Principle of Vaccinology Elham Ahmadnezhad MD. MPH. PhD Student of Epidemiology Farshid fayyaz Jahani MD. MPH. Specialist in Infectious Disease & Tropical

Principle of Vaccinology

Elham Ahmadnezhad MD. MPH. PhD Student of Epidemiology

Farshid fayyaz Jahani MD. MPH. Specialist in Infectious Disease & Tropical Medicine

Tehran University of Medical SciencesTehran University of Medical Sciences

10/10/2011 Vaccinology. 1

Brief History of Lecturers

• Elham & Farshid from Tehran, Iran are couple since 3 years ago

(2008). Farshid graduated from Medical School in Infectious disease

and Tropical medicine’ specialist and Elham now senior student in PhD

of Epidemiology.

• They have common interest in infectious disease epidemiology then

developed some lecturers such as this (Vaccinology).

Hope it’s useful for all target groups.Our Email:

[email protected]&

[email protected]


OUTLINE

Introduction & Definition

Vaccination policy option

Mass Vaccination

Surveillance System of Vaccination

Vaccine Development

Vaccine Evaluation

Vaccine Safety

Reporting Immunizations

Reliable Web sits

Vaccine Training Course

Review of National Immunization Coverage


What is Vaccine

• Dictionary (Dorland 30Dictionary (Dorland 30thth edition 2008) edition 2008)

Attenuated or killed microorganisms or proteins derived from them, administered for

the prevention, treatment, or amelioration of infectious diseases

• WikipediaWikipedia

A vaccine is a biological preparation that improves immunity to a particular disease. A

vaccine typically contains an agent that resembles a disease-causing microorganism, and

is often made from weakened or killed forms of the microbe. The agent stimulates the

body's immune system to recognize the agent as foreign, destroy it, and "remember" it,

so that the immune system can more easily recognize and destroy any of these

microorganisms that it later encounters.


What is Vaccinology?

• Vaccinology is the science of developing

vaccines to prevent diseases


Vaccines-Historical Perspective• 7th century7th century- Indian Buddhists' drank snake venom to protect against snake bite.

• 10th century10th century- Variolation to prevent smallpox in China and Turkey.

• Early 1700sEarly 1700s- Variolation introduced into England.

• 1760-701760-70- The Jennerian era.

• 1875-19101875-1910- Dawn of Immunological Science.

• 1910-301910-30- Early bacterial vaccines, toxins and toxoids.

• 1930-501930-50- Early viral vaccines: yellow fever and Influenza.

• 1950-19701950-1970- The tissue culture revolution: poliomyelitis, measles, mumps and rubella.

• 1970-19901970-1990- Dawn of the molecular era: hepatitis B, Streptococcus pneumonia, Hemophilus influenza B.

• TodayToday- Glycoconjugate vaccines, rotavirus vaccine, human papilloma virus vaccine and herpes zoster

vaccine.

10/10/2011Vaccinology. 6

Aims of Immunisation Programmes

• To protect those at highest risk (selective immunisation strategy) or• To eradicate, eliminate or control disease (mass immunisation strategy)

Currently, it is estimated that vaccination saves the lives of 3 million3 million children a year

• EradicationEradication Infection (pathogen) has been removed worldwide e.g. smallpox

• EliminationElimination Disease has disappeared from one area but remains elsewhere e.g. polio, measles

• ControlControl Disease no longer constitutes a significant public health problem e.g. neo-natal tetanus


Vaccines Achievements1

• With sanitation and nutrition, vaccines are hailed as one of the most

important public health achievements of the 20th century.

• The history of vaccinology lends itself to discussion of its progress in

terms of periods or eras, in which new advances were made.

• Once only targeted against serious childhood diseases, vaccinology has

become a tool for preventing infectious diseases or their complications

and outcomes in all age groups.

