PROFESSOR GC ONYEMELUKWE MON Ahmadu Bello University Teaching Hospital Zaria Pfizer Advisory Board Meeting 2017 WORLD WIDE DISTRIBUTION OF PNEUMOCOCCAL DISEASE Brien K O et al Lancet 2009 347893902 ID: 1048451
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1. BURDEN OF PNEUMOCOCCAL AND MENINGOCOCCAL DISEASESPROFESSOR G.C. ONYEMELUKWE (MON)Ahmadu Bello University Teaching Hospital, ZariaPfizer Advisory Board Meeting (2017)
2. WORLD WIDE DISTRIBUTION OF PNEUMOCOCCAL DISEASE.Brien K O et al. Lancet 2009; 347:893-902
3. 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%7million Nigerians with IPD – 380/100,000 mortality 57% Pneumococcal deaths in Africa Nigeria in Pneumococcal belt of Africa with high child and adult mortality despite antibiotics
4. PNEUMOCOCCAL BUBBLE OF DEATHS IN CHILDREN < 5 YEARS OF AGE.Brien K O et al. Lancet 2009; 347:893-902
5. Numbers of cases of disease by regionsSyndrome Global AFRO PAHO EMRO EURO SEARO WPRO Pneumonia 13.8m 3.81m 648k 1.45m 238K 5.33m 2.34m 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 5.48m 2.43k
6. J. Med. Microbiol. – Vol. 51 (2002), 98 – 104
7. Pre – Vaccination Nasopharyngeal Pneumococcal Carriage in a Nigerian Population: Epidemiology and Population BiologyIfedayo M. O. Adetifa1*, Martin Antonio1, Christy A. N. Okoromah2, Chinelo Ebruke1, Victor Inem3, David Nsekpong1, Abdoulie Bojang1, Richard A. Adegbola1*¤ PLOS 1 2012:7(1) e30548Results: The prevalence of pneumococcal carriage was 52.5%. Carriage was higher in children compared to adults (67.4% vs. 26%), highest (<90%) in infants aged ,9 months and reduced significantly with increasing age (P,0.001).Serotypes 19F (18.6%) and 6A (14.4%) were most predominant. Potential vaccine coverage was 43.8%, 45.0% and 62% for PCV-7, PCV-10 and PCV-13 respectively.
8. There were 16 novel alleles, 72 different sequence types (STs) from the isolates and 3 Sequence Types (280, 310 and 5543) were associated with isolates of more than one serotype indicative of serotype switching.Antimicrobial resistance was high for cotrimoxazole (93%) and tetracycline (84%), a third of isolates had intermediate resistance to penicillin. Young age was the only risk factor significantly associated with carriage.Serotypes 6, 14, 19, 23 most antibiotic resistant paediatric serotypescoverage of serotypes in this study, PCV-13 is the obvious choice to reduce disease burden and prevalence of drug resistant pneumococci.
9. Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6–70.8) in children less than 5 years, 42.6% (95% CI: 29.9–55.4) in children 5–15 years and 28.0% (95% CI: 19.0–37.0) in adults older than 15 years.Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates.PCV vaccination in children aged 9–24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes.Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally.
10. Concentration and High Avidity of Pneumococcal Antibodies Persist at Least 4 Years after Immunization with Pneumococcal Conjugate Vaccine in InfancyNina Ekström, Heidi Åhman,* Arto Palmu, Sinikka Grönholm, Terhi Kilpi, Helena Käyhty, for The FinOM Study Group National Institute for Health and Welfare (THL), Helsinki, Finland Journals ASM.org 2013: 20 (7) 1034Finnish Otitis Media (FinOM) Vaccine Trial was conducted.Children with complete follow-up in the FinOM trial up to 24 months of age were invited to a single visit in their fifth year of life.Children had been vaccinated at 2, 4, 6, and 12 months of age with 7-valent pneumococcal capsular polysaccharide, CRM197 conjugate vaccine (PCV7), or a control vaccine.Serum IgG antibody concentrations to vaccine serotypes remainedsignificantly higher in children who had received PCV7 than in control children for 4 years after the fourth PCV7 dose.Four doses of PCV7 given in infancy elicit long-lasting antibody responses with high avidity.
11. 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 (< 5years age) 1980 – 2007. Johnson et al 2010
12. Pneumococcal Conjugate Vaccines (PCV)Capsular polysaccharide + CRM197 = PCV1. 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.
13. PCV HISTORY 2002 PCV available, recommended for at risk groups under 2 years in UK2003 PCV recommended for > 65 years old in UK2004 PCV for at risk children under 5 years of age in UK2006 PCV added to routine childhood immunization program in UK2014 PCV Nigeria adopted pneumococcal vaccination nationally
14. 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
15. 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.
