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HIV Vaccines: The challenges ahead


Wednesday, September 28, 2022

Just two years ago, AVAC highlighted the connections between COVID-19 and HIV, and outlined their implication. Two years later, those insights on Platforms, Process, Partnerships, Payers and Participatory Practices that Drive Vaccine Development remain critical. The field has continued to build on those insights as it considers priorities for the HIV vaccine field today—and tomorrow.

Because recent results from major HIV vaccine trials have had disappointments and reframed the questions the field must ask, AVAC hosted a 2022 webinar series on the progress in HIV vaccines in light of a rapidly changing research landscape. This document provides highlights from the presentations and discussions as part of this series to help advocates understand and mobilize around an agenda for HIV vaccine research and access.

graphic promoting our HVAD webinar series

People will only care about and accept an HIV vaccine if ultimately the preclinical and clinical data and efficacy are compelling, and the safety data are convincing. Also, we are now in a period with a number of other HIV prevention interventions in the pipeline. While that is certainly positive news, HIV vaccines will need to advance in this context and be tested within this broader environment of multiple prevention interventions. —Bart Haynes

The current conversations have shown that the field now recognizes that an effective HIV vaccine must be durable, show high efficacy and be designed for global delivery.They also made clear from the COVID-19 lessons that an HIV vaccine will need to accommodate broad use in lower and middle income countries at an affordable cost to achieve global impact.

Scientists recognize that HIV vaccines will need to solicit potent and sustained responses from parts of the immune system that generate B-cells and antibodies. This is “humoral” immunity. These antibodies must include broadly neutralizing antibodies capable of neutralizing the broad diversity of HIV strains that are circulating in a community. Non-neutralizing immune responses at the site of initial infection may also be required to complement or enhance the effect of neutralizing antibodies in order to achieve sterilizing immunity. Such non-neutralizing responses may come from T-cells, the innate immune response, or other parts of the immune system.

Platforms: mRNA

Following the great success of mRNA vaccines for COVID-19, it is important to distinguish between mRNA as a platform and the immunogens (proteins that induce an immune response) expressed using the mRNA platform. mRNA is basically an efficient method for making targeted proteins to stimulate a desired immune response. But the mRNA must carry the right coding to produce the necessary proteins for triggering the kind of immune response the body needs to resist infection. Just what proteins to produce against HIV is not yet known.

mRNA is not a panacea for the HIV vaccine effort. Now that the mRNA platform has been proven once and used globally, it can now be further developed for expanded use against future pandemics, including innovations particularly around testing, manufacturing, and delivery systems. As use of mRNA for HIV vaccine research progresses, it will also be important to remember some of the key considerations related to COVID-19 vaccine development: The COVID vaccines are not very effective in preventing transmission, though they’re very good at preventing severe disease. –Robin Shattock

mRNA was not the only reason why COVID vaccine development went so quickly… the ability to rapidly manufacture and test the mRNA platform, rapid mobilization of funding, rapid leveraging of existing clinical trials infrastructure, rapid enrollment of clinical trials, rapid regulatory approval processes— all of those pieces came forward together to enable the incredible speed of development of COVID vaccines. While we can leverage some of that for HIV vaccines, in particular the mRNA platform and the speed with which it can be manufactured and evaluated, ...unfortunately, I think it will be challenging to leverage all of the things that happened in COVID, given the crisis nature of what happened there. –Nina Russell

The federal government had an enormous role in the COVID response. Project Warp Speed was funded at about $18 billion by 2020, and NIH funding alone for COVID-19 response 2020-2022 was $4.8B, more than all of HIV prevention and treatment combined. –Dale Hu

Processes: Newer Approaches for Employing Vaccine Clinical Trials

Speakers and panelists agree that it has become ever more expensive and unacceptable simply to put wishful candidates into large efficacy trials. The field needs a better understanding of the underlying science so that large trials can be conducted with a greater level of confidence that the candidates they are testing may well work.

Experimental Medicine Vaccine Trials (EMVTs) are small clinical trials undertaken only to test or generate a scientific hypothesis that advances vaccine discovery and development. While they provide no direct preventive or therapeutic benefit to volunteers, that same limitation has always been true for Phase 1 and some Phase 2 trials. EMVTs can safely answer important questions about successful vaccine design in human volunteers that can't be addressed as directly in animal models.

EMVTs present a way to get iterative vaccine candidates, which test different immunogens (proteins that trigger an immunse response), into clinical trials more quickly. Regulatory approval for EMVTs can be obtained for a series of studies supported by a single pivotal toxicology study. In contrast, traditional approaches require individual toxicology studies for every immunogen variation. EMVTs involve more intense biological sampling than conventional Phase 1 or Phase 2 studies. This sampling can include biopsies or blood draws to collect as much systemic data as possible. EMVTs could also save time and money in a number of other ways, such as requiring shorter timelines, using standardized manufacturing, toxicology and regulatory procedures, and testing multiple candidates in parallel.

EMVTs opportunities and challenges graphic

Click image to enlarge.