• This has seen the number of vaccine-preventable diseases rising to around

26.10/10/2011 Vaccinology. 8

Vaccines Achievements2

• “At the end of the 20th century the US Centers for Disease

Control and Prevention (CDC) cited vaccination as the

number one one public health achievement of that century”

• “The elimination in 1977 of smallpox as a human disease

must rank as oneone of the major achievements of modern

medicine”


The Ideal Vaccine

• Immunogenic

• Long lasting immunity

• Safe

• Stable in field conditions

• Combined

• Single dose

• Affordable (and accessible) to all


Categorization of Current Vaccines

• Live attenuated: Viruses (oral polio, measles, mumps, rubella,

yellow fever), Bacteria (BCG, cholera)- Long lasting immunity, very

fragile (cold chain), mutation to pathogenicity

• Killed Vaccines: Viruses (hep. A, Salk polio) Bacteria (pertussis,

cholera)-intermediate immunity, several doses may be required

• Sub-unit vaccines incl: Toxoids: (tetanus, hep b.,occellular

vaccines), Conjugate polysacaride vaccines linked with suitable

carrier proteins (Hib). Also single or polyvalent vaccines.


Viral Vaccines


Bacterial Vaccines


Target Fungal Vaccines


Target Parasitic Disease

• Malaria

• Trypanosomiasis

• Leishmaniasis

• Toxoplasmosis


Selective Vaccination

• Vaccine given specifically to those at increased risk of disease:

• High risk groupsHigh risk groups e.g. Pneumococcal vaccine

• Occupational riskOccupational risk e.g. Hepatitis B, influenza

• TravellersTravellers e.g. Yellow fever, rabies, meningitis

• Outbreak controlOutbreak control e.g. Hepatitis A. vaccine, measles


Pipelines for Developing Countries

Much needed vaccines for the developingdeveloping world• Malaria• Tuberculosis• HIV• Hookworm• Dengue• Enterotoxigenic Escherichia coli• Shigella


More Possibilities• Therapeutic vaccines: Identification of specific tumor

antigens provide immune targets for which immunogenic

vaccines may conceivably be designed. Examples: Leukemia

Breast cancer

Melanoma

Prostate cancer

Colon cancer

• Vaccines against autoimmune diseases


Similarities between Vaccines and other Drug

• Vaccines are also medicines

• Potential for adverse effects

• Multiple ingredients

• Potential for interaction with disease and other

medicines

• Also need to comply with standards of safety, efficacy

and quality


Vaccination Policy Options


Eradication Activities New Vaccine Introduction

Outbreak vs. routine control of epidemic diseases

?

Newer Vaccine Research and Development

Role of disease burden studies in the development and Role of disease burden studies in the development and introduction of new and underutilized vaccinesintroduction of new and underutilized vaccines

Disease-Burden StudiesDisease-Burden Studies

Disease Epidemiology• Geographical distribution• Age groups• Seasonality, risk factors

Vaccine Design

Clinical Evaluation• Study sites• Vaccination schedules & Strategies

Vaccine Utilization• Target groups• Impact• Cost-effectiveness


Mass Vaccination

Objective: Objective: Make hosts resistant to infection without

having to experience disease


Impact of Mass Vaccination Programmes

• Reduce sizesize of susceptible population

• Reduce numbernumber of cases Reduce risk of infection in population

Reduce contact of susceptible to cases

Lengthening of epidemic cycle -> honeymoon phase

Increase in mean age of infection


No Mass Vaccination


Each host in contact with infected host becomes infected (with a certain probability)

Mass Vaccination


Outbreak attenuated (or averted) by lack of susceptible hosts

Impact of Mass Immunisation Programme

Annual measles notifications & vaccine coveragePoland 1960-2000

0.0

100.0

200.0

300.0

400.0

500.0

600.0

Year 1964 1969 1974 1979 1984 1989 1994 1999

Year

Cas

es/1

00 0

00

0

10

20

30

40

50

60

70

80

90

100

Imm

un

isation

coverag

e (%)

Vaccination at 12-15 mo Vaccination at 6 years Cases /100 000


Surveillance of Vaccine Preventable Disease

• Vaccine uptake

• Vaccine effectiveness

• Serological surveillance

• Adverse events

• Knowledge and attitudes

• Vaccine uptake

• Disease incidence


Objectives of SurveillanceVaccine Preventable Diseases

• Pre-implementationPre-implementation

Estimate burden

Decide vaccination strategy

• Post implementationPost implementation Monitor impact and effectiveness

• Nearing eliminationNearing elimination Identify pockets of susceptible

Certification process


Disease Incidence• Main sources of dataMain sources of data

Statutory notification

Laboratory reporting

Death registrations

• Other sourcesOther sources

Hospital episodes

Sentinel GP reporting

Paediatric surveillance


Measles Case Definitions

• Suspect caseSuspect case Rash and fever

• Probable caseProbable case Rash, fever, and either: cough, coryza or conjunctivitis

