SScientists have spent decades trying to develop an HIV vaccine, with limited success. Now, research published in Nature this week (September 21) suggests that part of the key to achieving effective protection may lie in how the vaccine is administered. By dividing the initial dose of a vaccine into multiple increasing doses over a period of almost two weeks, a team of researchers from the La Jolla Institute of Immunology were able to generate a longer-lasting immune response in rhesus macaques (macaca mulatta) and higher levels of neutralizing antibodies after a booster dose compared to a traditional single injection approach.
There are still many steps to take before this can translate into HIV treatment for humans, says Elizabeth Connick, who studies HIV pathogenesis and cure strategies at the University of Arizona College of Medicine and was not involved in this study. For example, she says it’s crucial to determine whether neutralizing antibodies observed in vitro “actually protect people.” But so far, she adds, the potential clinical implications of this study are “very exciting,” and not just for HIV; the approach also holds promise for the development of vaccines against other targets.
Previous to research published in 2019 by the same team, led by the La Jolla Institute for Immunology researcher Shane Croty, found that rhesus monkeys that received a dose of HIV vaccine via a slow-release osmotic pump or through an initial increasing series of injections had a better immune response – for example, an increased amount and diversity of antibodies – than those who had received the same dose in a single injection. “At the end of the day, the best vaccines are the ones that can actually mimic what a real infection looks like without making you sick, [and] slow delivery is probably better at that,” says Henry Sutton, also at the La Jolla Institute for Immunology and co-author of the new study. These earlier data, in which Sutton was not involved, showed that the immune response was still quite robust at the time of the end of the study, eight weeks after the first injection and six weeks after the last. “The obvious question,” says Sutton, was what might happen if the experiment continued “for a few more months: How long would it take for this response to actually fade?”
Ultimately, the best vaccines are those that can actually mimic what a real infection looks like without making you sick, [and] slow delivery is probably better at that.
—Henry Sutton, La Jolla Institute of Immunology
One of the key factors in triggering an effective immune response is to train B cells to generate antibodies that bind to and neutralize the pathogen in question. Once the vaccine antigen enters the body, B cells begin to evolve through a process of random mutation and selection of cells that produce antibodies with higher affinity for the antigen. This entrainment takes place in structures called germinal centers which arise transiently in the lymph nodes closest to the vaccination site. Among the hypotheses derived from their previous work, Crotty’s team wondered if the gradual delivery of antigens favors the initial period of this evolution and if it lengthens the life of these training centers to give more time to B cells to perfect their antibodies and ultimately succeed against an elusive target. like HIV.
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To test this idea, the team has now decided on a longer study period. They immunized 14 monkeys against the virus envelope protein in their left and right thighs using three different strategies: group 1 (six monkeys) received conventional immunization in a single dose; its formulation included a classic adjuvant used in human vaccines called Alum. Groups 2 and 3 (four individuals each) received an increasing dose every other day over a 12-day period; instead of alum, the formulation included a new immunostimulating adjuvant called saponin/MPLA nanoparticle. Finally, groups 1 and 2 received a single dose booster at week 10, while group 3 did so at week 30.
The immune response of those with slow labor has been particularly successful. During week 10, before any booster administration, the frequency of binding of germinal center B cells to the HIV protein was 186 times higher in groups 2 and 3 than in group 1. B of group 3 monkeys (who waited more than six months before receiving a booster) continued to have gene expression signatures that characterize active germinal centers, also showing improved affinity towards the target, probably due to the extended training period. This suggests that, even without new antigen input, the initial vaccine-triggered bootcamp in these monkeys was still functioning at least 191 days after the last vaccine.
University of Queensland immunologist Di Yuwho was not involved in this study, says Crotty’s team’s earlier work sort of foreshadowed some of the new findings, adding that “the really exciting part” is that they were now using “technology to analyze stage step by step what happens in the immune system, rather than simply [looking] in the result. The team is able to demonstrate, using this strategy, “what we hoped to see in a successful vaccine” – a continuous and functional germinal center in which B cells continue to be formed and, thus, increase affinity antibodies with the target, he says.
The longer spacing between the first and the encores in Group 3 also seemed to pay off. When Sutton and colleagues tested the antibodies in the sera of vaccinated and boosted monkeys against 12 different HIV variants in vitro, they found that the highest quality antibodies were those from group 3. While only one monkey in the group 2 had the antibodies to neutralize more than half of the variants (ten), in group 3, the antibodies from three monkeys could neutralize eleven, ten and eight variants respectively. That a vaccine can generate antibodies to deal with different variants is generally desirable, but it’s an even more pressing issue in the case of HIV, which mutates very rapidly.
Connick says it’s clear that their strategy resulted in the production of largely neutralizing antibodies, but she says it will be important to determine to what extent this successful result is related to the use of a different adjuvant and in what measure to the slowness of the administration. Sutton acknowledges that they cannot disentangle the role of the two methodological aspects, but the team is currently aiming to do so in follow-up studies. Additionally, the experimental methodology and results published in 2019 suggest that the role of the adjuvant may be important, but “we are quite confident that slow administration also plays a major role,” he writes in an e follow-up email.
Sutton further acknowledges that the strategy used in this new paper may not necessarily be protective against HIV – monkeys have never been infected with the virus, he notes. However, he and his colleagues are collaborating with other teams to combine their vaccination strategy with the design of specific proteins that trigger immune responses known to lead to broadly neutralizing antibodies. This new slow delivery study is just a proof-of-concept that can be useful when designing vaccines against difficult targets, Sutton says. For example, this model could also aid in the development of a universal flu vaccine that provides protection against many different strains.