Retrospective Analysis of Sex-Disaggregated Immune Responses to ALVAC-HIV and Bivalent Subtype C gp120/MF59 HIV Vaccines

Cassie G Ackerley^1*Srilatha Edupuganti¹Chenchen Yu²Alison C Roxby²Kelly Seaton³Linda-Gail Bekker⁴Mary Allen⁵Stephen De Rosa²Nicole Yates⁶Jack Heptinstall⁶Nonhlanhla Mkhize⁷Mookho Malahleha⁷Kathryn Therese Mngadi⁸Brodie Daniels⁹Craig Innes¹⁰Briana D Furch²Marguerite Koutsoukos¹¹Guido Ferrari⁶Lynn Morris¹²David Montefiori⁶M. Juliana McElrath²Georgia D Tomaras⁶Fatima Laher¹³Zoe Moodie²

• ¹Department of Medicine, Emory University, Atlanta, United States
• ²Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States
• ³Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Center for Human Systems Immunology, Duke University, Durham, California, United States
• ⁴Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa
• ⁵Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIH), Bethesda, Maryland, United States
• ⁶Department of Surgery, Duke Human Vaccine Institute, School of Medicine, Duke University, Durham, North Carolina, United States
• ⁷Setshaba Research Centre, Soshanguve, South Africa
• ⁸Aurum Institute, Tembisa Clinic 4, Ekurheleni, South Africa
• ⁹South African Medical Research Council, Durban, South Africa
• ¹⁰Aurum Institute, Klerksdorp Research Centre, Klerksdorp, South Africa
• ¹¹GlaxoSmithKline (Belgium), Rixensart, Belgium
• ¹²National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa
• ¹³Perinatal HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa

Introduction: Generally, individuals assigned female at birth (AFAB) develop greater immunogenicity to various vaccines than individuals assigned male at birth (AMAB). Little is known about sex-disaggregated immunogenicity to HIV-1 vaccines. We disaggregated immune responses to an experimental HIV vaccine regimen.Methods: We retrospectively analyzed data from HVTN 100, a clinical trial conducted in South Africa during which 143 adults AMAB and 109 AFAB aged 18-40 years without HIV received ALVAC-HIV vCP2438 +- bivalent subtype C gp120/MF59/placebo at 0, 1, 3, 6, and 12 months. Eligible data were from per-protocol vaccine recipients at month 6.5. We measured IgG binding antibodies, neutralizing antibodies, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and CD4+ IFN and/or IL2 responses. We compared sex-based differences in response rates using Barnard’s test and response magnitudes using Wilcoxon Rank Sum test. P-values were Holm-adjusted for multiple comparisons.Results: Of 185 vaccine recipients, 73 were AFAB and 112 were AMAB. Vaccine recipients AFAB had greater ADCC response rate (57.5% versus 29.5%; padj = 0.0003) and greater ADCC magnitude (area under the net % granzyme B activity vs log10 curve (AUC), 16.1 versus 11.2; padj = 0.05) to vaccine-matched antigen TV1.C gp120 compared to AMAB. Vaccine recipients AMAB had higher CD4+ T cell response rates to 2/3 vaccine-matched antigens at month 6.5 (ZM96.C gp120, [54.1% versus 36.8%; padj = 0.04]; 1086.C gp120, [44.1% versus 29.4%; padj = 0.05]) than AFAB. CD4+ T cell response magnitudes were similar by sex. IgG binding antibody response rate to B.CaseA V1V2 antigen (associated with reduced HIV acquisition risk in the RV144 trial) was 56.8% among AMAB vaccine recipients versus 38.9% among AFAB (padj = 0.08). There were no sex-based differences in neutralizing antibody or ADCP responses. Discussion: We identified sex-based differences in immune responses to an HIV vaccine regimen, but they varied by immunologic assay. While vaccine recipients AFAB demonstrated higher ADCC responses, AMAB exhibited higher CD4+ T cell response rates. Future analyses should investigate whether vaccine factors such as platform, dosing and adjuvants contribute to sex-based differences in immunogenicity of experimental HIV vaccines.