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Pneumococcal disease and Pneumococcal vaccines
Dr.R.Jayaprada
Introduction
• The description by Sir William Osler, “Pneumonia remains now, as then, the
most serious acute disease with which physicians have to deal; serious
because it attacks the old, the feeble … persons who are not able to
withstand the sudden sharp onset of the malady,” still stands the test of
time.
1) Silverman ME, Murray TJ, Bryan CS. The Quotable Osler. Philadelphia: American College of Physicians; 1998:139.
Pneumococcal disease• Streptococcus pneumoniae (pneumococcus) is a gram-positive bacterium with more than
90 known serotypes.
• Pneumococcus is spread by airborne droplets and is a leading cause of serious illness,
including bacteremia, meningitis, and pneumonia among children and adults
worldwide(2,3).
• Approximately, 1 million children under 5 years of age die of pneumococcal disease
annually (3). • In 2005, WHO estimated that 1.6 million people die of pneumococcal disease every year;
this estimate includes the deaths of 0.7–1 million children 3 aged <5 years, most of whom live in developing countries.
(2)Nuorti JP, Whitney CG. Prevention of pneumococcal disease among infants and children—use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010; 59(RR-11): 1–18.
(3)Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States, 1998–2007. N Engl J Med. 2011; 364(21):
2016–25.
Review of S.pneumoniae and pneumococcal diseases (1/2)
• Invasive Pneumococcal Disease (IPD) carries high risk of mortality (4).
• S. pneumoniae is the leading cause of Community-acquired pneumonia (CAP) (5)
– >90 serotypes of S. pneumoniae (6)
– 8-10 cause two-thirds of serious infections in adults (7)
Review of S.pneumoniae and pneumococcal diseases (2/2)
• Pneumococcal diseases are serious and associated with significant mortality (6)– 1 in every 20 adults who gets pneumococcal pneumonia die.– 2 out of every 10 adults who get bacteremia die.– 3 out of every 10 adults who get meningitis die.
(4) World Health Organization. Weekly Epidemiological Record. Pneumococcal vaccines No. 14, 2003, 78, 97-120.
(5) Jokinen C, Heiskanen L, Juvonen H et al. Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland. Clin
Infect Dis. 2001 Apr 15;32(8):1141-54.
(6) Fedson DS, Musher D. Pneumococcal polysaccharide vaccine. In: Plotkin A, Orenstein WA editors. Vaccines. 4th ed. Philadelphia, USA: WB Saunders Company;
2004. p. 529-88. (4) Pneumococcal. In: The green book chapter 25. Immunization against infectious disease. London, United Kingdom Department of Health;
2006.
(7) Musher DM. Streptococcus pneumoniae. In: Mandell G, Bennett JE, Dolin R editors. Principles and practice of infectious disease. 4th ed. New-York, USA:
Churchill Livingstone, Inc.; 1995. p. 1811-26.
Invasive pneumococcal disease
Invasive pneumococcal disease
Pneumococcal pneumonia
Meningitis, arthritis,pleuritis etc.
Overlap between pneumococcal pneumonia and invasive pneumococcal disease
(8) Adapted from Fedson DS. Pneumococcal vaccination for older adults—the first 20 years. Drugs Aging 15(suppl 1):21–30, 1999.
Serotypes 1 and 5 (epidemic serotypes)
account for 29% of IPD in India .
Invasive Pneumococcal DiseaseIncidence by Age Group
0
50
100
150
200
250
<1 1 2 3 4 5-17 18-34 35-49 50-64 65+
Age Group (Yrs)
Ra
te
Rate per 100,000 population. Active Bacterial Core Surveillance/EIP Network
Study in India
• In India, the Invasive Bacterial Infection Surveillance (IBIS) network and
South Asian Pneumococcal Alliance (SAPNA) have been involved in
collection of important data regarding serotype distribution and antimicrobial
resistance of pneumococcal infections for more than 12 years.
• The program has been funded by INCLEN with financial assistance from
United States Agency for International Development (USAID) and the
Pneumococcal vaccines Accelerated Developmental and Introduction Plan
(Pneumo ADIP) of the Global Alliance for Vaccine and Immunization (GAVI).