• Laboratory confirmedLaboratory confirmed• Saliva/serum IgM positive


Predictive Value of Notified MeaslesEffect of Change in Incidence


1

10

100

1000

10000

100000

1000000

Pre-vaccine Low coverage High coverage Near elimination

Num

ber o

f cas

es

0%

20%

40%

60%

80%

100%

PV+

Non-measles Genuine measles

Surveillance of Vaccine Coverage• Vaccine distributed• Vaccine administered Sampling population assessment e.g. Cluster

Total population assessment (administrative)

Number of doses of vaccine given/used Total (target-)population


Use of Administrative Coverage Data

• Usually total population

• Monitor trends over time

• Look for pockets of poor coverage

• Compare with disease epidemiology

• Estimate vaccine effectiveness


Steps on Vaccine Development1

• Recognize the diseasedisease as a distinct entity

• Identify etiologicetiologic agent

• Grow agent in laboratorylaboratory

• Establish in animal model animal model for disease

• Identify an immunologic correlate immunologic correlate for immunity to the disease- usually

serum antibody

• InactivateInactivate or attenuateattenuate the agent in the laboratory- or choose antigens

• Prepare candidatecandidate vaccine following GOOD manufacturing Procedures

• Evaluate candidatecandidate vaccine(s) for ability to protect animals



• Prepare protocolprotocol(ss) for human studies

• Apply to MCC for investigational New drug (IND)

approval

• Phase I Phase I human trials- Safety and immugenicity,

dose response

• Phase II Phase II trials- Safety and immugenicity

• Phase III Phase III trials- Efficacy



• Submit Product LicensureLicensure Application MCC approval

• Advisory CommitteesCommittees review and make recommendations

• Marketing Post- Licensure Surveillance for safety and effectiveness

(Phase IVPhase IV)

• Long and ComplicatedComplicated process

Usually takes 1010-1515 years

ManyMany vaccine candidates fail for every success

Costs: $$ 100100- $$ 700700 million per successful vaccine


Vaccine Evaluation

Pre-licensingRandomised, Blinded, Controlled Clinical Trials

Vaccine efficacy: Protective Effect under

Idealised Conditions

RCT: controlled experiments, simple interpretation

Post-licensing Observational Studies

Vaccine effectiveness: Protective Effect under

Ordinary Conditions of a public health programme

prone to bias, more complex interpretation


Efficacy, Effectiveness, Impact and Herd Immunity

•Efficacy is the direct protection to a vaccinated individual as estimated from clinical trial

•Effectiveness is an estimate of the direct protection in a field study post licensure.

•Herd Immunity is an indirect effect of vaccination due to reduced disease transmission.

•Impact is the population level effect of a vaccination programme. This will depend on

many factors such as vaccine coverage, herd immunity and effectiveness.


Basic Calculation of VE % reduction in attack rate of disease in vaccinated (ARV)

compared to unvaccinated (ARU) individuals

VE (%) = (ARU-ARV) X 100 ARU

Where

and

Consequently, VE = 1-RR (preventive fraction)


ARU

ARU1

ARV

ARURR

0,9 – 0,2

0,9 VE = = 78%

Vaccinated

IV = 2/10 = 0,2

IU = 9/10 = 0,9

Unvaccinated

Basic Calculation of VE


Methods to Assess VE• Pre-licensure:

Randomised control trial (RCT)

• Post-licensure:

Observational/Field investigation • Screening method

• Cohort study

• Household contact study

• Case-control study10/10/2011 Vaccinology. 41

Observational study: Screening Method

• Used with Routine Surveillance Data Take population vaccine coverage (PPVPPV)

Compare with coverage in cases (PCVPCV)

VE = 1 - PCV x (1-PPV) (1-PCV) x PPV


Observational study: Screening Method


Relationship between VE, PPV and PCV

0

0.2

0.4

0.6

0.8

1

0.5 0.6 0.7 0.8 0.9 1

Proportion of population vaccinated

Pro

po

rtio

n o

f ca

ses

vacc

inat

ed

VE=60%

VE=80%VE=90%

VE=95%

Potential Pitfalls....

• Case definition;

• Vaccine history;

• Case ascertainment;

• Comparability of vaccinated/unvaccinated groups.


