UPDATE ON PNEUMOCOCCAL DISEASE SEROTYPES:

TOWARDS THE INTRODUCTION OF VACCINATION IN NIGERIA

PROFESSOR G.C. ONYEMELUKWE (MON)Ahmadu Bello University Teaching Hospital, Zaria

EXPERT PANEL MEETING ABUJA JUNE 16TH 2010 ON INVASIVE PNEUMOCOCCAL DISEASE (IPD)

1. Honourable Minister of Health, Prof. Onyebuchi Christian Chukwu Represented by Dr. Michael Anibueze, Director Public Health FMoH

2. Executive Secretary/CEO NPHCDA, Dr. Mohammed Ali pate Represented by Dr. E. Abanida, Director, Disease Control and Immunization

3. Prof. G.C Onyemelukwe MON Professor of Medicine and Immunology Member National Certification Committee (NCC) on Polio Eradication

4. Dr. Amgad GamilRegional Medical Director; VaccinesPfizer, Africa and Middle East Region

5. Prof William OgalaProfessor of Paediatrics and Immediate Past President, Paediatric Association of Nigeria (PAN)

6. Prof. Alice Nte Represented by Dr. Yaguo Ide, University of Port Harcourt Teaching Hospital

7. Prof. A.G Falade Professor of Paediatrics Represented by Dr. Regina Oladokun, University College Hospital, Ibadan

8. Dr. U. Nnebe – AgumaduPaediatrician, University of AbujaMember HERFON Committee on Non-Communicable Diseases

9. Dr. Abdulrazaq G. HabibAminu Kano Teaching Hospital, KanoPresident, Nigeria infectious Diseases Society

10. Dr. Stephen ObaroAssociate Professor of infectious DiseasesMichigan State University, USA

11. Dr. Beckie TagboInstitute of Child Health, University of Nigeria Teaching Hospital, EnuguMember, PAN Immunization Committee

12. Dr. Adejumoke AyedePeadiatrician, University College Hospital, Ibadan

13. Dr. Kodjoh SorohMedical Director, Pfizer NEAR

14. Dr. Wadzani GashauChairman, National Teaching Working Group (TWG), Antiretroviral Treatment

WORLD WIDE DISTRIBUTION OF PNEUMOCOCCAL DISEASE.

Brien K O et al. Lancet 2009; 347:893-902

PNEUMOCOCCAL BUBBLE OF DEATHS IN CHILDREN < 5 YEARS OF AGE.

Brien K O et al. Lancet 2009; 347:893-902

Numbers of cases of disease by regions

• Syndrome Global AFRO PAHO EMRO EURO SEAROWPRO

• Pneumonia 13.8m 3.81m 648k 1.45m 238K 5.33m2.34m

• Meningitis 103k 43k 9500 9700 3300 24k 13k

• NonP-NonM 538k 215k 55k 51k 19k 122k 76k

• Total 14.5m 4.06m 713k 1.51m 260k 5.48m2.43k

JUSTIFICATION 1. Director General (WHO) Dr. Margaret Chan (2009),

Pneumonia and Malaria kill More Children.pneumonia, a “Forgotten Disease “

2. MDG 4- Child and Maternal mortality reduction by (2015)

3. Global burden – India 27%China 17%Nigerian 5%

4. 7million Nigerians with IPD – 380/100,000 mortality 5. 57% Pneumococcal deaths in Africa 6. Nigeria in Pneumococcal belt of Africa with high child

and adult mortality despite antibiotics

Justification: 800,000 children die per year* IPD > 90% developing countries (Africa, Asia, Latin America).* Findings 1. Six to eleven serotypes cause more than 70% IPD2. Seven commonest 1,5,6A,6B, 14, 19F, 23F.3. Serotype global ranking 14, 6B, 1, 23F, 5, 19F, 6A,

19A, 9V, 18C, 2, 4, 7F, 12F, 3, 12A. 8, 46, 15B, 454. Africa 14, 1,5, 23F, 19F, 3, 6B5. 19A most common antibiotic resistance

Pneumococcal Global Serotype Project (< 5 years age) 1980 – 2007.

Johnson et al 2010

Pneumococcal Conjugate Vaccines (PCV)

Capsular polysaccharide + CRM197 = PCV

1. PCV 7 (4,6B, 9V, 14, 18C, 19F, 23F)

2. PCV 10 (Addition: 1, 5, 7F)3. PCV 13 (Addition: 3, 6A, 19A)- Conjugate vaccine immunogenic in 2 months of age- Serotype specific efficacy after 4th dose - Vaccine schedule: 2, 4, 6, months of age, 4th dose at 15 months

(USA)- Protects against meningitis, pneumonia, bacteremia, otitis

media.Black et al., 2002.