Pneumococcal sero type distribution- Indian scenario
• Invasive Pneumococcal Disease (IPD) serotypes 6, 1, 19, 14, 4, 5, 45, 12,
7, 23 are the most prevalent .
• Serotypes 1 and 5 accounting for 29% of invasive pneumococcal disease
(Invasive Bacterial Infection Surveillance (IBIS) study (1993-1997).
• The most prevalent serotypes in India are 6 (17%), 1 (12.5%), 5 (9.6%), 14
(9.6%), 19 (7.7%) and 23 (5.8%) -- common among children (South Asian
Pneumococcal Alliance (SAPNA) ( 2006-2007)
Serotype distribution in adults
Serotype 1 and type 3 were common serotypes (Fig. 1) in all age
groups (22–50, 51– 64, >64 years).
Risk factors
• Age (6)
• Chronic illnesses (8)
• Functional or anatomical asplenia (8)
• Immunodeficiency (8)
• Environmental factors (6)
(7) Musher DM. In Mandell G, Bennett JE, Dolin R editors. Principles and practice of infectious disease.
4th ed. New York, USA: Churchill Livingstone, Inc.; 1995. p.1811-26.
(9) CDC. Recommendations of the ACIP. Prevention of pneumococcal disease. MMWR 1997; 46 (N° RR-
8): 1-2
Streptococcus pneumoniae
• Common inhabitant of the respiratory tract (nasopharynx of 5-70% healthy
adults)
• Asymptomatic carriage:
– Vary with age, environment & + of URTI
• 5-10% of adults w/o children
• 27-58% of residents in schools/orphanages
• 50-60% of service personnel
– Duration of carriage varies & is generally longer in children than in adults
Figure 1. Diseases caused by Streptococcus pneumoniae. Pneumococci colonise the nasopharynx, evade host immunity and spread to the middle ear, sinus, lower respiratory tract, blood and meninges. Pneumococci cause otitis media in the middle ear,
sinusitis in the sinus, pneumonia in the lower respiratory tract, bacteraemia in blood and meningitis in the meninges. The incidences of different types of pneumococcal infection are inversely related to the severity of disease: otitis media is the most common but the least severe. Redrawn and redesigned with permission from Ref. [2]. Bogaert, D. et al. (2004) Streptococcus pneumoniae colonisation: the
keyto pneumococcal disease. Lancet Infect. Dis. 4, 144–154
Pneumococcal disease
• Pneumococcal disease is the term used to describe infections caused by the
bacterium Streptococcus pneumoniae (also called Pneumococcus).
• S. pneumoniae is an encapsulated gram-positive coccus.
• The capsule is the most important virulence factor of S. pneumoniae;
pneumococci that lack the capsule are normally not virulent.
• Over 90 different capsular types have been characterized.
• About 66% of the serious infections in adults and about 80% of invasive
infections in children are caused by eight to ten capsular types (Health
Protection Agency, 2003).
Characteristics of S.pneumoniae• S. pneumoniae has typical characteristics:
• 1. It has specific polysaccharide capsule which is demonstrated by quellung
reaction. Capsular polysaccharides are the primary basis for pathogenicity;
antigenic; basis for serotypes.
• 2. Bile solubility.
• 3. Optochin sensitivity.
• 4. Ferments inulin which is the differentiating feature from other streptococci.
• 5. Lancet-shaped, Gram positive diplococci, alpha-hemolytic
• 6.Catalase(-) : requires source of catalase to grow on agar plates e.g. blood,
generate H2O2
Typing of pneumococcus
• Pneumococci are classified into types based on the antigenic nature of the
capsular polysaccharide.
• Pneumococci isolated from lobar pneumonia were originally classified into three
types I, II and III, and a heterogeneous group IV.
• Members of group IV were later classified into types, and now more than 90
different serotypes are recognized, named 1, 2, 3, and so on.
Typing of pneumococcus
• Typing may be carried out by
• (1)Agglutination of the cocci with the type specific antiserum by Co-
agglutination (Co-A); test
• (2) Precipitation of the SSS with the specific serum by counter current
immunoelectrophoresis(CIEP); or
• (3) By the capsule swelling reaction described by Neufeld (1902).
• More than 90 capsule types and serotypes are known in S. pneumoniae
(Hausdorff et al., 2002).
• Out of which 23 serotypes cause human infection.
