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MLT_GIB/OTH/0007/17m
Date of preparation: March 2018

Bexsero: The first vaccine designed using reverse vaccinology 1-3

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This novel approach was necessary to overcome challenges linked to traditional vaccines. 3

  • Capsular vaccines have proven poorly immunogenic due to the structural homology between the B polysaccharide and human tissue leading to immunological tolerance. 4,5
  • Outer Membrane Vesicle-based Vaccines have proven immunogenic and effective for a single serogroup B strain 6,7and therefore limited in the ability to help protect against different meningococcal serogroup B strains. 3

Reverse vaccinology explained: 3,8-11

Reverse vaccinology

The illustration above has been independently created by GSK 3,8-11

  • The N.meningitidis serogroup B genome had previously been sequenced in full. 1
  • From this sequence, 2158 open reading frames were identified.. 1 570 proteins that were likely to induce bactericidal antibodies were identified using bioinformatics. 1,10
  • 350 of these open reading frames were cloned in an E.coli expression system. These recombinant proteins were purified and used to immunize mice. 1,10
  • These 350 proteins, were then assayed where 91 proteins were identified to either be expressed on the cell surface or have serum bactericidal activity. 1,10
  • Of these 91 proteins, 28 were able to actually induce antigens with bactericidal activity against multiple MenB strains. 1,10
  • The 3 most immunogenic antigens NHBA, fHbp, and NadA were selected as well as the Porin protein, PorA, to be part of the composition of the Bexsero vaccine. 1,11

Bexsero Mechanism of Action

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Bexsero is an innovative vaccine developed to achieve a robust immune response across age groups against a range of diverse MenB strains. 12

Bexsero uniquely targets 4 distinct antigens—fHbp, NadA, PorA P1.4, and NHBA which together may help protect against MenB strains which are highly variable in the types and amounts of antigens they express. 11,13-16

By targeting 4 distinct antigens, BEXSERO offers the potential to protect against invasive MenB strains, even when the expression of 1 component is low or antigenically different. 11,14-17

This multiple-antigen approach in BEXSERO may provide synergistic killing, improve strain coverage, and insure against mutations of individual target proteins. 18

* MeNZB was developed by Chiron Vaccines in association with the Norwegian Institute of Public Health 19

The four immunogenic components of Bexsero are: 11

Antigens

References:

  1. Del Tordello E and Serruto D. Brief Funct Genomics. 2013;12:328–340.
  2. Seib KL,Zhao X, Rappuoli R, Clin. Microb.and Infec. 2012;18:109-116.
  3. Giuliani MM, et al. PNAS. 2006;103:10834–10839.
  4. Finne J, et al. J Immunol. 1987;138:4402-4407.
  5. Wyle FA, et al. J Infect Dis. 1972;126:514-521.
  6. Sadarangani M, et al. Lancet Infect Dis. 2010;10:112-124;
  7. Tan LK, et al. N Engl J Med. 2010;362:1511-1520;
  8. Serruto D, et al. J Biotechnol. 2004;113:15-32;
  9. Tettelin H, et al. Science. 2000;287:1809-1815;
  10. Pizza et al, Science. 2000;287:1816-1820.
  11. BEXSERO Summary of Product Characteristics.
  12. Donnelly. Donnelly PNAS 2010, Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines; 1-6.
  13. Bai X et al. Expert Opin Biol Ther 2011;11(7):969–985.
  14. Biagini M, Spinsanti M, De Angelis G, et al. Expression of factor H binding protein in meningococcal strains can vary at least 15-fold and is genetically determined. Proc Natl Acad Sci USA. 2016;113:2714-2719.
  15. Livorsi DJ, Stenehjem E, Stephens DS. Virulence factors of gram-negative bacteria in sepsis with a focus on Neisseria meningitidis. Contrib Microbiol. 2011;17:31–47.
  16. Hao W, Ma JH, Warren K, et al. Extensive genomic variation within clonal complexes of Neisseria meningitidis. Genome Biol Evol. 2011;3:1406–1418.
  17. Vogel U, Taha M-K, Vasquez JA, et al. Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis. 2013;13:416-425.
  18. Vesikari T, Esposito S, Prymula R, et al; the EU Meningococcal B Infant Vaccine Study Group. Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials. Lancet. 2013;381:825-835.
  19. Martin DR, et al. Clin Vaccine Immunol. 2006;13(4):486–491.
  20. Madico G, Welsch JA, Lewis LA, et al. The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol. 2006;177:501-510.
  21. Schneider MC, Prosser BE, Caesar JJE, et al. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature. 2009;458:890-893.
  22. Comanducci M, Bambini S, Brunelli B, et al. NadA, a novel vaccine candidate of Neisseria meningitidis. J Exp Med. 2002;195:1445-1454.
  23. Capecchi B, Abu-Bobie J, Di Marcello F, et al. Neisseria meningitidis NadA is a new invasin which promotes bacterial adhesion to and penetration into human epithelial cells. Mol Microbiol. 2005;55:687-698.
  24. Mazzon C, Baldani-Guerra B, Cecchini P, et al. IFN-γ and R-848 dependent activation of human monocyte-derived dendritic cells by Neisseria meningitidis adhesin A.J Immunol. 2007;179:3904-3916.
  25. Martin DR, Ruijne N, McCallum L, O’Hallahan J, Oster P. The VR2 epitope on the PorA P1.7-2,4 protein is the major target for the immune response elicited by the strain-specific group B meningococcal vaccine MeNZB. Clin Vaccine Immunol. 2006;13:486- 491.
  26. Serruto D, Spadafina T, Ciucchi L, et al. Neisseria meningitidis GNA2132, a heparin-binding protein that induces protective immunity in humans. Proc Natl Acad Sci USA. 2010;107:3770-3775.

Bexsero is a registered trademark of the GlaxoSmithKline Group of Companies