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

Abstract

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 AS01 B . 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.

Exploring synergies between B- and T-cell vaccine approaches to optimize immune responses against HIV—workshop report

“…Burton discussed an engineered nanoparticle vaccine immunogen referred to as eOD-GT8 60 mer, which was developed by scientists at Scripps Research, Fred Hutchinson Cancer Center (through the HIV Vaccine Trial Network, HVTN), NIAID, and IAVI and tested in Phase 1 clinical trials. The vast majority of vaccinees (97%) showed VRC-01-class bNAb precursors with a median frequency of 0.1% IgG + B cells in blood, indicating that reverse immunogen engineering can stimulate and expand rare germline B cells 11 , 12 .…”

“…Researchers are also testing the eOD-GT8 immunogen expressed from mRNA encapsulated in lipid nanoparticles (IAVI G002, NCT05001373), and, according to Burton, this approach appears even more promising than the equivalent nanoparticle protein previously tested 12 . The goal now is to continue this work and to test eOD-GT8 and other germline-targeting immunogens singly and in combination with more native-like stabilized HIV envelope trimers.…”

New Vaccine Platforms—Novel Dimensions of Economic and Societal Value and Their Measurement

“…In fact, several combination vaccine candidates against seasonal respiratory diseases utilizing next-generation vaccine platforms (e.g., Flu-COVID, Flu-RSV, and Flu-COVID-RSV) are currently being tested in Phase 2/3 clinical programs and vaccines with multiple strains of the same virus are already available to the public (e.g., FluMist Quadrivalent) [ 60 , 63 ]. mRNA-based vaccine development has even opened the doors to targeting diseases caused by latent viruses (e.g., cytomegalovirus [CMV] and human immunodeficiency virus [HIV]), enteric viruses (e.g., noroviruses), and bacteria (e.g., Lyme disease) [ 64 , 65 , 66 , 67 , 68 , 69 ].…”

Nanovaccines for Advancing Long-Lasting Immunity against Infectious Diseases

“…Nanotechnology offers insights into protein-based NP properties that are crucial for strong immunity and can help fight against infectious diseases. Both chemical conjugation and genetic fusion are useful methods for loading antigens onto scaffolds, and increasing numbers of studies have shown that both strategies are advantageous for immunogen design. , …”

“…Both chemical conjugation and genetic fusion are useful methods for loading antigens onto scaffolds, and increasing numbers of studies have shown that both strategies are advantageous for immunogen design. 135,136 Nonprotein Immunogens Can Enable Long-Lasting Immunity. Due to their high surface energy, multiple functional chemical groups, and special interface characteristics, nanomaterials possess large capacity for biomolecule adsorption.…”