December 6, 2023 – The end of the year 2023 brings another setback and disappointment for the HIV vaccine research field. Following the early termination of the HVTN 702 (Uhambo) in February 2020, HVTN 705 (Imbokodo) in September 2021 and HVTN 706 (Mosaico) in January 2023, the PrEPVacc trial bites the dust with investigators announcing today the discontinuation of immunizations in the vaccine arms of this Multi-Arms-Multi-Steps (MAMS) trial at the International Conference on AIDS and STIs in Africa (ICASA 2023) in Zimbabwe.
The trial conducted in three countries in eastern and southern Africa (Uganda, Tanzania and South Africa) had completed enrolment in March 2023. However, a recent review conducted by its Independent Data Monitoring Committee (IDMC) recommended stopping vaccination and continuing with the oral PrEP component of the study.
This “last roll of the dice for HIV vaccine [efficacy] trials” for the decade, in the words of one of the principal investigators, was innovative in several ways. Its design included a registration cohort and multiple arms combining two vaccine regimens, and two different PrEP formulations.
There have been only 10 HIV vaccine efficacy trials since the identification of the virus that causes AIDS 40 years ago. None but one showed marginal efficacy, the RV144 “Thai trial” which results were published 14 years ago. Since then, one efficacy trial attempted to reproduce the result observed in Thailand in South Africa (HVTN 702), adapting the vaccine candidates to the regional epidemiological context, and two tested a combination of products hoped to be globally effective (HVTN 705 and HVTN 706).
All four trials relied on a prime-boost regimen not specifically designed to stimulate the production of neutralizing antibodies but aimed to replicate a protective response similar to that observed in RV144. With each of them failing to provide satisfactory protection against HIV acquisition, this last setback likely signifies the demise of vaccine strategies that do not prioritize the induction of broadly neutralizing antibodies — a direction the field has already embraced.
That so few efficacy trials were conducted over four decades shows the challenges of taking promising vaccine candidates through clinical testing up to efficacy studies. The complex PrEPVacc study alongside is predecessors, promises valuable insight across a range of research areas and a promising array of vaccine products, platforms, and strategies are currently in or soon to enter phase 1 studies. Such timescale is also a stark reminder of the unpredictability of science and a lesson to learn for the future development of HIV vaccines.
While frustration and weariness are understandable reactions, they should not divert our attention from the persistent need to pursue a HIV vaccine for the sustained control of the epidemic. In the rapidly evolving landscape of HIV prevention, which predominantly revolves around antiretroviral-based tools, it becomes imperative to persuade all stakeholders involved in HIV prevention — including the affected community, researchers, funders, and policymakers— of this ongoing neccessity.
The case for an HIV vaccine needs to also evolve so that everyone can understand where an HIV vaccine sits in the biomedical HIV prevention landscape, who will need it and who will want it, and what it should and could contribute to current and future HIV prevention. The question is no longer “Why” we need an HIV vaccine, but “what” we expect from it. It is imperative to review our advocacy messages and to power HIV vaccine advocacy with data to support, strengthen and advance the case for continuing vaccine R&D — a position I will elaborate on in a future post.
Meanwhile, let’s set aside the doom and gloom, and extend our congratulations to investigators and clinical trial teams and send a heartfelt thank you to the study participants for their time, willingness, and dedication to contribute to challenging clinical research.
Once more unto the breach, dear friends, once more.
Henry V, William Shakespeare