Kumamoto University

http://www.great-partnership.eu

https://www.eavi2020.org

https://doi.org/10.33548/SCIENTIA538

Although HIV-1/AIDS pandemic has become a managed chronic disease and has gotten out of the focus of many funding bodies, it remains one of the global public health priorities. An effective preventive vaccine against HIV-1 can avert millions of new infections, empower women, protect children, circumvent the stigma and discrimination facing men-who-have-sex-with-men and all HIV-1-positive individuals, and help many others beyond the reach of today’s HIV-1 treatment and prevention options. Millions of people already living with HIV around the world will benefit from the HIV cure. With the renewed focus on infectious diseases, pandemics and demonstrated societal impact pathogens can have on communities and state and even global economies, the time has never been better to widen our understanding of host-pathogen interactions, gather novel information on protective responses against viruses and their induction, develop new skills and expand the toolbox of antiviral vaccines and human vaccinology. 

Professor Tomáš Hanke's research aims to make significant contributions towards the development of a safe and effective HIV-1 vaccine through induction of protective T-cell responses. His basic research aims to understand what constitutes protective killer T cells against viral infections and is balanced with vaccine conception 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 co-ordinates translational Experimental Medicine trials in the UK, Europe, the US and in Africa, where his partners and he enhance research capacity and infrastructure.

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. Therefore, Professor Hanke's hypothesis postulates 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 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 such a 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 a series of 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 a durable virus control after stopping virus inhibition by ART in vaccinated patients treated during primary HIV-1 infection. Upgraded 3rd iteration 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 and generate unique human samples, which will further our understanding of protective  killer T-cell responses against HIV-1, the most difficult of viruses.