Persisting Immune Responses Indicating Long-Term Protection after Booster Dose with Meningococcal Group B Outer Membrane Vesicle Vaccine

ABSTRACT MenBvac is an outer membrane vesicle vaccine against systemic meningococcal disease caused by serogroup B Neisseria meningitidis. In this placebo-controlled double-blind study including 374 healthy adolescents, the safety and immunogenicity of a schedule of three primary doses 6 weeks apart followed by a fourth dose a year later were evaluated. Antibody responses to the vaccine strain and heterologous strains (non-vaccine-type strains) and the persistence of these antibodies were measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay up to 1 year after the last dose. The proportion of subjects with SBA titers of ≥4 against the vaccine strain increased from 3% prevaccination to 65% after the third dose. Ten months later, this proportion had declined to 28%. The fourth dose induced a booster response demonstrated by 93% of subjects achieving a titer of ≥4. One year after the booster dose, 64% still showed SBA titers of ≥4. Cross-reacting antibodies were induced against all heterologous strains tested, although the magnitude of SBA titers differed widely between the different strains. All four doses of MenBvac were safe. Both MenBvac and the placebo had reactogenicity profiles of mild to moderate local and systemic reactions. Pain, the most common reaction, was reported with similar frequencies in both groups. No serious adverse events occurred in the MenBvac group. This study confirmed the good immunogenicity of the primary course of MenBvac and demonstrated prolonged persistence and increased cross-reactivity of functional antibodies elicited by a booster dose.

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Combined Administration of Meningococcal Serogroup B Outer Membrane Vesicle Vaccine and Conjugated Serogroup C Vaccine Indicated for Prevention of Meningococcal Disease Is Safe and Immunogenic

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.12.5.599-605.2005 ◽

2005 ◽

Vol 12 (5) ◽

pp. 599-605 ◽

Cited By ~ 5

Author(s):

Ingeborg S. Aaberge ◽

Philipp Oster ◽

Oddveig S. Helland ◽

Anne-Cathrine Kristoffersen ◽

Ellen Ypma ◽

...

Keyword(s):

Immune Responses ◽

Outer Membrane ◽

Meningococcal Disease ◽

Membrane Vesicle ◽

Enzyme Linked Immunosorbent Assay ◽

Outer Membrane Vesicle ◽

Active Components ◽

Serious Adverse Events ◽

Group B ◽

Combined Vaccine

ABSTRACT MenBvac and Menjugate are safe and efficacious vaccines. The purpose of this study was to evaluate safety and immunogenicity of the combination (MenB/C) of the lyophilized active components of the conjugated group C vaccine Menjugate when reconstituted with the full liquid group B outer membrane vesicle vaccine MenBvac compared to MenBvac and Menjugate given separately. At 6-week intervals, healthy adults were given one dose of MenB/C followed by two doses of MenBvac (MenB/C group), three doses of MenBvac (MenB group), or one dose of Menjugate and two doses of placebo (MenC group). Injection site reactions were frequent in all groups. However, most reactions were short lasting and mild or moderate in intensity, and the vaccines were found to be well tolerated, with no vaccine-related serious adverse events. MenB/C was immunogenic with regard to both serogroup B and C meningococci. Both the serum bactericidal assay and the enzyme-linked immunosorbent assay analyses showed that the immune responses of the combination vaccine were similar to the immune responses of its separate components MenBvac and Menjugate for both serogroup B and C. In conclusion, the combined MenB/C vaccine is safe and immunogenic. The two vaccines do not interact negatively with each other and can easily be administered in the same syringe. The induced immune responses suggest that the combined vaccine is likely to confer protection against systemic group B disease caused by the vaccine strain as well as against group C meningococcal disease.

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Comparison and Correlation of Neisseria meningitidis Serogroup B Immunologic Assay Results and Human Antibody Responses following Three Doses of the Norwegian Meningococcal Outer Membrane Vesicle Vaccine MenBvac

Infection and Immunity ◽

10.1128/iai.00466-06 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4557-4565 ◽

Cited By ~ 41

Author(s):

Jamie Findlow ◽

Stephen Taylor ◽

Audun Aase ◽

Rachel Horton ◽

Robert Heyderman ◽

...

