic cells
in terms of cell subsets and cytokine production and (2) the exact
role of colonic dendritic cells in the development of diseases of
the large intestine.
Transcutaneous Immunization Against Enteric Diseases
As mentioned above, vaccination through the skin is
particularly advantageous, as the epidermis is replete with
Langerhans cells. However, the exact role of Langerhans cells in
inducing mucosal immune responses needs to be clarified. The
goals of the Mucosal Immunology Laboratory in this field are to
better understand (1) how Langerhans cells migrate to the
mucosal compartment after antigen uptake, (2) what other cells
are involved, and (3) whether transcutaneous vaccination is
effective in preventing enteric infections such as Salmonella
typhi and Shigella.
Animal Models for the Development of Mucosal Shigella Vaccines
Many mutant and recombinant Shigella strains have been
developed and tested as candidate vaccines, however, none of
them has yet proven to be sufficiently immunogenic in children
living in the developing world. A major obstacle to optimizing and
rationalizing the preclinical stages of Shigella live-attenuated
vaccine candidates is the lack of an appropriate animal model.
Shigella species do not cause acute rectocolitis in mice, even
upon straight intra-rectal or intra-colonic inoculation. Although a
model of jejunal invasion by Shigella in newborn mice following
intragastric inoculation has recently been developed, this model
does not permit immunological and vaccination studies. Thus,
the Mucosal Immunology Laboratory, in close collaboration with
Professor Sansonetti’s group at Institut Pasteur, will be
conducting research to develop alternative shigellosis murine
models for pre-clinical screening of Shigella vaccine candidates.
The objectives of the Mucosal Immunology Laboratory are:
To facilitate the development of mucosal vaccines by characterizing the mucosal immune system, specifically, to determine
the roles of mucosal dendritic cells in the development of intestinal inflammation, infection, and immunity.
To develop strategies for mucosal vaccines by developing new mucosal vaccines targeting M cells and by establishing
efficient and novel delivery routes for mucosal vaccines, such as transcutaneous immunization.
To develop animal models for mucosal vaccine development.
Mucosal Immunology
44
BackgroundThe Cellular Immunology Laboratory was initiated in March
2004 to conduct studies on the molecular processes involved in
the immunological recognition of microbial antigens and in the
differentiation of cells that mediate effector mechanisms. This
knowledge is required for the rational design of many new
vaccines. Whereas antibody responses are sufficient to protect
against infections by many pathogens such as pneumococci or
meningococci, cellular responses may be needed to prevent
diseases caused by intracellular microorganisms such as
viruses, chlamydiae, certain bacteria, or parasites (e.g.,
toxoplasma, malaria, leishmania). If, as some studies suggest,
CD4 T helper (Th-1) cells are required for the clearance of such
infected cells, vaccines directed against intracellular
microorganisms should induce this pattern of response.
Furthermore, vaccines inducing long-term protection are also
critical to sustaining immunization programs in developing
countries, where re-vaccination constitutes a financial and
programmatic challenge. Long-term protection can be achieved
through the induction of immunological memory. Memory B and
T cells do not prevent infection per se, but they quickly proliferate
and differentiate into effectors upon re-exposure to pathogens.
This rapid recall response is critical in controlling the extent of
infection and preventing disease. There are still many questions,
however, about the role of immunological memory in protecting
against infections. The underlying molecular mechanisms that
induce and sustain immunological memory are also a major
research target of this laboratory.
Progress in 2003-2004The first six months of 2004 have been devoted to equipping
the Cellular Immunology Laboratory and setting up the systems
and assays necessary to measure cellular immune responses.
These include:
A flow cytometry assay with four-color staining to detect the
phenotypes of memory cells (Figure 1).
A proliferation assay based upon the reduction of tetrazolium
salts for determining in vitro cell proliferative activity using
antigenic stimulants or mitogens as positive controls.
ELISA for the detection of human cytokines. The assays will
be used to test the concentration of cytokines from in vitro
supernatant cultures or samples from clinical trials.
Future ActivitiesTwo major projects will be launched to assess cell-mediated
immune responses against enteric pathogens. The first, in
collaboration with Gothenburg University, Sweden, and
Chonnam National University, Korea, will investigate the
importance of CD8 natural killer cells in protecting against V.
cholerae. A second project will measure cell-mediated immune
45
Cellular Immunology
IVI scientific staff doing research in the Cellular Immunology Laboratory.
Naive cells
responses (e.g., changes in cell-mediated immunity and
memory-cell phenotype after vaccination) of volunteers orally
immunized with a live, genetically attenuated Salmonella typhi
strain ZH9, produced by Microscience.
In order to develop the cell-line related assays required to
study the pathogenesis of intracellular bacteria and some
viruses, a cell culture laboratory will be established.
The Cellular Immunology Laboratory will also continue to set
up the following systems and assays: proliferation assay (non-
radioisotope); ELISPOT for the detection of antibody or cytokine
secreting cells; cytometric bead array (CBA) for the detection of
Th1/Th2 cytokines, inflammatory cytokines, and chemokines;
real-time PCR tests for the molecules involved in signaling
pathways; methods for sub-grouping cells after sorting based on
surface phenotype using FACSaria (cell sorter); and the
production of dendritic cells from CD14 derived monocytes.
The objectives of the Cellular Immunology Laboratory are:
To elucidate the cell-mediated immunological mechanisms involved in protection against infections by bacteria
and viruses.
To investigate the underlying mechanisms generating B cell memory responses.
Cellular Immunology
46
Figure 1. CD4 effector memory cells.
BackgroundThe Humoral Immunology Laboratory was established at the
IVI in 2004 to support both disease burden studies and vaccine
development and evaluation activities through the development,
standardization, and validation of assays measuring humoral
immune responses. Laboratory assays as surrogates of
protective immunity are often essential to the approval of
vaccines or to prove that the vaccine can be manufactured to the
same immunological potency. New Hib, pneumocococcal, and
meningococcal conjugate vaccines are good examples of this. It
is essential that the antibody surrogate is based upon a well-
standardized and accepted immune correlate and that the
biological basis of protection is well understood; for example,
neutralization of toxin or opsonophagocytosis of bacteria. The IVI
is developing its laboratory capacity to support its translational
research program by establishing appropriate assays to
demonstrate the immunological potency of vaccines
manufactured by partner producers, as well as evaluating the
humoral immune responses from vaccinated individuals in the
DOMI program’s large demonstration projects for typhoid and
cholera vaccines.
An accurate assessment of the disease burden of infectious
diseases is critical for prioritizing efforts and providing rational
evidence to policymakers of the feasibility and impact of
introducing new vaccine tools into public-health programs. The
availability of accurate, low-cost serological assays for diseases
of the poor may provide improved disease burden estimates and
allow more accurate evaluations of specific disease control
measures, such as drug therapy and vaccines. The situation is
particularly difficult for diseases such as typhoid fever. For
typhoid, although diagnosis is established using a bacterial
culture from biological samples, such as blood or bone-marrow,
culture-based diagnosis has several limitations. One such
limitation is the need for a large blood sample (5 ml), which is
particularly difficult to obtain from young children, and the
variability of the sample depending on the number of days the
specimen was obtained after the onset of illness. Despite the fact
that there are several rapid assays for typhoid fever, including
Felix/Widal, Tubex, and Typhidot, improvements are needed.
