Influence of sequence variability on bactericidal activity sera induced by Factor H binding protein variant 1.1

Factor H binding protein (fHbp), one of the main antigens of new vaccines against serogroup B meningococcus, varies in amino acid sequence and level of expression in different clinical isolates. To evaluate the contribution of amino acid sequence variability to vaccine coverage, we constructed a strain that is susceptible to bactericidal killing only by anti-fHbp antibodies and engineered it to express equal levels of 10 different fHbp sub-variants from a constitutive promoter. Testing of these isogenic strains showed that sera from mice or adult volunteers vaccinated with fHbp variant 1.1 were bactericidal against all sub-variants 1 sequences, however the titer against the most distant sequences were several times lower. Sera from vaccinated infants were more susceptible to amino acid variations and they had lower or no bactericidal activity against the distant sub-variants 1 sequences in comparison with sera from adults given the same vaccines. The low coverage provided by fHbp could be overcome using a multicomponent vaccine. We conclude that fHbp is a very important antigen that induces bactericidal antibodies in animals, adults and infants. However, given its high variability of sequence and expression level, it is unlikely that fHbp alone can provide good protection in infants against the distant amino acid sequence variants and therefore multicomponent vaccines inducing protective immunity also against other antigens are more likely to induce a broad protective immunity in all age groups.