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Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses.

ABSTRACT: The impact of anti-vector immunity on the elicitation of insert-specific immune responses is important to understand in vaccine development. HVTN 055 was a 150 person phase I randomized, controlled HIV vaccine trial of recombinant modified vaccinia Ankara (rMVA) and fowlpox (rFPV) with matched HIV-1 inserts which demonstrated increased CD8+ T-cell immune responses in the heterologous vaccine group. The controls used in this study were the empty vectors (MVA and FPV).Anti-MVA and anti-vaccinia neutralizing antibodies (NAbs) were measured and compared with cellular and humoral HIV-1-specific immune responses.Elicitation of anti-vector responses increased with increasing dose of MVA and up to 2 administrations. Further inoculations of MVA (up to 5) did not increase the magnitude of the anti-MVA response but did delay the anti-vector NAb titre decay. There was no evidence that the insert impaired the anti-vector response, nor that anti-vector immunity attenuated the insert-specific responses.Two doses of MVA may be ideal for the elicitation of orthopoxvirus immune responses with further doses maintaining increased titres against the vector. We found no evidence that eliciting HIV insert- or MVA vector-specific immune responses interfered with elicitation of immune responses to the other.

SUBMITTER: Walsh SR

PROVIDER: S-EPMC3566524 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses.

Walsh Stephen R SR Seaman Michael S MS Grandpre Lauren E LE Charbonneau Cherie C Yanosick Katherine E KE Metch Barbara B Keefer Michael C MC Dolin Raphael R Baden Lindsey R LR

Vaccine 20121107 1

<h4>Background</h4>The impact of anti-vector immunity on the elicitation of insert-specific immune responses is important to understand in vaccine development. HVTN 055 was a 150 person phase I randomized, controlled HIV vaccine trial of recombinant modified vaccinia Ankara (rMVA) and fowlpox (rFPV) with matched HIV-1 inserts which demonstrated increased CD8+ T-cell immune responses in the heterologous vaccine group. The controls used in this study were the empty vectors (MVA and FPV).<h4>Method ...[more]

PMID: 23142302

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Project description:Poxvirus prime-protein boost used in the RV144 trial remains the only immunization strategy shown to elicit a modest level of protection against HIV-1 acquisition in humans. Although neutralizing antibodies (NAb) were generated, they were against sensitive viruses, not the more resistant "tier 2" isolates that dominate circulating strains. Instead, risk reduction correlated with antibodies recognizing epitopes in the V1/V2 region of HIV-1 envelope glycoprotein (Env). Here, we examined whether tier 2 virus NAb and V1/V2-specific non-NAb could be elicited by a poxvirus prime-gp120 boost strategy in a rabbit model. We studied two clade B Envs that differ in multiple parameters, including tissue origin, neutralization sensitivity, and presence of the N197 (N7) glycan that was previously shown to modulate the exposure of conserved epitopes on Env. We demonstrate that immunized rabbits generated cross-reactive neutralizing activities against >50% of the tier 2 global HIV-1 isolates tested. Some of these activities were directed against the CD4 binding site (CD4bs). These rabbits also generated antibodies that recognized protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. However, there are subtle differences in the specificities and the response rates of V1/V2-specific antibodies between animals immunized with different Envs, with or without the N7 glycan. These findings demonstrate that antibody responses that have been correlated with protection against HIV-1 acquisition in humans can be elicited in a preclinical model by a poxvirus prime-gp120 boost strategy and that improvements may be achievable by optimizing the nature of the priming and boosting immunogens.The only vaccine approach shown to elicit any protective efficacy against HIV-1 acquisition is based on a poxvirus prime-protein boost regimen (RV144 Thai trial). Reduction of risk was associated with nonneutralizing antibodies targeting the V1/V2 loops of the envelope protein gp120. However, the modest efficacy (31.2%) achieved in this trial highlights the need to examine approaches and factors that may improve vaccine-induced responses, including cross-reactive neutralizing activities. We show here that rabbits immunized with a novel recombinant vaccinia virus prime-gp120 protein boost regimen generated antibodies that recognize protein scaffolds bearing V1/V2 sequences from diverse HIV-1 isolates and mediated antibody-dependent cellular cytotoxicity. Importantly, immunized rabbits also showed neutralizing activities against heterologous tier 2 HIV-1 isolates. These findings may inform the design of prime-boost immunization approaches and help improve the protective efficacy of candidate HIV-1 vaccines.

Project description:BackgroundEmerging evidence suggests heterologous prime-boost COVID-19 vaccination as a superior strategy than homologous schedules. Animal experiments and clinical observations have shown enhanced antibody response against influenza variants after heterologous vaccination; however, whether the inoculation order of COVID-19 vaccines in a prime-boost schedule affects antibody response against SARS-CoV-2 variants is not clear.MethodsWe conducted immunological analyses in a cohort of health care workers (n = 486) recently vaccinated by three types of inactivated COVID-19 vaccines under homologous or heterologous prime-boost schedules. Antibody response against ancestral SARS-CoV-2 (Wuhan-Hu-1) was assessed by total antibody measurements, surrogate virus neutralization tests, and pseudovirus neutralization assays (PNA). Furthermore, serum neutralization activity against SARS-CoV-2 variants of concern was also measured by PNA.FindingsWe observed strongest serum neutralization activity against the widely circulating SARS-CoV-2 variant B.1.617.2 among recipients of heterologous BBIBP-CorV/CoronaVac and WIBP-CorV/CoronaVac. In contrast, recipients of CoronaVac/BBIBP-CorV and CoronaVac/WIBP-CorV showed significantly lower B.1.617.2 neutralization titers than recipients of reverse schedules. Laboratory tests revealed that neutralizing activity against common variants but not the ancestral SARS-CoV-2 was associated with the inoculation order of heterologous prime-boost vaccines. Multivariable regression analyses confirmed this association after adjusting for known confounders.ConclusionsOur data provide clinical evidence of inoculation order-dependent expansion of neutralizing breadth against SARS-CoV-2 in recipients of heterologous prime-boost vaccination and call for further studies into its underlying mechanism.FundingNational Key R&D Program of China, National Development and Re-form Commission of China, National Natural Science Foundation of China, Shenzhen Science and Technology Innovation Commission, and US Department of Veterans Affairs.

Dataset Information

Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses.

Publications

Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses.

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