Keyword(s):

Neisseria Meningitidis ◽

Outer Membrane ◽

Membrane Vesicle ◽

Enzyme Linked Immunosorbent Assay ◽

Human Antibody ◽

Outer Membrane Vesicle ◽

Phagocytic Cells ◽

Bactericidal Antibody ◽

Antibody Elisa ◽

Immunologic Assays

ABSTRACT The prediction of efficacy of Neisseria meningitidis serogroup B (MenB) vaccines is currently hindered due to the lack of an appropriate correlate of protection. For outer membrane vesicle (OMV) vaccines, immunogenicity has primarily been determined by the serum bactericidal antibody (SBA) assay and OMV enzyme-linked immunosorbent assay (ELISA). However, the opsonophagocytic assay (OPA), surface labeling assay, whole blood assay (WBA), and salivary antibody ELISA have been developed although correlation with protection is presently undetermined. Therefore, the aim of the study was to investigate further the usefulness of, and relationships between, MenB immunologic assays. A phase II trial of the OMV vaccine, MenBvac, with proven efficacy was initiated to compare immunologic assays incorporating the vaccine and six heterologous strains. Correlations were achieved between the SBA assay, OMV ELISA, and OPA using human polymorphonuclear leukocytes and human complement but not between an OPA using HL60 phagocytic cells and baby rabbit complement. Correlations between the surface labeling assay, the SBA assay, and the OMV ELISA were promising, although target strain dependent. Correlations between the salivary antibody ELISA and other assays were poor. Correlations to the WBA were prevented since many samples had results greater than the range of the assay. The study confirmed the immunogenicity and benefit of a third dose of MenBvac against the homologous vaccine strain using a variety of immunologic assays. These results emphasize the need for standardized methodologies that would allow a more robust comparison of assays between laboratories and promote their further evaluation as correlates of protection against MenB disease.

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Antibody Avidity and Immunoglobulin G Isotype Distribution following Immunization with a Monovalent Meningococcal B Outer Membrane Vesicle Vaccine

Infection and Immunity ◽

10.1128/iai.70.2.584-590.2002 ◽

2002 ◽

Vol 70 (2) ◽

pp. 584-590 ◽

Cited By ~ 55

Author(s):

C. L. Vermont ◽

H. H. van Dijken ◽

C. J. P. van Limpt ◽

R. de Groot ◽

L. van Alphen ◽

...

Keyword(s):

Outer Membrane ◽

Immunoglobulin G ◽

Protective Immunity ◽

Membrane Vesicle ◽

Booster Vaccination ◽

Phase Iii ◽

Enzyme Linked Immunosorbent Assay ◽

Outer Membrane Vesicle ◽

Before And After ◽

Avidity Maturation

ABSTRACT The avidity maturation and immunoglobulin G (IgG) isotype distribution of antibodies after vaccination with a meningococcal B outer membrane vesicle (OMV) vaccine were evaluated as indicators of protective immunity. Pre- and postvaccination sera from 134 healthy toddlers (ages, 2 to 3 years) immunized with a monovalent meningococcal B OMV (serosubtype P1.7-2,4) vaccine adsorbed with AlPO4 or Al(OH)3 were analyzed by enzyme-linked immunosorbent assay (ELISA) methods. The children were vaccinated three times with intervals of 3 to 6 weeks between vaccinations or twice with an interval of 6 to 10 weeks between vaccinations. A booster was given after 20 to 40 weeks. The avidity index (AI) of antibodies increased significantly during the primary series of vaccinations and after the booster was given. No differences in AIs were found when the results obtained with the two vaccination schedules or with the two adjuvants were compared. After vaccination, IgG1 was the predominant IgG isotype, followed by IgG3. No IgG2 or IgG4 was detected. There was a strong correlation between serum bactericidal activity (SBA) and ELISA titers (r = 0.85 [P < 0.0001] for total IgG, r = 0.83 for IgG1 [P < 0.0001], r = 0.82 for IgG3 [P < 0.0001], and r = 0.84 [P < 0.0001] for the avidity titer). When two subgroups with similar anti-OMV IgG levels were compared before and after the booster vaccination, the higher AI after the booster vaccination was associated with significantly increased SBA. We concluded that avidity maturation occurs after vaccination with a monovalent meningococcal B OMV vaccine, especially after boosting, as indicated by a significant increase in the AI. Vaccination with the monovalent OMV vaccine induced mainly IgG1 and IgG3 isotypes, which are considered to be most important for protection against meningococcal disease. An increase in the AI of antibodies is associated with increased SBA, independent of the level of specific IgG and the IgG isotype distribution. Measuring the AI and IgG isotype distribution of antibodies after vaccination can be a supplementary method for predicting protective immunity for evaluation in future phase III trials with meningococcal serogroup B vaccines.

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Functional and Specific Antibody Responses in Adult Volunteers in New Zealand Who Were Given One of Two Different Meningococcal Serogroup B Outer Membrane Vesicle Vaccines

Clinical and Vaccine Immunology ◽

10.1128/cvi.00039-07 ◽

2007 ◽

Vol 14 (7) ◽

pp. 830-838 ◽

Cited By ~ 37

Author(s):

E. Wedege ◽

K. Bolstad ◽

A. Aase ◽

T. K. Herstad ◽

L. McCallum ◽

...