• Type-specific Ab to capsular polysaccharide is protective.
• These Abs & complement interact to opsonize pneumococci.
• Antibodies to some pneumococcal capsular polysaccharides may cross-react
with related types
Hausdorff, W. P., Bryant, J., Paradiso, P. R. & Siber, G. R. (2000). Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 30, 100–121.
American and Danish Nomenclature for Streptococcus pneumoniae Serotypes
• USA Denmark USA Denmark USA Denmark USA Denmark USA Denmark
• 1 1 21 21 41 34 61 35C 81 44
• 2 2 22 22F 42 33B 62 35A 82 48
• 3 3 23 23F 43 11A 63 22A 83 12A
• 4 4 24 24F 44 18A 64 23B 84 47A
• 5 5 25 25F 45 40 65 24A ? 10B
• 6 6A 26 6B 46 23A 66 35B ? 10C
• 7 7A 27 27 47 35A 67 32A ? 11D
• 8 8 28 28F 48 7B 68 9V ? 12B
• 9 9N 29 29 49 9L 69 39 ? 16A
• 10 10F 30 15A 50 7C 70 33F ? 25A
• 11 11F 31 31 51 7F 71 38 ? 33D
• 12 12F 32 32F 52 47F 72 45 6C 6C
• 13 13 33 9A 53 11C 73 46 • 14 14 34 10A 54 15B 74 41A • 15 15F 35 35F 55 18B 75 43 • 16 16F 36 36 56 18C 76 11B • 17 17F 37 37 57 19A 77 15C • 18 18F 38 41F 58 19B 78 17A • 19 19F 39 33C 59 19C 79 28A • 20 20 40 33A 60 24B 80 42
• Physicians’ Desk Reference (49th Edition, 1995, page 1610), Laboratory Diagnosis of Pneumococcus Infections by E. Lund (Bull. Wld. Hlth. Org. 23:5-13, 1960), H. Russell, et al (J. Clin. Microbiol. 8:355-359, 1978), J. Henrichsen (J. Clin. Microbiol. 33:2759-2762, 1995), and I. Park (J. Clin. Microbiol. 45:1225-1233 , 2007)
Gram’s stained smear of sputum
Pathogenesis1. CAPSULE
• Surface capsular poysaccharide
• Basis for serotyping (90 diff serotypes)
• 6, 14, 18, 19, 23 60-80% of infections
• Major antiphagocytic surface element
2. ADHERENCE
• Exports proteins which noncovalently link to human cell carbohydrate
or rPAF
Pneumococcal adherence
Pathogenesis3. INVASION
• Invade cells poorly, up to 10 x less than other streptococci
• Promoted by cell wall, adhesins, & cytotoxin pneumolysin• Inhibited by capsular polysaccharide• CHOLINE – cell wall component; ligand for rPAF; “mimicry”; activation
of host cells to upregulate rPAF*• Endocytosis Transcytosis
• *1 study showed adenovirus-infected cells in vitro showed increased binding & uptake of S. pneumoniae
Pathogenesis
4. REGULATORY MECHANISMS
• Use many regulatory mechanisms for surface changes in response to
new environment
• Secrete pneumolysin – pore formation; promotes intraalveolar
replication, penetration & dissemination of pneumococci
Pathogenesis
HOST INFLAMMATORY RESPONSE
• Cell wall – important virulence determinant (induce strong IL-1 response exceeding that of endotoxin by at least 10 fold)
• Teichoic acid & Lipoteichoic acid of cell wall contribute strongly to host defense response
• Activate complement (alternative pathway)• Bind CRP• Activate procoagulant activity on endothelial surface• Induce production of cytokines, nitric oxide, and PAF• Initiate the influx of neutrophils
Pneumococcal disease• MAJOR & MINOR CLINICAL SYNDROMES:
1. Pneumonia
2. Bacteremia
3. Meningitis
4. Otitis media
5. Sinusitis
Pneumococcal disease1. PNEUMONIA
• Among adults, most common
• Account for 36% of adult CAP & 50% HAP
• Abrupt onset, fever, chills, pleuritic chest pain, productive cough,
SOB, tachypnea, hypoxia, tachycardia, malaise
• Common bacterial complication of influenza & measles
• CFR is 5-7%, higher in elderly
Pneumococcal disease2. BACTEREMIA
• Occurs in 25-30% with pneumococcal pneumonia• CFR ~20; up to 60% in elderly• Rates higher in extremes of age• Asplenia – fulminant course
3. MENINGITIS• 13-19% of all bacterial meningitis.• CFR ~30%, up to 80% among elderly• Neurologic sequelae common among survivors
4. OTITIS MEDIA
28-55% of middle ear aspirates
• Childhood pneumonia is most commonly caused by serotypes 6, 14,
18,19,23.