The Humoral Immunology Laboratory will be working to improve
current serologic diagnostic assays for evaluating typhoid
infection.
Progress in 2003-2004
Cholera Toxin and LPS Content in WC Cholera Vaccines
In order to facilitate the use of the oral WC cholera vaccine
produced by Vabiotech in Vietnam, the IVI is transferring the
cholera vaccine manufacturing technology from this company to
a number of qualified local manufacturers in Asia, including
BioFarma in Indonesia and Shantha Biotechnics in India (see the
Technology Transfer Program). To assure that the quality control
procedures used by these and other manufacturers of the
vaccine comply with WHO recommendations, the Humoral
47
Humoral Immunology
IVI scientist Dr. Cheol-heui Yun and Prof. Jan Holmgren work on an experiment in Sweden.
Immunology Laboratory will be running three different assays
with the bulk vaccine, namely: (1) a vibriocidal assay for
measuring seroresponses in vaccinees, (2) GM-1 ELISA for
quantitatively measuring the content of whole cholera toxin in the
vaccines, and (3) an LPS inhibition ELISA for measuring the
cholera LPS content in the vaccines. In order to set up the
assays at IVI, staff were trained at Gothenburg University,
Sweden. The GM-1 ELISA has already been set-up at the IVI
laboratories and samples from VaBiotech in Vietnam have been
tested for cholera toxin content. Both the vibrocidal and LPS
inhibition ELISA assays are currently being set up.
Sero-diagnostic Assays for Typhoid Fever
A training course in the three currently available sero-
diagnostic assays was held at the IVI. Samples from surveillance
at a DOMI typhoid field site were analyzed. Head-to-head
comparisons of the three assays, Felix/Widal, Tubex, and
Typhidot, are ongoing using standard parameters, including
sensitivity, specificity, likelihood ratios, and positive and negative
predictive values.
Future Activities
Evaluation of Immune Response to Bacterial Polysaccharide Antigens
For several bacteria the polysaccharide (PS) capsule is an
important determinant of virulence. Serum antibody to the PS
capsule confers protection against encapsulated bacteria by
activating complement-mediated bacteriolysis and/or
opsonization. Most PS vaccines are safe and effective in older
children and adults. However, most PS vaccines are also poor
immunogens in young infants and fail to induce immunological
Humoral Immunology
48
The objectives of the Humoral Immunology Laboratory are:
To establish a reference laboratory for the standardization and validation of serological assays of antibodies against
encapsulated bacteria.
To evaluate humoral immune responses to bacterial polysaccharide antigens.
To develop new low-cost rapid diagnostic tests for targeted infections.
IVI staff working in the Humoral Immunology Laboratory.
memory at all ages. In addition, immune hyporesponsiveness is
observed after repeated vaccination with some PS vaccines
(e.g., group C polysaccharide meningococcal vaccine), which
may represent a problem for individuals requiring long-term
protection. Finally, PS vaccines against encapsulated respiratory
bacteria induce only transient or no protection against bacterial
colonization. To improve current PS vaccines, it is important to
understand the immune responses to bacterial PS antigens. The
Humoral Immunology Laboratory will investigate various types of
model PS antigens, such as LPS of Gram-negative bacteria
(Salmonella typhi, Vibrio cholerae, Escherichia coli, Helicobacter
pylori, etc.), lipoteichoic acid (LTA) of Gram-positive bacteria
(Streptococcus pneumoniae, Staphylococcus aureus, Bacilus
subtilis, etc.), and the capsule PS of S. typhi (Vi) and S.
pneumoniae (serotype-specific PS and C-PS). The project will be
supported for the next three years with a US$ 100,000 grant from
the Korea Research Institute of Bioscience and Biotechnology
(KRIBB).
Reference Laboratory
To complement the translational research programs on
pneumococcal and typhoid fever vaccines, the Humoral
Immunology Laboratory will be setting up a reference laboratory
to: (1) standardize and validate IgG ELISA to measure serotype-
specific antibodies in serum for pneumococcal conjugate and Vi
vaccines, (2) standardize and validate an opsonophagocytic-
killing assay to measure functional antibodies induced by
pneumococcal conjugate vaccines, and (3) establish assays for
serotyping invasive pneumococcal strains.
49
50
BackgroundRecent developments in the fields of molecular epidemiology
and population genetics have altered our perspective on how to
classify the bacteria that cause invasive disease. Molecular
epidemiological studies based on multilocus enzyme
electrophoresis (MLEE) and multilocus sequence typing (MLST)
have demonstrated that, while certain bacterial pathogens such
as Salmonella, Shigella, Vibrio cholerae, and meningococci are
genotypically diverse, specific complexes of related hypervirulent
isolates have been responsible for epidemics across the world.
Horizontal genetic exchange occurs continually within
populations of pathogenic bacteria. This not only provides the
mechanism by which hypervirulent isolates continue to emerge,
through the acquisition of genes that enhance pathogenicity, but
also facilitates the exchange of genes that encode variable
antigens. The latter has important implications for the design of
vaccines because the organism has the ability to switch antigen
genes within the pathogen’s gene pool and thereby evade the
immune response. Molecular epidemiology provides a tool to
predict epidemics caused by hypervirulent clones and to monitor
the effectiveness of vaccination programs.
Progress in microbial genetics and advances in genetic
engineering are an essential part of the ongoing vaccine
revolution. Identifying the molecular basis of virulence and the
microbial antigens essential for inducing successful defense
mechanisms in the host enables the construction of “intelligent”
vaccines, such as genetically engineered, attenuated micro-
organisms or live vectors carrying foreign genes relevant for
protection. For example, the identification of virulence genes in
Shigella, enterotoxigenic E. coli, S. typhi, and V. cholerae has
led, through selective deletion of these virulence genes, to the
production of attenuated strains, and thus of live candidate
vaccines. Such attenuated strains can also be used as vectors
that carry foreign genes in their bacterial genomes. Deciphering
the entire genomes of the most important human pathogens has
also had a marked impact on vaccine development. Genes of
specific interest for vaccine design are identified by a
computerized analysis of genomic sequences and searching for
sequence homologies between different microorganisms. The
Molecular Microbiology Department has been established to
tackle the problems of vaccine development using state-of-the-
art techniques of molecular biology and bioinformatics, and is
divided in two laboratories: Molecular Epidemiology and
Molecular Vaccinology.
Progress in 2003-2004
Establishment of the Molecular Microbiology Department
The department was established by the appointment of Doctor
Jongsik Chun from the School of Biological Sciences, Seoul
National University (SNU), as acting Head in April 2004. Doctor
Chun leads the Laboratory of Bacteriology and Bioinformatics at
Overall work flow for the Molecular Microbiology Department
Molecular Microbiology
SNU. Necessary equipment for the long-term storage of
cultures, molecular typing, microbiology, molecular biology, and
bioinformatics has been ordered. All laboratory functions are
expected to be operational by the end of 2004.
