Experimental HIV vaccine trialled in humans

Monday, 05 April, 2021

Experimental HIV vaccine trialled in humans

Researchers from IAVI and Scripps Research have developed a novel vaccine approach to prevent HIV which has produced promising results in a phase 1 clinical trial. It’s a bold claim to make, given that HIV is known to be among the most difficult viruses to target with a vaccine — in large part because it constantly evolves into different strains to evade the immune system.

For decades now, HIV researchers have pursued the Holy Grail of stimulating the immune system to create rare but powerful antibodies that can neutralise diverse strains of HIV. Known as ‘broadly neutralising antibodies’, or bnAbs, these specialised blood proteins could attach to HIV spikes, proteins on the virion surface that allow the virus to enter human cells, and disable them via important yet difficult-to-access regions that don’t vary much from strain to strain.

“We and others postulated many years ago that in order to induce bnAbs, you must start the process by triggering the right B cells — cells that have special properties giving them potential to develop into bnAb-secreting cells,” said Professor William Schief, an immunologist at Scripps Research and Executive Director of Vaccine Design at IAVI’s Neutralizing Antibody Center.

“In this trial, the targeted cells were only about one in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells.”

The strategy of targeting naïve B cells with specific properties is called ‘germline targeting’, as these young B cells display antibodies encoded by unmutated or ‘germline’ genes. The priming step would be the first stage of a multistep vaccine regimen aimed at eliciting many different types of bnAbs, Prof Schief said.

The trial

The clinical trial, IAVI G001, was sponsored by IAVI and took place at two sites: The George Washington University in Washington, DC, and the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle, enrolling 48 healthy adult volunteers. Participants received either a placebo or two doses of the vaccine compound, eOD-GT8 60mer, along with an adjuvant developed by pharmaceutical company GSK.

The vaccine showed success in stimulating production of rare B cells needed to start the process of generating antibodies against the fast-mutating virus; the targeted response was detected in 97% of participants who received the vaccine. Prof Schief presented the results on behalf of the study team at the International AIDS Society’s HIV Research for Prevention (HIVR4P) virtual conference in February 2021.

“This study demonstrates proof of principle for a new vaccine concept for HIV — a concept that could be applied to other pathogens as well,” Prof Schief said. “With our many collaborators on the study team, we showed that vaccines can be designed to stimulate rare immune cells with specific properties, and this targeted stimulation can be very efficient in humans. We believe this approach will be key to making an HIV vaccine and possibly important for making vaccines against other pathogens.”

“This is a landmark study in the HIV vaccine field, demonstrating success in the first step of a pathway to induce broad neutralising antibodies against HIV-1,” added Dr Julie McElrath, Senior Vice President and Director of Fred Hutch’s Vaccine and Infectious Disease Division, who served as lead investigator at the Fred Hutch trial site.

“The novel design of the immunogen, the clinical trial and the molecular B cell analyses provide a roadmap to accelerate further progress toward an HIV vaccine.”

HIV and beyond

The study sets the stage for additional clinical trials that will seek to refine and extend the approach — with the long-term goal of creating a safe and effective HIV vaccine. As a next step, IAVI and Scripps Research are partnering with biotechnology company Moderna to develop and test an mRNA-based vaccine that harnesses the approach to produce the same beneficial immune cells. Using mRNA technology could significantly accelerate the pace of HIV vaccine development.

“Given the urgent need for an HIV vaccine to rein in the global epidemic, we think these results will have broad implications for HIV vaccine researchers as they decide which scientific directions to pursue,” said Dr Mark Feinberg, President and CEO of IAVI. “The collaboration among individuals and institutions that made this important and exceptionally complex clinical trial so successful will be tremendously enabling to accelerate future HIV vaccine research.”

Beyond HIV, the researchers believe the germline-targeting approach could be applied to vaccines for other challenging pathogens such as influenza, dengue, Zika, hepatitis C viruses and malaria.

“This is a tremendous achievement for vaccine science as a whole,” said Professor Dennis Burton, Chair of the Department of Immunology and Microbiology at Scripps Research, Scientific Director of the IAVI Neutralizing Antibody Center and Director of the NIH Consortium for HIV/AIDS Vaccine Development.

“This clinical trial has shown that we can drive immune responses in predictable ways to make new and better vaccines, and not just for HIV. We believe this type of vaccine engineering can be applied more broadly, bringing about a new day in vaccinology.”

Pictured: A computer image of HIV’s outermost layer, densely coated with sugar molecules (purple) that do not trigger an immune response. Most of the surface not covered in sugars (in red and yellow) is highly variable, making it difficult for the immune system to generate antibodies capable of neutralising the virus. Image credit: Sergey Menis, IAVI.

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