A Large Portion of Meningococcal Antigen Typing System-Negative Meningococcal Strains from Spain Is Killed by Sera from Adolescents and Infants Immunized with 4CMenB

Abstract

A new vaccine (the 4CMenB 4-component protein vaccine [Bexsero], which includes PorA, factor H-binding protein [fHbp], neisserial heparin-binding antigen [NHBA], and Neisseria adhesin A [NadA]) against serogroup B meningococci has recently been approved for use in people older than age 2 months in Europe, Australia, and Canada. Preapproval clinical efficacy studies are not feasible for invasive meningococcal disease because its incidence is low/very low, and the serum bactericidal antibody (SBA) titer (or the human SBA [hSBA] titer when human complement is used in the assay) has been used as a surrogate marker of protection. However, the hSBA assay cannot be used on a large scale, and therefore, a meningococcal antigen typing system (MATS) was developed. MATS combines conventional PorA genotyping with an enzyme-linked immunosorbent assay (ELISA) that quantifies both the expression and the cross-reactivity of antigenic variants. The assay has been used to evaluate the potential of the 4CMenB meningococcal group B vaccine to cover group B strains in several countries. Some recent data suggest that MATS is a conservative predictor of strain coverage. We used pooled sera from adolescents and infants to test by the hSBA assay 10 meningococcal group B strains isolated in Spain that were negative for the 3 antigens (n ‫؍‬ 9) or that had very low levels of the 3 antigens (n ‫؍‬ 1) by MATS. We found that all strains were killed by sera from adolescents and that 5 of the 10 strains were also killed, although at a low titer, by sera from infants. Our data confirm that MATS underestimates vaccine coverage. In spite of the development of effective conjugate vaccines against meningococci of serogroups A, C, Y, and W over the last 15 years (1) Clinical efficacy studies required for the approval of vaccines are not feasible in the case of invasive meningococcal disease because its incidence is low/very low. For this reason, for the authorization of conjugate vaccines, the use of a surrogate marker of protection as a replacement for the findings of formal efficacy studies has been proposed. The marker used is the serum bactericidal antibody (SBA; or the human SBA [hSBA] when human complement is used in the assay), and SBA assays can be used to measure the ability of serum antibodies to kill a specific meningococcal strain (2). However, due to the diversity of the sequences of the antigens included in this novel vaccine and their different levels of expression, the use of hSBA requires the testing of many serum samples with large panels of isolates to evaluate the bactericidal killing of many different meningococcal strains, making this approach not feasible (3, 4). Therefore, the development of alternative methods that can give information about immunologic recognition, the level of expression of the antigens, and the association of those parameters with killing in the hSBA assay has been critical in this history. As a result, a meningococcal antigen typing system (MATS; which combines conventional PorA genotyping [porA variable...

Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) Index: a Rapid and Accessible Tool that Exploits Genomic Data in Public Health and Clinical Microbiology Applications

“…For Bexsero ® vaccine, MATS studies (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) were identified through literature searches. With the exception of two studies (34,40) that used PBT for fHbp of 0.012, all other antigen RP were assessed against the PBT of 0.021 for fHbp, 0.294 for NHBA, and 0.009 for NadA (18).…”

Recomendações Sobre a Vacina Contra Neisseria meningitidis

“…13 Contudo, dados mais recentes, sugerem que esta técnica é conservadora, correspondendo 70% de cobertura estimada pelo MATS a 88% de atividade bactericida do soro humano. 14,15 No entanto, a cobertura estimada poderá variar ao longo do tempo numa mesma região. 16 A eficácia de Bexsero® foi inferida pela demonstração de indução de anticorpos séricos bactericidas, avaliados pelo human serum bactericidal assay (hSBA), utilizando um conjunto de quatro estirpes de referência de N. meningitidis do grupo B. Ao longo do processo de desenvolvimento da vacina foram realizados vários ensaios clínicos em lactentes com idade superior a 2 meses, adolescentes e adultos para avaliação da imunogenicidade e segurança.…”

Multivalent meningococcal serogroup B vaccines: challenges in predicting protection and measuring effectiveness

“…Correlation between MATS and hSBA is done using pooled serum, which will tend to increase titers and may lack applicability to individuals. Nevertheless, studies conducted to date suggest that MATS may underestimate protection in toddlers and adolescents [106][107][108]. Pooled serum in studies published until now is frequently referred to as 'infant' serum, when the age at sampling is 12 months or older (i.e., toddler serum).…”