Molecular Epidemiology of Vibrio choleraeVibrio cholerae O1 El Tor strains isolated from the DOMI site
in Mozambique were shown to have a distinctive genomic
feature that differs from other pandemic strains. In order to
understand the identity of these unusual strains, MLST analysis
was employed. A total of nine loci were chosen and are being
sequenced in collaboration with ICDDR,B in Bangladesh. This
information will be used to elucidate the genomic features and
evolutionary origin of these vibrios.
Future ActivitiesMolecular Epidemiology Laboratory
Culture collection: A culture collection system will be
established at the IVI, in order to create an IVI bio-bank. All
biological and logging information will be incorporated and
maintained in an integrated database management system.
Reference laboratory for the molecular epidemiology of
pathogens: The following methods will be established:
automated ribotyping, pulsed field gel electrophoresis (PFGE),
microarray diagnosis, variable number tandem repeats analysis
(VNTR), antimicrobial susceptibility, and general microbiological
diagnosis.
Bioinformatics: A bioinformatics unit will be established to
create an integrated database management system for the
Laboratory Sciences Division. A multi-user, intranet-based
computer server will be generated to store information on
biological resources in the IVI bio-bank (Strains, DNA, sera,
blood, etc.) and to provide sophisticated bio-data analysis in a
user-friendly interface.
Molecular Vaccinology Laboratory
Genetic and functional analysis of virulence factors of
infectious diseases: Many Gram-negative bacterial pathogens
use a type III secretion system to inject virulence factors through
the host cell membrane. The Laboratory of Molecular
Vaccinology will focus on virulence factor(s) involved in the
down-regulation of the immune response. A number of
techniques will be employed: construction of a knock-out
mutation of each virulence factor gene, complemented strain
construction, infectivity and dissemination tests of mutants,
purification of each virulence factor, and biochemical and cellular
analysis of the purified virulence factors.
Analysis of the DNA sequence of virulence plasmids:
Virulence factors, their secretion apparatus, and their regulators
are carried by an extrachromosomal plasmid in some pathogens.
These plasmids are large (50-200 kb), exist in a small number of
copies, and are composed of multiple-origin DNA fragments,
including insert sequences. Virulence plasmids of pathogens will
be collected and their DNA sequences analyzed.
Development of live genetically-attenuated vaccines against
shigellosis: Besides the development of sub-unit vaccines (see
Vaccine Development and Process Research), the IVI is also
interested in the development of improved live-attenuated
vaccine candidates against shigellosis. Using the knowledge
acquired from the research on virulence factors, the Laboratory
of Molecular Vaccinology will focus on the construction of
genetically modified strains and the characterization of these
strains by a number of tests (infectivity, dissemination, and rabbit
and mouse models), which could lead to the development of new
vaccine candidates against Shigella.
The objectives of the Molecular Microbiology Department are:
To establish a world-class standard culture collection.
To establish a state-of-the-art reference laboratory for the molecular epidemiology of pathogens.
To establish a state-of-the-art laboratory for molecular vaccinology.
To establish a laboratory for bioinformatics.
51
52
BackgroundThe introduction and routine use of a vaccine in developing
countries requires a reliable supply of the vaccine at a
reasonable price. For vaccines of importance to developing
countries this will probably require that vaccines be produced by
international manufacturers and by manufacturers in developing
countries.
The quality control and regulatory practices that govern
vaccine production are not optimal in some developing countries.
For this reason, developing countries may be reluctant to obtain
vaccines from other developing countries unless the
manufacturers and their national regulatory authorities (NRA) are
WHO pre-qualified.
The production of vaccines by developing country manufacturers
is dependent on whether these producers have access to
production technologies. For this to happen, there are different
models that can be followed, ranging from an alliance with
established vaccine manufacturers or academic institutions to a
complex series of partnerships with developers and sub-
contractors. These models have rarely been successful in the past.
Implementing the successful and sustainable transfer of vaccine
technologies while honoring patent rights is the goal of the
Technology Transfer Program. It is the intention of the IVI to
thoroughly and continuously train the staff of vaccine manufacturing
partners in production procedures and quality-control testing for any
vaccine that the IVI transfers to developing countries. It is also the
goal of the IVI to work with the appropriate NRAs and to train their
staff in the appropriate vaccine quality-control and release
procedures. Training will take place at the manufacturer’s facility,
the NRA, and on some occasions, at the IVI.
Progress in 2003-2004The IVI is currently transferring manufacturing technology for
killed, oral cholera vaccine, owned by VaBiotech in Vietnam, to
Shantha Biotechnics of India, to BioFarma of Indonesia, and to
Sinovac of China. VaBiotech has been manufacturing cholera
Technology Transfer Program
From left to right, Dr. Aldo Tagliabue (IVI), Dr. Luis Jodar (IVI), Dr. John D. Clemens (IVI), Mr. Varaprasad Reddy (Shantha Biotechnics), and Mr. Rodney Carbis (IVI) inIndia for the Technology Transfer Program.
Killed oral WC cholera vaccine to BioFarma
in Indonesia
Killed oral WC cholera vaccine to Shantha
Biotechnics in India
Killed oral WC cholera vaccine to Sinovac Biotech
in China
Typhoid Vi vaccine to BioFarma in Indonesia
Typhoid Vi vaccine to Shantha Biotechnics in India
Typhoid Vi vaccine to Amson Vaccines & Pharma
in Pakistan
53
vaccine for several years and produces the vaccine for the EPI in
Vietnam, but does not export to any other country. For this
reason, the IVI is also providing assistance to VaBiotech and the
Vietnamese NRA to upgrade the quality of production and
regulation of this vaccine to meet WHO standards. The IVI is
also providing assistance with the transfer of Vi polysaccharide
vaccine to both BioFarma and Shantha, as well as to Amson in
Pakistan.
Future ActivitiesThe Technology Transfer Program will complete the transfer of
cholera and Vi vaccine technologies as described above, and will
begin technology transfer initiatives for both cholera and typhoid
vaccines to other countries. Specific plans are as follows:
Complete and submit to regulatory authorities in India the
documentation required for importing the Vietnamese killed,
WC cholera vaccine in preparation for an upcoming cholera
field trial.
Train IVI scientists in cholera vaccine control assays with a
view to the future training at the IVI of appropriate people from
developing country manufacturers in these assays.
Develop in-house at the IVI a standardized ELISA for the
quantification of antibodies to typhoid Vi vaccine.
Develop a licensing agreement with NIH (U.S.) for typhoid Vi
vaccine technology and Vi conjugation technology for future
technology transfers to developing countries.
Recruit staff to perform technology transfers and training.
Train IVI staff in cholera and typhoid Vi vaccine production and
control testing.
The goals of the Technology Transfer Program are:
To obtain suitable vaccine technologies that can be transferred to manufacturers in developing countries and to review the
suitability of these technologies for transfer.
To hold discussions with selected vaccine manufacturers and the appropriate national regulatory authorities regarding the
introduction of new vaccines.
To train IVI staff in production and quality-control procedures and to provide training in production and quality control to
partner vaccine producers and national regulatory authorities.
To produce small scale lots at partner vaccine producers under IVI supervision.
To assist with obtaining and/or developing all the appropriate documentation for licensing the new vaccine in the specified
country.
Training and Capacity Building
IVI Scientific Publications
Administration and Finance
Organizational Chart
Financial Statements
Donors to the IVI
Korea Support Committee
International Collaborators
Board of Trustees
Building Success
Training on the Clinical Evaluation of Vaccines
For the past four years, the IVI has conducted annual training
courses for professionals in developing countries on the clinical
evaluation of vaccines. The sponsors for these courses have
been the Rockefeller Foundation, GlaxoSmithKline, Sartorius,
and Becton-Dickenson. In 2004, the IVI hosted at its new
headquarters its fourth annual course for a group of participants
that included health professionals from Australia, Bangladesh,
Cambodia, China, India, Indonesia, South Korea, Malaysia,
Nepal, Pakistan, the Philippines, Singapore, Taiwan, Thailand,
and Vietnam. The course aimed at strengthening the overall
vaccinology capacity of countries from the Asia-Pacific region by
providing participants with a comprehensive overview of the
vaccine continuum, from vaccine development, evaluation, and
regulatory principles, to production, introduction, and policy
issues. The new strategy of including representatives from both
developed and developing countries of Asia led to a very fruitful
exchange of perspectives. It is planned that next year’s course
will be followed by a course for the WHO Global Training
Network at the IVI’s headquarters. This course will focus on
evaluating evidence from clinical vaccine trials and will target
national regulatory authorities in developing countries.
Advanced Course in Epidemiologyand Vaccinology at Seoul NationalUniversity
The IVI has established a course on advanced epidemiology
and vaccinology for graduate students at the School of Public
Health at Seoul National University. The course is attended by
approximately thirty students with diverse backgrounds, including
medical and pharmaceutical graduates, nurses, public-health
specialists, and scientists from the private sector. The course
aims to provide students with knowledge and skills that will
enable them to make valuable contributions to vaccine research
and immunization programs. It bridges the disciplines of
epidemiology, laboratory sciences, and public health and policy
Training and Capacity Building
55
Participants in the Fourth International Advanced Course on Vaccinology in the Asia-Pacific region in March 2004.
in order to train or retrain students who wish to work directly on a
multidisciplinary practical approach to the control of infectious
diseases through immunization programs. The goal is to equip
students with specialized skills that will facilitate a career in the
control of infectious diseases as staff of health ministries,
regional or local health departments, national or international
disease control agencies, international aid organisations, or
universities.
By the end of this course, students will have acquired a basic
understanding and knowledge of contemporary vaccinology and
will be able to: (1) demonstrate a basic knowledge and
understanding of the principles underlying immunological and
56
Training and Capacity Building
molecular biological techniques as they are applied to vaccine
development and research; (2) demonstrate an advanced
knowledge and understanding of the role of epidemiology and its
contribution to vaccine introduction; (3) demonstrate knowledge of
methods for the pre-licensure clinical evaluation of experimental
vaccines leading to product licensure and registration; (4)
demonstrate knowledge of methods for post-marketing
assessments of vaccine safety and effectiveness; (5) understand
the principles and approaches to the economic analyses of
vaccines and their impact; and (6) demonstrate knowledge of the
key issues confronting the development of vaccines against
several key pathogens affecting Asian populations.
57
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geographic information system for defining spatial risk for
dengue transmission in Bangladesh: role for Aedes
albopictus in an urban outbreak. American Journal of
Tropical Medicine and Hygiene 69(6):634-40.
Blum L.S., Nahar N. 2004. Cultural and social context of
dysentery: implications for the introduction of a new vaccine.
Journal of Health, Population and Nutrition 22(2):159-69.
Bresee J., Fang Z.Y., Wang B., Nelson E.A., Tam J., Soenarto Y.,
Wilopo S.A., Kilgore P., et al. 2004. Asian Rotavirus
Surveillance Network. First report from the Asian Rotavirus
Surveillance Network. Emerging Infectious Diseases
10(6):988-95.
Butraporn P., Pach A., Pack R.P., Masngarmmeung R., Maton
T., Sri-aroon P., Nyamete A., Chaicumpa W. 2004. The
health belief model and factors relating to potential use of a
vaccine for shigellosis in Kaeng Koi district, Saraburi
province, Thailand. Journal of Health, Population and
Nutrition 22(2):170-81.
Chowdhury A., Ishibashi M., Thiem V.D., Tuyet D.T., Tung T.V.,
Chien B.T., von Seidlein L., Canh do G., Clemens J., Trach
D.D., Nishibuchi M. 2004. Emergence and serovar transition
of Vibrio parahaemolyticus pandemic strains isolated
during a diarrhea outbreak in Vietnam between 1997 and
1999. Microbiology and Immunology 48(4):319-27.
Clemens J., Savarino S., Abu-Elyazeed R., Safwat M., Rao M.,
Wierzba T., Svennerholm A.M., Holmgren J., Frenck R.,
Park E., Naficy A. 2004. Development of pathogenicity-
driven definitions of outcomes for a field trial of a killed oral
vaccine against enterotoxigenic Escherichia coli in Egypt:
application of an evidence-based method. Journal of
Infectious Diseases 189(12):2299-307.
Clements C.J., Larsen G., Jodar L. 2004. Technologies that make
administration of vaccines safer. Vaccine 22(15-16):2054-8.
Deen J. 2004. The challenge of dengue vaccine development
and introduction[editorial]. Tropical Medicine and
International Health 9(1):1-3.
DeRoeck D., Deen J., Clemens J.D. 2003. Policymakers' views
on dengue fever/dengue haemorrhagic fever and the need
for dengue vaccines in four southeast Asian countries.
Vaccine 22(1):121-9.
Dong B.Q., Tang Z.Z., Lin M., Li C.Y., Tan D.M., Liang D.B., Liao
H.Z., Liu X.Z., Quan Y., Fang J.S., Wu X.H., Qin W.W.,
Kilgore P.E., Kennedy W.A., Xu Z.Y., Clemens J.D. 2004.
[Epidemiologic surveillance for bacterial meningitis in 140
000 children under 5 years of age in Nanning district,
Guangxi province]. Zhonghua Liu Xing Bing Xue Za Zhi
25(5):391-5.
England L., Brenner R., Bhaskar B., Simons-Morton B., Das A.,
Revenis M., Mehta N., Clemens J. 2003. Breastfeeding
practices in a cohort of inner-city women: the role of
contraindications. BMC Public Health 3(1):28-36.
Frenck R.W. Jr., Clemens J. 2003. Helicobacter in the developing
world. Microbes and Infection 5(8):705-13.
