Scientists reveal encouraging results in the first human clinical trial to evaluate an HIV vaccine approach – ScienceDaily

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While scientists have struggled in the past to create an effective HIV vaccine, a new vaccine design strategy pursued by researchers at Scripps Research, IAVI, Fred Hutch Cancer Center, National Institutes of Health, and National Institute of Allergy and Infectious Disease Vaccine Research Center (NIAID) emerges. ) is a promising new drug, according to the data of the first human clinical trial.

In a paper published in Sciences On December 2, 2022, scientists revealed important new insights into their new vaccine strategy, which includes a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants.

The data we publish Sciences It shows for the first time that one can design a vaccine that produces custom-made antibodies in humans. We had previously defined some of the molecular properties of the antibodies we wanted to elicit, and the results of this experiment showed that our vaccine antigen consistently triggered precisely those types of antibodies,” says co-author William Schaeff, PhD, professor and immunologist at Scripps Research and director. Executive Director of Vaccine Design at IAVI’s Neutralising Antibody Centre, whose lab developed the vaccine antigen.”We believe that this vaccine design strategy will be essential to making an HIV vaccine and may help the field create vaccines for other challenging pathogens.”

The Phase 1 trial, known as IAVI G001, is testing the first phase in the multistage HIV vaccine regimen the researchers are developing. Trial results show that the vaccine had favorable safety profiles and stimulated a targeted response in 97% of vaccinated subjects. Most importantly, that Sciences The study also provides a detailed immunological analysis of vaccine responses.

“HIV represents an area of ​​acute unmet need around the world, which is what makes the results from our Phase 1 clinical trial so encouraging,” says Mark Feinberg, MD, PhD, president and CEO of IAVI. “With the close collaboration of many different scientists, disciplines, and institutions, we are much closer to designing an effective vaccine that can help end the HIV pandemic.”

Priming the immune system

Broadly neutralizing antibodies (bnAbs) are a rare type of antibody that can fight off and protect against many different variants of a virus – including HIV. This is why scientists have tried to develop an HIV vaccine that induces bnAbs, but so far without success.

In the study, researchers use a strategy known as “germline targeting” to eventually produce bnAbs that can protect against HIV. The first step to targeting the germline involves stimulating rare immune cells — known as bnAb precursor B cells — which can eventually develop into cells that produce the bnAbs needed to block the virus. To accomplish this first step, the researchers engineered a custom molecule — known as an immunomodulatory factor — that would “prime” the immune system and trigger responses from these rare bnAb precursor cells.

The overarching goal of the IAVI G001 trial was to determine whether the vaccine has an acceptable safety profile and can induce responses from these bnAb precursor cells.

“By extensive monitoring of safety and tolerability during the trial, we have shown that the vaccine has an adequate safety profile, while still stimulating the necessary target cells,” says study author Dagna Laufer, MD, vice president and chief of clinical development at IAVI. “This represents a major step forward in developing an HIV vaccine that is both safe and effective.”

To determine whether the targeted bnAb precursor B cells were induced, the researchers performed a complex analytical process.

“Workflows in multidimensional immunoanalyses have moved clinical trial evaluation to the next level,” says co-senior author Adrian B. McDermott, PhD, former chief of the Immunoassay Program at NIAID VRC. “In assessing these important immunological factors, we helped explain why the vaccine antigen was able to trigger a targeted response in 97% of vaccine recipients.”

IAVI G001 was sponsored by IAVI and took place at two sites: George Washington University (GWU) in Washington, D.C., and Fred Hatch in Seattle, where 48 healthy adult volunteers were enrolled. Participants received either a placebo or two doses of the vaccine antigen, eOD-GT8 60mer, along with an adjuvant developed by the pharmaceutical company GSK. Julie McElrath, MD, PhD, co-principal author, senior vice president and director of the Division of Vaccine and Infectious Diseases at Fred Hatch, and David DeMert, professor of medicine in the GWU College of Medicine and Health Sciences, were principal investigators at the trial sites.

Deeper immunization dive

The study also carefully examined the properties of antibodies and B cells triggered by the vaccine antigen, in what Schief is like “looking under the hood of a car” to understand how the immune system works in response to a vaccine. One analysis showed that the vaccine antigen first stimulated an average of 30 to 65 different bnAb precursors per vaccinated person, and then caused those cells to multiply. This helped explain why the vaccine induced the desired response in nearly all participants.

Other analyzes investigated the specific mutations that the bnAb precursor B cells acquire over time and how tightly they bind to the vaccine antigen. These investigations showed that after each dose of vaccine, bnAb progenitor B cells acquired affinity and persisted along appropriate maturation pathways.

One concern for this type of vaccine approach is the notion of “competitors”—in other words, vaccine antigen-stimulated B cells that are not bnAb precursors. Researchers have extensively studied the ‘competitor’ responses, and the results are very encouraging. Although the majority of B cells generated by immunization were, in fact, ‘competitors’, these unwanted B cells could not match the binding strength of the desired bnAb precursor and did not appear to impede the maturation of bnAb precursor responses.

“These results were very encouraging, indicating that the design principles of immunogens we used can be applied to many different epitopes, both for HIV and even for other pathogens,” adds Schief.

With this promising data in hand covering both security and immune responses, researchers will continue to replicate and design immune enhancers that can eventually induce the required bnAbs and provide protection against the virus. These findings also come shortly after two additional studies in immunity Published in September 2022, which helped validate a germline targeting approach for HIV vaccination.

“Working with IAVI, Scripps Research, VRC, GWU, additional investigators at Fred Hutch, and many others, this trial and additional analyzes will help design the remaining stages of a candidate HIV vaccine system—while also enabling others in the field to develop vaccine strategies for two viruses. extra,” says McElrath of Fred Hutch.

IAVI, Scripps Research, NIAID, the Bill & Melinda Gates Foundation, and the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID) are partnering with biotech company Moderna to develop and test mRNA delivery of these antigens for an HIV vaccine. Two Phase 1 clinical trials based on IAVI G001 are underway, one (IAVI G002) at four sites in the United States and the other (IAVI G003) at the Family Health Research Center in Kigali, Rwanda, and the Aurum Institute in Tembisa, South Africa. Both are testing mRNA delivery of the 60mer eOD-GT8 evaluated as a recombinant protein in IAVI G001, and the US trial includes a booster antigen designed by Schief’s lab and delivered using Moderna mRNA technology. A third trial (HVTN302), at ten US sites, is testing mRNA delivery for three different HIV adjuvants designed in the Schief lab that are candidates for late-stage enhancers in multistage vaccines intended to induce bnAbs. The use of mRNA technology could greatly accelerate the pace of HIV vaccine development because it allows for faster production of clinical trial materials.

This work was supported by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI neutralizing antibody concentrate; nayed. The Scripps Center for HIV/AIDS Vaccine Immunology and Immune Gene Discovery and The Scripps Consortium for HIV/AIDS Vaccine Development; and the Ragon Institute at MGH, MIT, and Harvard. Other collaborating organizations include the Duke Human Vaccine Institute, Karolinska Institutet, and La Jolla Institute.

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