16. EXPERT COMMITTEE RECOMMENDATION PCV 13 VACCINATION IN NIGERIA Routine immunization of children in Nigeria in a three or four dosage schedule at 6 weeks to 5 years of age Vulnerable population such as sickle cell disease patients at any age HIV infected children and adultsElderly people aged 65 years and aboveOther major disease conditions such as malignancies, renal failure, nephrotic syndrome, liver cirrhosis, diabetes mellitus, alcoholism and chronic lung diseases
17. AFRICA: ANTIBIOTIC RESISTANCE OF 375 Isolates of Strep. 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 69.9Intermediate 18.1 8.2 53.1 34.5 25.6Resistant 4.3 1 8.6 6.9 4.8Amoxicillin 3.6 1 3.7 8.6 3.7Cefotaxime-ceftriaxone 8.8 1 15 3.6 7.3Chloramphenicol 11 2 14.8 5.2 8.6
18. CONTINUED Erythromycin 52.6 4.1 11.4 32.8 28Tetracycline 67.5 12.2 29 34.5 38.3Rifampicin 5.8 0 0 0 2.1Cotrimoxazole 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
19. Streptococcus pneumoniae is a gram positive diplococcusSee Capsule
20. FOUR MAJOR VIRULENCE FACTORSCapsular polysaccharides – Antiphagocytic and Anti-complementPneumolysin – Inhibits lymphocyte proliferation and neutrophil chemotaxis etc.IgA1 protease – Cleaves submucosal IgAAutolysin – breaks down peptidoglycan of cell wall to aid release of pneumolysin
21. STREPTOCOCCUS PNEUMONIAE STRUCTURE
22. PNEUMOCOCCAL SEROTYPES IN ZARIA, NORTHERN NIGERIAST1234591011121517181921232541454648TMN23310212222111151PN20412210113541142170PP11CJ2114PID112BC83611120T53728218111413741335321KEYST=SEROTYPES, MN=MENINGITIS, PN= PNEUMONIA, PP=PRIMARY PERITONITS, CJ=PRIMARY CONJUCTIVITIS, PID= PELVIC INFLAMATORY DISEASE, BC= BACTEREMIA/ANTIGENEMIA, T=TOTAL
23. DISRIBUTION OF SEROTYPES IN CHILDREN UNDER 12 YEARS (NUMBER OF CASES - 40) SEROTYPE%147.5317.52, 46 , 58.3 each482.5232.5412.5122.5
24. MORTALITY RELATED TO SEROTYPES IN ADULTS AND CHILDRENSerotypeMeningitisCase Fatality (%)PneumoniaCase Fatality (%)123482020310501241.6525010202525011004511002100*G.C. ONYEMELUKWE AND B.M. GREENWOOD JOURNAL OF INFECTION (1982) 5, 157-163
25. CONDITIONS ASSOCIATED WITH PNEUMOCOCCAL DISEASEYOUNG AGEMEASLES – 15 (CHILDREN )SICKLE CELL DISEASE (3 CHILDREN)PREGNANT WOMEN (6 ADULTS)CIRRHOSIS (2 ADULTS)PERIPARTUM HEART FAILURE (1 ADULT)*G.C. ONYEMELUKWE AND B.M. GREENWOODJOURNAL OF INFECTION (1982) 5, 157-163
26. AGES OF SEROTYPED PNEUMOCOCCAL MENINGITIS PATIENTSTwo year study of pneumococcal meningitis with 39% mortality50% : under 10 years32.5% : 1- 10 years17.6% : < 1 year2.65% < 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
27. 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 cases481 (49.8%)- Meningitis399 (33%) – Pneumonia330 (27.2%) – Bacteremia11 out of 23 Streptococcus pneumonia isolates were typedType 4 – 3 casesType 5 – 5 casesType 19 F- 3 cases
28. Epidemic of Pneumococcal meningitis in 2014 in Ghana due to serotype IPneumococci are not usually considered to be cause of meningitis epidemicImplications of this unusual epidemic for the region Pneumococcal serotype I epidemic – (Greenwood in Editorial - Ghana and Burkina Faso)Leimkugel J et al., An outbreak of serotype I Streptococcus pneumoniae meningitis in northern Ghana with features that are characteristic of Neisseria meningitidis epidemics. J Infect Dis 2005; 192:192-9
29. The Meningitis Belt in Sub-Saharan Africa
30. Important meningococcal serogroups, capsular structures, operon composition and geographical prevalence
31. EPIDEMIC CYCLES AND SEROGROUPS3 – 5 -7 years cycles of epidemics of Meningococcal meningitis in the meningitis belt of LAPEYSONNIE normally in the dry season of December to June.Serotypes A, C, W135, Serotype X in Northern Ghana Gagneux S et al., J Infect Dis 2002; 185:618-26In 2002 major epidemic of W135 epidemic occurred in Burkina Faso (Decosas J. et al., Chronicle of an outbreak foretold: meningococcal meningitis W135 in Burkina Faso. Lancet Infect Dis 2002; 2:763-5)
32. EVADING THE IMMUNE SYSTEM Meningococcal Capsule. LPS and the meningococcal capsule (CP) are the two major virulence factors of N. meningitidis. Specifically, the capsule displays a large variability of surface antigens, on the basis of which 13 different N. meningitidis serogroups have been identified.During the first phase of infection, meningococcus has to avoid the surface defences of the nasopharynxProduce abundant OM vesicles (OMVs), thus managing to hide its surface antigens and to deflect the action of the surface defences from the bacterial cell.Major and Minor Adhesion Mechanisms of N. meningitidis. N. meningitidis possesses a multifaceted system of adhesins, such as pili and other systems of adhesion (i.e., opacity-associated proteins OpA and OpC).
