Fisher Leigh H, Lazarus Erica, Yu Chenchen, Moodie Zoe, Stieh Daniel J, Yates Nicole, Zhang Lu, Sawant Sheetal, De Rosa Stephen C, Cohen Kristen W, Morris Daryl, Grant Shannon, Randhawa April, Miner Maurine D, Hendriks Jenny, Wegmann Frank, Gill Katherine M, Laher Fatima, Bekker Linda-Gail, Gray Glenda E, Corey Lawrence, McElrath M Juliana, Martin Troy, Gilbert Peter B, Tomaras Georgia, Walsh Stephen R, Baden Lindsey R
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.
Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
PLOS Glob Public Health. 2025 Apr 11;5(4):e0004250. doi: 10.1371/journal.pgph.0004250. eCollection 2025.
Although clade-specific and cross-clade mosaic prime-boost HIV-1 vaccine regimens were advanced to the HVTN 702 and HVTN 705 efficacy trials, neither regimen prevented HIV acquisition. The respective Phase 1/2a studies, HVTN 100 (NCT02404311) and HVTN 117/HPX2004 (NCT02788045), provided rich immunological data, including previously identified correlates of risk, for comparing immune responses elicited by these vaccine regimens over time. We analyzed antibody responses measured by binding antibody multiplex assay, and CD4+ and CD8+ T-cell responses measured by intracellular cytokine staining in per-protocol vaccinees in HVTN 100 (n=186) vs. HVTN 117/HPX2004 (n=99) after the months 6 and 12 vaccinations (months 6.5/7 and 12.5/13), and 6 months after the last vaccination (month 18). At month 12.5/13, both regimens induced similarly high IgG breadth against gp120, gp140, and V1V2 antigens, and similar IgG responses to gp70-BCaseA V1V2. IgG V1V2 responses were more durable in HVTN 117/HPX2004, with the largest difference in the gp70-BCaseA V1V2 IgG response rate at month 18 (17.8% in HVTN 100 vs 61.9% in HVTN 117/HPX2004, p<0.001). IgG3 responses to consensus Env antigens were higher and more durable in HVTN117/HPX2004; for example, IgG3 response rate to the consensus gp140 antigen was 65.9% in HVTN 117/HPX2004 vs 6.3% in HVTN 100 at month 18 (TMLE p<0.0001). At month 18, both regimens induced similar IgG3 responses to gp70-BCaseA V1V2 (3.2% in HVTN 100 vs 1.1% in HVTN 117/HPX2004). Polyfunctional CD4+ Env was significantly higher in HVTN 100, and polyfunctional CD4+ Gag was higher in HVTN 117/HPX2004. CD8+ T-cell responses were not seen in HVTN 100, while CD8+ T-cell response rates in HVTN 117/HPX2004 reached up to 42%. Despite the distinct immune responses induced by the two HIV vaccine regimens, the lack of demonstrated efficacy suggests that broader, higher magnitude, and possibly qualitatively different immune responses are needed for protection against HIV acquisition. Trial registration: ClinicalTrials.gov NCT02404311 and NCT02788045; South African National Clinical Trials Registry (DOH-27-0215-4796).
尽管特定分支和跨分支嵌合初免-加强HIV-1疫苗方案已推进至HVTN 702和HVTN 705疗效试验，但两种方案均未能预防HIV感染。各自的1/2a期研究，即HVTN 100（NCT02404311）和HVTN 117/HPX2004（NCT02788045），提供了丰富的免疫学数据，包括先前确定的风险相关因素，以便比较这些疫苗方案随时间引发的免疫反应。我们分析了在HVTN 100（n = 186）与HVTN 117/HPX2004（n = 99）中，按照方案接种疫苗者在第6个月和第12个月接种疫苗后（第6.5/7个月和第12.5/13个月）以及最后一次接种疫苗后6个月（第18个月），通过结合抗体多重分析测量的抗体反应，以及通过细胞内细胞因子染色测量的CD4 +和CD8 + T细胞反应。在第12.5/13个月时，两种方案诱导的针对gp120、gp140和V1V2抗原的IgG广度同样高，并且对gp70-BCaseA V1V2的IgG反应相似。HVTN 117/HPX2004中的IgG V1V2反应更持久，在第18个月时，gp70-BCaseA V1V2 IgG反应率差异最大（HVTN 100中为17.8%，HVTN 117/HPX2004中为61.9%，p<0.001）。HVTN117/HPX2004中对共有Env抗原的IgG3反应更高且更持久；例如，在第18个月时，HVTN 117/HPX2004中对共有gp140抗原的IgG3反应率为65.9%，而HVTN 100中为6.3%（TMLE p<0.0001）。在第18个月时，两种方案诱导的对gp70-BCaseA V1V2的IgG3反应相似（HVTN 100中为3.2%，HVTN 117/HPX2004中为1.1%）。HVTN 100中的多功能CD4 + Env显著更高，而HVTN 117/HPX2004中的多功能CD4 + Gag更高。HVTN 100中未观察到CD8 + T细胞反应，而HVTN 117/HPX2004中的CD8 + T细胞反应率高达42%。尽管两种HIV疫苗方案诱导的免疫反应不同，但缺乏已证明的疗效表明，需要更广泛、更高强度且可能在质量上不同的免疫反应来预防HIV感染。试验注册：ClinicalTrials.gov NCT02404311和NCT02788045；南非国家临床试验注册中心（DOH-27-0215-4796）。
