Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
J Clin Invest. 2023 Feb 15;133(4):e163338. doi: 10.1172/JCI163338.
BACKGROUNDMosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models.METHODSThis double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara-vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped.RESULTSEnv-specific CD4+ T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2-4.2) for mosaic recipients, 1.6 (95% CI, 0.82-2.6) for CON-S recipients, and 1.1 (95% CI, 0.62-1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4+ T cell responses.CONCLUSIONPriming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02296541.FUNDINGUS NIH grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069412, UL1 RR025758, P30 AI064518, UM1 AI100645, and UM1 AI144371, and Bill & Melinda Gates Foundation grant OPP52282.
马赛克和共识 HIV-1 免疫原提供了两种不同的方法来引发对全球流行的 HIV-1 的更大覆盖范围，并在非人类灵长类动物模型中显示出改善的免疫广度。
这项双盲随机试验招募了 105 名健康的 HIV 未感染成年人，他们接受了 3 剂三价全球马赛克、组 M 共识（CON-S）或天然 clade B（Nat-B）gp160 env DNA 疫苗，然后接受了 2 剂异源改良痘苗安卡拉载体 HIV-1 疫苗或安慰剂。我们在第一次免疫后 70 天和 238 天进行了预设的盲法免疫原性分析。对疫苗抗原和 5 种异源 Env 变体的 T 细胞反应进行了全面映射。
马赛克疫苗接种者中有 71%诱导出 Env 特异性 CD4+ T 细胞反应，而 CON-S 接种者中有 48%，天然 Env 接种者中有 48%。马赛克组识别的 T 细胞表位数量平均为 2.5（95%CI，1.2-4.2），CON-S 组为 1.6（95%CI，0.82-2.6），Nat-B 组为 1.1（95%CI，0.62-1.71）。使用总体（P = 0.014）、主要匹配（P = 0.002）、异源（P = 0.046）和增强匹配（P = 0.009）措施，马赛克组的平均广度明显大于 Nat-B 组。总体 T 细胞广度主要归因于 Env 特异性 CD4+ T 细胞反应。
用马赛克抗原进行初级免疫可显著增加 Env 特异性 T 细胞识别的表位数量，并使更多（尽管仍然有限）异源变体能够交叉识别。马赛克和共识免疫原是解决 HIV-1 全球多样性的有前途的方法。
ClinicalTrials.gov NCT02296541。
美国国立卫生研究院拨款 UM1 AI068614、UM1 AI068635、UM1 AI068618、UM1 AI069412、UL1 RR025758、P30 AI064518、UM1 AI100645 和 UM1 AI144371，以及比尔和梅琳达盖茨基金会赠款 OPP52282。
