Dataset Information

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial.

ABSTRACT: BACKGROUNDRV144 is the only preventive HIV vaccine regimen demonstrating efficacy in humans. Attempting to build upon RV144 immune responses, we conducted a phase 1, multicenter, randomized, double-blind trial to assess the safety and immunogenicity of regimens substituting the DNA-HIV-PT123 (DNA) vaccine for ALVAC-HIV in different sequences or combinations with AIDSVAX B/E (protein).METHODSOne hundred and four HIV-uninfected participants were randomized to 4 treatment groups (T1, T2, T3, and T4) and received intramuscular injections at 0, 1, 3, and 6 months (M): T1 received protein at M0 and M1 and DNA at M3 and M6; T2 received DNA at M0 and M1 and protein at M3 and M6; T3 received DNA at M0, M1, M3, and M6 with protein coadministered at M3 and M6; and T4 received protein and DNA coadministered at each vaccination visit.RESULTSAll regimens were well tolerated. Antibodies binding to gp120 and V1V2 scaffold were observed in 95%-100% of participants in T3 and T4, two weeks after final vaccination at high magnitude. While IgG3 responses were highest in T3, a lower IgA/IgG ratio was observed in T4. Binding antibodies persisted at 12 months in 35%-100% of participants. Antibody-dependent cell-mediated cytotoxicity and tier 1 neutralizing-antibody responses had higher response rates for T3 and T4, respectively. CD4+ T cell responses were detectable in all treatment groups (32%-64%) without appreciable CD8+ T cell responses.CONCLUSIONThe DNA/protein combination regimens induced high-magnitude and long-lasting HIV V1V2-binding antibody responses, and early coadministration of the 2 vaccines led to a more rapid induction of these potentially protective responses.TRIAL REGISTRATIONClinicalTrials.gov NCT02207920.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069511, UM1 AI069470, UM1 AI069534, P30 AI450008, UM1 AI069439, UM1 AI069481, and UM1 AI069496; the National Center for Advancing Translational Sciences, NIH (grant UL1TR001873); and the Bill & Melinda Gates Foundation (grant OPP52845).

SUBMITTER: Rouphael NG

PROVIDER: S-EPMC6819112 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial.

Rouphael Nadine G NG Morgan Cecilia C Li Shuying S SS Jensen Ryan R Sanchez Brittany B Karuna Shelly S Swann Edith E Sobieszczyk Magdalena E ME Frank Ian I Wilson Gregory J GJ Tieu Hong-Van HV Maenza Janine J Norwood Aliza A Kobie James J Sinangil Faruk F Pantaleo Giuseppe G Ding Song S McElrath M Juliana MJ De Rosa Stephen C SC Montefiori David C DC Ferrari Guido G Tomaras Georgia D GD Keefer Michael C MC

The Journal of clinical investigation 20191101 11

BACKGROUNDRV144 is the only preventive HIV vaccine regimen demonstrating efficacy in humans. Attempting to build upon RV144 immune responses, we conducted a phase 1, multicenter, randomized, double-blind trial to assess the safety and immunogenicity of regimens substituting the DNA-HIV-PT123 (DNA) vaccine for ALVAC-HIV in different sequences or combinations with AIDSVAX B/E (protein).METHODSOne hundred and four HIV-uninfected participants were randomized to 4 treatment groups (T1, T2, T3, and T4 ...[more]

