Scientists have long struggled to create an effective vaccine for HIV, but a novel vaccine design strategy utilized by researchers at Scripps Research, IAVI, Fred Hutchison Cancer Center, the National Institutes of Health, and the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center reveals promising findings in their first-in-human clinical trial.
"The data we are publishing in Science demonstrates for the first time that one can design a vaccine that elicits made-to-order antibodies in humans. We specified in advance certain molecular properties of the antibodies that we wanted to elicit, and the results of this trial show that our vaccine antigen consistently induced precisely those types of antibodies," says co-senior author William Schief, Ph.D., professor and immunologist at Scripps Research and executive director of vaccine design at IAVI's Neutralizing Antibody Center, whose laboratory developed the vaccine antigen. "We believe this vaccine design strategy will be essential to make an HIV vaccine and may help the field create vaccines for other difficult pathogens."
Researchers have been attempting to develop an HIV vaccine that includes broadly neutralizing antibodies (bnAbs), a rare type of antibody that can fight and protect against many different viral variants, including HIV. In the paper published in the journal Science, the team utilized a "germline targeting" strategy to produce bnAbs that protect against HIV.
The work began with a Phase 1 trial to test the first stage of a multi-stage HIV vaccine regime developed by the team. The trial results revealed that the vaccine had a favorable safety profile and included the targeted response in 97% of vaccinated people. The team also included a detailed immunological analysis of the vaccine responses in their paper.
"HIV represents an area of dire unmet need across the world, which is what makes the findings from our Phase 1 clinical trial so encouraging," says Mark Feinberg, MD, PhD, president and CEO of IAVI. "Through the close-knit collaboration of many different scientists, disciplines and institutions, we are that much closer to designing an effective vaccine that could help end the HIV pandemic."
The first stem of germline targeting involves stimulating bnAb-precursor B cells that eventually evolve into cells that produce bnAbs. To accomplish this, the scientists designed a customized immunogen that would "prime" the immune system and elicit a response from the bnAb-precursor cells.
"Through extensive safety and tolerability monitoring during the trial, we showed the vaccine had a favorable safety profile, while still inducing the necessary target cells," says study author Dagna Laufer, MD, vice president and head of clinical development at IAVI. "This represents a large step forward in developing an HIV vaccine that is both safe and effective."
Next, the team conducted sophisticated analytical analyses to determine if the targeted bnAb-precursor B cells were induced in the body. "The workflow of multidimensional immunological analyses has taken clinical trial evaluation to the next level," says co-senior author Adrian B. McDermott, PhD, former chief of the Vaccine Immunology Program at the NIAID VRC. "In evaluating these important immunological factors, we helped show why the vaccine antigen was able to induce the targeted response in 97% of vaccine recipients."
The study also examined the properties of antibodies and B cells introduced by the vaccine antigen. One analysis revealed that the vaccine antigen first stimulated an average of 30-65 different bnAb precursors per person vaccinated and then caused those cells to multiply. This helped the team understand how the vaccine induced the desired response in almost all participants.
While many challenges still lay ahead, such as navigating "competitor" B cells induced by the vaccine antigen that are not bnAb precursors, the team remains optimistic about their findings thus far. "These findings were very encouraging, as they indicated that immunogen design principles we used could be applied to many different epitopes, whether for HIV or even other pathogens," says Schief.