Definition and induction of broadly protective responses against HIV-1

Despite remarkable progress achieved in decreasing HIV transmission and AIDS-related deaths in the last decade due to development of over 30 antiretroviral drugs, HIV continues to spread in a virtually uncontrolled manner. An effective HIV vaccine remains one of the priorities of HIV/AIDS research and will always be the best solution and likely key to any strategy for halting the AIDS epidemic. The biggest challenge in developing such a vaccine is the enormous HIV variability, which dwarfs that of any other virus except hepatitis C virus. However, all parts of HIV cannot easily change; to remain alive, HIV has to keep some smaller regions of its proteins more or less constant to maintain function. Our vaccine strategy takes advantage of this and focuses the body defenses on these conserved parts of HIV, its Achilles heel. Because conserved regions are common to most of the global HIV variants, the vaccine, if successful, could be used in Africa, Asia, Europe, America and Australia: it would be universal. The 1st generation conserved-region vaccine was very safe and induced strong immune responses in adult volunteers in the UK and Africa. In 2014, the pharmaceutical company GSK acquired a small biotech company, which developed one of the benign viruses we used for vaccine delivery, and unilaterally decided that we could no longer use the jointly owned vaccine in high risk people. Thus we needed to switch to an alternative vaccine virus and this provided an opportunity to also substantially improve the 1st generation vaccine. These modifications are based on our experience from human vaccine testing and other developments in the HIV vaccine field over the last 10 years since its original design. Thus, the 2nd generation vaccine was born, using a new vaccine virus (ChAdOx1) owned by Oxford University and combining conserved regions with computer-designed proteins (mosaics), which significantly increase the vaccine match to global HIV variants. (Note that even the highly conserved regions are still somewhat variable.) Vaccines should match circulating HIVs as much as possible to stop them efficiently. The 2nd generation vaccines have been constructed, shown to induce strong immune responses in animal models and are now bound for testing in human volunteers. The requested funds will allow to us see how well the 2nd generation vaccine works in trying to get rid of HIV from already infected individuals and for larger scale testing in HIV-1 negative healthy volunteers in Africa. The latter study will aim first evidence that the vaccine can stop HIV from infecting healthy people. The funding will also allow clinical testing of the vaccine enabling further improvements including some new aimed at keeping ahead of HIV.

Development of an effective vaccine against HIV/AIDS remains one of the top global health priorities even in the context of broader prevention landscape. It is generally accepted that development of HIV vaccine is a gradual iterative process that will take many years. It is very positive that significant inroads have been made into identifying what constitutes both protective T cells and broadly neutralizing Abs (bnAb) for this most difficult of vaccines.

The biggest challenges for vaccines are HIV variability and escape. Compelling evidence for an important role of CD8 T cells in controlling HIV has accumulated over the last 30 years. My group is taking a multipronged approach to HIV T-cell vaccine development combining our experimental data with novel vaccine strategies. The hypothesis we pursue is that focusing T cells on the functionally conserved regions of HIV proteins will enable early control or elimination of the transmitted/reactivated viruses. To achieve this, the vaccines must match as much as possible all HIV variants and the T cells must be robust enough to stay strong when facing natural infection, altering the natural immunodominance.

This PG Renewal will support a team of scientists led by Tomas Hanke, who are at the heart of a highly rational and promising T-cell vaccine approach. We demonstrated the concept of the conserved region strategy in European and African HIV seronegative adults and also in infected patients on ART. We are now adding a new element to the vaccine, the mosaic concept and are moving towards testing this much improved 2nd generation vaccine for HIV cure and small efficacy trials. The aim for the latter will be to complement induction of Abs when bnAb vaccines remain suboptimal. In the next 5 years, we will develop next generation of vaccine vectors and immunogens; evaluate the induction and role of non-canonical CD8 T cells for human vaccine use; asses the role of conserved T-cell responses in HIV cure and prevention.

Who will benefit from this research?

Since the first report of AIDS in 1981, an estimated 60,000,000 people have become infected with HIV-1, of whom some 25,000,000 have died. Over 90% of new infections take place in countries with limited resources. Globally the rate of new infections has decreased by 33% since year 2001. Nevertheless in 2013, still 240,000 children became newly infected with HIV-1 and 50 young women became infected every hour, thus a control of the HIV-1 epidemic remains one of the global health priorities.
Effective preventive vaccine against HIV-1 can avert millions of new infections, empower women, protect children, circumvent the stigma facing men-who-have-sex-with-men, and help many other beyond the reach of today's HIV-1 treatment and prevention options. Millions of already infected people around the word will benefit from HIV cure, either functional (drug-free control of HIV-1) or sterile (complete elimination of the virus from the body).

How will they benefit from this research?

ART has revolutionized survival, but is far from an ideal solution, because antiretroviral drugs are not available on a regular reliable basis in many resource-poor settings, they have long-term side effects, their effective use requires rigorous daily compliance and the circulating and/or transmitted viruses develop resistance. In any case, ART alone is unable to eradicate the virus because of an inaccessible pool of HIV-1-infected cells, in which the virus is dormant (the proviral reservoir). Thus, with or without reactivation by latency reverting agents, effective T-cell vaccine will be a key to HIV cure. The gained understanding and approach stimulating CD8+ T cells specific for conserved regions, would be greatly preferable to simply reactivating the pre-antiretroviral treatment T-cell responses that had failed to control the virus. Similarly, efficient and early recognition of transmitted/founder viruses will control the virus spread and prevent damage to the immune system in healthy exposed individual. Our strategy is applicable to other immunological problems where variability is a major roadblock in developing effective preventive or therapeutic tools.
The MRC Programme Grant Renewal proposes science on the forefront of the biotechnology engineering and HIV-1 vaccine development, thus strengthening the UK's world-class excellence in science, fostering industrial leadership to support business including innovation by small and medium-sized enterprises (Immune Design (US), Clinical Biomanufacturing Facility) and even big Pharma will become re-engagement if a real promise is observed in an efficacy trial. Bioengineering is a proven driver of a long-term sustainability and economic growth, we shall demonstrate the feasibility and functional validation of novel designs and biotechnologies developed by academia and manufactured by industries, spur scientific innovation across a broad sector of public and animal health and contribute to educated societal debates on issues associated with novel biotechnologies.
Ultimately, vaccine research will provide a basis for clinical decision making and policy-making for governments, policy-makers and advocates to develop evidence-based policies and advocacy aiming at prioritizing investments in HIV-1 research (clinical and basic science), allowing for an efficient use of limited funds, supporting research that has a greater potential to deliver results at population level.