Keyword(s):

Flow Cytometry ◽

New Zealand ◽

Outer Membrane ◽

Membrane Vesicle ◽

Serum Antibody ◽

Enzyme Linked Immunosorbent Assay ◽

Outer Membrane Vesicle ◽

Igg Binding ◽

Antibody Levels ◽

Adult Volunteers

ABSTRACT This study presents detailed analyses of total and specific serum antibody levels among 26 and 24 adult volunteers before vaccination and after the third dose of the meningococcal serogroup B outer membrane vesicle (OMV) vaccines MeNZB and MenBvac, respectively, in a clinical trial in New Zealand (V. Thornton, D. Lennon, K. Rasanathan, J. O'Hallahan, P. Oster, J. Stewart, S. Tilman, I. Aaberge, B. Feiring, H. Nokleby, E. Rosenqvist, K. White, S. Reid, K. Mulholland, M. J. Wakefield, and D. Martin, Vaccine 24:1395-1400, 2006). With the homologous vaccine strains as targets, both vaccines induced significant increases in serum bactericidal and opsonophagocytic activities and in the levels of immunoglobulin G (IgG) to OMV antigens in an enzyme-linked immunosorbent assay (ELISA) and to live meningococci by flow cytometry. They also induced high levels of activity against the heterologous strains, particularly in terms of opsonophagocytic activity and IgG binding to live bacteria. The antibody levels with the homologous and heterologous strains in the four assays showed high and significant positive correlations. Specific IgG binding to 10 major OMV antigens in each vaccine was measured by scanning of immunoblots; ELISAs for two antigens, lipopolysaccharide and Neisseria surface protein A (NspA), were also performed. Both vaccines elicited significant increases in IgG binding to all homologous and heterologous OMV antigens except NspA. The total IgG band intensity on the blots correlated significantly with the IgG levels determined by the OMV ELISA and flow cytometry. In conclusion, the results of the various immunological assays showed that both OMV vaccines gave rise to high levels of specific and cross-reacting antibodies.

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Antigen-Specific T-Cell Responses in Humans after Intranasal Immunization with a Meningococcal Serogroup B Outer Membrane Vesicle Vaccine

Infection and Immunity ◽

10.1128/iai.67.2.921-927.1999 ◽

1999 ◽

Vol 67 (2) ◽

pp. 921-927 ◽

Cited By ~ 33

Author(s):

Fredrik Oftung ◽

Lisbeth Meyer Næss ◽

Lee M. Wetzler ◽

Gro Ellen Korsvold ◽

Audun Aase ◽

...

Keyword(s):

T Cell ◽

Outer Membrane ◽

Booster Dose ◽

Mononuclear Cells ◽

Membrane Vesicle ◽

T Cell Responses ◽

T Cell Response ◽

Outer Membrane Vesicle ◽

Unrelated Control ◽

Cell Responses

ABSTRACT We have studied the ability of the Norwegian group B meningococcal outer membrane vesicle (OMV) vaccine, when administered intranasally without adjuvant, to induce T-cell responses in humans. A group of 12 vaccinees was immunized with four doses of OMVs (250 μg of protein/dose) at weekly intervals, and a single booster dose was given 5 months later. In vitro T-cell proliferation in response to the OMV vaccine, purified PorA (class 1) protein, PorB (class 3) protein, and one unrelated control antigen (Mycobacterium bovis BCG) was measured by [3H]thymidine incorporation into peripheral blood mononuclear cells obtained from the vaccinees before and after the immunizations. The nasal OMV immunizations induced antigen-specific T-cell responses in the majority of the vaccinees when tested against OMVs (7 of 12) and the PorA antigen (11 of 12). None of the vaccinees showed a vaccine-induced T-cell response to the PorB antigen after the initial four doses. Although some individuals responded to all the vaccine antigens after the booster dose, this response was not significant when the vaccinees were analyzed as a group. We have also demonstrated that the PorA antigen-specific T-cell responses correlated with anti-OMV immunoglobulin A (IgA) levels in nasal secretions, with anti-OMV IgG levels in serum, and with serum bactericidal activity. In conclusion, we have shown that it is possible to induce antigen-specific T-cell responses in humans by intranasal administration of a meningococcal OMV vaccine without adjuvant.

