Kumamoto University

http://www.great-partnership.eu

https://www.eavi2020.org

https://doi.org/10.33548/SCIENTIA538

The world needs an HIV-1 vaccines. 

Professor Tomáš Hanke's research aims to significantly contribute to developing a safe and effective HIV-1 vaccine by induction of protective T-cell responses. His basic research seeks to understand what constitutes protective killer T cells against HIV-1. It underpins vaccine design and construction, testing novel vaccine strategies in pre-clinical models while focusing on iterative improvements of the vaccine design (immunogen and delivery) driven by human data. He coordinates a programme of Experimental Medicine trials on five continents testing the 3rd generation of candidate killer T-cell vaccines called HIVconsvX alone and in combination with cutting-edge tools for HIV cure and prevention.

HIV-1 diversity is astonishing and remains the single biggest challenge for HIV-1 vaccine development. Viruses with highly variable genomes, such as HIV-1, rapidly mutate epitopes to escape T-cell and Ab recognition, and the immune pressure selects the fittest escaped variants to overgrow. This immediately suggests that epitopes that are easily mutated and escape with minimal fitness cost are less protective than epitopes in the protein regions constrained by function. Professor Hanke's hypothesis posits that (re)focusing from the onset of virus infection or reactivation killer T cells by vaccination on the most conserved, and therefore vulnerable regions of HIV-1, which are common to most global variants and are hard to mutate, will help slow and control HIV-1. Conserved regions contain epitopes typically subdominant and therefore underutilized in natural HIV-1 infection due to domination by their hypervariable non-protective ‘decoy’ counterparts. If the conserved region vaccine strategy proves effective, its cross-clade reach offers a global vaccine deployment: it would be universal despite the HIV-1 diversity. To this end, Professor Hanke and colleagues demonstrated in several phase 1 and 2 trials in humans induction of robust broadly specific T cells targeting vulnerable parts of HIV-1. These T cells inhibited viruses representative of four major global clades and provided a signal of durable virus control after stopping virus inhibition by cART in vaccinated PLWH treated during primary HIV-1 infection. The latest version of the vaccine design called HIVconsvX with optimized conserved regions and increased match to global HIV-1 variants by a bivalent mosaic design entered clinical evaluations in 2019. These and other upcoming trials will provide the first hints of efficacy (or lack of) and generate unique human samples, which will enable us to improve our understanding of protective killer T-cell responses against HIV-1.