As an example, the AMP Studies proved that bnAbs can be protective. Yet B-cells that make bnAbs develop along a particular path. It is important to test the start of a vaccine strategy (“prime”) before moving on to test the final regimen. You need EMVT to ensure you’re on the right path, or you may need to make adjustments to the vaccine regimen as you proceed. - Gail Broder

A study known as G003 is an Experimental Medicine HIV Vaccine Trial aimed at answering important questions around inducing the desired B-cell responses. At the same time, this study is building the required [research] capacity in African centers. – Pontiano Kaleebu

In tandem with EMVT, there can be a more refined use of animal studies, in particular parallel non-human primate (NHP) SHIV challenge studies, and studies in mice who have been given transplants of human immune cells. These animal studies have the potential for rapid iteration to advance a scientific question. One of the early challenges with mounting numerous EMVTs will be manufacturing capacity and enrollment.

This approach ushers in a new paradigm for how the field thinks about clinical trials. Instead of targeting resources – money, time, sweat, knowledge, collaboration – at a single shot at goal and investing all in its potential success, EMVTs focus on intense scientific analysis to test many pathways ...where volunteers recognize that they are “research partners”. – Robin Shattock

Learning Everything We Can from Past Experiments

Since the webinars in May, correlates from the two efficacy trials HVTN 702 and HVTN 705 have been published or presented. This data begins to fill in a big gap; while the field awaits further analysis, there are indications of some common immune responses to HIV vaccine candidates that need to be interrogated further. The findings to date suggest that some non-neutralizing responses and some T-cell responses from HVTN 505 may reduce infection risk, and at least cannot be ruled out.

Learning how to get durable immunity at the mucosal barriers [parts of the body that block out toxins or bacteria while allowing fluids to pass through such as the vagina or rectum] where HIV generally enters, learning how to sustain those levels at the barrier, learning how to harness all arms of the immune system not just the T-cells or the antibodies, but really think of it holistically—those are experimental studies that could happen today. We need to reevaluate immunological dogma and challenge the notions of how we think vaccine development has to proceed in order to counteract and come up with creative solutions for this particular pathogen. – Galit Alter

The HIV response must not only make best use of financial resources, but human resources as well. Community engagement work is more important than ever. Advocates and researchers must continue to argue for the urgency and need for a protective HIV vaccine. The world has become complacent about HIV being a chronic condition that can be controlled with treatment. And public health experts know that while the world has better and better prevention methods, ultimately an effective vaccine is essential to ending the epidemic. The COVID pandemic provides both a lesson and possibly an opportunity for scientists and advocates to work together to increase the urgency around HIV and vaccine development, especially in the context of pandemic preparedness.

HIV infects and establishes lifelong infection. It is incredibly evasive and highly mutable, and it has complex mechanisms to subvert and eliminate the master orchestrator of all immunological function: the CD4 cell. With HIV, we are dealing with an unprecedented challenge.

Moving forward, the HIV response needs to consider how to incorporate new prevention interventions within vaccine development. The age of trials investigating vaccines compared to placebo alone is at an end, with proven PrEP products finally at hand. Designing vaccine trials for this context is ever more urgent and important.

Prospects and Conclusions

When considering all three webinars together, a theme emerged. Innovative trial designs, including experimental medicine vaccine trials (EMVTs), may help the field save time and money. This approach can quickly ask and answer key scientific questions, which then can inform the selection of vaccine candidates to advance into larger trials. Developing quick, iterative trials designs has become crucial, as the field is still seeking the answer to a fundamental question, what immune response needs to be triggered for effective protection against HIV. This knowledge will come from basic immunological and virological research, testing ideas quickly, and by fully analyzing how and why previous trials failed to meet efficacy targets despite having had plausible hypotheses at the time.

The three webinars framed topics that could benefit from further engagement and joint action with advocates and community partners.

I. A new emphasis on experimental medicine vaccine trials that strengthen HIV vaccine research and development must maintain trust and enthusiasm from volunteers, and continue to prioritize their safety and fair treatment. This will require:

  • A robust scientific strategy with input from all stakeholders
  • Clear explanations for each trial and what it will accomplish
  • Detailed plans for community and advocate engagement to fortify trust in the process, with support for an effective vaccine as the ultimate goal

II. Questioning dogma and encouraging diverse approaches to vaccine development is important. This requires re-invigorated collaboration, recognizing the quest for an HIV vaccine as one of the greatest scientific challenges of the modern era. Priorities include:

  • Capitalizing on momentum from COVID vaccine development and stronger public-private partnerships
  • Expanding the availability of mRNA and other new technologies
  • Incentivizing pharma, contract manufacturers and other stakeholders to make small lots of clinical grade material for multiple exploratory studies
  • Increasing diversity in biomedical interventions—commit to complementary and back-up approaches that move forward in parallel, as opposed to hopping quickly to novel, untested solutions and “group think” behavior in the field

III. How the field envisions the role of an HIV vaccine must be up to date with the evolution of interventions for HIV prevention. Undertaking this work involves:

  • Addressing Target Product Profiles (TPP)—the field should refresh the expected requirements of an HIV vaccine, especially threshold efficacy levels to encourage iterative improvements over time and establish benchmarks for acceptable levels of uptake globally
  • Reinforcing the ultimate need for an HIV vaccine as an addition to other prevention approaches