MenBvac and MeNZB are safe and efficacious outer membrane vesicle (OMV) vaccines against serogroup B meningococcal disease. Antibody responses have previously been investigated in a clinical trial with these two OMV vaccines given separately (25 g/dose) or in combination (12.5 and 12.5 g/dose) in three doses administered at 6-week intervals. Here, we report the results from analyzing cellular immune responses against MenBvac and MeNZB OMVs in terms of antigen-specific CD4 ؉ T cell proliferation and secretion of cytokines. The proliferative CD4؉ T cell responses to the combined vaccine were of the same magnitude as the homologous responses observed for each individual vaccine. The results also showed cross-reactivity in the sense that both vaccine groups receiving separate vaccines responded to both homologous and heterologous OMV antigen when assayed for antigen-specific cellular proliferation. In addition, a multiplex bead array assay was used to analyze the presence of Th1 and Th2 cytokines in cell culture supernatants. The results showed that gamma interferon, interleukin-4 (IL-4), and IL-10 responses could be detected as a result of vaccination with both the MenBvac and the MeNZB vaccines given separately, as well as when given in combination. With respect to cross-reactivity, the cytokine results paralleled the observations made for proliferation. In conclusion, the results demonstrate that cross-reactive cellular immune responses involving both Th1 and Th2 cytokines can be induced to the same extent by different tailor-made OMV vaccines given either separately or in combination with half the dose of each vaccine. N eisseria meningitidis serogroup B vaccines based on outer membrane vesicles (OMVs) from defined serogroup B strains have been shown to be efficacious to control clonal outbreaks in several countries, including Norway, Cuba, and New Zealand (1-3). The PorA protein is the immunodominant antigen in OMV vaccines and elicits protective immune responses (4). PorA shows large sequence variation between strains, and a limitation of OMV vaccines is that they induce mainly strain-specific antibodies (5), but cross-protective antibodies against other B strains have been observed in small children and adults (3, 5). The OMV vaccine MenBvac was developed based on the B:15:P1.7,16 strain representative of the previous meningococcal epidemic in Norway. Based on several clinical trials, this vaccine has been shown to be safe, immunogenic, and to confer protection against meningococcal B disease (6-9). MenBvac has also recently been used to combat an outbreak of serogroup B disease in France demonstrating that OMV vaccines can be efficient against heterologous B strains provided that they are sufficiently immunologically close (10, 11).A similar meningococcal serogroup B OMV vaccine (MeNZB) based on a different strain (B:4:P1.7-2,4) was developed and introduced in 2004 to control the meningococcal epidemic in New Zealand (12)(13)(14) showing more than 70% effectiveness (3). However, in most geographical regions ...