Biology of Neisseria meningitidis: implications for vaccine development Richard Moxon: University of Oxford

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1 Biology of Neisseria meningitidis: implications for vaccine development Richard Moxon: University of Oxford

2 Biology of N.meningitidis infection

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4 Within hours, the disease may progress to shock with multi-organ failure and death

5 Meningococci in peripheral blood (courtesy of P. Brandtzaeg)

6 Molecular model meningococcal LPS molecule courtesy JR Brisson Ex vivo meningococcal bacterium courtesy Per Branzaeg

7 LPS and mortality (n=135) LPS Number Dead % (EU/mL) of patients < > Brandtzaeg et al. J.Clin. Invest. 1992

8 Need for a vaccine!

9 Biology of meningococcus

10 Key molecules in pathogenesis function example adhesin invasin scavenger evasin toxin pilus Opa proteins Fe uptake proteins capsule LPS

11 Possible stages in pathogenesis where a vaccine might act Mucosal and submucosal sites in upper respiratory tract (adhesins and invasins) During dissemination to and within bloodstream (evasins) At target sites of tissue injury (exo- or endotoxins)

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13 Adhesins of N.meningitidis Pili HrpA PilC PorB PilQ NadA Opa Opc LPS fhbp PorA

14 Possible stages in pathogenesis where a vaccine might act Mucosal and submucosal sites in upper respiratory tract During dissemination to and within bloodstream (capsular polysaccharide) At target sites of tissue injury

15 Key role of capsule in mediating reduced Nm killing and opsonophagocytosis Capsule inhibits complement (C ) and antibody mediated killing Role of complement underscored by observations in humans with C deficiency and the strong correlates of serum bactericidal killing as a proxy of protection GWA studies identify human factor H polymorphisms in susceptibility to Nm disease

16 meningococcal capsular polysaccharides A B C Y W135 N-acetyl mannosamine-1-phosphate α2-8 N-acetyl neuraminic acid α2-9 N-acetyl neuraminic acid Co-polymer of NANA with glucose Co-polymer of NANA with galactose

17 Biology of capsular polysaccharides Are there biological differences in commensal and virulence behaviour that are attributable to the different capsular polysaccharides of Nm? What is the role of capsule in carriage and transmission and is it different for the distinct capsular polysaccharides?

18 N is total tested strains. Other includes other serogroups and non groupable strains * Provisional data Canada 2003 Worldwide distribution of meningococci Source: E Muros-Le Rouzic et al. Meningitis Research Foundation Conference 2005, London, Nov 2005.

19 Capsular polysaccharide 1 Major virulence factor and antibodies to capsular antigen are protective Each capsule is a stable structure although there are several distinct antigens A, B, C etc Using glycoconjugates, major progress has been achieved towards prevention of invasive Nm diseases

20 BUT Capsular polysaccharide 2 Variations in prevalence over time and in different geographical regions Vaccine selection pressure may drive serotype replacement Capsule switching

21 Clone complex Association of clone complexes with carriage, disease and serogroup No. of isolates Disease Carriage B C Y W135 * including 1 serogroup A ** including 2 serogroup A No. of isolates of serogroup: Other or not serogroupable ST ST ST ST * ST ** ST ST-41/ Yazdankhah et al. J. Clin. Microb. 2004

22 Serogroup B capsular antigen is a poor immunogen and a self-antigen

23 MenB capsular polysaccharide is a self antigen

24 The new era of meningococcal vaccines The biological rationale for Nm vaccines changes It is no longer a capsule (serogroup) world! Diversity of candidate antigens is a major challenge

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26 Outer Membrane Vesicle (OMV) Vaccines obtained by detergent extraction of whole bacteria SDS PAGE of OMV Vaccine blebbing meningococcus extracted OMV vesicles purified LPS-depleted OMV

27 loop 1 outer membrane PorA a basis for sub-typing based on allelic variation loop 4 hypervariable regions porin protein

28 OMV vaccine has been successful in New Zealand

29 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Number of cases % 90% 80% 70% % dose 3 coverage Start of vaccination campaign 50% dose 3 coverage 85% dose 3 coverage 0, 1 or 2 doses 3 or more doses % dose 3 coverage 60% 50% 40% 30% 20% 10% 0%

30 LPS Porin Lipoprotein Membrane proteins pilus capsule outer membrane peptidoglycan cell wall cytoplasmic membrane A B C Y W135 AJ Pollard

31 Targeting PorA exemplifies the challenge of new generation Nm vaccines o o o Phase variation, allelic diversity Vaccine selection pressure Replacement, switching

32 The surface located molecules of N. meningitidis display antigenic variability For an individual strain Phase variation Gene conversion Variable transcription and post-translation modification Between strains Allelic variation

33 Multiple Mechanisms of Phase Variation of PorA VAN DER ENDE et al. INFECTION AND IMMUNITY

34 N N N Five-Antigen Recombinant Protein MenB Vaccine GNA 2091 GNA 2132 NadA Giuliani et al, PNAS 2006 fhbp GNA 1030 C Antigen elicits SBA Accessory Antigen C C

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36 Carriage and transmission o Duration of carriage (often weeks, months) o Nm must adapt: strategy is to diversify and to sequester in sub-mucosal tissues of upper respiratory tract o Potential for invasion and systemic disease -- but this is a rare event!

37 Sim, Harrison, Moxon and Tang. Lancet. 2000

38 Where do meningococci reside in the human nasopharynx? NP lumen submucosal tissues

39 Dynamic transition between lumen and submucosa selects for high frequency reversible phenotypic variation NP lumen submucosal tissues

40 Carriage and transmission o Duration of carriage (often weeks, months) o Adaptive biology intra-strain and inter-strain variations in surface molecules o Penetration into sub-mucosal tissues occasionally results in invasive disease

41 The challenges Selection of candidate antigens must take into account variations in the natural population of N.meningitidis Future studies must index variations occurring over time and in differing geographical contexts. Importance of herd immunity a two-edged sword

42 Theodosius Dobzhansky Nothing in biology makes sense, except in the light of evolution

43 Summary Severity and rapidity of invasive meningococcal diseases argue powerfully for vaccines Clinical observations have provided pivotal biological insights into vaccine development Spectacular progress has been made in the prevention of invasive Nm disease through glycoconjugates Non-capsule based vaccines present a challenge because of the extent of antigenic variation