Abstract:Immunogenicity of vaccines against meningococcal serogroup B (MenB) has been assessed pre-licensure with a human serum bactericidal activity assay (hSBA), tested against small numbers of strains. We report the qualification/validation of an alternative qualitative hSBA which uses endogenous complement (enc-hSBA) present in the vaccinee’s serum. Serum samples were collected from adults pre-vaccination and post-vaccination with the 4-component MenB vaccine (4CMenB). A representative panel of invasive isolates an… Show more
“…Antibodies against the pathogen of interest in the complement source may require immunodepletion, as described in published methods for the standardised depletion of IgG and IgM in pooled human plasma [ 94 ]. It is also recommended that freeze–thaw cycles are avoided, although the reported effects of this on complement activity can vary from a loss of activity with just one freeze–thaw cycle using serum from various fish species [ 95 ], compared to conserved bactericidal activity following up to 3 [ 96 ] and 5 [ 97 ] freeze–thaw cycles with human serum.…”
Section: Considerations and Future Applicationsmentioning
Neutralisation assays are commonly used to assess vaccine-induced and naturally acquired immune responses; identify correlates of protection; and inform important decisions on the screening, development, and use of therapeutic antibodies. Neutralisation assays are useful tools that provide the gold standard for measuring the potency of neutralising antibodies, but they are not without limitations. Common methods such as the heat-inactivation of plasma samples prior to neutralisation assays, or the use of anticoagulants such as EDTA for blood collection, can inactivate the complement system. Even in non-heat-inactivated samples, the levels of complement activity can vary between samples. This can significantly impact the conclusions regarding neutralising antibody potency. Restoration of the complement system in these samples can be achieved using an exogenous source of plasma with preserved complement activity or with purified complement proteins. This can significantly enhance the neutralisation titres for some antibodies depending on characteristics such as antibody isotype and the epitope they bind, enable neutralisation with otherwise non-neutralising antibodies, and demonstrate a better relationship between in vitro and in vivo findings. In this review, we discuss the evidence for complement-mediated enhancement of antibody neutralisation against a range of viruses, explore the potential mechanisms which underpin this enhancement, highlight current gaps in the literature, and provide a brief summary of considerations for adopting this approach in future research applications.
“…Antibodies against the pathogen of interest in the complement source may require immunodepletion, as described in published methods for the standardised depletion of IgG and IgM in pooled human plasma [ 94 ]. It is also recommended that freeze–thaw cycles are avoided, although the reported effects of this on complement activity can vary from a loss of activity with just one freeze–thaw cycle using serum from various fish species [ 95 ], compared to conserved bactericidal activity following up to 3 [ 96 ] and 5 [ 97 ] freeze–thaw cycles with human serum.…”
Section: Considerations and Future Applicationsmentioning
Neutralisation assays are commonly used to assess vaccine-induced and naturally acquired immune responses; identify correlates of protection; and inform important decisions on the screening, development, and use of therapeutic antibodies. Neutralisation assays are useful tools that provide the gold standard for measuring the potency of neutralising antibodies, but they are not without limitations. Common methods such as the heat-inactivation of plasma samples prior to neutralisation assays, or the use of anticoagulants such as EDTA for blood collection, can inactivate the complement system. Even in non-heat-inactivated samples, the levels of complement activity can vary between samples. This can significantly impact the conclusions regarding neutralising antibody potency. Restoration of the complement system in these samples can be achieved using an exogenous source of plasma with preserved complement activity or with purified complement proteins. This can significantly enhance the neutralisation titres for some antibodies depending on characteristics such as antibody isotype and the epitope they bind, enable neutralisation with otherwise non-neutralising antibodies, and demonstrate a better relationship between in vitro and in vivo findings. In this review, we discuss the evidence for complement-mediated enhancement of antibody neutralisation against a range of viruses, explore the potential mechanisms which underpin this enhancement, highlight current gaps in the literature, and provide a brief summary of considerations for adopting this approach in future research applications.
“…More recently, the enc-hSBA assay has been developed to complement immunogenicity results obtained with the traditional hSBA assay, enabling a more complete assessment of the performance of 4CMenB in clinical trials. The enc-hSBA assay uses endogenous complement present in each vaccinated person’s serum to provide a measure of the killing activity of vaccine-specific antibodies present in sera at a single dilution against each strain tested, 184 , 185 while the traditional hSBA assay uses an exogenous complement source from seronegative donors and measures vaccine-induced responses against four antigen-specific indicator strains ( Figure 7 ). The enc-hSBA assay accounts for intersubject heterogeneity in complement-mediated bactericidal killing of MenB strains and the synergistic effects of antibodies raised by multiple MenB vaccine antigens against circulating strains with diverse genetic features.…”
Section: Evaluating Multicomponent Menb Vaccines Before the Rwe Eramentioning
confidence: 99%
“…The enc-hSBA assay accounts for intersubject heterogeneity in complement-mediated bactericidal killing of MenB strains and the synergistic effects of antibodies raised by multiple MenB vaccine antigens against circulating strains with diverse genetic features. 184 Figure 7. Characteristics of the traditional human serum bactericidal antibody (hSBA) assay and the endogenous complement hSBA (enc-hSBA) in relation to the assessment of meningococcal serogroup B (MenB) vaccines.…”
Section: Evaluating Multicomponent Menb Vaccines Before the Rwe Eramentioning
confidence: 99%
“… Characteristics of the traditional human serum bactericidal antibody (hSBA) assay and the endogenous complement hSBA (enc-hSBA) in relation to the assessment of meningococcal serogroup B (MenB) vaccines. 159 , 184–186 . …”
Section: Evaluating Multicomponent Menb Vaccines Before the Rwe Eramentioning
“…The vaccine contained the factor H binding protein (fHbp) from two mutant strains and gained accelerated FDA approval after it was shown to elicit potent immune responses in phase II clinical trials [ 168 ]. The human serum bactericidal assay (hSBA) was utilized to measure antibodies in vaccinees immunized with the MenB vaccine [ 169 ]. Immunogenicity and safety studies conducted in adolescents upon immunization with the bivalent rLP2086 vaccine demonstrated robust hSBA responses and the vaccine was well tolerated, with three doses eliciting the strongest immune response against MenB strains expressing vaccine-heterologous subfamily B fHbps [ 170 ].…”
Section: From Research To Real-world Experience: Currently Approved A...mentioning
The clinical use of antibiotics has led to the emergence of multidrug-resistant (MDR) bacteria, leading to the current antibiotic resistance crisis. To address this issue, next-generation vaccines are being developed to prevent antimicrobial resistance caused by MDR bacteria. Traditional vaccine platforms, such as inactivated vaccines (IVs) and live attenuated vaccines (LAVs), were effective in preventing bacterial infections. However, they have shown reduced efficacy against emerging antibiotic-resistant bacteria, including MDR M. tuberculosis. Additionally, the large-scale production of LAVs and IVs requires the growth of live pathogenic microorganisms. A more promising approach for the accelerated development of vaccines against antibiotic-resistant bacteria involves the use of in silico immunoinformatics techniques and reverse vaccinology. The bioinformatics approach can identify highly conserved antigenic targets capable of providing broader protection against emerging drug-resistant bacteria. Multi-epitope vaccines, such as recombinant protein-, DNA-, or mRNA-based vaccines, which incorporate several antigenic targets, offer the potential for accelerated development timelines. This review evaluates the potential of next-generation vaccine development based on the reverse vaccinology approach and highlights the development of safe and immunogenic vaccines through relevant examples from successful preclinical and clinical studies.
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