Researchers from Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch), and the National Institute of Health’s National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) are pursuing a new vaccine design technique that shows new hope in a first-in-human clinical study, despite the fact that scientists have previously struggled to generate an effective HIV vaccine.
This new vaccine strategy, which comprises a step-by-step approach to creating antibodies capable of targeting a wide spectrum of HIV variations, is detailed in a report published in Science on December 2, 2022, and the findings are groundbreaking.
The findings show for the first time that it is possible to create a vaccination that induces specific antibodies in individuals. Co-senior author William Schief, PhD, professor and immunologist at Scripps Research and executive director of vaccine design at IAVI’s Neutralizing Antibody Center, explains that his lab consistently activated the types of antibodies they had hoped to respond in developing the vaccine antigen. The researchers think this vaccine design approach will be crucial in developing an HIV vaccine, and it may also be useful in developing vaccines against other challenging infections.
The IAVI G001 Phase 1 trial evaluated the primary component of a multi-component HIV vaccination regimen under development. According to the data collected throughout the clinical trials, 97% of those who received the vaccine experienced the desired effect after vaccination. The Science paper also includes a comprehensive immunological evaluation of the vaccine’s effects.
Mark Feinberg, MD, PhD, president and CEO of IAVI stated that the results from the Phase 1 clinical trial are so encouraging because HIV represents an area of acute unfulfilled need around the world. The researchers have come a long way toward developing a vaccine that could put an end to the HIV pandemic thanks to the intensive cooperation of numerous experts from various fields and institutes.
Rare antibodies known as broadly neutralizing antibodies (bnAbs) provide protection from many distinct virus strains. This is why researchers have been unsuccessful in their efforts to create an HIV vaccine that triggers the production of bnAbs.
The researchers are utilizing a technique called “germline targeting” to create bnAbs that can block HIV infection. When using germline targeting, the first step is to stimulate the rare immune cells that can develop into the cells that create the bnAbs needed to stop the virus. These cells are called bnAb-precursor B cells. To “prime” the immune system and induce reactions from these uncommon bnAb-precursor cells, the researchers produced a specialized chemical, known as an immunogen.
IAVI G001 was designed to test the vaccine’s safety and its ability to elicit a response from these bnAb-precursor B cells.
The vaccine induces the required target cells while maintaining a good safety profile, according to research author and IAVI vice president/head of clinical development Dagna Laufer, MD. According to the researchers, this is a major advance toward creating an HIV vaccine that is both safe and effective.
Researchers employed a complex analytical procedure to determine whether or not the intended bnAb-precursor B cells were generated.
The process of multidimensional immunological analysis has pushed clinical trial review to the next level according to co-senior author and former head of the Vaccine Immunology Program at the NIAID VRC, Adrian B. McDermott, PhD. By analyzing these key immunological parameters, the researchers provided evidence for why 97% of vaccinees developed the desired immune response to the vaccine antigen.
IAVI G001 enrolled 48 healthy adults and was conducted at two locations (George Washington University (GWU) and Fred Hutch in Washington, D.C.). Participants were given either a placebo or two injections of the eOD-GT8 60mer vaccine antigen with an adjuvant created by the pharmaceutical company GSK. Site principal investigators included Julie McElrath, MD, PhD, senior vice president and director of the Vaccine and Infectious Disease Division at Fred Hutch, and David Diemert, MD, professor of medicine at the George Washington University School of Medicine and Health Sciences.
Schief compares the study to “peeking under the hood of a car” to see how the immune system responded to the vaccine. The study took a close look at the characteristics of the antibodies and B cells generated by the vaccine antigen. One study found that each dose of vaccination activated between 30 and 65 unique bnAb precursors in each immunized individual. To some extent, this clarified why nearly everyone who received the vaccine responded well.
Other studies looked at how firmly the bnAb-precursor B cells adhered to the vaccination antigen and what mutations the bnAb-precursor B cells acquired over time. These studies demonstrated that bnAb-precursor B cells acquired affinity and progressed down beneficial maturation pathways after each vaccination dose.
However, “competitors,” or the B cells generated by the vaccine antigen that are not bnAb precursors, are a cause for worry when using this strategy. The researchers looked into the responses from the “competitors,” and what they found was quite promising. Vaccination did not seem to inhibit the maturation of bnAb-precursor responses, even though the bulk of the B cells triggered were “competitors” that could not match the binding strength of the targeted bnAb precursors.
Schief clarifies that these findings were very encouraging, as they indicated that immunogen design techniques they utilized might be applied to many different epitopes, whether for HIV or even other diseases.
The researchers will continue to experiment and construct boosting immunogens in the hopes that they would eventually induce the desired bnAbs and provide protection against the virus. These results follow closely on the heels of two other research published in Immunity same month (September 2022) and that provided additional support for the validity of the germline-targeting strategy for HIV vaccination.
Working closely with IAVI, Scripps Research, the VRC, GWU, additional investigators at Fred Hutch, and many others, this trial and additional analyses will assist shape design of the remaining stages of a possible HIV vaccine regimen according to McElrath of Fred Hutch.
Sources:
Leggat, D. J., Cohen, K. W., Willis, J. R., Fulp, W. J., deCamp, A. C., Kalyuzhniy, O., Cottrell, C. A., Menis, S., Finak, G., Ballweber-Fleming, L., Srikanth, A., Plyler, J. R., Schiffner, T., Liguori, A., Rahaman, F., Lombardo, A., Philiponis, V., Whaley, R. E., Seese, A., Brand, J., … Schief, W. R. (2022). Vaccination induces HIV broadly neutralizing antibody precursors in humans. Science (New York, N.Y.), 378(6623), eadd6502. https://doi.org/10.1126/science.add6502
https://www.scripps.edu/news-and-events/press-room/2022/20221202-schief-hiv.html
