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Pneumococcal Vaccines: Review

Dr. Chandki Kishore Consulting Pediatrician

S. Pneumoniae & Vaccines

Pneumococcal Vaccines


> 6 weeks

> 2 years

PCV-7 PCV-13



S. Pneumoniae & Vaccines

Conjugated Vaccine
A polysaccharide antigen combined with a carrier protein makes it a strong immunogenic molecule Create a more powerful, combined immune response Typically the polysaccharide being presented would not generate a strong immune response on its own, while the carrier protein would

Polysaccharide Vaccine
Against the molecule in the capsule; but these molecules are small, and not very immunogenic Tend not to be effective in infants & young children (<1824 months) Induce only short-term immunity there is a slow immune response, do not induce a T-cell response. Only protect for a few years

Difference between PCV13 and PPV23

Valency Target population Minimum age of vaccination Immune response ---- at 6 weeks of age ---- at 2 years of age Duration of immunity Vaccine efficacy- children < 2 years Important reductions in nasopharyngeal carriage Indirect protection Important reductions in the prevalence of antibiotic resistant isolates 13 valent Healthy Children > 6 weeks Strong Strong Long term Yes Yes

23 valent

At risk population
> 2 years (High Risk) Absent to weak Moderate to Strong Short term None No effect

Reported Reported

Unlikely Not established

1. PCV for childhood immunization WHO position paper Weekly Epidemiological Record. 2007, 12 (82): 93104. 2. Prevenar13 Prescribing Information Wyeth Limited* 2010 (*A subsidiary of Pfizer Inc.) 3. 23-valent pneumococcal polysaccharide vaccine - WHO position paper. WHO Weekly Epidemiological Record. 2008; 83(42): 373384

Diseases caused by S. Pneumoniae


Non-invasive disease
Sinusitis Otitis media Pneumonia

Invasive disease
Bacteraemia (blood)

More than 90 strains/ Serotypes are known Immunocompromised & Children < 2 years at risk

Meningitis (CNS) Endocarditis (heart) Peritonitis (body cavity) Septic arthritis (bones and joints) Others (appendicitis, salpingitis, soft-tissue infections)

Musher, in Principles and Practice of Infectious Diseases, 1995

Diseases caused by S. Pneumoniae

US: Estimated number of cases per year 30% CFR 20% CFR 1,400 17,000 71,000





5 million

Otitis media

Under 5 year Child Deaths: Causes

Pneumonia: Burden
Pneumonia remains the leading killer of children1 410,000 children < 5 die of pneumonia every year, claiming a young life every 20 seconds1,2

25% of all child deaths are due to pneumonia3 Meta-analysis of 4 CTs suggest 30-40% of all severe pneumonia in children is pneumococcal In Indian context, around 123,000 to 164,000 children <5 years die annually from pneumococcal pneumonia1 The fight against pneumonia can be won. Estimates indicate that more than one million childrens lives can be saved annually with widespread use of vaccines and improved access to antibiotics
1. 2. 3. Levine OS et al Indian Pediatrics 2007; 44:491-496 Pneumonia The forgotten killer of children, WHO, UNICEF, 2006 Thacker N. IPD burden - An Indian Perspective. Pediatrics Today 2006; 9(4): 208-213

Pneumococcal Conjugate Vaccine (PCV)

India >>>> China

Pneumococci: Antibiotic Resistance

oStrains of drug-resistant S. pneumoniae (DRSP) have become increasingly common in all parts of the world oIn some areas, as many as 35% of isolates have intermediate- or high-level resistance to penicillin (CDC, based on MIC) oMany penicillin-resistant pneumococci are also resistant to other drugs (e.g., erythromycin, cotrimoxazole, & extended-spectrum cephalosporins) oHigh-level penicillin resistance & MDR often complicate the management of infection and make choosing empiric antimicrobial therapy for suspected cases of meningitis, pneumonia, & otitis media increasingly difficult oEmerging resistance further emphasizes the need for preventing pneumococcal infections by vaccination

