Antibody and cellular responses to HIV vaccine regimens with DNA plasmid as compared with ALVAC priming: An analysis of two randomized controlled trials


Autoři: Zoe Moodie aff001;  Stephen R. Walsh aff002;  Fatima Laher aff005;  Lucas Maganga aff006;  Michael E. Herce aff007;  Sarita Naidoo aff008;  Mina C. Hosseinipour aff009;  Craig Innes aff010;  Linda-Gail Bekker aff011;  Nicole Grunenberg aff001;  Philipp Mann aff001;  Chenchen Yu aff001;  Allan C. deCamp aff001;  Maurine D. Miner aff001;  Nicole L. Yates aff012;  Jack Heptinstall aff012;  Nonhlanhla N. Mkhize aff013;  One Dintwe aff001;  Nicole Frahm aff001;  Kristen W. Cohen aff001;  Mary Allen aff015;  Julia Hutter aff015;  Ralf Wagner aff016;  Giuseppe Pantaleo aff017;  M. Juliana McElrath aff001;  Georgia D. Tomaras aff012;  Lynn Morris aff013;  David C. Montefiori aff012;  Erica Andersen-Nissen aff001;  Glenda E. Gray aff018;  Peter B. Gilbert aff001;  James G. Kublin aff001
Působiště autorů: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America aff001;  Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America aff002;  Harvard Medical School, Boston, Massachusetts, United States of America aff003;  Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America aff004;  Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa aff005;  NIMR-Mbeya Medical Research Center, Mbeya, Tanzania aff006;  University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff007;  HIV Prevention Research Unit, South African Medical Research Council, Durban, South Africa aff008;  UNC Project Malawi, Lilongwe, Malawi aff009;  Aurum Institute, Klerksdorp, South Africa aff010;  Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa aff011;  Duke Human Vaccine Institute, Department of Surgery Duke University, Durham, North Carolina, United States of America aff012;  National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa aff013;  Cape Town HVTN Immunology Laboratory, Hutchinson Center Research Institute of South Africa, Cape Town, South Africa aff014;  National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland United States of America aff015;  Institute of Medical Microbiology and Hygiene, University of Regensberg, Regensberg, Germany aff016;  Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland aff017;  South African Medical Research Council, Cape Town, South Africa aff018
Vyšlo v časopise: Antibody and cellular responses to HIV vaccine regimens with DNA plasmid as compared with ALVAC priming: An analysis of two randomized controlled trials. PLoS Med 17(5): e32767. doi:10.1371/journal.pmed.1003117
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003117

Souhrn

Background

DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle.

Methods and findings

The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%–32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42–3.92, p < 0.001) and B.CaseA V1V2 (GM 2314.0 versus 744.6, ratio = 3.11, 95% CI 1.51–6.38, p = 0.002). nAb response rates were >98% in both trials, with significantly higher 50% inhibitory dilution (ID50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67–2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48–2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%–56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%–63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%–82.7%, p < 0.001 for Gag LAI/ZM96). The study’s main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non–vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects.

Conclusions

In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy.

Klíčová slova:

Antibodies – Antibody response – Antigens – HIV vaccines – Immune response – Plasmid construction – T cells – Vaccines


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