Methodological Issues: Case Definition1

• Lower specificity: Case definition based only on clinical

criteria may result in false-positive diagnoses

ARV > ARU

VE (%) = (ARU-ARV) X 100 ARU

artificial reduction in VE



Changes in MUMPSMUMPS vaccine effectivenessCase definition

Diagnosis by school nurseARV 18% (12/67) 89 ARU 28% (77/272) 25% (68/272)VE 37% 52%

Kim Farley et al 1985 AJE


Changes in MUMPSMUMPS vaccine effectivenessCase definition

Diagnosis by school nurse Parotitis > 2 daysARV 18% (12/67) 12% (8/67)ARU 28% (77/272) 25% (68/272)VE 37% 52%

Kim Farley et al 1985 AJE



Methodological issues: Vaccine History Ascertainment

• Avoid misclassification of vaccination status

• Equal effort to confirm vaccination status

amongst cases and non-cases Vaccination histories should be documented using GP, clinic,

hand-held or computer records

Persons with missing vaccination records should be excluded


Vaccine effectiveness: Post licensure monitoring of VE

Post-licensure: maintenance of VE • Problems in vaccine delivery

Cold chain failure, schedule violation, n° of doses, vaccine strain substitution

• Epidemiological factors

Pathogen changes

• Methodological bias

Selection bias, confounding, chance effects

• Low protective efficacy

Bad batch, different target population, alternative patterns of use, vaccine

strain used


Summary of VE• Multiple sources of data are valuablevaluable to

evaluate vaccine programmes

• Source of data and case definitions change

with stagestage of vaccination programme

• Monitoring VE is integral

• VE can be carefully estimated from routineroutine

data


Let’s GO An Example


A Randomized, Controlled Experiment

• 400,000 elementary school students

participated in the experiment.

• 200,000 chosen at random from 400.000 in

the treatment group got the vaccine.

• The remaining 200,000 in the control group

did not get the vaccine.


A Randomized, Controlled Double-Blind Experiment

• The 200,000 children in the control got a fake

vaccination called a placebo.

• The children and their parents were not told if

they got the real vaccine or not.

• Even the doctors and nurses didn’t know; only

the statisticians knew


Experimental Results

Looks promising but is it significant?


Size Rate

Treatment 200,000 28

Control 200,000 71

Total 400,000 99

Analysis: The Devil’s Advocate

• Let’s play the devil’s advocate. Let’s assume

the vaccine has no effect.

• Then the 99 cases of polio were split into the

two groups purely at random.

• Is it very likely only 25 fall in the treatment

group?


A Probability Model

• Put 400,000 balls in an urn with 99 black and the rest white.

• Draw 200,000 (for the treatment group) and count the

number of black balls.

• What is the chance of a split as extreme or more extreme

than 28 in the treatment group and 71 in the control group.

• About one in a billion


Calculating Probabilities• A statistician relies on the theory of probability to

calculate probabilities.

• The number of black balls X in the treatment group

follows the hypergeometric distribution.

•


99 399901

200000

400000

200000x x

Conclusion: Get vaccinated!

• We must reject the hypothesis that the treatment has no

effect; otherwise we must believe we are incredibly

unlucky.

• We can therefore recommend mass vaccination.

• We also note a vaccination does not prevent polio. Your

best protection is to get vaccinated and encourage

everyone to be vaccinated.


Vaccine Safety


Today’s Agenda

• The Good

The benefits of vaccination

Ongoing safety monitoring

• The Bad

Vaccines “rocky” past

Acceptable risk?

• And the Ugly

Wealth of misinformation

Vaccine refusal


Vaccines Work

JAMA 2007 298(18)2156-2163MMWR August 22, 2008 903-913


Pre-licensure Safety Monitoring1


Pre-licensure Safety Monitoring2

• Vaccine Adverse Event Reporting System (VAERS)

Limitations

• Vaccine Safety Datalink (VSD)

Established in 1990 by CDC and 8 HMOs

Database on 8.8 million lives


Safety Monitoring -Who looks at all that data?