• Pneumonia in adults is caused by serotypes 1,3,4,7,8 & 12.
• Growing resistance of S. pneumoniae to commonly used antibiotics (penicillins, cephalosporins, trimethoprim–sulfamethoxazole, macrolides and fluoroquinolones) underlines the urgent need for vaccines to be used to control pneumococcal disease
Pneumococcal vaccines
Policy decisions for use of pneumococcal vaccines
• The policy decisions for use of pneumococcal vaccines should be based on
following key factors:
• (i) incidence of the pneumococcal disease in the country
• (ii) distribution of its serotypes in the country and
• (iii) the anti-microbial resistance pattern of the invasive isolates in that
country
Pneumococcal vaccine
There are two types of pneumococcal vaccine:
● Pneumococcal polysaccharide vaccine (PPV) contains purified capsular
polysaccharide from each of 23 capsular types* of pneumococcus
● Pneumococcal conjugate vaccine (PCV) contains polysaccharide from thirteen
common capsular types.
These are conjugated to protein (CRM197) using similar manufacturing
technology to that for Haemophilus influenzae type b (Hib) and
meningococcal C conjugate vaccines.
History of pneumococcal vaccine
• PNEUMOCOCCUS - First identified in 1881 by Pasteur & Sternberg (10).
• The first preventive strategy was introduced by Sir Almroth E. Wright in 1911,
who suggested that inoculation of killed, whole pneumococci might induce a
protective effect against pneumococcal infections (11).
• In 1926, Felton and Bailey (12) for the first time isolated pneumococcal capsular
polysaccharides which directly led to the first capsular PS vaccine.
• Its effectiveness was proved by successfully aborting an outbreak of pneumonia
at a state hospital in Worcester, MA in 1931 (13).(10)Austrian R. The pneumococcus at the millennium: not down, not out. J Infect Dis 1999;179(Suppl 2):S338–41.
(11)Watson DA, Musher DM. A brief history of the pneumococcus in biomedical research. Semin Respir Infect 1999;14(3):198–208.
(12)Felton L, Baily G. Biologic significance of the soluble specific substance of pneumococci. J Infect Dis 1926;38:131–44.(13) Smillie W, Warnock G, White H. A study of a type I pneumococcus epidemicat the state hospital in Worcester, MA. Am J Public Health1938;28:293–302.
History of pneumococcal vaccine
• Emergence of multidrug-resistant (resistant to penicillin & cephalosporins) clones
with serotypes 6B, 9V, 14, 19A, 19F and 23F (14) have lead to renewed interest
in vaccine strategies, resulting in the production of a 14-valent pneumococcal PS
vaccine by Robert Austrian and coworkers in 1977 (15).
• This vaccine was expanded in 1983 to a 23-valent vaccine and had a theoretical
coverage of ≥80% of the pneumococci causing infections in adults.
• This vaccine was less immunogenic in small children and immunocompromised
patients (16).
(14) Kroon FP, van Dissel JT, de Jong JC, Zwinderman K, van Furth R. Antibody response after influenza vaccination in HIV-infected individuals: a consecutive 3-year study. Vaccine 2000;18(26): 3040–9.(15)Austrian R, Gold J. Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964;60:759–76. (16)Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997, 46(RR-8), 1–24.
Pneumococcal vaccines
1977 - 14-valent polysaccharide vaccine was first licensed
1983 - 23-valent polysaccharide vaccine licensed (PPSV23)
2000 - 7-valent polysaccharide conjugate vaccine was first licensed (PCV7)
2002 - Pneumococcal conjugate vaccine became available and was recommended for immunisation of at-risk groups under the age of two years
2003 -Pneumococcal polysaccharide immunisation was recommended for all people aged 65 and over
2004 -Conjugate vaccine policy was extended to at-risk children under five years of age
2006 - Pneumococcal conjugate vaccine containing polysaccharide from seven common capsular types was added to the routine childhood immunisation programme (PCV7)
2010 -Pneumococcal conjugate vaccine containing polysaccharide from thirteen common capsular types (including the seven capsular types in the earlier vaccine) replaced the seven valent conjugate vaccine (PCV13).
