HIV vaccines for prevention and the quest for a cure

The National Research Foundation (NRF) of South Africa joins with people across the globe in commemorating World Aids Day 2020. This year, at a time when the world is challenged by the global Covid-19 pandemic, HIV/AIDS remains a major global public health issue. We asked researchers at the DSI-NRF Centre of Excellence in HIV Prevention, and the DSI-NRF Research Chair in HIV Vaccine Translational Research to update us on the status of HIV/AIDS research and the progress that has been made in finding a cure.

The Road to an Effective HIV Vaccine for Prevention

By Professor Caroline T. Tiemessen, DSI-NRF Research Chair of HIV Vaccine Translational Research, University of the Witwatersrand

What we know so far

2020 marks a year where the HIV vaccine field has been delivered another blow – the Phase IIb/III trial called HVTN 702 or Uhambo, which started in 2016, showed no reduced risk of contracting HIV and vaccinations were stopped in February. This large-scale efficacy trial enrolled 5 407 South African men and women. While there was every hope that this HVTN 702 regimen, by design, would have improved on the modest efficacy of 31% seen in the 2009 RV144 vaccine trial conducted in Thailand, there is much we can learn from its failure that will inform future vaccine efforts. The answer lies in one or more of the differences. The HVTN 702 vaccine regimen was adapted for clade C infection (the most common clade in Southern Africa); a different adjuvant was included to enhance responses; and booster vaccinations added to prolong these responses. Another difference lies in the populations vaccinated and warrants a careful evaluation of the contribution of host genetics and environment to these outcomes.

Ongoing large-scale efficacy HIV vaccine trials

Two other large-scale vaccine trials have been underway, using “mosaic-based” vaccines designed to more broadly target different HIV clades across the world. The Phase IIb trial HPX2008/HVTN 705 or Imbokodo, has enrolled 2 600 women in five sub-Saharan African countries (South Africa, Zimbabwe, Mozambique, Malawi and Zambia), while the Phase III trial HVTN 706/HPX3002, or Mosaico, is enrolling 3 800 men who have sex with men (MSM) and transgender people in Argentina, Brazil, Italy, Mexico, Peru, Poland, Spain, and the United States.

Two Phase IIb trials are testing the concept of passive immunisation (direct infusion of a neutralising antibody VRCO1) for protection against acquiring HIV infection. These antibody-mediated prevention (AMP) trials have been conducted in 1 900 sub-Saharan African women (HVTN 703/HPTN 081), and in 2 700 men and transgender persons who have sex with men (HVTN 704/HPTN 085) in Brazil, Peru, Switzerland, and the United States. Results from these AMP trials are imminent.

The COVID-19 pandemic has resulted in the delay of the start of a planned Phase IIb trial of a novel combination approach of oral PreP and experimental vaccines. This trial, called PrEPVacc, will enrol 1 668 men and women from Uganda, South Africa, Tanzania and Mozambique.

There are many other promising vaccine approaches in earlier stages of development.

The ongoing quest to find an HIV cure

Sadly, 2020 marks the loss of a fierce advocate for HIV cure research – Timothy Ray Brown. Also known as the “Berlin patient,” he was the first patient recognised as cured of HIV. He received two bone marrow transplants, a year apart, from the same donor with a mutation in CCR5, which prevents HIV from entering cells. Following in his footsteps as the second case of cure through stem cell transplantation also from a CCR5-deficient donor, the “London patient” was identified in 2019. Recent findings in a study of elite controllers (people who naturally suppress their virus to undetectable levels in the absence of antiretroviral drugs) identified a single patient who may have eliminated all cells that contain HIV that can replicate (known as replication-competent virus). The thinking is that vigorous immune responses may have eliminated such cells over time, leaving only cells containing remnants of HIV DNA that cannot produce the virus. Post-treatment controllers (who, usually following a period of early antiretroviral treatment, suppress virus to undetectable levels) are another group of interest.  A recent report of the “Brazilian patient” who was not treated early but received an intensified regimen of antiretroviral drugs, achieved undetectable virus off drugs for 15 months. Our local example of a South African post-treatment controller child who received early treatment for a year which was then stopped continues to maintain undetectable virus with standard tests – now 12 years off antiretroviral treatment. To date, we have found no evidence of replication-competent virus with more sophisticated tests, however these are ongoing.

Examples of remarkable cases that have achieved undetectable HIV with or without some intervention tell us that it is possible to achieve an HIV cure. The scientific challenge remains how we use the knowledge we gain from these examples and turn them into effective strategies for cure. Among the approaches being pursued are therapeutic vaccines, broadly neutralising antibodies, toll-like receptor agonists and gene therapies.