Hyporesponsiveness: Time To Stop Using Meningococcal Polysaccharide Vaccines?

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1 Hyporesponsiveness: Time To Stop Using Meningococcal Polysaccharide Vaccines? Lee H. Harrison, M.D. Professor of Medicine and Epidemiology University of Pittsburgh First Regional Meningococcal Symposium March 19, 2012 Buenos Aires

2 Disclosures Lee H. Harrison, MD Research Funding (to Univ. of Pittsburgh): Sanofi Pasteur SA Consulting Agreements: GlaxoSmithKline, Merck, Novartis Vaccines, Pfizer, Sanofi Pasteur Speakers Bureau/Honorarium Agreements: Sanofi Pasteur and Novartis Vaccines Financial Interests/Stock Ownership: None Discussion of Off-Label, Investigational, or Experimental Drug Use: Investigational meningococcal vaccines

3 Meningococcal polysaccharide and conjugate vaccines: Historical timeline 1940 First meningococcal capsular polysaccharide vaccines developed Poorly immunogenic, probably because of degradation of capsular polysaccharide during purification New method which allowed purification of high molecular-weight capsular polysaccharide Development of monovalent (A and C) polysaccharide vaccines Development of quadrivalent (ACYW135) polysaccharide vaccines Licensure of monovalent C conjugate (MCC) vaccines Licensure of first quadrivalent (ACYW135) conjugate vaccine Licensure of monovalent A conjugate vaccine

4 Polysaccharide vaccine production N. meningitidis Polysaccharide capsule Vaccine

5 Conjugate vaccine production N. meningitidis Vaccine Diphtheria toxoid Tetanus toxoid CRM 197

6 Why are Conjugate Vaccines Better Than Polysaccharide Vaccines? Property Polysaccharide Conjugate T-cell-dependent immune response No Yes Efficacy in infants No Yes Persistence of protection No Yes Immune memory No Yes Reduction of carriage No Yes Herd protection No Yes Booster effect No Yes Hyporesponsiveness Yes No Granoff DM, Pelton SI, Harrison LH. Vaccines. 6th ed, in press

7 % subjects with SBA titres 8 Age-specific immunogenicity of serogroup C component of quadrivalent meningococcal polysaccharide vaccine Pre-vaccination Post-vaccination 6 mths 12 mths 18 mths 2 yrs 3 yrs 4 yrs 5-9 yrs yrs Age Al-Mazrou Y et al. Infect Immun 2005 and Khalil M et al. Clin Diagn Lab Immunol 2005.

8 Polysaccharide vaccines: Antibody kinetics and persistence Antibody levels peak between 2 and 4 weeks following immunization In adults, antibody levels then decline over approximately 3-5 years In contrast, children's antibody levels decline more rapidly To maintain high antibody levels, revaccination required

9 Polysaccharide vaccines: Efficacy, herd protection, and safety Efficacy: Polysaccharide vaccines are efficacious in adults and older children, although efficacy wanes rapidly over time. Not efficacious in infants. Effect on colonization: (herd protection): At best, polysaccharide vaccines provide transient and incomplete protection against nasopharyngeal carriage Safety: Polysaccharide vaccines safe and well tolerated

10 Hyporesponsiveness Antibody response to re-vaccination lower than that of first vaccination For serogroup C, seen in infants, toddlers, adults Can last as long as 4-5 years Polysaccharide vaccine can also impair response to subsequent conjugate vaccine Also seen with W-135 and Y polysaccharide See boosting with serogroup A polysaccharide, atypical for polysaccharide vaccine Clinical significance of hyporesponsiveness unknown! Granoff DM, Harrison LH, and Borrow R. Vaccines. 5th ed.

11 Hyporesponsiveness: Gambian infants challenged at age 19.7 mos (mean) with A/C polysaccharide vaccine relative to previous 2 doses of vaccine in first 6 months of life Leach A et al., J Infect Dis 1997

12 Polysaccharide vaccines: Immunology Lack of production of new memory B cells and depletion of memory B- cell pool, such that subsequent immune responses are decreased. This is due to apoptosis. Pollard et al., Nat Rev 2009 and Brynjolfsson SF et al. J Infect Dis 2012;205:422

13 Conjugate vaccines: Immunology T-cell help for production of both plasma cells and memory B cells Pollard et al., Nat Rev 2009

14 Serogroup C SBA titres following 1 or more doses of meningococcal A/C polysaccharide vaccine in Saudi Arabian adolescents Men C SBA GMTs *P< Pre-vaccination 1 month post- vaccination Naïve One Two or more Previous doses of polysaccharide vaccine Jokhdar H et al. Clin Diag Lab Immunol 2004;11:83-88.

15 Polysaccharide vaccines: Uses Due to immunologic properties of polysaccharide vaccines, not generally used for routine immunization Settings in which conjugate vaccines not licensed/available Used to be frequently used for high-risk populations Travelers Military Laboratory workers Epidemic and outbreak control (reactive vaccination) In populations with high risk of disease Phenomenon of hyporesponsiveness and other limitations has dampened enthusiasm for polysaccharide vaccines

16 Time To Stop Using Meningococcal Polysaccharide Vaccines? YES!* *Unless conjugate vaccines are not available

17 Special Thanks To Ray Borrow

18 Basura

19 Meningococcal serogroup C and W135 immunological hyporesponsiveness in African toddlers Findlow H et al. Clin Vaccine Immunol 2011;18:

20 Group C SBA responses of Gambian children challenged with meningococcal A/C polysaccharide vaccine at 5 years of age Children vaccinated between 2 to 6 months and again at ~19.7 months of age. Conj., Conj. A + C conjugate vaccine at both ages; Conj., IPV, Conjugate vaccine at 2 to 6 months and inactivated polio vaccine at 19.7 months; Conj., PS, Conjugate vaccine at 2 to 6 months and meningococcal polysaccharide at 19.7 months. Group given conjugate vaccine as infants followed by polysaccharide as toddlers lost ability to mount memory response at age 5 years None, nil; Vaccine-naïve control children challenged with A + C polysaccharide vaccine at age 5 years. MacLennan J et al. J Infect Dis 2001;183:

21 Serogroup C SBA GMT (95% CI) Meningococcal serogroup C and W135 immunological hyporesponsiveness in African toddlers Serogroup W135 SBA GMT (95% CI) Serogroup C Serogroup W Pre-Vaccination 28 days postprimary 10mths postprimary 7-days postbooster 28-days postbooster 1 Pre-Vaccination 28 days postprimary 10mths postprimary 7-days postbooster 28-days postbooster Group 1 (No PS-ACW135Y) Group 3 (1 PS-ACW135Y at primary) Group 2 (PS-ACW135Y at booster) Group 4 (2 PS-ACW135Y Findlow H et al. Clin Vaccine Immunol 2011;18: