Although the serogroup B meningcoccal epidemic starting in 1974 in Norway has abated, the need for preparedness to prevent future outbreaks of group B meningococcal disease in Norway or elsewhere (e.g., New Zealand or, more recently, Normandy, France) warrants further studies and development of MenBvac. This was the first study evaluating a regimen with three primary doses of MenBvac followed by a booster dose. It was shown that there was a statistically significant increase in bactericidal antibodies after the third dose compared to the second. Nonetheless, the response to the homologous strain after the booster dose reached SBA levels much higher than after the third dose, and the subsequent decline was slower than after the third dose, resulting in a longer-lasting response, thus indicating an increased duration of protection after the booster dose.
Serum bactericidal antibodies, the functional antibodies measured in this study, are generally accepted as the best surrogate for protection for all serogroups of meningococci. For serogroup B, the proportion of vaccinees with SBA titers of ≥4 has been suggested to correlate to clinical efficacy (4
Following vaccination with OMV vaccines, antibody responses against a wide range of outer membrane proteins (e.g., PorA and PorB porins, reduction modifiable protein [Rmp], OpcA invasin) and lipopolysaccharide (LPS) are induced (11
). The subtype-specific PorA proteins are the most abundant and the immunodominant antigens in OMV vaccines; they are a main target for SBA activity (4
). We have shown here that sera from teenagers vaccinated with MenBvac have similar bactericidal activities against vaccine-type strains and the French strain (LNP20404 [B:14:P1.7,16]), which contains the same PorA antigen as the vaccine strain but differs in the PorB protein. These results indicate that antibodies against PorB do not contribute significantly to the SBA titers, which is in agreement with previous findings (15
). Since PorA is the most important antigen in OMV vaccines, the French strain carrying the same PorA as the vaccine strain might be considered a homologous strain.
Outer membrane proteins other than PorA can, however, also contribute to the bactericidal activity (4
). MenBvac has earlier been shown to induce bactericidal antibodies against several heterologous strains (20
). In this trial we have included more recently isolated strains and shown that MenBvac gives rise to functional antibody responses also to strains currently causing disease and strains responsible for ongoing epidemics, although these strains differ in PorA or PorB. The panel of heterologous strains tested was, however, limited with regard to diversity of subtypes.
The Norwegian isolate N13/99 has an LPS immunotype different from that of the other P1.7-2,4 strains, L8 instead of L3,7 (Table ). The differences between these strains (measured as the proportion of subjects with SBA titers of ≥4) indicate that the immunotype may influence the level of bactericidal activity. Possible differences in the expression of other antigens, e.g., OpcA, may also contribute to the different susceptibilities to bactericidal activity.
The SBA analyses showed an increase in cross-reactive bactericidal antibodies after the third primary dose compared with the second, confirming that a primary immunization schedule of three doses is advantageous. The booster dose resulted in further increased levels of bactericidal antibodies against the heterologous strains tested. At 6 weeks after the booster dose, the percentage of subjects with titers of ≥4 against the tested strains ranged from 21% to 90%. The results indicate that MenBvac gives rise to antibody responses against outer membrane proteins other than PorA and that at least among teenagers, MenBvac may have the potential to protect also against meningococcal group B disease caused by some non-vaccine-type strains. This supports earlier findings from efficacy studies in Norway and Brazil that the protection induced by OMV vaccines is not strictly strain specific (8
). Protection against even more strains could be obtained by combining OMVs from different strains in one vaccine. Further combination with a meningococcal group C conjugate vaccine could confer protection also against group C meningococci (1
The SBA levels observed in this study were lower than those reported from studies with MenBvac conducted during the epidemic in Norway (11
). This may be due to the different epidemiological situation. At the start of this study, the incidence of meningococcal disease in Norway was about 1.7 per 100,000 (12
), much lower than the incidence observed during the epidemic (13
). The change of SBA method from the agar overlay assay to the tilt assay may also contribute to the somewhat lower titers observed in studies analyzed by the tilt method, although the overall results with the two methods are similar (5
). Independently of the number of primary doses administered and the epidemiological situation, a booster dose is of benefit for a long-lasting response.
In accordance with earlier studies with this age group, MenBvac was found to be moderately reactogenic without any safety concerns. Local and systemic reactions are very common for intramuscularly administered aluminum hydroxide-containing vaccines, and therefore MenBvac was expected to have such a profile. The most common adverse reaction was local pain, which is consistent with earlier data (18
). The frequency of some of the reactions was high in the placebo group also. Most of the local and systemic reactions were of mild or moderate intensity. Among those subjects who experienced local reactions of severe intensity after the first vaccine dose, only a few reported local reactions of severe intensity after the subsequent doses. No serious adverse events occurred in the group receiving MenBvac, and the four-dose regimen was found to be safe.
In conclusion, the results from this study demonstrated that MenBvac was safe with an acceptable reactogenicity profile. The immunogenicity profile with the large increase in SBA titers and in the proportion of subjects with titers of ≥4 after the booster dose demonstrates immunological memory and a strong booster response after priming with three doses. Furthermore, the slower decline in antibody response after the booster dose compared with the response after the primary immunization indicates that a booster dose could significantly extend the persistence of serum bactericidal antibodies against the vaccine-type strains as well as that of cross-reactive antibodies against some heterologous strains, presumably resulting in prolonged protection against meningococcal serogroup B disease.