While scientists have struggled in the past to develop an effective vaccine against HIV, researchers from Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch) and the National Institutes of Health, National Institute of Allergy and The Vaccine Research Center ( VRC) of Infectious Diseases (NIAID) shows promise according to data from a first human clinical trial.
In a publication in Science On December 2, 2022, the scientists are announcing important new insights into their novel vaccine strategy, which involves a step-by-step approach to produce antibodies capable of targeting a wide range of HIV variants.
“The data in which we publish Science shows for the first time that it is possible to develop a vaccine that elicits tailor-made antibodies in humans. We specified in advance certain molecular properties of the antibodies we wanted to elicit, and the results of this study show that our vaccine antigen consistently induces precisely these types of antibodies,” says co-senior author Dr. William Schief, a professor and immunologist at Scripps Research and executive director for vaccine design at IAVI’s Neutralizing Antibody Center, whose lab developed the vaccine antigen. “We believe this vaccine design strategy will be essential to producing an HIV vaccine and can help the field develop vaccines for other difficult pathogens.”
The Phase 1 trial, known as IAVI G001, tested the first stage of a multi-stage HIV vaccine regimen the researchers are developing. The study results show that the vaccine had a favorable safety profile and elicited the desired response in 97% of those vaccinated. Important that Science Study also provides detailed immunological analysis of vaccine responses.
“HIV represents an area of urgent need worldwide, which is what makes the results 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 developing an effective vaccine that could help end the HIV pandemic.”
Preparation of the immune system
Broad neutralizing antibodies (bnAbs) are a rare type of antibody that can fight and protect against many different variants of a virus, including HIV. For this reason, 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 ultimately create bnAbs that can protect against HIV. The first step in germline targeting involves stimulating the rare immune cells — known as bnAb precursor B cells — which can eventually develop into the cells that produce the bnAbs needed to block the virus. To achieve this first step, the researchers designed a custom-made molecule – known as an immunogen – that would ‘prime’ the immune system and elicit responses from these rare bnAb progenitor cells.
The overall objective of the IAVI G001 study was to determine whether the vaccine has an acceptable safety profile and can elicit responses from these bnAb progenitor B cells.
“Through extensive safety and tolerability monitoring throughout the study, we have demonstrated that the vaccine has a favorable safety profile while inducing the required target cells,” said study author Dagna Laufer, MD, vice president and head 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 analysis procedure.
“The workflow of multidimensional immunological analysis has taken clinical trial evaluation to the next level,” said co-senior author Adrian B. McDermott, PhD, former director of the Vaccine Immunology Program at NIAID VRC. “By assessing these important immunological factors, we were able to show why the vaccine antigen was able to elicit the targeted response in 97% of vaccine recipients.”
Sponsored by IAVI, IAVI G001 was held at two locations: George Washington University (GWU) in Washington, DC and Fred Hutch in Seattle, and involved 48 healthy adult volunteers. Participants received either a placebo or two doses of the eOD-GT8 60mer vaccine antigen, along with an adjuvant developed by 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 the lead authors Investigators study sites.
A deeper immunological dive
The study also carefully examined the properties of the antibodies and B cells induced by the vaccine antigen, which Schief likens to “looking under the hood” to understand how the immune system functioned in response to the vaccine. Analysis showed that the vaccine antigen initially stimulated an average of 30 to 65 different bnAb precursors per vaccinated person and then caused these cells to multiply. This helped explain why the vaccine elicited the desired response in almost all participants.
Other analyzes looked at the specific mutations that the bnAb precursor B cells acquired over time and how tightly they are bound to the vaccine antigen. These studies showed that after each dose of vaccine, the bnAb progenitor B cells gained affinity and propagated along favorable maturation pathways.
A problem with 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. Researchers extensively examined the “competitors'” responses, and the results were very encouraging. Although the majority of B cells elicited by vaccination were indeed “competitors,” these unwanted B cells could not match the binding strength of the desired bnAb precursors and did not appear to impede the maturation of the bnAb precursor responses.
“These results were very encouraging as they showed that the immunogen design principles we used could be applied to many different epitopes, be it for HIV or even other pathogens,” adds Schief.
With this promising data, which includes both safety and immune responses, the researchers will continue to iterate and develop booster immunogens that could eventually induce the desired bnAbs and provide protection from the virus. These findings also come in shortly after two other studies immunity published in September 2022, which helped validate the germline targeting approach for vaccination against HIV.
“In collaboration with IAVI, Scripps Research, VRC, GWU, additional researchers at Fred Hutch and many others, this study and additional analysis will help inform the design of the remaining phases of an HIV vaccine candidate – while empowering others in the field.” to develop vaccine strategies for other viruses,” says Fred Hutch’s McElrath.
IAVI, Scripps Research, NIAID, the Bill & Melinda Gates Foundation and the US President’s Contingency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID) are collaborating with biotechnology company Moderna to identify the mRNA Advancement to develop and test these HIV vaccine antigens. Two Phase I clinical trials are ongoing that build on IAVI G001, one (IAVI G002) at four sites in the US and another (IAVI G003) at the Center for Family Health Research in Kigali, Rwanda and at The Aurum Institute in Tembisa , South Africa. Both test mRNA delivery of the eOD-GT8 60mer evaluated as a recombinant protein in IAVI G001, and the US study includes a boost antigen developed by the Schief lab and delivered with mRNA technology from Moderna. A third study (HVTN302) at ten US sites is testing the mRNA delivery of three different stabilized HIV trimers developed in the Schief lab, which are candidates for late-stage boosters in multi-stage vaccines aimed at inducing bnAbs . The use of mRNA technology could significantly speed up the development of HIV vaccines by enabling faster production of clinical trial material.
This work was supported by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; the IAVI Center for Neutralizing Antibodies; NIAID; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and Scripps Consortium for HIV/AIDS Vaccine Development; and the Ragon Institute of MGH, MIT and Harvard. Other collaborating organizations include the Duke Human Vaccine Institute, the Karolinska Institutet, and the La Jolla Institute.