Sci Transl Med. 2023 May 24; 15(697):eadf3309.

PubMed ID: 37224227

A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses

Cohen KW, De Rosa SC, Fulp WJ , deCamp AC, Fiore-Gartland A, Mahoney CR, Furth S, Donahue J, Whaley RE, Ballweber-Fleming L, Seese A, Schwedhelm K, Geraghty D, Finak G, Menis S, Leggat DJ, Rahaman F, Lombardo A, Borate BR, Philiponis V, Maenza J, Diemert D, Kolokythas O, Khati N, Bethony J, Hyrien O, Laufer DS, Koup RA, McDermott AB, Schief WR, McElrath MJ

The engineered outer domain germline targeting version 8 (eOD-GT8) 60-mer nanoparticle was designed to prime VRC01-class HIV-specific B cells that would need to be matured, through additional heterologous immunizations, into B cells that are able to produce broadly neutralizing antibodies. CD4 T cell help will be critical for the development of such high-affinity neutralizing antibody responses. Thus, we assessed the induction and epitope specificities of the vaccine-specific T cells from the IAVI G001 phase 1 clinical trial that tested immunization with eOD-GT8 60-mer adjuvanted with AS01B. Robust polyfunctional CD4 T cells specific for eOD-GT8 and the lumazine synthase (LumSyn) component of eOD-GT8 60-mer were induced after two vaccinations with either the 20- or 100-microgram dose. Antigen-specific CD4 T helper responses to eOD-GT8 and LumSyn were observed in 84 and 93% of vaccine recipients, respectively. CD4 helper T cell epitope ""hotspots"" preferentially targeted across participants were identified within both the eOD-GT8 and LumSyn proteins. CD4 T cell responses specific to one of these three LumSyn epitope hotspots were observed in 85% of vaccine recipients. Last, we found that induction of vaccine-specific peripheral CD4 T cells correlated with expansion of eOD-GT8-specific memory B cells. Our findings demonstrate strong human CD4 T cell responses to an HIV vaccine candidate priming immunogen and identify immunodominant CD4 T cell epitopes that might improve human immune responses either to heterologous boost immunogens after this prime vaccination or to other human vaccine immunogens.