Immunogenicity and Safety of a Combination of Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines

Sandbu, Synne; Feiring, Berit; Oster, Philipp; Helland, Oddveig S.; Bakke, Hilde; Næss, Lisbeth Meyer; Aase, Audun; Aaberge, Ingeborg S.; Kristoffersen, Anne-Cathrine; Rydland, Kjersti Margrethe; Tilman, Sandrine; Nøkleby, Hanne; Rosenqvist, Einar

doi:10.1128/cvi.00094-07

Cited by 51 publications

(49 citation statements)

References 26 publications

(41 reference statements)

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“…Importantly, preclinical studies in mice have suggested that half the normal antigen dose of each OMV vaccine could elicit similar immune responses compared to full doses when administered in combination (16) and that sequential immunization with heterologous OMV strains could elicit broadly protective serum antibodies (17). The safety profile and immunogenicity of a combined OMV vaccine, consisting of MenBvac and MeNZB (half dose each) adsorbed to aluminum hydroxide, were then tested in a clinical trial design consisting of three primary doses given with 6-week intervals and a fourth booster-dose given 1 year later (18). With respect to antibody responses measured as serum bactericidal activity (SBA), opsonophagocytosis, and enzyme-linked immunosorbent assay (ELISA), the results showed that the immune responses to the combined vaccines were of the same magnitude as the homologous responses observed in control groups receiving individual vaccines (18).…”

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confidence: 99%

“…The safety profile and immunogenicity of a combined OMV vaccine, consisting of MenBvac and MeNZB (half dose each) adsorbed to aluminum hydroxide, were then tested in a clinical trial design consisting of three primary doses given with 6-week intervals and a fourth booster-dose given 1 year later (18). With respect to antibody responses measured as serum bactericidal activity (SBA), opsonophagocytosis, and enzyme-linked immunosorbent assay (ELISA), the results showed that the immune responses to the combined vaccines were of the same magnitude as the homologous responses observed in control groups receiving individual vaccines (18). In addition, the safety profile of the combined vaccine was not different from those previously seen after the administration of separate monovalent vaccines (1,6,9).…”

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confidence: 99%

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Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Oftung

Korsvold

Aase

et al. 2016

Clin Vaccine Immunol

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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 ...

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Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Oftung

Korsvold

Aase

et al. 2016

Clin Vaccine Immunol

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“…In contrast to synthetic particulate systems, these OMV vaccines represent a unique system where the antigen and delivery vehicle together are derived from the Neisseria meningitidis pathogen itself (15,16). The proven safety and efficacy records of these OMV vaccines, particularly in The Netherlands (17) and in Norway (12,18), together with the knowledge that vesicles are produced by nearly all species of Gram-negative bacteria (including Escherichia coli), present the possibility of employing OMVs for the delivery of recombinant protein antigens. To date, however, antigens that are foreign to the parental bacteria remain notably absent from OMVs largely because of challenges associated with the transport of heterologous proteins to the vesicles (19).…”

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Delivery of foreign antigens by engineered outer membrane vesicle vaccines

Chen

Osterrieder

Metzger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

254

247

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As new disease threats arise and existing pathogens grow resistant to conventional interventions, attention increasingly focuses on the development of vaccines to induce protective immune responses. Given their admirable safety records, protein subunit vaccines are attractive for widespread immunization, but their disadvantages include poor immunogenicity and expensive manufacture. We show here that engineered Escherichia coli outer membrane vesicles (OMVs) are an easily purified vaccine-delivery system capable of greatly enhancing the immunogenicity of a low-immunogenicity protein antigen without added adjuvants. Using green-fluorescent protein (GFP) as the model subunit antigen, genetic fusion of GFP with the bacterial hemolysin ClyA resulted in a chimeric protein that elicited strong anti-GFP antibody titers in immunized mice, whereas immunization with GFP alone did not elicit such titers. Harnessing the specific secretion of ClyA to OMVs, the ClyA-GFP fusion was found localized in OMVs, resulting in engineered recombinant OMVs. The anti-GFP humoral response in mice immunized with the engineered OMV formulations was indistinguishable from the response to the purified ClyA-GFP fusion protein alone and equal to purified proteins absorbed to aluminum hydroxide, a standard adjuvant. In a major improvement over current practice, engineered OMVs containing ClyA-GFP were easily isolated by ultracentrifugation, effectively eliminating the need for laborious antigen purification from cell-culture expression systems. With the diverse collection of heterologous proteins that can be functionally localized with OMVs when fused with ClyA, this work signals the possibility of OMVs as a robust and tunable technology platform for a new generation of prophylactic and therapeutic vaccines.protein subunit | adjuvant

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“…In contrast, SBA was strictly dependent on the presence of both C2 and high anti- on May 10, 2018 by guest http://iai.asm.org/ body levels. Consequently, it seems that complement-mediated opsonophagocytosis of meningococci can occur even in the presence of low background levels of antimeningococcal antibodies, while higher levels of antimeningococcal antibodies obtained by immunization are needed for detectable SBA to occur (37). The specificity of antimeningococcal antibodies probably also determines whether opsonphagocytosis or bactericidal effects will be effective (1).…”

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confidence: 99%

Critical Roles of Complement and Antibodies in Host Defense Mechanisms againstNeisseria meningitidisas Revealed by Human Complement Genetic Deficiencies

et al. 2010

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Certain complement defects are associated with an increased propensity to contract Neisseria meningitidis infections. We performed detailed analyses of complement-mediated defense mechanisms against N. meningitidis 44/76 with whole blood and serum from two adult patients who were completely C2 or C5 deficient. The C5-deficient patient and the matched control were also deficient in mannose-binding lectin (MBL). The proliferation of meningococci incubated in freshly drawn whole blood was estimated by CFU and quantitative DNA real-time PCR. The serum bactericidal activity and opsonophagocytic activity by granulocytes were investigated, including heat-inactivated postvaccination sera, to examine the influence of antimeningococcal antibodies. The meningococci proliferated equally in C2-and C5-deficient blood, with a 2 log 10 increase of CFU and 4-to 5-log 10 increase in DNA copies. Proliferation was modestly decreased in reconstituted C2-deficient and control blood. After reconstitution of C5-deficient blood, all meningococci were killed, which is consistent with high antibody titers being present. The opsonophagocytic activity was strictly C2 dependent, appeared with normal serum, and increased with postvaccination serum. Serum bactericidal activity was strictly dependent on C2, C5, and high antibody titers. MBL did not influence any of the parameters observed. Complement-mediated defense against meningococci was thus dependent on the classical pathway. Some opsonophagocytic activity occurred despite low levels of antimeningococcal antibodies but was more efficient with immune sera. Serum bactericidal activity was dependent on C2, C5, and immune sera. MBL did not influence any of the parameters observed.

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Immunogenicity and Safety of a Combination of Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines

Cited by 51 publications

References 26 publications

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Cellular Immune Responses in Humans Induced by Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines Given Separately and in Combination

Delivery of foreign antigens by engineered outer membrane vesicle vaccines

Critical Roles of Complement and Antibodies in Host Defense Mechanisms againstNeisseria meningitidisas Revealed by Human Complement Genetic Deficiencies

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