PMID: 31566579

Similar Datasets

Project description:BackgroundIntradermal priming with HIV-1 DNA plasmids followed by HIV-1MVA boosting induces strong and broad cellular and humoral immune responses. In our previous HIVIS-03 trial, we used 5 injections with 2 pools of HIV-DNA at separate sites for each priming immunization. The present study explores whether HIV-DNA priming can be simplified by reducing the number of DNA injections and administration of combined versus separated plasmid pools.MethodsIn this phase IIa, randomized trial, priming was performed using 5 injections of HIV-DNA, 1000 μg total dose, (3 Env and 2 Gag encoding plasmids) compared to two "simplified" regimens of 2 injections of HIV-DNA, 600 μg total dose, of Env- and Gag-encoding plasmid pools with each pool either administered separately or combined. HIV-DNA immunizations were given intradermally at weeks 0, 4, and 12. Boosting was performed intramuscularly with 108 pfu HIV-MVA at weeks 30 and 46.Results129 healthy Tanzanian participants were enrolled. There were no differences in adverse events between the groups. The proportion of IFN-γ ELISpot responders to Gag and/or Env peptides after the second HIV-MVA boost did not differ significantly between the groups primed with 2 injections of combined HIV-DNA pools, 2 injections with separated pools, and 5 injections with separated pools (90%, 97% and 97%). There were no significant differences in the magnitude of Gag and/or Env IFN-γ ELISpot responses, in CD4+ and CD8+ T cell responses measured as IFN-γ/IL-2 production by intracellular cytokine staining (ICS) or in response rates and median titers for binding antibodies to Env gp160 between study groups.ConclusionsA simplified intradermal vaccination regimen with 2 injections of a total of 600 μg with combined HIV-DNA plasmids primed cellular responses as efficiently as the standard regimen of 5 injections of a total of 1000 μg with separated plasmid pools after boosting twice with HIV-MVA.Trial registrationWorld Health Organization International Clinical Trials Registry Platform PACTR2010050002122368.

Project description:The RV144 vaccine trial revealed a correlation between reduced risk of HIV infection and the level of nonneutralizing-antibody (Ab) responses targeting specific epitopes in the second variable domain (V2) of the HIV gp120 envelope (Env) protein, suggesting this region as a target for vaccine development. To favor induction of V2-specific Abs, we developed a vaccine regimen that included priming with DNA expressing an HIV V1V2 trimeric scaffold immunogen followed by booster immunizations with a combination of DNA and protein in rhesus macaques. Priming vaccination with DNA expressing the HIV recombinant subtype CRF01_AE V1V2 scaffold induced higher and broader V2-specific Ab responses than vaccination with DNA expressing CRF01_AE gp145 Env. Abs recognizing the V2 peptide that was reported as a critical target in RV144 developed only after the priming immunization with V1V2 DNA. The V2-specific Abs showed several nonneutralizing Fc-mediated functions, including ADCP and C1q binding. Importantly, robust V2-specific Abs were maintained upon boosting with gp145 DNA and gp120 protein coimmunization. In conclusion, priming with DNA expressing the trimeric V1V2 scaffold alters the hierarchy of humoral immune responses to V2 region epitopes, providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection.IMPORTANCE The aim of this work was to design and test a vaccine regimen focusing the immune response on targets associated with infection prevention. We demonstrated that priming with a DNA vaccine expressing only the HIV Env V1V2 region induces Ab responses targeting the critical region in V2 associated with protection. This work shows that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region, in the absence of immune interference by other epitopes. This induced immune responses with improved recognition of epitopes important for protective immunity, namely, V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial.

Project description:BackgroundA vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA).MethodsForty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart.ResultsThe vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding antibodies to subtype C Env (included in HIV-DNA and protein boost), subtype B Env (included only in HIV-DNA) and CRF01_AE Env (included only in HIV-MVA) were significantly boosted by the CN54rgp140/GLA-AF immunizations. Functional antibodies detected using an infectious molecular clone virus/peripheral blood mononuclear cell neutralization assay, a pseudovirus/TZM-bl neutralization assay or by assays for antibody-dependent cellular cytotoxicity (ADCC) were not significantly boosted. In contrast, T-cell proliferative responses to subtype B MN antigen and IFN-γ ELISpot responses to Env peptides were significantly enhanced. Four volunteers not primed with HIV-DNA and HIV-MVA before the CN54rgp140/GLA-AF immunizations mounted an antibody response, while cell-mediated responses were rare. After the two Env subtype C protein immunizations, a trend towards higher median subtype C Env binding antibody titers was found in vaccinees who had received HIV-DNA and HIV-MVA prior to the two Env protein immunizations as compared to unprimed vaccinees (p = 0.07).ConclusionWe report excellent tolerability, enhanced binding antibody responses and Env-specific cell-mediated immune responses but no ADCC antibody increase after two immunizations with a subtype C rgp140 protein adjuvanted in GLA-AF in healthy volunteers previously immunized with HIV-DNA and HIV-MVA.Trial registrationInternational Clinical Trials Registry PACTR2010050002122368.

Dataset Information

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial.

Publications

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets