While scientists have previously failed to create an effective vaccine against HIV, results from a first-in-human clinical study indicate that a novel vaccine design approach being used by scientists offers new potential. Researchers from Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch), and the National Institutes of Health’s (NIH) Vaccine Research Center (VRC) published their findings in a paper in the journal Science. They provided important new insights into their novel vaccine strategy, which involves a stepwise method of producing antibodies capable of targeting a wide range of HIV variants.
“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,” 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 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.”
The initial step of the multi-stage HIV vaccination regimen that researchers are designing was evaluated in the Phase 1 study, known as IAVI G001. The study results demonstrate that the vaccination had a good safety profile and elicited the desired reaction in 97% of recipients. The Science research, which is significant, also offers a thorough immunological examination of the vaccination reactions.
“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 initial step of the multi-stage HIV vaccination regimen that researchers are designing was evaluated in the Phase 1 study, known as IAVI G001. The study results demonstrate that the vaccination had a good safety profile and elicited the desired reaction in 97% of recipients. The Science research, which is significant, also offers a thorough immunological examination of the vaccination reactions.
The immune system’s preparation
A uncommon class of antibodies known as broadly neutralising antibodies (bnAbs) can combat and provide protection from a wide range of viral types, including HIV. This is the reason why researchers have attempted, but so far failed, to create an HIV vaccine that causes bnAbs.
To eventually develop bnAbs that can defend against HIV, the study’s researchers are employing a technique known as “germline targeting.” The initial stage in germline targeting is to stimulate the bnAb-precursor B cells, which are a subset of the rare immune cells that can ultimately develop into cells that make the bnAbs required to stop the virus.
In order to complete this initial stage, the researchers created an immunogen, a specially engineered chemical that would “prime” the immune system and trigger reactions from these uncommon bnAb-precursor cells.
The main objective of the IAVI G001 experiment was to evaluate the vaccine’s safety profile and its ability to elicit responses from these bnAb-precursor B 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.”
The researchers used a complex analytical procedure to evaluate if the targeted bnAb-precursor B cells were induced. “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.”
IAVI G001, which recruited 48 healthy adult volunteers, was funded by IAVI and held at two locations: Fred Hutch in Seattle and George Washington University (GWU) in Washington, D.C. The vaccine antigen, eOD-GT8 60mer, was given in two doses coupled with an adjuvant created by the pharmaceutical company GSK, or the placebo. Lead investigators at the study locations were David Diemert, MD, professor of medicine at GWU School of Medicine and Health Sciences, and Julie McElrath, MD, PhD, co-senior author, senior vice president, and director of Fred Hutch’s Vaccine and Infectious Disease Division.
Additional Immunological Detail
In order to understand how the immune system responded to the vaccination, the study also carefully studied the characteristics of the antibodies and B cells that were produced by the vaccine antigen. Schief compares this to “looking under the hood” of a car. According to one study, the vaccination antigen initially activated an average of 30 to 65 distinct bnAb precursors per individual who received the shot before inducing the growth of those cells. This made it easier to understand why virtually all individuals responded as expected after receiving the vaccination.
Other investigations focused on the precise alterations the bnAb-precursor B cells accumulated over time and the degree of their affinity for the vaccination antigen. These studies demonstrated that the bnAb-precursor B cells increased their affinity and progressed along advantageous maturation paths following each dosage of the vaccination.
The idea of “competitors,” or the B cells produced by the vaccination antigen but not precursors to bnAb, is one worry for this kind of vaccine technique. The “competitor” answers were thoroughly analysed by the researchers, and the findings were quite positive. In spite of the fact that the bulk of the B cells activated by vaccination were “competitors,” they were unable to match the affinity of the required bnAb precursors and did not appear to obstruct the development of the bnAb-precursor responses.
“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,” adds Schief. The researchers will continue to iterate and construct boosting immunogens in order to finally induce the required bnAbs and give protection against the virus. With these encouraging results in hand covering both safety and immune responses.
These results also came soon after two further studies in Immunity, which were published in September 2022 and supported the germline-targeting strategy for HIV vaccination.
“Working together with IAVI, Scripps Research, the VRC, GWU, additional investigators at Fred Hutch and many others, this trial and additional analyses will help inform design of the remaining stages of a candidate HIV vaccine regimen — while also enabling others in the field to develop vaccine strategies for additional viruses,” said McElrath of Fred Hutch.