UNITED KINGDOM PCV HISTORY

2002 PCV available, recommended for at risk groups under 2 years

2003 PCV recommended for > 65 years old 2004 PCV for at risk children under 5 years of

age 2006 PCV added to routine childhood

immunization program

POST LICENSE SURVEILLANCE (USA)(as part of universal infant immunization)

1.Reduction in invasive and non-invasive disease due to vaccine serotypes in vaccinated and older unvaccinated population (herd immunity)

2. Fall in rate of penicillin-resistant pneumococcal infections.

3. Small increase in invasive disease due to non-vaccine serotypes (Serotype Replacement)

Black et al., 2004; Whitney et al., 2003

UN ASSEMBLY 2010 22ND SEPTEMBER MDG RESOLUTION

“Every woman, Every child” – Mr. Ban Ki – moon1. Saving sixteen million women by 2015, prevent 33 million

unwanted pregnancies 2. Protect 120 million children from pneumonia, 88 million from

stunting.- Stakeholders – governments, policy makers, donor countries,

NGO’s, communities, health workers, business sector, professional associations, academic/ research institutions.

Nigerian commitment and endorsement 2010 – 2015 as part of National Health Plan: 20-2020 National Vision 31.63 US dollars per capital, 5% - 15% Federal, State, Local Government Budget.

EXPERT COMMITTEE RECOMMENDATION PCV 13 VACCINATION IN NIGERIA

1. Routine immunization of children in Nigeria in a three or four dosage schedule at 6 weeks to 5 years of age

2. Vulnerable population such as sickle cell disease patients at any age

3. HIV infected children and adults4. Elderly people aged 65 years and above5. Other major disease conditions such as

malignancies, renal failure, nephrotic syndrome, liver cirrhosis, diabetes mellitus, alcoholism and chronic lung diseases

CURRENT WORLD STATUS OF PCV USE (JANUARY 2010)

No current program 134

countries

Introduced into NIP: risk 16

countries 8%

introduced into NIP: Universal 41

countries 21%

Widespread coverage through private market 2 countries 1%

* NIGERIA

Lèvine et al 2010

AFRICA: RESISTANCE OF 375 Isolates of S. Pneumoniae

Ivory coast Morocco Senegal Tunisia Total Antibiotics (n = 138) (n = 98) (n = 58) (n = 58) (n = 375)

Penicillin G

Susceptible 77.5 90.8 38.3 58.6 69.9

Intermediate 18.1 8.2 53.1 34.5 25.6

Resistant 4.3 1 8.6 6.9 4.8

Amoxicillin 3.6 1 3.7 8.6 3.7

Cefotaxime-ceftriaxone 8.8 1 15 3.6 7.3

Chloramphenicol 11 2 14.8 5.2 8.6

CONTINUED

Erythromycin 52.6 4.1 11.4 32.8 28

Tetracycline 67.5 12.2 29 34.5 38.3

Rifampicin 5.8 0 0 0 2.1

Cotrimoxazole 60.5 14.8 29 19.4 36.4

*Ibadan Hospitals Study .. Intermediate resistant to tetracycline and

all fully resistant to cotrimoxazole

• Jos Study 70.27% sensitive to penicillin

29.72% resistant to penicillin

Streptococcus pneumoniae is a gram positive diplococcus

See Capsule

FOUR MAJOR VIRULENCE FACTORS

1. Capsular polysaccharides – Antiphagocytic and Anti-complement

2. Pneumolysin – Inhibits lymphocyte proliferation and neutrophil chemotaxis

3. IgA1 protease – Cleaves submucosal IgA4. Autolysin – breaks down peptidoglycan of

cell wall to aid release of pneumolysin

STREPTOCOCCUS PNEUMONIAE STRUCTURE

PNEUMOCOCCAL SEROTYPES IN ZARIA, NORTHERN NIGERIA

ST 1 2 3 4 5 9 10 11 12 15 17 18 19 21 23 25 41 45 46 48 T

MN 23 3 10 2 1 2 2 2 2 1 1 1 1 51

PN 20 4 12 2 10 1 1 3 5 4 1 1 4 2 1 70

PP 1 1

CJ 2 1 1 4

PID 1 1 2

BC 8 3 6 1 1 1 20

T 53 7 28 2 18 1 1 1 4 1 3 7 4 1 3 3 5 3 2 1

KEYST=SEROTYPES, MN=MENINGITIS, PN= PNEUMONIA, PP=PRIMARY PERITONITS, CJ=PRIMARY CONJUCTIVITIS, PID= PELVIC INFLAMATORY DISEASE, BC= BACTEREMIA/ANTIGENEMIA, T=TOTAL

DISRIBUTION OF SEROTYPES IN CHILDREN UNDER 12 YEARS (NUMBER OF CASES - 40) SEROTYPE %

1 47.5

3 17.5

2, 46 , 5 8.3 each

48 2.5

23 2.5

41 2.5

12 2.5

MORTALITY RELATED TO SEROTYPES IN ADULTS AND CHILDREN

Serotype Meningitis Case Fatality (%)

Pneumonia Case Fatality (%)