33. EVADING THE IMMUNE SYSTEM Cont.N. meningitidis: Avoidance Mechanisms against Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), and Antimicrobial Peptides (AMPs). When in contact with the mucosa of the nasopharynx, N. meningitidis can implement several strategies of adhesion, but it must overcome many barriers of innate immunity.Another interesting mechanism is the strategy whereby N. meningitidis escapes the attempts of the host to sequester nutrients essential for growth and survival of the pathogen. This process has been termed “nutritional immunity”The microbe is endowed with OM receptors (such as HmbR,HpuA orHpuB, TbpA or TbpB, and TdfF) for acquiring iron and other important metals
34. EVADING THE IMMUNE SYSTEM Cont.How Meningococcus Circumvents the Complement System the classic pathway, the alternative pathway, andthe lectin pathwayFactor H recognizes host associated molecular patterns (HAMPs).Meningococci produce three different variants (1, 2, and 3) of a protein that binds factor H.Other Immunoescape Strategies. Temperature fluctuation plays an important, although underscored, role in microbial pathogenesis, colonization, invasion, and host evasion
35. WHO | Rapidly growing outbreak of meningococcal disease in NigerRapidly growing outbreak ofmeningococcal disease in NigerThis is the first large‐scale meningitis outbreak caused by Neisseria meningitides serogroup C to hit any country in Africa’s meningitis belt.Serogroup C in the affected areas, with Nm serogroup W also being identified in several patient samples. Although serogroup C has been the predominant cause of meningitis in wealthy countries, it has never been of high concern in Africa.Over the past 40 years, serogroup C has caused only sporadic cases and a few localized outbreaks in Africa, generally of mixed serogroup A and C origin. These outbreaks occurred in Nigeria in 1975, in Niger in 1991, and in Nigeria in 2013–2014.
36.
37. FACTORS THAT ENHANCE ADHESION, INVASION, ANTICOMPLIMENT CAPACITY AND SPREAD
38. SICKLE CELL ANEMIA
39. GENETICS1989 (Adeyanju) 5 million born 900,000 SSNational survey 25% AS (1978, 2013)HbSS disease or sickle cell anemia (the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survivalHbS/b-0 thalassemia - Double heterozygote for HbS and b-0 thalassemia; clinically indistinguishable from sickle cell anemia (SCA)HbS/b+ thalassemia - Mild-to-moderate severity with variability in different ethnicitiesHbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severityHbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotypeHbS/HbE syndrome - Very rare with a phenotype usually similar to HbS/b+ thalassemiaRare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia, HbO Arab, and others
40. INFECTIONLower serum immunoglobulin M (IgM) levels, Impaired opsonization, and Sluggish alternative complement pathway activation Tuftsin deficiency Functional anatomic asplenia including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli. Parvovirus B19 infection causes aplastic crises.
41. REFERENCESOnyemelukwe GC, Greenwood BM. Pneumococcal serotypes, epidemiological factors and vaccine strategy in Nigerian Patients. Journal of Infection (1982) 5, 157-163.Onyemelukwe GC. Polymorph function, complement and immunoglobulins in Nigerian patients with pneumococcal infections. Journal of Infection (1983) 7, 118-124Taqi AM, Onyemelukwe GC. Serotypes and pneumococcal meningitis in Nigerian Children. East African Medical Journal of Infection. (1986) 63 (1), 42-47Onyemelukwe GC,Leinoen, M MakelaH, Greenwood BM. Response to pneumococcal vaccination in normal and post-infected Nigerians. J Infect. 1985 Sep;11(2):139-44.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.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.
42. REFERENCES cont.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.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: 1239-46Traore 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
43. 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: 812-22Johnson 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 References cont.