How mRNA Could Help Create an HIV Vaccine

While antiretroviral treatments now allow millions of people with HIV to live healthy lives, the virus continues to spread globally, and a safe and effective protective vaccine remains one of medicine’s greatest unmet needs.

A new study published last month in Science Translational Medicine offers grounds for cautious optimism. Scientists tested an mRNA-based vaccine that, like the one used for COVID-19, provides cells with the genetic instructions needed to make a version of the HIV envelope protein (Env), the viral protein spike that antibodies must target to block infection.

The challenge for researchers is that HIV’s envelope protein is constantly mutating, it hides some of its own key immunogenic regions (regions capable of producing an immune response), and it is covered by a dense coat of sugars. Imagine a cake under one of those glass domes—you can reach it only if the dome is lifted. In the same way, all these mechanisms prevent antibodies from reaching immunogenic regions of the envelope protein.

To address this, the researchers designed an mRNA vaccine that makes a “membrane-bound” version of Env, anchoring it in the cell membrane, much like it is on the virus itself. The idea is to mimic the virus more faithfully while inducing an effective immune response—in a way, lifting the glass dome and exposing the cake.

The vaccine was tested in rabbits and monkeys. The membrane-bound version of Env successfully generated neutralizing antibodies capable of blocking infection and only a few “off-target” antibodies. Some monkeys developed clear neutralizing responses after three doses, a result not typically seen with other types of vaccines. In addition, the vaccine triggered killer T cell responses that can destroy infected cells. This feature is usually harder to achieve with protein-based vaccines but is a hallmark of mRNA-based approaches.

The vaccine approach was subsequently tested in a human trial, HVTN 302. Early results confirmed that the approach is feasible, and some participants developed neutralizing antibodies after three doses, an important milestone in HIV vaccine research.

However, the trial also produced an unexpected safety signal: about 7% (seven of 108) of participants developed a rash after vaccination, which in four cases persisted for up to a year. The researchers couldn’t pinpoint a clear cause and the reactions were usually manageable with antihistamines, but the findings highlight the need for ongoing monitoring as mRNA HIV vaccines advance in clinical testing. The four affected individuals continue to be monitored.

We should view these results with both optimism and caution. The membrane-bound mRNA vaccine guides the immune system toward useful antibody responses more effectively than older designs. At the same time, the reported skin reactions underscore the complexity of developing new vaccine platforms and the importance of more research to understand what caused the reactions and to improve the current formulation.

Despite the promise and potential of this line of research, federal policy is shifting. In early August, the U.S. Department of Health and Human Services announced it would wind down mRNA vaccine development, canceling or truncating projects worth nearly $500 million, citing concerns about the effectiveness of mRNA vaccines, which are proven to be safe and have been extremely successful at preventing SARS-Cov2 infection and the disease and death caused by COVID-19. Decisions like this could undermine future innovation and health-threat preparedness.

Stopping research is never the right answer. While no single study can provide all the solutions, this and previous work shows that mRNA technology is not just promising, but could hold the key to an effective HIV vaccine.

Dr. Gramatica is an amfAR vice president and director of research.

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