While scientists have struggled in the past to create an effective vaccine against HIV, a novel vaccine design strategy shows new promise, according to data from a first-in-human clinical trial.
In a paper published in Science, the researchers reveal critical new insights into their novel vaccine strategy, which involves a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants.
The team combined scientists 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).
“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, a professor and immunologist at Scripps Research and Executive Director of Vaccine Design at IAVI’s Neutralizing Antibody Center.
The Phase I trial (IAVI G001) tested the first stage in a multi-stage HIV vaccine regimen the researchers are developing. The trial results show that the vaccine had a favourable safety profile and induced the targeted response in 97% of people who were vaccinated.
“HIV represents an area of dire unmet need across the world, which is what makes the findings from our Phase I clinical trial so encouraging,” added Mark Feinberg, 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.”
Steps to producing bnAbs
Immune cells were isolated from recipients who received the vaccine or placebo. Antibody sequences from vaccine-binding B cells were then analyzed to measure bnAb-precursor response rate among participants and the frequency of bnAb-precursor B cells among memory B cells (MBCs) in each participant. Credit: Christopher Cottrell; created with Biorender.comBroadly neutralising antibodies (bnAbs) are a rare type of antibody that can fight and protect against many different variants of a virus.
The researchers used ‘germline targeting’ to produce bnAbs that can protect against HIV. The first step involves stimulating the rare immune cells – known as bnAb-precursor B cells – that can eventually evolve into the cells that produce the bnAbs needed to block the virus.
To accomplish this first step, the researchers designed a customised molecule – known as an immunogen – that would ‘prime’ the immune system and elicit responses from these rare bnAb-precursor cells.
Analysis showed that the vaccine antigen first stimulated an average of 30 to 65 different bnAb precursors per person vaccinated, and then caused those cells to multiply. This helped explain why the vaccine induced the desired response in almost all participants.
One concern for this type of vaccine approach is the notion of ‘competitors’ i.e., the B cells induced by the vaccine antigen that are not bnAb precursors. However, these undesired B cells could not match the binding strength of the desired bnAb precursors and did not seem to impede maturation of the bnAb-precursor responses.
Further investigations using mRNA delivery
IAVI, Scripps Research, NIAID, the Bill & Melinda Gates Foundation and the US President’s Emergency Plan for AIDS Relief (PEPFAR) are partnering with the biotechnology company Moderna to develop and test mRNA delivery of these HIV vaccine antigens.
Two Phase I clinical trials are underway that build on IAVI G001, which are testing mRNA delivery of the eOD-GT8 60mer that was evaluated as recombinant protein in IAVI G001. One of the trials includes a boost antigen designed by the Schief lab and delivered with Moderna mRNA technology.
A third trial (HVTN302) is testing mRNA delivery of three different stabilised HIV trimers designed in the Schief laboratory that are candidates for late-stage boosters in multi-stage vaccines aiming to induce bnAbs.
Using mRNA technology could significantly accelerate the pace of HIV vaccine development as it allows for faster production of clinical trial material.