Pneumococci: Antibiotic Resistance

Simes A S et al. J. Clin. Microbiol. 2011;49:2810-2817

S. Pneumoniae & Pneumonia Burden in India

o In India, Pneumonia is the single most important cause of death among children in the post-neonatal period, contributing as much as 27.5% of total underfive mortality o It appears that about 10-15% of childhood pneumonias are caused by H. influenzae and RSV each; and 12-35% by pneumococcus* o Vaccines that protect against pneumonia: Pneumococcal Haemophilus influenzae type b (Hib) Pertussis (whooping cough) Varicella (chickenpox) Measles, & Influenza (flu) vaccine
* Mathew J et al. ARI & Pneumonia in India A systematic review . Indian Pediatrics, March 2011

Pneumococcal Conjugate Vaccine (PCV)

oEstimates of IPD incidence for developing countries are difficult to obtain o90% of bacteremia, 30-50% of severe community acquired pneumonia, 30-45% of pyogenic meningitis and 30-60% of all bacterial AOM are estimated to be caused by pneumococcus oThe mortality rate of invasive disease is 6% 20% and there are long term sequels like CNS squeal in survivors of meningitis and deafness in children with recurrent AOM

Lacunae in Dx & Tx
oCommon inhabitant of the respiratory tract (nasopharynx of 5-70% healthy adults). Asymptomatic carriage, duration of carriage varies & is generally longer in children than in adults oClinicians often do not obtain cultures oLaboratories are not able to identify the organism because of poor technique, although only a few serotypes produce the majority of pneumococcal infections oSome children die of sepsis/pneumonia despite good antibiotics oGram positive, alpha hemolytic streptococci

Lacunae in Dx & Tx

Efficacy and Effectiveness of PCV

Proven Efficacy:
Invasive disease


Proven Effectiveness:
Invasive disease Pneumonia
Effectiveness relates to how well a treatment works in practice, as opposed to efficacy, which measures how well it works in clinical trials or laboratory studies.

NP colonization Herd immunity

Vaccine Efficacy Studies

Cochrane review (2009) 113,044 children worldwide (Africa, US, Finland & Philippines)
IPD by vaccine serotypes 80 % IPD by any serotype 58 % radiological pneumonia - 27% clinical pneumonia 6% All-cause mortality 11%

Systematic Review from developing countries (9 & 11 valent vaccines)

Radiological pneumonia 26 % Clinical pneumonia 7 % Clinically severe pneumonia 7 % All-cause mortality 15 % IPD by vaccine serotypes 89 % IPD by any serotype 63% to 74%

Safety & immunogenicity study of PCV 13 from India non-inferiority

Phase 3 double blind multi-centre RCT 179 children received PCV 13, 176 received PCV 7 Responder rates > 80 % for both vaccines for the common serotypes Responder rates between 80-99 % against additional 6 serotypes Incidence of both local & systemic reactions were similar, and mild

Amdekar Y, et al. Safety and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine in Healthy Infants Given With Routine Vaccines in India. 7th International Symposium on Antimicrobial Agents and Resistance, Bangkok, Thailand, March 18-20, 2009

Impact of Vaccination With PCV


Indirect Effect



Office Visits

Antibiotic Resistance and Use of Antibiotics

OM= otitis media. IPD=invasive pneumococcal disease.

