Analysis of the HVTN 702 Phase 2b-3 HIV-1 vaccine trial in South Africa assessing RV144 antibody and T cell correlates of HIV-1 acquisition risk

Title

Analysis of the HVTN 702 Phase 2b-3 HIV-1 vaccine trial in South Africa assessing RV144 antibody and T cell correlates of HIV-1 acquisition risk

Presenter

Zoe Moodie

Authors

Z. Moodie * (1), S. Sawant (2,3), O. Dintwe (1,4), D. Grove (1), Y. Huang (1,5,6), H. Janes (1,7), J. Heptinstall (2,3), F. Laher Omar (4), K. Cohen (1), S.C. De Rosa (1,8), L. Zhang (2,3), N.L. Yates (2,3), M. Sarzotti-Kelsoe (3,9), K.E. Seaton (2,3), F. Laher (10), L.-G. Bekker (11), M. Malahleha (12,13), C. Innes (14), S. Kassim (11), N. Naicker (15), V. Govender (16), M. Sebe (17), N. Singh (16), P. Kotze (18), E. Lazarus (10), M. Nchabeleng (19), A.M. Ward (20,21), W. Brumskine (22), T. Dubula (23), A.K. Randhawa (1), N. Grunenberg (1), J. Jin Kee (1), L.N. Carpp (1), J. Hural (1), M. Allen (24), P. D'Souza (24), J. Tartaglia (25), C.A. DiazGranados (25), M. Koutsoukos (26), P.B. Gilbert (1,6,7), J.G. Kublin (1), L. Corey (1,8), E. Andersen-Nissen (1,4), G.E. Gray (10,16), G.D. Tomaras (2,3,9,27), M.J. McElrath (1,28), HVTN 702 Protocol Team

Institutions

(1) Fred Hutchinson Cancer Center, Vaccine and Infectious Disease Division, Seattle, United States, (2) Duke University, Center for Human Systems Immunology, Durham, United States, (3) Duke University, Department of Surgery, Durham, United States, (4) Hutchinson Centre Research Institute of South Africa, Cape Town HVTN Immunology Laboratory, Cape Town, South Africa, (5) University of Washington, Department of Global Health, Seattle, United States, (6) Fred Hutchinson Cancer Center, Public Health Sciences Division, Seattle, United States, (7) University of Washington, Department of Biostatistics, Seattle, United States, (8) University of Washington, Department of Laboratory Medicine and Pathology, Seattle, United States, (9) Duke University, Department of Immunology, Durham, United States, (10) University of the Witwatersrand, Perinatal HIV Research Unit, Faculty of Health Sciences, Johannesburg, South Africa, (11) University of Cape Town, Desmond Tutu HIV Centre, Cape Town, South Africa, (12) Setshaba Research Centre, Soshanguve, South Africa, (13) Synergy Biomed Research Institute, East London, South Africa, (14) The Aurum Institute, Klerksdorp, South Africa, (15) Centre for the AIDS Programme of Research in South Africa, Durban, South Africa, (16) South African Medical Research Council, Durban, South Africa, (17) Aurum Institute, Tembisa, South Africa, (18) Qhakaza Mbokodo Research Centre, Ladysmith, South Africa, (19) Sefako Makgatho Health Sciences University, Mecru Clinical Research Unit, Pretoria, South Africa, (20) University of Cape Town, Department of Medicine, Cape Town, South Africa, (21) University of Cape Town, Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Cape Town, South Africa, (22) Aurum Institute, Johannesburg, South Africa, (23) Walter Sisulu University, Nelson Mandela Academic Clinical Research Unit and Department of Internal Medicine and Pharmacology, Mthatha, South Africa, (24) National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, United States, (25) Sanofi-Pasteur, Swiftwater, United States, (26) GSK, Wavre, Belgium, (27) Duke University, Department of Molecular Genetics and Microbiology, Durham, United States, (28) University of Washington, Department of Medicine, Seattle, United States

BACKGROUND: Whether the immune correlates of HIV-1 acquisition risk identified in the Thai HIV-1 vaccine efficacy trial of an ALVAC/gp120 pox-protein vaccine regimen (RV144) generalize to other at-risk populations is a critical question. Although the clade C-adapted vaccine regimen was not efficacious in preventing HIV-1 acquisition in South African participants, HVTN 702 (NCT02968849) provides a unique opportunity to answer this important question and to raise hypotheses regarding the observed lack of efficacy.
METHODS: Among 3909 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative controls were sampled. HIV-1-specific CD4+ T-cell and binding antibody (bAb) responses were measured by intracellular cytokine staining and bAb multiplex assays 2 weeks post-fourth and fifth immunizations. Three primary vaccine-matched immunological endpoints that were strong inverse correlates of HIV-1 risk in RV144 were assessed as predictors of HIV-1 acquisition among vaccinees using Cox proportional hazards models: Env-ZM96-specific CD4+ polyfunctionality score based on six markers and total IgG and IgG3 binding antibody responses to A244 and 1086.C V1V2. Secondary endpoints included polyfunctional CD4+ T-cell responses to other Env vaccine inserts, IgG bAbs to gp120 and Env consensus antigens, and IgA bAbs. Interactions among pre-specified primary and secondary endpoints were also assessed using Cox models, with low/medium/high categories defined by tertiles.
RESULTS: Although no significant association was observed between any T-cell or bAb response and HIV-1 acquisition, significant interactions were seen in pre-specified analyses (multiplicity-adjusted p-values <=0.03). Among those with highest tertile IgG A244 V1V2 bAb responses, vaccine-matched CD4+ T-cell endpoints (polyfunctional scores to Env-ZM96 and 1086, triple-functional cells expressing IFN-g, IL2, and CD40L to Env-ZM96) were associated with decreased HIV-1 acquisition risk with estimated hazard ratios=0.40-0.49 per 1-SD increase in the respective CD4+ T-cell endpoint.
CONCLUSIONS: Our study interrogated previously identified correlates of HIV-1 risk and their interplays for an ALVAC/gp120 vaccine in the South African population. We hypothesize that due to low IgG V1V2 bAb responses in HVTN 702 vs. RV144, Env-specific CD4+ T-cell responses were not confirmed as predictors of risk. Higher bAb V1V2 responses in combination with polyfunctional CD4+ T-cell responses may be necessary to reduce HIV-1 acquisition.

Download the e-Poster (Movie)

Download the e-Poster (PDF)