Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines


Autoři: Fatima Laher aff001;  Zoe Moodie aff002;  Kristen W. Cohen aff002;  Nicole Grunenberg aff002;  Linda-Gail Bekker aff003;  Mary Allen aff004;  Nicole Frahm aff002;  Nicole L. Yates aff005;  Lynn Morris aff006;  Mookho Malahleha aff008;  Kathryn Mngadi aff009;  Brodie Daniels aff010;  Craig Innes aff011;  Kevin Saunders aff005;  Shannon Grant aff002;  Chenchen Yu aff002;  Peter B. Gilbert aff002;  Sanjay Phogat aff012;  Carlos A. DiazGranados aff012;  Marguerite Koutsoukos aff013;  Olivier Van Der Meeren aff013;  Carter Bentley aff002;  Nonhlanhla N. Mkhize aff006;  Michael N. Pensiero aff004;  Vijay L. Mehra aff004;  James G. Kublin aff002;  Lawrence Corey aff002;  David C. Montefiori aff005;  Glenda E. Gray aff001;  M. Juliana McElrath aff002;  Georgia D. Tomaras aff005
Působiště autorů: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa aff001;  Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America aff002;  Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa aff003;  Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America aff004;  Departments of Surgery and Immunology, Duke Human Vaccine Institute, Durham, North Carolina, United States of America aff005;  National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa aff006;  Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa aff007;  Setshaba Research Centre, Soshanguve, South Africa aff008;  Centre for the AIDS Programme of Research in South Africa, Durban, South Africa aff009;  South African Medical Research Council, Durban, South Africa aff010;  Aurum Institute, Klerksdorp Research Centre, Klerksdorp, South Africa aff011;  Sanofi Pasteur, Swiftwater, Pennsylvania, United States of America aff012;  GSK Vaccines, Rixensart, Belgium aff013
Vyšlo v časopise: Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines. PLoS Med 17(2): e32767. doi:10.1371/journal.pmed.1003038
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003038

Souhrn

Background

HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses.

Methods and findings

A phase 1–2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2_gp70_V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%–22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%–24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%–22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%–36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%–35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%–35.5%, P = 0.002) for CaseA2_gp70_V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%–76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%–33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%–37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%–38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain.

Conclusions

In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination.

Trial registration

ClinicalTrials.gov NCT02404311.

South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796).

Klíčová slova:

Antibodies – Antibody response – Booster doses – Immune response – Memory T cells – T cells – Vaccination and immunization – Vaccines


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