Pneumococcal Vaccine: Rationale

Pneumococci: important cause of pneumonia & serious infections Important cause of deaths Nasopharyngeal carriage: easy spread Droplet transmission: spreads by coughing or sneezing Children under 2 years are most susceptible Encapsulated bacteria: patient with splenic dysfunction/immune deficiency are prone Many pneumococci are drug resistant Effective vaccine available with negligible side effects

Key Strains Worldwide

Serotype 1

Clinical Implications
High prevalence in many regions of the world Associated with Epidemic outbreaks Causes complicated pneumonia (with empyema), especially in children aged 2 -5 years Associated with Epidemic outbreaks (along with serotype 1 account for 29 % IPD in India) Common serotype in Latin America and Africa Increasingly important cause of IPD, particularly in Europe and North America High case-fatality rate compared with other serotypes Among the most common isolates in older children. Associated with severe childhood pneumonias & lung necrosis Associated with antibiotic resistance Commonly found in nasopharyngeal isolates Increasingly important cause of serious pneumococcal disease

Serotype 5

Serotype 7F

Serotype 3 Serotype 6A

Serotype 19A Most common serotype in nasopharyngeal colonization

Increasingly resistant to antibiotics and has been associated with multidrug resistance

Serogroup distribution in India

IBIS Group. The Lancet 1999; 353: 1216-1221

% SEROGROUP coverage of different PCV

80 70 60 50 52.5 75.4 75.4

40 30 20 10 0





7V 10V 13V

4 4 4

6B 6B 6B

9V 9V 9V

14 14 14

18C 18C 18C

Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India IBIS Group. The Lancet 1999; 353: 1216-1221 19F 23F 19F 23F 1 5 7F 19F 23F 1 5 7F 19A 6A

S. Pneumoniae Conjugate vaccines, Potential vaccine protection

Type Contains Serotype % of target strains A layman calculation
50% 70%

PCV-7 PCV-13 PCV-10 PPV-23

4, 6B, 9V, 14, 18C, 19F, 23F 1, 5, 7F, 3, 6A & 19A, 4, 6B, 9V, 14, 18C, 19F, 23F

1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, & 60% 23F 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 90% 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F

Target serotypes for India are 6, 1, 19, 14, 4, 5, 45, 12, 7, 23

S. Pneumoniae Conjugate vaccines, Potential vaccine protection

% Pneumococcal disease caused by different serotypes included into the conjugated North Latin Africa Asia Europa America Amrica Oceania (%) (%) (%) (%) (%) (%) PCV7 PCV10 39.3% 62.5% 48% 66.2% 67.1% 76.2% 54.4% 73.6% 78.1% 80.6% 64.5% 71.1%








Cobertura de serotipos calculada a partir de datos del Global Serotype Project (GSP) 1980 - Jun 2007.

Dinleyici E, et al. Expert Rev Vaccines. 2009;8:977-986. GAVI Pneumococcal AMC TPP, Nov 2008. http://www.vaccineamc.org/files/TPP_codebook.pdf. Accessed September 3, 2009.

PPV-23: Review
oThe unconjugated pneumococcal polysaccharide vaccine is a 23 valent vaccine (PPSV 23) oT cell independent vaccine that is poorly immunogenic below the age of 2 yrs, has low immune memory, does not reduce nasopharyngeal carriage and does not provide herd immunity. It has at best 70% efficacy against prevention of IPD in the high-risk population but offers no protection against non bacteremic pneumonia/ otitis media oDose is 0.5 ml subcutaneous/intramuscularly. It is a safe vaccine with occasional local side effects. Not more than two life time doses are recommended, as repeated doses may cause immunologic hyporesponsiveness oDuration of protection is around 5 years

PPV-23: Indications
oAll adults age 65 years or older oAnyone age two years or older who has a long-term health problem such as cardiovascular disease, sickle cell anemia, alcoholism, lung disease, diabetes, cirrhosis, or leaks of cerebrospinal fluid oAnyone who has or is getting a cochlear implant oAnyone age two years or older who has a disease or condition that lowers the body's resistance to infection, such as Hodgkin's disease, kidney failure, nephrotic syndrome, lymphoma, leukemia, multiple myeloma, HIV infection or AIDS, damaged spleen or no spleen, or organ transplant oAnyone age two years or older who is taking any drug or treatment that lowers the body's resistance to infection, such as long-term steroids, certain cancer drugs, or radiation therapy oAdults ages 1964 who have asthma oAdults ages 1964 who smoke cigarettes