Ha S.J., Jeon B.Y., Kim S.C., Kim D.J., Song M.K., Sung Y.C.,
Cho S.N. 2003. Therapeutic effect of DNA vaccines
combined with chemotherapy in a latent infection model
after aerosol infection of mice with Mycobacterium
tuberculosis. Gene Therapy 10(18):1592-9.
Han S.H., Kim J.H., Martin M., Michalek S.M., Nahm M.H. 2003.
Pneumococcal lipoteichoic acid (LTA) is not as potent as
staphylococcal LTA in stimulating toll-like receptor 2.
Infection and Immunity 71(10):5541-8.
Hino A., Kweon M.N., Fujihashi K., McGhee J.R., Kiyono H.
2004. Pathological role of large intestinal IL-12p40 for the
induction of Th2-type allergic diarrhea. American Journal of
Pathology 164(4):1327-35.
Jang M.H., Kweon M.N., Iwatani K., Yamamoto M., Terahara K.,
Sasakawa C., et al. 2004. Intestinal villous M cells: an
antigen entry site in the mucosal epithelium. Proceedings of
IVI Scientific Publications
Publications from July 2003 to July 2004
IVI Scientific Publications
58
the National Academy of Sciences USA 101(16):6110-5.
Jodar L., Butler J., Carlone G., Dagan R., Goldblatt D., Kayhty
H., et al. 2003. Serological criteria for evaluation and
licensure of new pneumococcal conjugate vaccine
formulations for use in infants. Vaccine 21(23):3265-72.
Jodar L., Griffiths E., Feavers I. 2004. Scientific challenges for
the quality control and production of group C meningococcal
conjugate vaccines. Vaccine 22(8):1047-53.
Kaljee L.M., Thiem V.D., von Seidlein L., Genberg B.L., Canh
D.G., Tho L.H., Minh T.T., Kim Thoa L.T., Clemens J.D.,
Trach., D.D. 2004. Healthcare use for diarrhoea and
dysentery in actual and hypothetical cases, Nha Trang, Viet
Nam. Journal of Health, Population and Nutrition 22(2):139-
49.
Kaljee L.M., Genberg B.L., von Seidlein L., Canh D.G., Kim Thoa
L.T., Thiem V.D., et al. 2004. Acceptability and accessibility
of a shigellosis vaccine in Nha Trang City of Viet Nam.
Journal of Health, Population and Nutrition 22(2):150-8.
Kang J.O., Kim M.N., Kim J., Suh H.S., Yoon Y., Jang S., Chang
C., Choi S., Nyambat B., Kilgore P.E. 2003. [Epidemiologic
trends of rotavirus infection in Republic of Korea, July 1999
through June 2002]. Korean Journal of Laboratory Medicine
23(6):382-7.
Khiem H.B., Huan le D., Phuong N.T., Dang D.H., Hoang do H.,
Phuong le T., Sac P.K., Chien T.M., Tai L.A., Dan N.T.,
Deen J.L., Seidlein L., Clemens J., Trach D.D. 2003. Mass
psychogenic illness following oral cholera immunization in
Ca Mau City, Vietnam. Vaccine 21(31):4527-31.
Kim Y.D., Park J.K. 2004. Comparison of interval estimation for
relative risk ratio with rare events. Korean Communications
in Statistics 11(1):181-188.
Kweon M.N. 2003. The mucosal immune system. BioWave
5(14):1-22.
Lee J.T., Yu S.S., Han E., Kim S., Kim S. 2004. Engineering the
splice acceptor for improved gene expression and viral titer
in an MLV-based retroviral vector. Gene Therapy 11(1):94-9.
Lim S.H., Koe Y.S., Jo D.S., Lee S.J., Hwang P.H., Kilgore P.,
Nyambat B., Kim J.S. 2003. [Pediatrician perspectives on
the evaluation and treatment of acute gastrointestinal
infections, Jeonbuk, South Korea, 2002]. Journal of the
Korean Pediatric Society 46(12):1217-23.
Magpusao N.S., Monteclar A., Deen J.L. 2003. Slow improvement
of clinically-diagnosed dengue haemorrhagic fever case
fatality rates. Tropical Doctor 33(3):156-9.
Park E., Kim Y. 2004. Analysis of longitudinal data in case-
control studies. Biometrika 91(2):321-30.
Park E.J., Takahashi I., Ikeda J., Kawahara K., Okamoto T.,
Kweon M.N., et al. 2003. Clonal expansion of double-
positive intraepithelial lymphocytes by MHC class I-related
chain a expressed in mouse small intestinal epithelium.
Journal of Immunology 171(8):4131-9.
Putnam S., Frenck R., Riddle M., El-Gendy A., Taha N., Pittner
B., Abu-Elyazeed R., Wierzba T., Rao M., Savarino S.,
Clemens J. 2003. Antimicrobial susceptibility trends in
Campylobacter jejuni and Campylobacter coli isolated
from a rural Egyptian pediatric population with diarrhea.
Diagnostic Microbiology and Infectious Diseases 47(4):601-8.
Qadri F., Ahmed T., Wahed M.A., Ahmed F., Bhuiyan N.A.,
Rahman A.S., Clemens J.D., Black R.E., Albert M.J. 2004.
Suppressive effect of zinc on antibody response to cholera
toxin in children given the killed, B subunit-whole cell, oral
cholera vaccine. Vaccine 22(3-4):416-21.
Rao M.R., Abu-Elyazeed R., Savarino S.J., Naficy A.B., Wierzba
T.F., Abdel-Messih I., Shaheen H., Frenck R.W. Jr.,
Svennerholm A.M., Clemens J.D. 2003. High disease
burden of diarrhea due to enterotoxigenic Escherichia coli
among rural Egyptian infants and young children. Journal of
Clinical Microbiology 41(10):4862-4.
Rhie G.E., Roehrl M.H., Mourez M., Collier R.J., Mekalanos J.J.,
Wang J.Y. 2003. A dually active anthrax vaccine that
confers protection against both bacilli and toxins. Proceedings
of the National Academy of Sciences USA 100(19):10925-30.
Ricci S., Macchia G., Ruggiero P., Maggi T., Bossu P., Xu L.,
Medaglini D., Tagliabue A., Hammarstrom L., Pozzi G.,
Boraschi D. 2003. In vivo mucosal delivery of bioactive
human interleukin 1 receptor antagonist produced by
Streptococcus gordonii. BMC Biotechnol 3(15):1472-6.
Samosornsuk S., Jitsanguansuk S., Sirima N., Sudjai S.,
Tapchaisri P., Chompook P., von Seidlein L., Robertson
S.E., Ali M., Clemens J.D., Chaicumpa W. 2004.
59
Preferences for treatment of diarrhoea and dysentery in
Kaengkhoi district, Saraburi province, Thailand. Journal of
Health, Population and Nutrition 22(2):113-8.
Shepard D.S., Suaya J.A., Halstead S.B., Nathan M.B., Gubler
D.J., Mahoney R.T., Wang D.N., Meltzer M.I. 2004. Cost-
effectiveness of a pediatric dengue vaccine. Vaccine 22(9-
10):1275-80.
Simanjuntak C.H., Punjabi N.H., Wangsasaputra F., Nurdin D.,
Pulungsih S.P., Rofiq A., Santoso H., Pujarwoto H.,
Sjahrurachman A., Sudarmono P., von Seidlein L., Acosta
C., Robertson S.E., Ali M., Lee H., Park J., Deen J.L., Agtini
M.D., Clemens J.D. 2004. Diarrhoea episodes and
treatment-seeking behaviour in a slum area of North
Jakarta, Indonesia. Journal of Health, Population and
Nutrition 22(2):119-29.
Sun L.W., Tong Z.L., Li L.H., Zhang J., Chen Q., Zheng L.S., Liu
J., Xie H.P., Wang C.X., Zhang L.J., Ivanoff B., Glass R.I.,
Bresee J.S., Jiang X.I., Kilgore P.E., Fang Z.Y. 2003.
[Surveillance finding on rotavirus in Changchun children's
hospital during July 1998-June 2001]. Zhonghua Liu Xing
Bing Xue Za Zhi 24(11):1010-2.
Sur D., Manna B., Deb A.K., Deen J.L., Danovaro-Holliday M.C.,
von Seidlein L., Clemens J.D., et al. 2004. Factors
associated with reported diarrhoea episodes and treatment-
seeking in an urban slum of Kolkata, India. Journal of
Health, Population and Nutrition 22(2):130-8.
Tagliabue A. 2003. Mucosal delivery of enteric vaccines.
Vaccines: Children & Practice 6:31-4.
Tong Z.L., Ma L., Zhang J., Hou A.C., Zheng L.S., Jin Z.P., Xie
H.P., Ma L., Zhang L.J., Ivanoff B., Glass R.I., Bresee J.S.,
Jiang X.I., Kilgore P.E., Fang Z.Y. 2003. [Epidemiological
study of rotavirus diarrhea in Beijing, China: a hospital-
based surveillance from 1998-2001]. Zhonghua Liu Xing
Bing Xue Za Zhi 24(12):1100-3.
Von Seidlein L., Greenwood B.M. 2003. Mass administrations of
antimalarial drugs. Trends in Parasitology 19(10):452-60.
Vu D.T., Hossain M.M., Nguyen D.S., Nguyen T.H., Rao M.R.,
Do G.C., Naficy A., Nguyen T.K., Acosta C.J., Deen J.L.,
Clemens J.D., Dang D.T. 2003. Coverage and costs of
mass immunization of an oral cholera vaccine in Vietnam.
Journal of Health, Population and Nutrition 21(4):304-8.
Vu D.T., Sethabutr O., von Seidlein L., Tran V.T., Do G.C., Bui
T.C., Le H.T., Lee H., Houng H.S., Hale T.L., Clemens J.D.,
Mason C., Trach D.D. 2004. Detection of Shigella by a PCR
assay targeting the ipaH gene suggests increased
prevalence of shigellosis in Nha Trang, Vietnam. Journal of
Clinical Microbiology 42(5):2031-5.
Wang M., Dong B., Yang J., Li C., Tang D., Tang Z., Ou S., Zeng
J., Zhang J., Wu X., Page A.L., Acosta C. 2003.
[Comparative research of Widal testing with domestic and
international reagents]. Guangxi Journal of Preventive
Medicine 9(5):302-4.
Wang X.Y., von Seidlein L., Robertson S.E., Ma J.C., Han C.Q.,
Zhang Y.L., Lee H.J., Liu W., Ali M., Clemens J.D., Xu Z.Y.
2004. A community-based cluster survey on treatment
preferences for diarrhoea and dysentery in Zhengding
county, Hebei province, China. Journal of Health, Population
and Nutrition 22(2):104-12.
Wang X.Y., Xu Z., Yao X., Tian M., Zhou L., He L., et al. 2004.
Immune responses of anti-HAV in children vaccinated with
live attenuated and inactivated hepatitis A vaccines. Vaccine
22(15-16):1941-5.
Wu J.H., Wu W.S., Jiang M.B., Zhang G.H., Ren J.Y., Cao H.L.,
Wang X.Y., Xu Z.Y. 2003. [Immune strategy and evaluation
of hepatitis B vaccine]. Chinese Journal of Biology
16(4):247-9.
Yamamoto M., Kweon M.N., Rennert P.D., Takachika T.,
Fujihashi K., McGhee J.R., et al. 2004. Role of gut-
associated lymphoreticular tissues in antigen-specific
intestinal IgA immunity. Journal of Immunology
173(2):762-9.
Yang J., Dong B.Q., Zeng J., Si G.A., Zhang J., Liang G.C.,
Huang H.X., Yang H.H., Ochiai R.L., Danovaro C., Park
J.K., Ali M., Acosta C.J. 2004. [Investigation of resident
environment and health behavior in Hechi city, Guangxi].
Guangxi Journal of Preventive Medicine 10(3):129-31.
Yang J., Dong B., Zeng J., Zhang J., Si G., Zhou T., Zeng H.,
Acosta C., Ali M. 2003. [The use of GIS in typhoid Vi
vaccine trial study]. Guangxi Journal of Preventive Medicine
9(6):321-4.
IVI Scientific Publications
60
Yang J., Dong B., Zeng J., Zhang J., Si G., Zhou T., Zeng H.,
Acosta C., Ali M. 2004. [Use of GIS on epidemiologic study].
Guangxi Journal of Preventive Medicine 10(2):199-21.
Yang J., Wei S., Liu L., Zhang J., Huang L., Wen X., Ochiai R.L.,
Ali M., Acosta C.J. 2004. [Applying verbal autopsy to
determine cause of death aged 5-60 years old in Hechi city].
Chinese Journal of Primary Health Care 18(6):19-20.
Youlong G., Stanton B.F., von Seidlen L., Xueshan F., Nyamette
A. 2004. Perceptions of Shigella and of Shigella vaccine
among rural Chinese: compatibility with Western models of
behavioral change. Southeast Asian Journal of Tropical
Medicine and Public Health 35(1):97-108.
Zeng J., Yang J., Dong B., Zhang J., Liang D., Liang H., Si G.,
Acosta C., Ochiai L. 2004. [A survey of adverse events
following a mass vaccination]. Chinese Journal of Primary
Health Care 18(3):43-4.
Zhang J., Yang J., Dong B., Ali M., Park J.K., Zhou B., Huang X.
2004. [Establishment and use of data management system
in DOMI Hechi project]. Guangxi Medical Journal
26(4):584-5.
Zhang J., Zhou B., Yang J., Dong B., Ali M., Park J.K., Huang H.
2004. [Application of Data Management System in DOMI
Hechi project]. Guangxi Journal of Preventive Medicine
10(2):112-4.
Zhang L.J., Du Z.Q., Zhang Q., Kang H.Y., Zheng L.S., Liu X.M.,
Xie H.P., Yang H.Y., Wang Y.C., Ivanoff B., Glass R.I.,
Bresee J.S., Jiang X., Kilgore P.E., Fang Z.Y. 2004.
[Rotavirus surveillance data from Kunming Children's
Hospital, 1998 - 2001]. Zhonghua Liu Xing Bing Xue Za Zhi
25(5):391-5.
