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HIV Vaccine Candidate Induces Broadly Neutralizing Antibodies in Humans

Photograph of a vaccine vial with a needle drawing liquid
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Infection with HIV is currently manageable with lifelong antiretroviral medications, but neither a vaccine nor a cure is available. A critical roadblock in preventative vaccine development has been the inability to induce B-cell lineages of broadly neutralizing antibodies (bnAbs) that can combat rapidly evolving strains of the virus.

Now, an HIV vaccine candidate has reportedly triggered low levels of HIV bnAbs among a small group of people enrolled in a 2019 clinical trial.

The findings, reported in the journal Cell, not only provide proof that a vaccine can elicit bnAbs to fight diverse strains of HIV but that it can also initiate the process within weeks.

Inducing HIV antibody responses in humans

The vaccine candidate developed at the Duke Human Vaccine Institute targets an area on the HIV-1 outer envelope called the membrane-proximal external region (MPER), which remains stable even as the virus mutates. bnAbs against this stable region in the HIV-1 outer coat can block infection by many different circulating strains of HIV-1.

Discussing the decision to target the MPER of the HIV-1 outer envelope, Dr. Barton Haynes, director of the Duke Human Vaccine Institute, told Technology Networks, “The MPER is targeted by the broadest of the neutralizing antibodies. We have isolated a version of MPER bnAbs from a person living with HIV that neutralized 99% of HIV strains.”

Why are bnAbs promising in HIV-1 prevention and therapy?

Interfering with the interaction of the HIV-1 outer envelope with its host cell receptors, bnAbs interrupt viral replication through a mechanism that differs from most antiretroviral drugs. bnAbs can augment host antiviral immune responses by engaging effector responses. Their long in vivo half-life and favorable safety profile make them attractive clinical application candidates.

Potent bnAbs develop in people living with HIV-1, but only rarely and after many months to years after transmission. “One of the questions we have worried about for many years is if it will take years to induce bnAbs with a vaccine like it takes for bnAbs to develop in people living with HIV,” explained Haynes. “Here we found that bnAb lineages developed after the second immunization.”

“Since this is the first and only human trial that resulted in bnAb B cells getting to heterologous neutralization, this is a big proof of concept for being able to induce bnAbs quickly with a vaccine in humans.”

The research team analyzed data from the HVTN 133 Phase 1 clinical trial. Twenty healthy, HIV-negative individuals enrolled in the trial. Fifteen participants received two of four planned doses of the investigational vaccine, and five received three doses.

After two immunizations, the vaccine showed a 95% serum response rate and a 100% blood CD4+ T-cell response rate, indicating strong immune activation.

Crucial immune cells remained in a state of development that allowed them to continue acquiring mutations so that they could evolve alongside the constantly changing virus.

The trial was halted when one participant experienced a non-life–threatening allergic reaction. “We suspect that the allergic reaction was a reaction to polyethelene glycol (PEG) and have studied such responses in vitro,” said Haynes. “We have evidence that this is the case and have remade the vaccine as a PEG-less MPER peptide-liposome for retesting in humans at lower doses. The latter lower doses because the vaccine worked better in the trial at the low dose.”

A route to successful HIV-1 vaccine development

While scientists have been striving to produce an HIV vaccine since the 1980s, several features of the virus have made it difficult to develop an effective vaccine.

A signature of HIV infection is its vast genetic diversity and the virus's ability to evolve rapidly within and between infected individuals. Scientists have identified that an effective HIV vaccine will need to be able to produce an immune response that can prevent infection by the diverse HIV strains circulating in the world.

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This work shows the feasibility of inducing antibodies with immunizations that neutralize the most difficult strains of HIV and has provided important insights into the design and feasibility of HIV-1 vaccine development efforts.

Discussing the steps they are taking to improve the vaccine, Haynes said, “We have added additional regions of the MPER to give the response more potency and breadth.  We have deleted PEG from the vaccine, and we have designed mRNAs that boost the responses induced by the original vaccine.”

The researchers stress there is still more work to be done to create a more robust response. They hope to replicate what was done in this research with immunogens that target the other vulnerable sites on the virus envelope.

Dr. Barton Haynes was speaking to Blake Forman, Senior Science Writer and Editor for Technology Networks.

About the interviewee:

Dr. Barton Haynes is the Frederic M. Hanes Professor of Medicine and Immunology, and director of the Duke Human Vaccine Institute. Haynes leads a team of investigators working on vaccines for emerging infections, including tuberculosis, pandemic influenza, emerging coronaviruses and HIV/AIDS.

Reference: Williams WB, Alam SM, Ofek G, et al. Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans. Cell. 2024. doi: 10.1016/j.cell.2024.04.033