Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: A phase III, randomized, multicentre, lot-to-lot consistency study

Perrett, Kirsten P.; McVernon, Jodie; Richmond, Peter; Marshall, Helen; Nissen, Michael D.; August, Allison; Percell, Sandra; Toneatto, Daniela; Nolan, Terry

doi:10.1016/j.vaccine.2015.06.103

Cited by 40 publications

(26 citation statements)

References 31 publications

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“…Factor H binding protein (fHbp) is a meningococcal virulence factor that can be successfully exploited as vaccine antigen [31, 32]. In mice, recombinant fHbp proteins generated antibodies with functional fine specificities against strains carrying fHbp IDs with a different sequence than the one used for immunisation; native outer membrane vesicles (NOMV) with over-expressed fHbp, instead, induced antibodies with higher cross-reactivity [3, 5, 6, 10, 16, 17, 21, 22].…”

Section: Discussionmentioning

confidence: 99%

Contribution of factor H-Binding protein sequence to the cross-reactivity of meningococcal native outer membrane vesicle vaccines with over-expressed fHbp variant group 1

et al. 2017

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Factor H-binding protein (fHbp) is an important meningococcal vaccine antigen. Native outer membrane vesicles with over-expressed fHbp (NOMV OE fHbp) have been shown to induce antibodies with broader functional activity than recombinant fHbp (rfHbp). Improved understanding of this broad coverage would facilitate rational vaccine design. We performed a pair-wise analysis of 48 surface-exposed amino acids involved in interacting with factor H, among 383 fHbp variant group 1 sequences. We generated isogenic NOMV-producing meningococcal strains from an African serogroup W isolate, each over-expressing one of four fHbp variant group 1 sequences (ID 1, 5, 9, or 74), including those most common among invasive African meningococcal isolates. Mice were immunised with each NOMV, and sera tested for IgG levels against each of the rfHbp ID and for ability to kill a panel of heterologous meningococcal isolates. At the fH-binding site, ID pairs differed by a maximum of 13 (27%) amino acids. ID 9 shared an amino acid sequence common to 83 ID types. The selected ID types differed by up to 6 amino acids, in the fH-binding site. All NOMV and rfHbp induced high IgG levels against each rfHbp. Serum killing from mice immunised with rfHbp was generally less efficient and more restricted compared to NOMV, which induced antibodies that killed most meningococci tested, with decreased stringency for ID type differences. Breadth of killing was mostly due to anti-fHbp antibodies, with some restriction according to ID type sequence differences. Nevertheless, under our experimental conditions, no relationship between antibody cross-reactivity and variation fH-binding site sequence was identified. NOMV over-expressing different fHbp IDs belonging to variant group 1 induce antibodies with fine specificities against fHbp, and ability to kill broadly meningococci expressing heterologous fHbp IDs. The work reinforces that meningococcal NOMV with OE fHbp is a promising vaccine strategy, and provides a basis for rational selection of antigen sequence types for over-expression on NOMV.

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Section: Discussionmentioning

confidence: 99%

Contribution of factor H-Binding protein sequence to the cross-reactivity of meningococcal native outer membrane vesicle vaccines with over-expressed fHbp variant group 1

et al. 2017

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“…Previous studies primarily measured the SBA titers against three indicator strains selected to provide information on antigen-specific bactericidal activity (21)(22)(23)(24)(25). However, the relationship between the SBA titer measured against the reference strains and broader protection against circulating serogroup B strains is unknown.…”

Section: Discussionmentioning

confidence: 99%

Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci

Giuntini

Lujan

Gibani

et al. 2017

Clin Vaccine Immunol

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MenB-4C is a meningococcal vaccine for the prevention of serogroup B disease. The vaccine contains factor H binding protein (FHbp) and three other antigens that can elicit serum bactericidal antibodies (SBA). For vaccine licensure, efficacy was inferred from the SBA responses against three antigen-specific indicator strains. The relation between those results and broad protection against circulating genetically diverse strains is not known. Twenty adults were immunized with two doses of MenB-4C given 1 to 2 months apart. SBA activity against 3 reference strains and 15 serogroup B test strains (6 from college outbreaks) was measured. Compared to the preimmunization titers, 70%, 95%, and 95% of subjects had Ն4-fold increases in the titers of anti-PorA P1.4, anti-NadA, and anti-FHbp antibodies against the reference strains, respectively. In contrast, only 25 to 45% of the subjects had Ն4-fold increases in responses to 10 of the 15 test strains, including 8 that expressed one to three of the antigens in the vaccine. At 1 month, the majority of subjects with Ͻ4-fold titer increases had serum titers of Ն1:4, which are considered sufficient for protection. However, the titers against four strains declined to Ͻ1:4 by 4 to 6 months in one-third to greater than 50% of the subjects tested. Clinically relevant isolates are often more resistant to SBA than the indicator strains used to measure antigenspecific SBA. A working model is that the percentage of subjects with titers of Ն1:4 at 1 month postimmunization correlates with short-term protection against that strain, whereas the percentage of subjects with Ն4-fold titer increases represents a more robust response. (The protocol used at the Oxford Vaccine Group has been registered at ClinicalTrials.gov under registration no. NCT02398396.)