1. Pneumococcal polysaccharide vaccine (23-valent)
Pneumovax
Dosing:0.5mL IM/SC
2. Pneumococcal conjugate vaccine (7-valent)
Prevnar
Dosing: 0.5mL IM
Polysaccharide vaccine• The polysaccharide vaccine consists of purified polysaccharides from 23 serotypes (1,
2, 3, 4, 5, 6b, 7F, 8,9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F
and 33F) (17).
• 23 valent pneumococcal polysaccharide vaccine (PPV) was licensed in 1983, replacing
the 14-valent vaccine introduced in 1977.
• Vaccine serotypes account for 86% of bacteremia, 83% of meningitis & 65% of AOM
among <6 yrs
• Pneumovax 23 produced by Merck Research Laboratories, USA.
• Immunity is induced primarily through stimulation of B-cells which release IgM (17) without
the assistance of T cells (18).
(17)Pletz MW, Maus U, Krug N, Welte T, Lode H (September 2008).
"Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species". Int. J. Antimicrob. Agents 32 (3): 199–206.
(18)Stein KE (June 1992). "Thymus-independent and thymus-dependent responses to polysaccharide antigens". J. Infect. Dis. 165 (Suppl 1): S49–52.
Recommendations to receive pneumococcal polysaccharide vaccine (PPSV23) PPSV23 is recommended for anyone who meets any of the criteria below:• Age 65 years and older• Age 2 through 64 years with any of the following conditions • cigarette smokers age 19 years and older • alcoholism• chronic liver disease, cirrhosis• chronic cardiovascular disease, excluding hypertension (e.g., congestive heart failure,
cardiomyopathies) • chronic pulmonary disease (including COPD and emphysema, and for adults age 19 years and older,
asthma)• diabetes mellitus• candidate for or recipient of cochlear implant • cerebrospinal fluid (CSF) leak • functional or anatomic asplenia (e.g., sickle cell disease, splenectomy) • immunocompromising conditions (e.g., HIV infection, leukemia, congenital immunodeficiency,
Hodgkin’s disease, lymphoma, multiple myeloma, generalized malignancy, immunosuppressive therapy)
• solid organ transplantation; for bone marrow transplantation, • chronic renal failure or nephrotic syndrome
Recommendations of PPSV by ACIP• Advisory Committee on Immunization Practices (ACIP) recommends PPS vaccine
in • (a) persons aged ≥65 years, • (b) immunocompetent children ≥5 years who are at increased risk for illness and
death associated with pneumococcal disease because of chronic illness,• (c) persons aged ≥5 years with functional or anatomic asplenia,• (d) immunocompromised patients aged ≥5 years who are at high risk for infection.
They also recommend• (e) vaccination for people living in high-risk environments with emphasis on
American Indians and Alaska natives (19,20).
(19)Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997, 46(RR-8), 1–24.
(20)Preventing pneumococcal disease among infants and young children.Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2000, 49(RR-9), 1–35.
Pneumococcal polysaccharide vaccine (PPSV 23)
• Not more than two life time doses are recommended, as repeated doses
may cause immunologic Hypo-responsiveness.
• The IAP COI recommends offering both PCV and PPSV 23 to all high-risk
children.
• The PCV vaccines provide robust immune response and immune memory
while PPV 23 provides expanded serotype coverage.
Pneumococcal polysaccharide vaccine (PPSV 23)
• 23-valent adult vaccine covered more than 80% of the serotypes identified
in Indian adults.
• Protection offered in different age groups was 77% in 22–50 years,87% in
51–64 years & 86% in > 64 years age group.
Problems with polysaccharide vaccine in children
• Not effective in children less than 2 years ( because of less mature immune
system)
• No effect on nasal carriage
• No herd effect
• Absence of immunologic memory
• Antibody level to several serotypes decline to pre-vaccination values within
3-7 years corresponding to a decline of clinical protection (Immunization is
not lifelong, so individuals must be re-vaccinated every 5–6 years (21).
