Ackerley Cassie G, Edupuganti Srilatha, Yu Chenchen, Roxby Alison C, Seaton Kelly E, Bekker Linda-Gail, Allen Mary, DeRosa Stephen C, Yates Nicole L, Heptinstall Jack, Mkhize Nonhlanhla N, Malahleha Mookho, Mngadi Kathryn, Daniels Brodie, Innes Craig, Furch Briana D, Koutsoukos Marguerite, Ferrari Guido, Morris Lynn, Montefiori David C, McElrath M Juliana, Tomaras Georgia D, Laher Fatima, Moodie Zoe
Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, United States.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.
Front Immunol. 2025 May 14;16:1557009. doi: 10.3389/fimmu.2025.1557009. eCollection 2025.
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.
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 plus bivalent subtype C gp120/MF59 or 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+ IFNγ and/or II-2 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.
Of 185 vaccine recipients, 73 were AFAB and 112 were AMAB. Vaccine recipients AFAB had greater ADCC response rate (57.5% versus 29.5%; = 0.0003) and greater ADCC magnitude (area under the net % granzyme B activity vs log10 curve (AUC), 16.1 versus 11.2; = 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%; = 0.04]; 1086.C gp120, [44.1% versus 29.4%; = 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 ( = 0.08). There were no sex-based differences in neutralizing antibody or ADCP responses.
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.
一般来说，出生时被指定为女性（AFAB）的个体对各种疫苗产生的免疫原性比出生时被指定为男性（AMAB）的个体更强。关于HIV-1疫苗的性别分类免疫原性知之甚少。我们对一种实验性HIV疫苗方案的免疫反应进行了分类分析。
我们回顾性分析了HVTN 100的数据，该临床试验在南非进行，期间143名18至40岁未感染HIV的成年AMAB和109名AFAB在0、1、3、6和12个月时接受了ALVAC-HIV vCP2438加二价C亚型gp120/MF59或安慰剂。符合条件的数据来自第6.5个月按方案接种疫苗的受试者。我们测量了IgG结合抗体、中和抗体、抗体依赖性细胞介导的细胞毒性（ADCC）、抗体依赖性细胞吞噬作用（ADCP）以及CD4+IFNγ和/或II-2反应。我们使用巴纳德检验比较了反应率的性别差异，并使用威尔科克森秩和检验比较了反应强度。P值经霍尔姆校正以进行多重比较。
在185名疫苗接种者中，73名是AFAB，112名是AMAB。与AMAB相比，AFAB疫苗接种者对疫苗匹配抗原TV1.C gp120的ADCC反应率更高（57.5%对29.5%；P = 0.0003），ADCC强度更大（净%颗粒酶B活性与log10曲线下面积（AUC），16.1对11.2；P = 0.05）。在第6.5个月时，AMAB疫苗接种者对2/3种疫苗匹配抗原的CD4+T细胞反应率高于AFAB（ZM96.C gp120，[54.1%对36.8%；P = 0.04]；1086.C gp120，[44.1%对29.4%；P = 0.05]）。CD4+T细胞反应强度在性别上相似。AMAB疫苗接种者中对B.CaseA V1V2抗原（与RV144试验中降低HIV感染风险相关）的IgG结合抗体反应率为56.8%，而AFAB中为38.9%（P = 0.08）。在中和抗体或ADCP反应方面没有性别差异。
我们确定了HIV疫苗方案免疫反应中的性别差异，但这些差异因免疫测定方法而异。虽然AFAB疫苗接种者表现出更高 的ADCC反应，但AMAB表现出更高的CD4+T细胞反应率。未来的分析应调查诸如疫苗平台、剂量和佐剂等疫苗因素是否导致实验性HIV疫苗免疫原性的性别差异。