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Meningococcal Outer Membrane Vesicle Vaccine Given Intranasally Can Induce Immunological Memory and Booster Responses without Evidence of Tolerance

Infection and Immunity ◽

10.1128/iai.69.8.5010-5015.2001 ◽

2001 ◽

Vol 69 (8) ◽

pp. 5010-5015 ◽

Cited By ~ 18

Author(s):

Hilde Bakke ◽

Kristian Lie ◽

Inger Lise Haugen ◽

Gro Ellen Korsvold ◽

E. Arne Høiby ◽

...

Keyword(s):

Cell Proliferation ◽

Spleen Cell ◽

Outer Membrane ◽

Membrane Vesicle ◽

Serum Antibody ◽

Immunological Memory ◽

Antibody Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Outer Membrane Vesicle ◽

Igg Antibody

ABSTRACT We have studied the ability of outer membrane vesicle (OMV) vaccines from Neisseria meningitidis serogroup B to induce vaccine-specific antibody and spleen cell proliferative responses in mice after being administered intranasally (i.n.) and/or subcutaneously (s.c.). A series of four weekly i.n. doses (25 μg) without adjuvant or a single s.c. dose (2.5 μg) with aluminum hydroxide was followed 2 months later by secondary i.n. or s.c. immunizations. After i.n. priming, both immunoglobulin G (IgG) antibody responses in serum, measured by enzyme-linked immunosorbent assay, and IgA antibodies in saliva and extracts of feces were significantly boosted by later i.n. immunizations. The IgG antibody responses in serum were also significantly augmented by secondary s.c. immunization after i.n. as well as s.c. priming. Sera from mice immunized i.n. reached the same level of bactericidal activity as after s.c. immunizations. The s.c. immunizations alone, however, had no effect on mucosal IgA antibody responses, but could prime for booster antibody responses in secretions to later i.n. immunizations. The i.n. immunizations also led to marked OMV-specific spleen cell proliferation in vitro. Both serum antibody responses and spleen cell proliferation were higher after i.n. priming and later s.c. immunizations than after s.c. immunizations alone. There was thus no evidence that i.n. priming had induced immunological tolerance within the B- or T-cell system. Our results indicate that a nonproliferating meningococcal OMV vaccine given i.n. can induce immunological memory and that it may be favorably combined with similar vaccines for injections.

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Cross-Reactivity of Antibodies against PorA after Vaccination with a Meningococcal B Outer Membrane Vesicle Vaccine

Infection and Immunity ◽

10.1128/iai.71.4.1650-1655.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 1650-1655 ◽

Cited By ~ 32

Author(s):

C. L. Vermont ◽

H. H. van Dijken ◽

A. J. Kuipers ◽

C. J. P. van Limpt ◽

W. C. M. Keijzers ◽

...

Keyword(s):

Outer Membrane ◽

Vaccine Strain ◽

Vaccine Coverage ◽

Membrane Vesicle ◽

Geometric Mean ◽

Cross Reactivity ◽

Outer Membrane Vesicle ◽

Specific Antibodies ◽

Fourfold Increase ◽

The Cross

ABSTRACT The cross-reactivity of PorA-specific antibodies induced by a monovalent P1.7-2,4 (MonoMen) and/or a hexavalent (HexaMen) meningococcal B outer membrane vesicle vaccine (OMV) in toddlers and school children was studied by serum bactericidal assays (SBA). First, isogenic vaccine strains and PorA-identical patient isolates were compared as a target in SBA, to ensure that the vaccine strains are representative for patient isolates. Geometric mean titers (GMTs) in SBA against patient isolates with subtypes P1.5-2,10 and P1.5-1,2-2 after vaccination with HexaMen were generally lower than those against vaccine strains with the same subtype, although the percentage of vaccine responders (≥4-fold increase in SBA after vaccination) was not affected. Using various P1.7-2,4 patient isolates, GMTs as well as the number of vaccine responders were higher than for the P1.7-2,4 vaccine strain, indicating that the use of the P1.7-2,4 vaccine strain may have underestimated the immunogenicity of this subtype in HexaMen. Secondly, the cross-reactivity of antibodies induced by MonoMen and HexaMen was studied using several patient isolates that differed from the vaccine subtypes by having minor antigenic variants of one variable region (VR), by having a completely different VR or by having a different combination of VRs. MonoMen induced P1.4-specific antibodies that were cross-reactive with P1.4 variants P1.4-1 and P1.4-3. HexaMen induced a broader cross-reactive antibody response against various patient isolates with one VR identical to a vaccine subtype or a combination of VRs included in HexaMen. Cross-reactivity, measured by a fourfold increase in SBA after vaccination, against these strains ranged from 23 to 92% depending on the subtype of the tested strain and was directed against both VR1 and VR2. The extended cross-reactivity of vaccinee sera induced by HexaMen against antigenic variants has important favorable implications for meningococcal B OMV vaccine coverage.

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