(21)Pletz MW, Maus U, Krug N, Welte T, Lode H (September 2008). "Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species". Int. J. Antimicrob. Agents 32 (3):
199–206.
Limitations of PPSV23 vaccine
• Antibody titers and efficacy appear to wane after 5 years (Shapiro, et al, NEJM, 1991)
• Effectiveness is very low in immunocompromised patients
• PPSV23 induces hyporesponsiveness to either another dose of PPSV23(Torling, et al
Vaccine, 2003) or to a dose of conjugate (deRoux, et al IDSA, 2005).
• Re-vaccinations cause more severe adverse events (Jackson, et al JAMA, 1999, Vaccine,
2005)
• Therefore, PPSV23 is generally given only once, which provides only a narrow
window of protection during a prolonged period of risk (ACIP recommendation: MMWR,
1997)
IMMUNOGENICITY & VACCINE EFFICACY OF PPSV
– >80% healthy adults develop Abs vs. vaccine-related serotypes
– Within 2-3 weeks after vaccination
– Poor Ab response in elderly, with chronic illness & <2yrs.
– Elevated Ab levels persist for at least 5 yrs in healthy adults & decline
more quickly in persons with chronic disease.• Antibody levels are likely to decline rapidly in individuals with no
spleen,splenic dysfunction or chronic renal disease (Giebink et al., 1981; Rytel et al., 1986) and therefore re-immunisation with 23-valent PPV is recommended every five years in these groups. Revaccination is well tolerated (Jackson et al.,1999).
– 60-70% effective in preventing invasive disease.
– No protection against pneumococcal pneumonia.
Pneumococcal conjugate vaccine
• Conjugated vaccine: consists of capsular polysaccharides covalently bound to a
nontoxic mutant of diphtheria toxin and the protein CRM197 or protein D of
noncapsulated Hib or DT and TT and finally Men OMP which is highly immunogenic
but non-toxic (23).
• This combination provokes a significantly more robust immune response by recruiting
CRM197-specific type 2 helper T cells, which allow for immunoglobulin type switching
(to produce non-IgM immunoglobulin) and production of memory B cells(23).
(23)Pletz MW, Maus U, Krug N, Welte T, Lode H (September 2008). "Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species". Int. J. Antimicrob. Agents
32 (3): 199–206.
Contd
• Conjugate vaccine results in mucosal immunity and eventual establishment
of lifelong immunity after several exposures(23).
• Conjugate vaccine does not induce hypo responsiveness to subsequent
PPSV23 or a 2nd dose of conjugate
Pneumococcal conjugate vaccine (PCV 7, Prevenar®)
• 7-valent pneumococcal conjugate vaccine Prevnar (Wyeth, USA) or Prevenar
(Wyeth, Europe), containing polysaccharides of serotype 4, 6B, 9V, 14, 18C, 19F
and 23F.
• Approved by the Food and Drug Administration (USA), and the Committee on
Proprietary Medicinal Products (Europe) for the prevention of invasive diseases
in children.
• These vaccines have a potential coverage of over 85% of the pneumococcal
isolates for the USA, 60–70% for Europe and around 55% for Asia.
PCV7• PCV7 was licensed in the USA in 2000, in Europe in 2001 & India August 2006.
• Remarkable results in USA & UK.
• A limited increase in IPD caused by non-PCV7 serotypes, particularly 19A
serotype has been registered to date
• However it covered only 55% of the serotypes prevalent in India.
• Dose is 0.5 ml IM.
PCV7
• PCV7 was initially categorized in cat-3 meaning to be given after one to one
discussion with parents in healthy children aged less than 2 years.
• It induces a T-cell dependent immune response characterized by immune
memory as well as a booster antibody response on subsequent challenge
with the pneumococcal polysaccharides included in the vaccine
Pneumococcal conjugate vaccine (Prevenar13®PCV13)
• In February 24th, 2010, a new 13-valent pneumococcal conjugate vaccine (PCV13) was
licensed by the Food and Drug Administration and recommended by the Advisory
Committee on Immunization Practices (ACIP) for prevention of invasive pneumococcal
disease in children.
