The Development of a Vaccine Against Meningococcus B Using Reverse Vaccinology

Abstract

The discovery of vaccine antigens through whole genome sequencing (WGS) contrasts with the classical hypothesis-driven laboratory-based analysis of microbes to identify components to elicit protective immunity. This radical change in scientific direction and action in vaccine research is captured in the term reverse vaccinology . The complete genome sequence of an isolate of Neisseria meningitidis serogroup B (MenB) was systematically analyzed to identify proteins predicted to be secreted or exported to the outer membrane. This identified hundreds of genes coding for potential surface-exposed antigens. These were amplified, cloned in expression vectors and used to immunize mice. Antisera against 350 recombinant antigens were obtained and analyzed in a panel of immunological assays from which 28 were selected as potentially protective based on the -antibody dependent, complement mediated- serum bactericidal activity assay. Testing of these candidate vaccine antigens, using a large globally representative strain collection of Neisseria species isolated from cases of disease and carriage, indicated that no single component would be sufficient to induce broad coverage and that a “universal” vaccine should contain multiple antigens. The final choice of antigens to be included was based on cross-protective ability, assayed by serum bactericidal activity and maximum coverage of the extensive antigenic variability of MenB strains. The resulting multivalent vaccine formulation selected consisted of three recombinant antigens (Neisserial Heparin Binding Antigen or NHBA, Factor H binding protein or fHbp and Neisseria Adhesin A or NadA). To improve immunogenicity and potential strain coverage, an outer membrane vesicle component obtained from the epidemic New Zealand strain (OMVNz) was added to the formulation to create a four component vaccine, called 4CMenB. A series of phase 2 and 3 clinical trials were conducted to evaluate safety and tolerability and to estimate the vaccine effectiveness of human immune responses at different ages and how these were affected by various factors including concomitant vaccine use and lot-to-lot consistency. 4CMenB was approved in Europe in 2013 and introduced in the National Immunization Program in the UK starting from September 2015 when the vaccine was offered to all newborns using a 2, 4, and 12 months schedule., The effectiveness against invasive MenB disease measured at 11 months after the study start and 5 months after the second vaccination was 83% and there have been no safety concerns.

Immunogenicity of trimeric autotransporter adhesins and their potential as vaccine targets

“…In general, three types of meningococcal vaccines are available: polysaccharide vaccines, polysaccharide-protein conjugated vaccines and vaccines based on OMPs (developed via reverse vaccinology) [13,103]. In the case of polysaccharide vaccines, bi-, tri-, or tetravalent vaccines exist, of which only the tetravalent vaccine is still available in Europe [103].…”

“…Nevertheless, recently, two proteinbased MenB vaccines were approved and licensed in several countries [105]. In 2013, the four component MenB vaccine 4CMenB (Bexsero ® ), using an OMV and three recombinant proteins [two protein-protein fusions and a single antigen (NadA)] was approved by the European Union (EU) [13,103,108]. Later, the recombinant protein vaccine MenB-FHbp was licensed in the USA (2014) and the EU (2018).…”

“…In 2006, Giuliani et al described a universal vaccine against MenB that makes use of 5 antigens discovered by reverse vaccinology and aluminium hydroxide as an adjuvant [124]. In 2013, the 4CMenB vaccine was approved by the EU, promptly followed by a vaccination campaign in infants in the UK [13,96]. Summarised, NadA and its discovery via reverse vaccinology, its analysis as an essential pathogenicity factor of N. meningitidis, and the further development as a vaccine component serve as a role model to expedite the development of TAA-based vaccines.…”

“…1). In this review, we focus on the immunogenicity and vaccine candidacy of trimeric autotransporter adhesins (TAA) as one particular group of outer membrane proteins (OMPs) of Gram-negative bacteria [12][13][14][15][16][17] Principally, the most important conditions necessary to be an effective vaccine component are (i) the in vivo expression of surface epitopes, (ii) a high strain coverage, and (iii) immunogenicity and induction of a protective immune response in the host [18,19]. In general, bacterial membrane proteins such as TAAs perform numerous important functions in pathogenesis, of which the first interaction with the extracellular environment in the mammalian host is of crucial importance.…”

Transforming vaccine development

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Approaches to transform vaccine development. Approach Benefit Reference Discovery and early development EPI Combined with genomic data can provide meaningful insights for vaccine candidate selection [ 34 ] CHIM Proof of efficacy in humans for fast-tracked decision-making process [ 4 , 6 ] H mAbs Rapid solution for active/passive immunization, tool for antigen discovery [ 11 , 35 ] Animal studies Required to test immunogenicity of vaccine candidates; identifies biomarkers to support further development [ 36 ] Classical serology Well established studies such as neutralization or bactericidal assays, necessary to assess vaccines immunological activity [ 37 ] Systems serology Omics approach to infer new biomarkers that correlates with vaccine efficacy [ 7 , 8 , 9 ] Machine Learning Recognize patterns from a large number of training examples to identify and model vaccine candidates with strong antibody binding and/or high likelihood of cell presentation [ 38 ] Platform technologies Readily adaptable to multiple vaccines, with simplified transfer of technical, regulatory, and manufacturing knowledge [ 39 ] Viral vectors Established approach for several mammalian, insect, and plant vectors; characterized by high immunogenicity and straightforward production [ 39 ...

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