While scientists have historically struggled to create an effective vaccine against HIV, a new vaccine design strategy is being pursued by researchers from Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch), and the National Institutes of Health , National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) shows new promise, according to data from a first-in-human clinical trial.
In an article published in Science on December 2, 2022, the scientists will reveal crucial new insights into their new vaccine strategy, which involves a step-by-step approach to producing antibodies that can target a wide range of HIV variants.
“The data in which we publish Science shows for the first time that one can design a vaccine that elicits custom antibodies in humans. We pre-specified molecular properties of the antibodies we wanted to elicit, and the results of this trial show that our vaccine antigen consistently induced exactly those types of antibodies,” said co-senior author William Schief, PhD, a professor and immunologist at Scripps. Research and executive director of vaccine design at IAVI’s Neutralizing Antibody Center, whose lab developed the vaccine antigen.” We believe this vaccine design strategy will be essential to making an HIV vaccine and can help the field make vaccines for other difficult pathogens .”
The Phase 1 trial, known as IAVI G001, tested the first phase of a multistage HIV vaccination regimen that the researchers are developing. The trial results show that the vaccine had a favorable safety profile and elicited the intended response in 97% of people who were vaccinated. It is important that the Science study also provides a detailed immunological analysis of vaccine responses.
“HIV represents an area of great unmet need around the world, which is what makes the findings of our Phase 1 clinical trial so encouraging,” said Mark Feinberg, MD, PhD, president and CEO of IAVI. “Through 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.”
Prime the immune system
Broadly neutralizing antibodies (bnAbs) are a rare type of antibody that can fight and protect against many different variants of a virus, including HIV. Therefore, scientists have tried to develop an HIV vaccine that induces bnAbs, but so far without success.
The researchers in the study use a strategy known as “germline targeting” to eventually produce bnAbs that can protect against HIV. The first step of germline targeting involves stimulating the rare immune cells – known as bnAb precursor B cells – which can eventually evolve into the cells that produce the bnAbs needed to block the virus. To accomplish this first step, the researchers designed a custom molecule – known as an immunogen – that would “prime” the immune system and elicit responses from these rare bnAb precursor cells.
The overarching goal of the IAVI G001 trial was to determine whether the vaccine had an acceptable safety profile and could induce responses from these bnAb precursor B cells.
“Through extensive safety and tolerability monitoring throughout the trial, we demonstrated that the vaccine had a favorable safety profile while still inducing necessary target cells,” said study author Dagna Laufer, MD, vice president and chief of clinical development at IAVI. “This represents a major step forward in the development of an HIV vaccine that is both safe and effective.”
To determine whether the targeted bnAb precursor B cells were induced, the researchers performed a sophisticated analytical process.
“The workflow of multidimensional immunology analyzes has taken clinical trial evaluation to the next level,” said co-senior author Adrian B. McDermott, PhD, former chief of the Vaccine Immunology Program at the NIAID VRC. “By evaluating these key immunological factors, we showed why the vaccine antigen was able to induce the 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, DC, and Fred Hutch in Seattle, with 48 healthy adult volunteers. Participants received 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-senior author, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division, and David Diemert, MD, professor of medicine at the GWU School of Medicine and Health Sciences, were principal investigators in the trial locations.
A deeper immunological dive
The study also carefully examined the properties of the antibodies and B cells induced by the vaccine antigen, in what Schief likens to “looking under the hood” to understand how the immune system worked in response to the vaccine. One analysis showed that the vaccine antigen first stimulated an average of 30 to 65 different bnAb precursors per vaccinee, then caused those cells to multiply. This helped explain why the vaccine elicited the desired response in nearly all participants.
Other analyzes delved into the specific mutations the bnAb precursor B cells acquired over time and how tightly they bound to the vaccine antigen. These studies showed that after each dose of the vaccine, the bnAb precursor B cells gained affinity and continued their favorable maturation trajectories.
A concern for this type of vaccine approach is the notion of “competitors” – in other words, the B cells induced by the vaccine antigen that are not bnAb precursors. The researchers have extensively studied the reactions of the “competitor” and the results have been very encouraging. Although the majority of vaccine-triggered B cells were in fact “competitors”, these unwanted B cells failed to match the binding strength of the desired bnAb progenitors and did not appear to hinder the maturation of the bnAb progenitor responses.
“These findings were very encouraging, as they indicated that the immunogen design principles we used could be applied to many different epitopes, both for HIV and other pathogens,” added Schief.
With this promising data in hand that spans both safety and immune responses, the researchers will continue to iterate and design stimulatory immunogens that can ultimately induce the desired bnAbs and provide protection against the virus. These findings also come shortly after two additional studies Immunity published in September 2022, which helped validate the germline targeting approach for HIV vaccination.
“In collaboration with IAVI, Scripps Research, the VRC, GWU, additional researchers at Fred Hutch and many others, this trial and additional analyzes will help design the remaining stages of a candidate HIV vaccination regimen – while also guiding others into enable the field to develop vaccine strategies for other viruses,” said Fred Hutch’s McElrath.
IAVI, Scripps Research, NIAID, the Bill & Melinda Gates Foundation, and the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID) are collaborating with the biotechnology company Moderna to advance mRNA delivery from this HIV vaccine antigens. Two Phase I clinical studies are underway building on IAVI G001, one (IAVI G002) at four US sites and another (IAVI G003) at the Center for Family Health Research in Kigali, Rwanda, and the Aurum Institute in Tembisa, South Africa. Both test mRNA release from the eOD-GT8 60mer that was evaluated as a recombinant protein in IAVI G001, and the US trial includes a boost antigen designed by the Schief lab and delivered with Moderna mRNA technology. A third trial (HVTN302), at ten US sites, is testing mRNA delivery of three different stabilized HIV trimers designed in the Schief lab that are candidates for late-stage boosters in multi-stage vaccines targeting the induce bnAbs. The use of mRNA technology could significantly accelerate the pace of HIV vaccine development, as it enables faster production of clinical trial materials.
This work was supported by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; the IAVI Neutralizing Antibody Center; NIAID; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and Scripps Consortium for HIV/AIDS Vaccine Development; and the Ragon Institute at MGH, MIT, and Harvard. Other collaborating organizations include Duke Human Vaccine Institute, Karolinska Institutet, and La Jolla Institute.