• PCV13 contains the serotypes found in PCV7, plus an additional six serotypes: 1, 3, 5,
6A, 7F, and 19A individually conjugated to a nontoxic diphtheria cross-reactive material
(CRM) carrier protein (CRM197) (25).
• PCV13 succeeds the 7-valent vaccine (PCV7) used in the routine childhood
immunization schedule since 2000.
• Presently Indian Market has two options from Wyeth-Pfizer-- PCV-7, PCV-13 (24) MMWR 2010;(RR- 59):253-61.(25)Prevnar 13 (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein]). Philadelphia, PA: Wyeth Pharmaceuticals; 2011.
Pneumococcal Conjugate Vaccine Recommendations
– All children 2-23 months
– Children >2-59months with cochlear implants
– Children 24-59months with Sickle Cell disease, Asplenia, HIV,
immunocompromising/chronic illnesses
(26) CDC. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59:258–61.
Prevenar®PCV7 as per ACIP• Infants 2-6 months: 4 doses at 2, 4, 6 & 12-15mos. • Previously Unvaccinated:
– 7-11months – 3 doses, 2 doses 4 wks apart then 3rd dose at 12-15mos.– 12-23 months – 2 doses, 2 months apart– 24-59 months – HEALTHY : 1 dose; CHRONIC/IMMUNOCOMPROMISED:
2 doses, 2 months apart
• Previously Vaccinated:– 7-11 months – (received 1-2 doses) 2 doses at 7-11months then 12-15
months, at least 2 months apart– 12-23 months – 1 dose, 2 months after last dose– 24-59 months – HEALTHY: 1 dose; CHRONIC/IMMUNOCOMPROMISED: 2
doses, 2 mos. apart
PCV13
• Dose : 0.5 ml IM Available as latex free, single -dose, prefilled syringes.
• Side effects: mainly local
• According to most recent estimates, PCV-13 covers around 73% of the
prevalent serotypes in India.
• Present IAPCOI recommendation do not have similar categorization for this
as there was for PCV – 7.
• Cost benefit ratio can be discussed with parents and let them take decision
on named child basis.
Prevenar®PCV13 as per ACIP
• Un-vaccinated infants and children: PCV13 is recommended for all children aged
2 through 59 months "3 plus 1" dosing schedule, with doses at 2, 4, and 6 months
and a booster dose at 12 to 15 months.
• Children incompletely vaccinated with PCV7: Children aged 24 to 59 months
who received 1 or more doses of PCV7 should complete their vaccine series with
PCV13.
• Children completely vaccinated with PCV7: Children aged 14 to 59 months who
have received all 4 doses of PCV7 should receive a single supplemental dose of
PCV13.
• {Age may be extended to 71 months for high-risk children (e.g., sickle cell disease, HIV infection or
other immunocompromising conditions, cochlear implant, or cerebrospinal fluid leaks}.
Prevenar®PCV13 as per ACIP• High-risk children aged 6 years and older: This permissive recommendation
for an off-label use states: "[v]accination with a single dose of PCV13 may be
appropriate for children 6 through 18 years of age who are at increased risk for
pneumococcal disease".
• Healthy older children should not receive the vaccine.
• Additional vaccine for children with underlying medical conditions:
Children aged 2 years and older who are at increased risk for invasive
pneumococcal disease should receive a 23-valent pneumococcal
polysaccharide vaccine after vaccination with PCV13.
Difference between PCV13 and PPV23PCV13 PPV23
Valency 13 valent 23 valent
Target population Healthy Children At risk population
Minimum age of vaccination > 6 weeks > 2 years (High Risk)
Immune response ---- at 6 weeks of age Strong
---- at 2 years of age, Absent to weak Moderate to Strong
Duration of immunity Long term Short term
Vaccine efficacy- children < 2 years
Yes None
Important reductions in nasopharyngeal carriage
Yes No effect
Indirect protection Reported Unlikely
Important reductions in the prevalence of antibiotic resistant isolates
Reported Not established
(21) PCV for childhood immunization – WHO position paper Weekly Epidemiological Record. 2007, 12 (82): 93–104. Prevenar13 Prescribing Information Wyeth Limited* 2010 (*A subsidiary of Pfizer Inc.). (22)23-valent pneumococcal polysaccharide vaccine - WHO position paper. WHO Weekly Epidemiological Record . 2008; 83(42): 373–384
Storage & Administration
• Storage
• Vaccines should be stored in the original packaging at +2°C to +8°C and protected from light.