Children at High Risk of Pneumococcal Disease

CHD Asthma Sickle cell anemia Thalassemia DM Nephrotic syndrome CRF

PCV: Review
oIn 2000, the first pneumococcal conjugate vaccine (PCV) was licensed in the U.S. This vaccine contained seven serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) of Streptococcus pneumoniae and became known as PCV7 (Prevnar by Wyeth, now Pfizer). Ten years later in February 2010, a new 13-valent product was licensed -- PCV13 (Prevnar 13, Pfizer) -- which added 6 new serotypes (1, 3, 5, 6A, 7F, and 19A). Together, these 13 serotypes account for the majority of invasive pneumococcal disease (IPD) in the U.S., including serotype 19A, which is the most common IPD-causing serotype in young children. In February 2010 ACIP recommended that healthcare providers transition from use of PCV7 to use of PCV13 for routine vaccination of children.

PCV: Review

PCV: Review
oPCV were developed primarily to address the problem of low immunogenicity of the polysaccharide vaccine in children below the age of 2 who are at high risk for pneumococcal disease oAccording to most recent estimates, PCV-13 covers around 73% and PCV-10 approximately 66% of prevailing pneumococcal serotypes in the region. oBoth the products appear to be almost providing equal protection against the prevailing pneumococcal disease. While PCV-13 offers wider serotype coverage, PCV-10 promises to provide better protection against otitis media o>90% Seroconversion after the 3rd dose! o0.5 mL IM is the dose.

PCV: Review
oChildren who have suffered from the disease, should also receive the vaccine, because of several serotypes oHigh risk groups (for pneumococcal) should be given both PCV & PPV-23 oChildren undergoing splenectomy should complete the series at least 2 weeks before the procedure oCommon side effects of PCV include redness or swelling of the skin where the vaccine was injected, sleep changes (potentially either more or less sleep than normal), reduced appetite, crying and fever. oThe only contraindication to PCV immunization is a severe hypersensitivity reaction to a previous dose of the vaccine

PCV: Recommendations
oWHO in 2007 recommended to include PCV in the National Immunization Program (NIP) of any country with under-5 MR of > 50/1000 live births or absolute child deaths of > 50,000 per year. With under-5 MR of 72/1000 live birth and nearly 2 million under-five deaths per year, India merits to include PCV in NIP with high priority oIndia has shown intent to include PCV in NIP by 2012-13 when PCV10/PCV13 will become available, which will cover > 75% of prevalent serotypes of pneumococcus as seen in children

PCV: Dosage & Vaccination Schedule

oMinimum age for administering first dose is 6 weeks. oMinimum interval between two doses is 4 weeks for children vaccinated at age <12 months whereas for those vaccinated at age >12 months, the minimum interval between doses is 8 weeks. oIAP recommends offering both PCV & PPV-23 to all high-risk children oThe PCV provides the robust immune response and immune memory while PPV-23 provides expanded serotype coverage oIf PCV can not be given, at least 2 PPV-23 should be given to high-risk children above 2 years oCDC recommends single dose of PCV to susceptible person up to 18 years of age. oUSFDA had approved for adult population also!

PCV: Dosage & Vaccination Schedule

PCV: Brand Comparison

Broadest serotype coverage US-FDA approved Ensures herd immunity

Less coverage Not yet No

Well documented safety data, Few studies Indian studies

Available in 115 countries, 58 NIP schedule

6-18 yrs only one dose in high risk group, Adult indications 2-5 years: two doses required

Take Home Message Pneumococcal disease is the leading &

preventable cause of death worldwide in children aged <5 years Data from India clearly points to vaccine preventable serotypes being common cause of Pneumococcal Disease! Physician should discuss the vaccine, its protective efficacy & effectiveness, cost & chance of getting infection in absence of that vaccine to that particular child bases with parents