Zhou J.J., Wu W.S., Sun C.M., Dai H.Q., Zhou L., Liu C.B., Cao
H.L., Wang X.Y., Xu Z.Y. 2003. [Long-term evaluation of
immune efficacy among newborns 16 years after HBV
vaccination]. Chinese Journal of Vaccines and Immunization
9(3):129-32.
61
Growing for the FutureThe Administration and Finance division provides logistics
support to the scientific divisions and manages the physical
facilities of the IVI. It is supported by the Accounting Department;
the Human Resources, Travel and Purchasing Departments; the
Computer Services Department; the Library; the Facilities and
Maintenance Department; and the Program Administrative
Department for Translational Research. Additionally, the
Administration and Finance division is supported by a
Government Liaison and Cooperation Unit which looks after
funding and liaison activities with various government ministries
in the host country of South Korea. As the IVI’s activities and
operations grow, and demands increase, the level of
administrative and financial services support will increase
appropriately.
Staff GrowthThe number of staff at the IVI has grown from 17 in 1999 to 79
in June 2004, and the composition of staff has changed
accordingly. In the scientific and technical areas, staff has
increased significantly, from 6 in 1999 to 32 in June 2004.
Scientific and technical support staff increased from 1 in 1999 to
25 in June 2004; administrative support staff has increased from
10 in 1999 to 22 in June 2004.
Revenue GrowthThe IVI’s income has increased from $2.5 million in 1999 to
$10.5 million in 2003. Unrestricted income over this period has
remained at the same yearly level of about $1.45 million, while
restricted project income has increased from $0.68 million in
1999 to $9.1 million in 2003. For further financial details, please
refer to audited financial statements.
Administrative Highlights from June 2003 to June 2004
The IVI moved into its new headquarters building in June
2003, initially occupying the first two floors.
The IVI celebrated its June move with an Inauguration
Symposium titled New Frontiers in Vaccinology Research, a
Scientific Advisory Group Meeting, a meeting of the IVI Board
of Trustees and the Institute Support Council, and played host
to the meeting of the Global Alliance for Vaccine and
Immunization (GAVI) here in Seoul, Korea.
A meeting of the Executive Committee of the Board of Trustees
was held on December 21 and 22, 2003, in Seattle, Washington.
The Division of Laboratory Sciences recruited two senior
positions: a Chief of Mucosal Immunology and a Head of
Vaccine Development. Laboratory equipment started to be
purchased to equip the new laboratories.
Three post-doctoral fellows returned in early 2004 after their
two-year fellowships to assume Research Scientist positions in
the Immunology and Molecular Microbiology laboratories.
Senior staff and key members of the IVI plant a tree in October 2003 to commemorate the sixth anniversary of the IVI.
Administration and Finance
Administration and Finance
62
A joint appointment with the Seoul National University was
made for an acting Head of Molecular Microbiology in 2004.
The Scientific Advisory Group (SAG) held their annual meeting
in Seoul on March 5 and 6, 2004.
A Director for the Pediatric Dengue Vaccine Initiative (PDVI)
was successfully recruited in mid-2004.
Financial Highlights for 2003
The IVI was awarded a $55 million grant over five years (to 2008)
from the Bill & Melinda Gates Foundation for the Pediatric
Dengue Vaccine Initiative (PDVI).
The Korea International Cooperation Agency (KOICA)
provided a grant of approximately $1.5 million over three years
in support of Japanese encephalitis projects in Cambodia,
Vietnam, and Indonesia.
The UBS Foundation awarded the IVI a three-year grant of
$700,000 for studies of paratyphoid fever.
Total revenue received and recognized as income for 2003
was $10.5 million. Compared with revenue in 2002 of $8.8
million, revenue in 2003 reflected a 19% increase.
Unrestricted revenue in 2003 amounted to $1.4 million, while
restricted revenue totaled $9 million.
Operating expenditures increased from $7.7 million in 2002 to
$10 million in 2003, largely due to planned staff increases as a
result of the move to the new headquarters building,
occupancy expenses related to utilities and maintenance in the
new facilities, and an increase in subcontracts that reflect
increases in project funding.
The 2003 year ended with an operating surplus of $851,004.
Current assets make up 96% of total assets, out of which 98%
or $25 million is in the form of cash and bank deposits.
The Institute’s financial position continues to be strong.
Figure 1. Staff Growth from 1999 to2003.
Figure 2. Revenue Growth from1999 to 2003.
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Organizational Chart
Organizational Chart
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Financial Statements
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Financial Statements
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Financial Statements
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Financial Statements
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Financial Statements
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Financial Statements
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Donors to the IVICore funding to the IVI is provided by the governments of
Korea and Sweden. In addition, donors from the public and the
private sector provide support for the Institute’s research and
technical assistance activities. The support of the following
donors is gratefully acknowledged:
AusAID
Bill & Melinda Gates Foundation
Children’s Vaccine Program ot PATH
Industry (Aventis Pasteur, Berna Biotech, CJ, Chiron,
GlaxoSmithKline, LG, Merck, Microscience, Nonghyup,
Sartorius, Wyeth)
Japan International Cooperation Agency
Japan Society for the Promotion of Science
Korea International Cooperation Agency (KOICA)
Korea Research Foundation
Korea Research Institute of Bioscience and Biotechnology
Korean Science and Engineering Foundation
Ministry of Education & Human Resource Development,
Republic of Korea
Rockefeller Foundation
Swedish International Development Cooperation Agency
UBS Optimus Foundation
United Nations Development Programme (UNDP)
U.S. National Institutes of Health
Wellcome Trust Labs, Ho Chi Minh city
Korea Support CommitteeA large number of prominent Korean citizens have joined
together to form the Korea Support Committee for the IVI. The
Committee is a vehicle for mobilizing resources within Korea. It is
under the leadership of Korea’s First Lady, Ms. Kwon Yang-suk.
Donors to the IVI and the Korea Support Committee
IVI Director Dr. John Clemens thanks Korea’s First Lady, Ms. Kwon Yang-suk.