Institute of Medicine (IOM)• Part of the National Academy of Science• Non-profit, non-governmental organization, volunteer• Provide the CDC, NIH and congress on data interpretation on matters of

bio-medical science• IOM Vaccine Safety Reports – The “Gold Standard” in vaccine safety

analysis MMR and Autism (2001) Thimerosal and Neurodevelopmental Disorders (2001) Multiple Immunizations and Immune Dysfunction (2002) HepB Vaccine and Demyelinating Neurological Disorders (2002) SV40 Contamination of Polio Vaccine and Cancer (2002) Influenza vaccines and Neurological Complications (2003) Vaccines and Autism (2004)


The Bad

• The Cutter IPV incident (1955)

• Vaccine associated paralytic polio

• Swine flu vaccine and GBS (1976-7)


The Cutter Incident

• 1950s Jonas Salk pioneering work with IPV

• 5 companies stepped forward to manufacture IPV

after licensure

• Cutter (the smallest) made a bad batch 100,000 children injected with live virus

70,000 got mild polio

200 were permanently paralyzed

10 died


Vaccine-Associated Paralytic Polio(VAPP)

• OPV is a live attenuated virus

• 1 out of 2.4 million doses VAPP

• 1997 a IPV/OPV schedule

• 2000 an all IPV schedule recommended


“Swine Flu” vaccine of 1976-1977

• Increased risk of Guillain-Barré syndrome (GBS)

• Risk period was 6-8 weeks after vaccine and most

>25 yrs of age

• Incident of 1 per 100,000

• Above the background rate of 0.87 per million

persons in a 6 week period


“Acceptable” Risk?• Local side effects

Swelling, redness

• Systemic side effects

Fever, pain, allergic reaction

• MMR and Thrombocytopenia

• MMR(V) and febrile seizures

• Adolescent vaccines and syncope

• Guillain-Barré and MCV4


MMR & Thrombocytopenia

• Yes

• 1 in 40,000 at 12-23 months

• Less common than after natural disease

Journal of Autoimmunity 2001 16: 309-18


MMR(V) & Febrile Seizures

• 10% develop fever after 1st MMR dose

• Febrile Seizure Risk

4 cases / 10,000 doses MMR + V

9 cases / 10,000 doses MMRV

MMWR 2008 57: 258-60


Syncope and Adolescent Vaccines

MMWR May 2, 2008 / 57(17);457-460


Guillain-Barré Syndrome and MCV4

• MCV4 (Menactra®) licensed in Jan 2005

• Sept 2005 alert by FDA/CDC:

2.5 million doses

5 cases of GBS in month following vaccine (VAERS data)


and the Ugly

• Wealth of misinformation

MMR and Autism

Mercury poisoning

Vaccines overwhelming the immune system

• Vaccine refusal


ReportingReporting ImmunizationImmunization RequirementsRequirements

• Documenting administration of vaccine

• Documenting record of immunization


Reporting immunization requirements: Documenting administration of vaccine Content

• Name and address of vaccine

• Medicare number

• Date of birth and gender

• Date of administration

• Name and lot number of vaccine

• Name of immunizer

• Other data as required

10/10/2011 Vaccinology. 7676

Reporting immunization requirements: Documenting administration of vaccine Content-Lot Number

3 lot numbers on packaging:

On antigen carton

On adjuvant carton

On shoe box

Document lot numberDocument lot numberon shoe box.on shoe box.

10/10/2011 Vaccinology. 7777

Immunization Practice Standards

• Vaccine management

• Informed consent

• Administration of vaccine

• Documentation

• Anaphylaxis management

• Reporting of adverse events


Immunization practice standards: Vaccine management-Storage and handling of vaccine

• Cold chain system

• Control procedure/mechanism/equipmentVaccine fridge

Dialer and data logger

Vaccine coolers

Cold and warm marks or minimum-maximum

thermometers

• Cold chain breach79

Immunization practice standards Informed consent

• Parental consent required for individuals

• less than 16 years old

• Risk vs. benefits (of receiving vaccine or not)

• General info about vaccine and potential side effects

• Ensure info is well understood

• Allow opportunities for questions

• Assess health with screening questions

• Document informed consent


Immunization practice standards Informed consent

Screening Questions (Screening Questions (ExamplesExamples))

• Is unwell today?

