Human B- and T-cell responses after immunization with a hexavalent PorA meningococcal outer membrane vesicle vaccine

Abstract

The PorA protein from Neisseria meningitidis, a potential vaccine candidate, induces human bactericidal antibodies which are serosubtype specific. We developed a hexavalent PorA outer membrane vesicle vaccine based on reference strain H44/76. This vaccine contains the six most prevalent PorA serosubtypes as found in many countries. We previously reported on the immune responses of 20 adult volunteers after a single immunization with this vaccine. In this study, the Band T-cell responses in three adult volunteers were studied after three consecutive immunizations (0, 2, and 11 months). The first immunization induced a strong B-cell response resulting in high immunoglobulin G levels in an outer membrane vesicle enzyme-linked immunosorbent assay. At least a fourfold increase in bactericidal activity was observed against the majority (four to six) of the vaccine antigens compared to prevaccination titers. Immunodominance was observed for one or two of the PorAs in the bactericidal assay with a set of six isogenic H44/76-derived PorA target strains. These strains carry the individual PorAs as present in the vaccine. The second and third immunizations did not induce a further increase in the immune responses. A decline in time with respect to PorA-specific antibodies was observed after each immunization. These observations were reflected by the T-cell proliferation responses. Two additional sets of isogenic H44/76-derived mutant strains were used to study the specificity and/or cross-reactivity of the induced bactericidal antibodies. These target strains differ only in expressing mutant family variants of either PorA P1.7,16 or P1.5,10, both present in the PorA vesicle vaccine. The bactericidal antibody responses found were directed predominantly against the P1.7 (loop 1 of P1.7,16) and the P1.10 (loop 4 of P1.5,10) epitopes. This indicates that different portions of PorA were involved in the induction of bactericidal antibodies depending upon the PorA serosubtype.

Cellular Immune Responses toNeisseria meningitidisin Children

“…In adults, T-cell proliferative responses occur following vaccination with OMV vaccines. Three adults immunized with the Dutch hexavalent PorA meningococcal OMV vaccine showed transiently increased in vitro PBMC proliferative responses and a rise in bactericidal antibody titers (49). Ten adult volunteers with low levels of meningococcal antibody given three doses of the Norwegian serogroup B meningococcal OMV vaccine developed strong primary and booster T-cell responses to both OMV and purified PorA OMP and a lesser response to PorB protein, although immune responses were higher after the second dose than after the third dose (41).…”

Antigenic Variation of the Class I Outer Membrane Protein in Hyperendemic Neisseria meningitidis Strains in The Netherlands

“…Therefore, there will be less selection for changes in the top of the epitope-encoding loop, and thus fewer variants will be found. Interestingly, in a vaccine trial with an hexavalent outer membrane vesicle vaccine containing both P1.10 and P1.4, stronger responses to P1.10 than to P1.4 were found (19). It may be that a reduced antibody response against the P1.4 epitope plays a role in the rise of meningococcal disease due to lineage III strains.…”

Human Opsonins Induced during Meningococcal Disease Recognize Outer Membrane Proteins PorA and PorB

“…Low levels of anti-OMV opsonic antibodies prior to infection may accordingly explain the occurrence of vaccine failures among the included patients. The finding of a suboptimal protective efficacy of 57% during a 29-month observation period (5) has intensified investigations concerning the OMV immunization scheme and routes and the search for the protective antigens for inclusion in improved vaccines (3,4,11,19,29,31,34,41,42,45,48).…”