Australia: The Queensland Institute of Medical Research
Bangladesh: ICDDR,B; Center for Health and Population
Research; Dhaka Shishu Hospital
Belgium: GlaxoSmithKline Biologicals
Cambodia: Communicable Disease Control, Ministry of
Health; Kantha Bopha Children’s Hospital; National
Immunization Program, Ministry of Health; National Pediatric
Hospital
Canada: Health Canada; University of Western Ontario
China: An Hui Province Anti-Epidemic Station; Beijing
Friendship Hospital; Changchun Children’s Hospital; Centers
for Disease Control; Dongnan University School of Public
Health; Fudan University; Guangxi Maternal and Child
Hospital; Guangxi Medical University; Guangxi Province Anti-
Epidemic Center; Guangxi Provincial Hospital; Hebei Province
Anti-Epidemic Station; Jiangsu Province Anti-Epidemic
Station; Kunming Children’s Hospital; Lanzhou Institute of
Biological Products; Lulong County Health and Anti-Epidemic
Center; Ma-An-Shan Hospital; Nanning Second City Hospital;
Sinovac Biotech; Suzhou Medical School; Wuhan Institute of
Biological Products; Wuming County Hospital; Yongning
County Hospital
Egypt: Ministry of Health and Population; U.S. Naval Medical
Research Unit 3; Vacsera
Finland: National Public Health Institute
France: Aventis Pasteur; Epicentre; Institut Pasteur
Germany: Sartorius Group
India: All India Institute of Medical Sciences; Indian Council of
Medical Research; International Center for Genetic
Engineering and Biotechnology; National Institute of Cholera
and Enteric Diseases; Shantha Biotechnics
Indonesia: BioFarma; Centers for Disease Control; Central
Public Health Laboratory; National Institute of Health Research
and Development; Udayana University; U.S. Naval Medical
Research Unit 2
Japan: National Institute of Infectious Diseases; Osaka
University; Research Institute for Microbial Diseases, The
Institute of Medical Science, University of Tokyo.
Korea: Catholic University, St. Paul’s Hospital and St. Mary’s
Hospital; Changwon Fatima Hospital; Chonbuk National
University; Chonbuk Provincial Department of Health; Chonju
Presbyterian Medical Center; Green Cross Reference
Laboratory; Hallym University Medical Center; Hanyang
University Hospital; Inha University Hospital; Cheju National
University Hospital; Jung-Eub Hospital; Korea Research
Institute of Bioscience and Biotechnology; Korea University;
Korea Food and Drug Administration; Korean National Institute
of Health; Kyung Hee University Medical Center; LG Life
Sciences; Namwon Medical Center; Pohang University of
Science and Technology; Pusan National University Hospital;
Samkwang Reference Laboratories; Seoul Clinical
Laboratories; Seoul National University; Samsung Medical
Center; Social Security Research Institute; SoonChunHyang
University Hospital; Ulsan University; Wonkwang University
Medical Center; Yonsei University
International Collaborators
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International Collaborators
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Laos: Mahosot Hospital; National Institute of Public Health,
Ministry of Health
Mongolia: Maternal and Child Health Research Center,
Ministry of Health
Mozambique: Ministry of Health
Pakistan: Aga Khan University; Amson Pharmaceuticals
Philippines: Cebu Institute of Medicine; Research Institute
for Tropical Medicine
Singapore: K.K. Women’s and Children’s Hospital
Sri Lanka: Epidemiology Unit, Ministry of Health; Lady
Ridgeway Hospital
Sweden: Swedish Bacteriological Laboratory; University of
Gothenburg
Switzerland: Berna Biotech; Medecins Sans Frontieres
Thailand: Armed Forces Research Institute of Medical
Sciences; Center for Disease Control, Ministry of Public
Health; Mahidol University
United Kingdom: Wellcome Trust Sanger Institute; Health
Protection Agency; Imperial College London; London School
of Hygiene & Tropical Medicine; Microscience; National
Institute of Biological Standards and Control
United States: Arizona State University; AVANT
Immunotherapeutics; Brandeis University; California Institute
of Technology; Center for Biologics Evaluation and Research,
Food and Drug Administration; Centers for Disease Control
and Prevention; Chiron; Colorado State University; Harvard
University; Johns Hopkins University; Merck; National
Institutes of Health; Naval Medical Research Center; Portland
University; Program for Appropriate Technology in Health;
Purdue University; University of Alabama; University of
California at Berkeley; University of California at Los Angeles;
University of Maryland; University of North Carolina at Chapel
Hill; University of Pennsylvania; University of Rochester
Medical Center; University of Texas Medical Branch at
Galveston; Walter Reed Army Institute of Research;
Washington University; Wayne State University; West Virginia
University; Wyeth
Vietnam: Bach Mai Hospital; Hanoi Health Service; Ha Tay
Province Preventive Medicine Center; Ho Chi Minh Pasteur
Institute; Hue City Hospital; Hue Province Preventive Medicine
Center; Institute of Vaccines and Biological Substances;
Khanh Hoa Provincial Hospital; National Institute of Hygiene
and Epidemiology; National Institute of Pediatrics; Nha Trang
Pasteur Institute; Ninh Hoa District Hospital; Phu Tho Province
Center for Preventive Medicine; Phu Tho Provincial Hospital;
VaBiotech; Wellcome Trust, Center for Tropical Diseases, Ho
Chi Minh City
International: World Health Organization
′
Prof. Samuel Katz - Chairman Professor Emeritus,
Department of Pediatrics, Duke University Medical
Center, Durham, North Carolina, USA
Prof. Jan Holmgren - Vice Chairman Professor,
Department of Medical Microbiology & Immunology,
University of Gothenburg, Gothenburg, Sweden
Prof. Maharaj Krishnan Bhan Secretary,
Department of Biotechnology, Ministry of Science
and Technology, New Delhi, India
Prof. Myung-Hee Chung Vice-President,
Seoul National University, Seoul,
Republic of Korea
Dr. John D. Clemens Director,
International Vaccine Institute, Seoul,
Republic of Korea
Prof. Gordon Dougan Professor,
Center for Molecular Microbiology and Infection,
Department of Biological Science, Imperial College of
Science, Technology and Medicine, London, United Kingdom
Dr. Michel Greco Former President,
Aventis Pasteur, Lyon, France
Prof. Ian David Gust Professor Emeritus,
University of Melbourne, Victoria, Australia
Dr. Nay Htun Professor and Executive Director,
University for Peace, New York, USA
Prof. Paul-Henri Lambert Professor,
Department of Pathology, University of Geneva,
Geneva, Switzerland
Dr. Hanna Maria Nohynek
Department of Vaccines, National Public Health
Institute, Helsinki, Finland
Mr. Joon Oh Director General,
Office of Policy Planning and International
Organizations, Ministry of Foreign Affairs & Trade,
Seoul, Republic of Korea
Dr. Shigeru Omi Regional Director,
WHO Regional Office for the Western
Pacific (WPRO), Manila, The Philippines
Dr. Samlee Plianbangchang Regional Director,
WHO Regional Office for South-East Asia (SEARO),
New Delhi, India
Dr. George Poste Director,
The Biodesign Institute at Arizona State University,
Tempe, Arizona, USA
Prof. Philip K. Russell Professor Emeritus,
Johns Hopkins Bloomberg School of Public Health,
Baltimore, Maryland, USA
Prof. Geoffrey Schild Professor,
Imperial College of Science, Technology, and Medicine,
London, United Kingdom
79
Board of Trustees
From the left to right in the first row, Dr. John D. Clemens, Prof. Samuel L. Katz, Dr. Hanna Maria Nohynek, Prof. Myung-Hee Chung, Dr. Shigeru Omi, Mr. Joon Oh; in the secondrow, Prof. Margaret Liu, Prof. Geoffrey Schild, Dr. Michel Greco, Prof. Ian David Gust, Prof. Philip Russell, Prof. Gordon Dougan, Prof. Jan Holmgren, Prof. Paul Henri Lambert