• Has history of severe life-threatening allergy to

Eggs

Previous dose of the vaccine; or

Any of its components

• Past history of Guillain Barre Syndrome

• Has disease or treatment lowering immunity

• Has severe bleeding disorder


Immunization practice standardsAdministration of vaccine

IntramuscularIntramuscular injection injection

IM in vastus lateralis (Birth to 18 months)

IM in deltoid(18 mths and over)

10/10/2011 Vaccinology. 82Source : http://www.health.gov.nl.ca/health/publications/immunization/S4/

ImmunizationImmunization practice standards practice standardsAdministration of vaccine

Post-vaccinationPost-vaccination

• Check

For bruising, redness, swelling

Client for any adverse event

• Instruct client

To wait 15 minutes

Of possible side effects and what to do

To call if adverse event in next 4 weeks

Need for a second dose


Immunization practice standards Documentation

• Consent form: Pandemic H1N1 Influenza

Immunization

• Client immunization record

• Adverse event following immunization

• CSDS – as directed


Immunization practice standards Anaphylaxis management

• Assess and manage ABCs

• Call for help

• Administer epinephrine

• Call 115

• Repeat dose as needed

• Document and share clinical info


8610/10/2011 Vaccinology. 86

Immunization practice standards Immunization practice standards ReportingReporting AEFI - AEFI -

CurrentCurrent surveillance process

• AEFI form to be completed by PH or physician

• Form submitted to RMOH

• PH enters data in CSDS and sends form to CDC

Unit

• CDC Unit faxes form to PHAC

• Refer to NB Immmunization Handbook

Immunizers: inform clients to call PH if severe or unusual reactions in the 4 weeks following

vaccination.

8710/10/2011 Vaccinology. 87

Immunization practice standards Immunization practice standards ReportingReporting AEFI - AEFI -Enhanced severe AEFI surveillance

• AEFI form to be completed by physician

• May be completed by PH when reported to PH first

• Form submitted to RMOH

• PH enters data entered in CSDS and sends form to CDC Unit

• Refer to GNB website for reporting process, case definition and form

http://www.gnb.ca/0053/h1n1/audience_professionals-e.asp

http://www.cdc.gov/vaccines

8810/10/2011 Vaccinology. 88

Immunization practice standards Immunization practice standards ReportingReporting AEFI - AEFI -

Enhanced severe AEFI surveillance

Weekly active AEFI reporting

• Internal medicine specialist and neurologists will submit weekly count

of cases meeting case definition of 8 conditions along with DOB and

name to CDC Unit via special email address.

• CDC Unit will send the information to MOH.

• Timely data to be used be regional PH to ensure complete reporting of

AEFI.

• Used injection material

Handling

Disposal

Sharp containers

Where to place

When to replace

How to dispose of

• Needle stick injury – refer to RHA policy

• Use of personal protective equipment and infection control measures


Immunization practice standards Immunization practice standards Occupational health issues

Reliable web sites


CDC Vaccines and ImmunizationContact Information

• Telephone 800.CDC.INFO

• Email [email protected]

• Website www.cdc.gov/vaccines• Vaccine Safety www.cdc.gov/od/science/iso


http://www.cdc.gov/vaccines


Promote Epidemiology Training & Research

• WHO Advanced Training Course on Immunology, Vaccinology,

and Biotechnology Applied to Infectious Diseases

• Liaison with epidemiology training programmers

INCLEN, FETP, EPIET

• WHO Collaborating Centers


References

• Geoffrey A. Weinberg and Peter G. Szilagyi. Vaccine Epidemiology: Efficacy, Effectiveness ,and the Translational Research Roadmap.

The Journal of Infectious Diseases 2010; 201 (11): 1607 -1610

• European Program for Intervention Epidemiology Training. Principle of Vaccinology. 2008

• EPI coverage survey, WHO. Available at: http://www.who.int/immunization_monitoring/routine/EPI_coverage_survey.pdf. Access

date: 10.10.2011

• Geert Leroux-Roels, Paolo Bonanni, Terapong Tantawichien,Fred Zepp. Understanding Modern Vaccines: Perspectives in Vaccinology

Vaccine development. Volume1/ Issue1/ 115-150

• Thomas D. Szucs. Health economic research on vaccinations and immunization practices—an intro uctory primer. Vaccine 23 (2005):

2095–2103

• NB Immunization Handbook, sections IV-III, IV-IV


http://www.who.int/immunization_monitoring/routine/EPI_coverage_survey.pdf

Documents

Principle of Vaccinology Elham Ahmadnezhad MD. MPH. PhD Student of Epidemiology Farshid fayyaz Jahani MD. MPH. Specialist in Infectious Disease & Tropical