1 23 48 20 20

3 10 50 12 41.6

5 2 50 10 20

25 2 50 1 100

45 1 100 2 100

*G.C. ONYEMELUKWE AND B.M. GREENWOOD JOURNAL OF INFECTION (1982) 5, 157-163

CONDITIONS ASSOCIATED WITH PNEUMOCOCCAL DISEASE

1. YOUNG AGE2. MEASLES – 15 (CHILDREN )3. SICKLE CELL DISEASE (3 CHILDREN)4. PREGNANT WOMEN (6 ADULTS)5. CIRRHOSIS (2 ADULTS)6. PERIPARTUM HEART FAILURE (1 ADULT)*G.C. ONYEMELUKWE AND B.M. GREENWOODJOURNAL OF INFECTION (1982) 5, 157-163

AGES OF SEROTYPED PNEUMOCOCCAL MENINGITIS PATIENTS

• Two year study of pneumococcal meningitis with 39% mortality

1. 50% : under 10 years2. 32.5% : 1- 10 years3. 17.6% : < 1 year4. 2.65% < 2 weeks of ageSeasonality of infection- All year roundPeak periods- Drier Months: January, February,

March, April*G.C. ONYEMELUKWE AND B.M. GREENWOODJOURNAL OF INFECTION (1982) 5, 157-163

Falade et al 2009 (Ibadan) (Clin Infect Dis. 2009 Mar 1;48 Suppl 2:S190-6.)

• 2 year hospital surveillance (Age 2-59 months) for pneumonia and meningitis- 1210 cases

• 481 (49.8%)- Meningitis• 399 (33%) – Pneumonia• 330 (27.2%) – Bacteremia• 11 out of 23 Streptococcus pneumonia isolates were

typedType 4 – 3 casesType 5 – 5 casesType 19 F- 3 cases

REFERENCES1. Onyemelukwe GC, Greenwood BM. Pneumococcal serotypes, epidemiological

factors and vaccine strategy in Nigerian Patients. Journal of Infection (1982) 5, 157-163.

2. Onyemelukwe GC. Polymorph function, complement and immunoglobulins in Nigerian patients with pneumococcal infections. Journal of Infection (1983) 7, 118-124

3. Taqi AM, Onyemelukwe GC. Serotypes and pneumococcal meningitis in Nigerian Children. East African Medical Journal of Infection. (1986) 63 (1), 42-47

4. Onyemelukwe GC,Leinoen, M MakelaH, Greenwood BM. Response to pneumococcal vaccination in normal and post-infected Nigerians. J Infect. 1985 Sep;11(2):139-44.

5. Falade AG, lagunja IA, Bakare RA, Odekanmi AA, Adegbola RA. Invasive pneumococcal disease in children aged <5 years admitted to 3 urban hospitals in Ibadan, Nigeria. Clin Infect Dis. 2009 Mar 1;48 Suppl 2:S190-6.

6. Bradford D Gessner, Judith E Mueller, Seydou Yaro. African meningitis belt pneumococcal disease epidemiology indicates a need for an effective serotype 1 containing vaccine, including for older children and adults. BMC Infectious Diseases 2010, 10:22. http://www.biomedcentral.com/1471-2334/10/22.

cont. REFERENCES

7. Brien KO, Wolfson L J, Watt JP, Henkle E, Knoll MD, McCall N, Lee E, Mulholland K, Levine OS, Cherian T. Burden of Streptococcus pneumoniae in children younger than five years: global estimates. Lancet 2009; 347:893-902.

8. Cutts FT, Zaman SMA, Jaffar S, Levine OS, Oluwalana C, Obaro SK, Leach A, McAdam KP, Biney E, Saaka M, Onwuchekwa U, Yallop F, Pierce NF, Adegbola RA.Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomized double-blind, placebo controlled trial.Lancet 2005; 365: 1239-46

9. Traore Y, Tameklo TA, Njanpop-Lafourcade B-E, Lourd M, Yarou S, Niamba D, Drabo A, Mueller JE, Koeck J-L, Gessner BD. Incidence, seasonality, age distribution and mortality of pneumococcal Meningitis in Burkina Faso and Togo.Clin Inf Dis 2009; 48: S181-9

10. French N, Gordon SB, Mwalukomo T, White SA, Mwafulirwa G, Longwe H,Mwaiponya M, Zijlstra, EE, Molyneux ME, Gilks C. A trial of a 7-valent Pneumococcal Conjugate Vaccine in HIV-Infected Adults. N Engl J Med 2010; 362: 812-22

11. Johnson H.L, Deloria – Knoll M, Levine OS, Stoszek S.K, Hance LF, Reithinger R, Muenz LR, O’Brien KL. Systematic evaluation and serotypes causing invasive pneumococcal disease among children under five: The Pneumococcal Global Serotype Project.

PLoS Medicine 2010. 7(10). E1000348.

12. Black S, Shinefield HR, Ling S et al. effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J. 2002, 21; 810 – 815.

13. Black S. et al., Post licensure surveillance for pneumococcal invasive disease after use of

heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004, 23; 485 – 489.

14. Whitney CG, Farley MM, Hadler J et al Decline in invasive pneumococcal disease after the

introduction of protein – polysaccharide conjugate vaccine N. Eng. J. Med 2003, 348 (18); 1737 - 46

cont. References

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