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“…Although this method has been used successfully for OMV vaccines to control meningococcal outbreaks and is the basis for the fourth component of the recently approved Bexsero 4CMenB vaccine (28), it has the downside that DOC treatment complicates processing and removes potentially protective lipoproteins such as fHbp, an antigen of N. meningitidis known to induce serum bactericidal antibodies (9)(10)(11). To circumvent the need for DOC treatment, ge- netic modification of the LPS structure, such as by deletion of the lpxL1 gene, has been shown to result in a safe vaccine based on spontaneously released OMVs (29,30).…”

Section: Discussionmentioning

confidence: 99%

Meningococcal Outer Membrane Vesicle Composition-Dependent Activation of the Innate Immune Response

et al. 2016

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cMeningococcal outer membrane vesicles (OMVs) have been extensively investigated and successfully implemented as vaccines. They contain pathogen-associated molecular patterns, including lipopolysaccharide (LPS), capable of triggering innate immunity. However, Neisseria meningitidis contains an extremely potent hexa-acylated LPS, leading to adverse effects when its OMVs are applied as vaccines. To create safe OMV vaccines, detergent treatment is generally used to reduce the LPS content. While effective, this method also leads to loss of protective antigens such as lipoproteins. Alternatively, genetic modification of LPS can reduce its toxicity. In the present study, we have compared the effects of standard OMV isolation methods using detergent or EDTA with those of genetic modifications of LPS to yield a penta-acylated lipid A (lpxL1 and pagL) on the in vitro induction of innate immune responses. The use of detergent decreased both Toll-like receptor 4 (TLR4) and TLR2 activation by OMVs, while the LPS modifications reduced only TLR4 activation. Mutational removal of PorB or lipoprotein factor H binding protein (fHbp), two proteins known to trigger TLR2 signaling, had no effect, indicating that multiple TLR2 ligands are removed by detergent treatment. Detergent-treated OMVs and lpxL1 OMVs showed similar reductions of cytokine profiles in the human monocytic cell line MM6 and human dendritic cells (DCs). OMVs with the alternative penta-acylated LPS structure obtained after PagL-mediated deacylation showed reduced induction of proinflammatory cytokines interleukin-6 (IL-6) and IL-1␤ but not of IP-10, a typical TRIF-dependent chemokine. Taken together, these data show that lipid A modification can be used to obtain OMVs with reduced activation of innate immunity, similar to what is found after detergent treatment. G ram-negative bacteria have the ability to naturally shed vesicles from the outer membrane. These spontaneous outer membrane vesicles (sOMVs) are composed of lipids, outer membrane proteins, lipopolysaccharide (LPS), and some periplasmic proteins. Shedding of sOMVs occurs without significant disruption in the integrity of the cell, and release of vesicles is increased by bacterial stress responses (1, 2). Some of the proposed functions of shedding of outer membrane blebs include protection and transport of secreted molecules, interaction with host cells, evasion of immunity by action as a decoy for antibodies and other antibacterial molecules, and action as nucleators in biofilm formation (3).The fact that OMVs are nonreplicating structures that contain many crucial surface components and virulence factors, in combination with pathogen-associated molecular patterns (PAMPs) that trigger innate immune responses, makes them attractive as candidate vaccines. This is evidenced by the successful control of meningococcal serogroup B epidemics using OMV vaccines (4-6) and experimental studies that have explored the vaccine potential of OMVs against other bacterial pathogens (7, 8). The isolation of OMVs from Neiss...

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Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: A phase III, randomized, multicentre, lot-to-lot consistency study

Cited by 40 publications

References 31 publications

Contribution of factor H-Binding protein sequence to the cross-reactivity of meningococcal native outer membrane vesicle vaccines with over-expressed fHbp variant group 1

Contribution of factor H-Binding protein sequence to the cross-reactivity of meningococcal native outer membrane vesicle vaccines with over-expressed fHbp variant group 1

Serum Bactericidal Antibody Responses of Adults Immunized with the MenB-4C Vaccine against Genetically Diverse Serogroup B Meningococci

Meningococcal Outer Membrane Vesicle Composition-Dependent Activation of the Innate Immune Response

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