• Both PCV and PPV are supplied as single doses of 0.5ml.
• Administration
• Vaccines are routinely given into the upper arm in children and adults or the anterolateral
thigh in infants under one year of age. This is to reduce the risk of localised reactions, which
are more common when vaccines are given subcutaneously (27).
(27) Mark et al., 1999; Diggle and Deeks, 2000; Zuckerman, 2000).
Pneumococcal Vaccines Adverse Reactions
• Local reactions
– polysaccharide 30%-50%
– conjugate 10%-20%
• Fever, myalgia
– Polysaccharide <1%
– conjugate 15%-24%
• Severe adverse rare
reactions
Serotypes included in the three pneumococcal vaccine formulations* available in the United States, 2010
Pneumococcal serotype VaccinePPSV23 PCV13 PCV7
4 X X X6B X X X9V X X X14 X X X18C X X X19F X X X23F X X X1 X X3 X X5 X X6A X7F X X19A X X2 X8 X9N X10A X11A X12F X15B X17F X20 X22F X33F X
* The 13-valent pneumococcal conjugate vaccine (PCV13) includes the seven serotypes in the 7-valent vaccine (PCV7) and six additional serotypes. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) includes 12 of the serotypes included in PCV13 (it does not include serotype 6A) and 11 additional serotypes.
Immunogenic proteins• Proteins including pneumolysin, pneumococcal surface protein A, pneumococcal
surface adhesin A, choline binding protein A (CbpA), neuraminidase, and autolysin
have been suggested as potential candidates.
• Proteins PspA, PsaA and pneumolysin are currently the leading vaccine
candidates (28,29).
(28) Briles DE, Hollingshead SK, Nabors GS, Paton JC, Brooks-Walter A. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumoniae. Vaccine 2000;19(Suppl 1):S87–95.
(29) Ogunniyi, A.D. et al. (2007) Development of a vaccine against invasive pneumococcal disease based on combinations of virulence proteins of Streptococcus pneumoniae. Infect. Immun. 75, 350–357
Immunogenic proteins
• An ideal mucosal vaccine would include several pneumococcal proteins
such as pneumolysin, PspA, PsaA or PspC.
• Thorough investigation of these proteins still is necessary before large-scale
immunization studies in humans will become within reach.
• Thorough investigation of the efficacy and safety of these vaccine
candidates and monitoring of side effects have to be performed before
human use is optimized.
Antigen or vaccine Route Immunogenicity Protection against:
PspA Intranasal Mucosal and systemic
Colonisation, pneumonia, sepsis
PspA/attenuated oral Mucosal and systemic
Pneumonia, bacteraemia
Salmonella PsaA oral Mucosal and systemic
Pneumonia, bacteraemia
PsaA/lactic acid bacteria
Intranasal Mucosal and systemic
Colonisation, Pneumonia, bacteraemia
PotD Intranasal Mucosal and systemic
Colonisation
PsaA and PspA Intranasal Mucosal and systemic
Pneumonia, bacteraemia
PspA and PspC Intranasal Mucosal and systemic
Colonisation, pneumonia
PCV Intranasal Mucosal and systemic
Colonisation, otitis media
Mouse models of mucosal immunisation with pneumococcal protein antigens
Abbreviations: PspA, pneumococcal surface protein A; PsaA, ‘pneumococcal surface adhesion A’ protein; PotD, PspC, pneumococcal surface protein C; PCV, pneumococcal conjugate vaccine
Recommendation from the Strategic Advisory Group of Experts (SAGE) on Immunization
• “…… WHO considers that is should be a priority to include pneumococcal conjugate vaccine in national immunization programmes, ……
• Countries with mortality among children aged <5 years of >50 deaths/1000 births
or with more than 50 000 children’s deaths annually should make the
introduction of PCV-13 a high priority for their immunization programmes.
(30)WHO Weekly Epidemiological Record, 23 Mar 2007
Pneumococcal Conjugate Vaccine for childhood immunization – WHO position paper.
23 March 2011, 82nd year. No. 12, 2011, 82, 93-104.
Thank you