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A shot for every limb: how splitting up the HIV may increase immunogenicity
HIV Vaccine Trials Network (HVTN)
MARCH 20, 2024 - BY A DONLAN
Vaccines are arguably one of the greatest scientific developments of the modern era and have reduced the burden of many infectious diseases worldwide. Effective immune responses generated from vaccines can involve antibodies and/or cell-based memory responses, allowing future exposure to actual pathogens to be recognized and cleared rapidly. Designing vaccines against viral pathogens can often be more easily accomplished than against bacteria or parasitic counterparts, as there are often fewer proteins for immune cells to respond to. Yet, despite these advantages, the path to developing effective viral vaccines isn’t always straightforward, which has been a frustrating reality for the HIV vaccine field. In the case of HIV, which integrates into host DNA and remains dormant, for years or even decades, before developing into Acquired Immunodeficiency Syndrome (AIDS), a successful vaccine would be to prevent the initial infection, a goal that remains unattained.
In a recent article in eBioMedicine the HIV Vaccine Trials Network (HVTN), written by Dr. Mindy Miner, at Fred Hutch decided to change up their approach to try to elicit a more robust immune response to the vaccine. Recent evidence has pointed to CD8 T cell responses as important for protection against infection, or once infected, protection from advancing disease. However, despite inducing these cytotoxic T-cell (CTL) responses, recent trials have not demonstrated protection. One hypothesis be that the specificity of the cytotoxic CD8 T cells is focused only on a few viral epitopes (portions of proteins that T cells recognize) which end up being unhelpful in the control of the virus. In animal studies, researchers have been able to broaden the variety of epitopes that the T cells recognize by using polytopic vaccination, where the vaccine is delivered to multiple anatomical sites. Using this as a basis for a human clinical trial, the HVTN devised a regimen comparing polytopic compared to standard vaccination and were “’happily’ surprised to find that polytopic vaccination did, in fact, increase the epitope breadth of T-cell responses,” stated Dr. Miner.
Image displaying vaccination groups (top) and how fractioned group showed largest breadth of responses to epitopes from vaccination (bottom). Participants receiving Standard vaccination also had the final formulation buffer (FFB) administered at the same sites as the participants receiving polytopic vaccination.
Image supplied by by Dr. Miner.
For this Phase I clinical trial, the research team devised three vaccine delivery strategies. Their first group received a standard protocol, where the vaccine containing major HIV proteins, or antigens (gag, pol, env), would be given in one dose (Standard), the second group received vaccines containing gag-pol and env proteins separately and given at four anatomical sites (Separated), and their third group received the mixed vaccine (all proteins) but delivered at four sites (Fractioned). The vaccine used here had failed to show efficacy in a previous HVTN study, so the primary goal with this trial was to see if the method of delivery improved CTL responses. They tested how the T cells were responding to the vaccine using a method called intracellular cytokine staining (ICS), which measures inflammatory proteins (cytokines) released from T cells when stimulated with the same antigens used in the vaccine. From this, they observed that CD4 T cell responses did not appear exceptionally different between any of the vaccinated groups, except for being higher against Pol 2 in the Separated group. Within CD8 T cells, they saw that responses against Env C were lower in the Standard group than either Separated or Fractioned. The Fractioned group was also higher than Standard in responses to multiple other antigens, except for Gag. Altogether, these data showed to them that the polytopic groups (Separated and Fractioned) had higher T cell responses, something that was more apparent in the Fractioned group, and was consistent with their initial hypothesis.
When antigens, such as Gag, Pol or Env, are processed by the immune system the proteins are broken down into very short peptides, to be displayed to T cells, which are epitopes. Even within only one protein, dozens of potential epitopes could be generated, and each T cell clone is specific to only one epitope. Therefore, because the research team’s hypothesis was that polytopic vaccine delivery would increase this breadth, they wanted to assess the variety of epitopes that T cells were responsive to. To do this, they utilized an assay called ELISpot where they can stimulate T cells with a large variety of epitopes from the HIV proteins used in the vaccine. When quantifying the number of targeted epitopes, they observed that the Fractioned group had a higher amount than Standard or Separated. In addition to cellular based responses, vaccines also result in the production of antibodies, which are proteins secreted by B cells that bind directly to pathogens to promote immune clearance. Interestingly, the Standard vaccination group had significantly higher levels of antibodies to certain antigens compared to Separated. However, there weren’t many other noticeable differences in antibody response between groups.
Despite using a vaccine that had previously not shown efficacy, the results from this trial provided insight to how multisite delivery of an HIV vaccine could increase the T cell responses. The authors are hopeful that polytopic vaccination resulting in higher breadth and magnitude of CD8 T cell responses may result in greater protective outcomes, as this may reduce the ability of the virus to evade the immune system by utilizing previously non-recognized epitopes. The research team did also speculate potential hypotheses as to why this method may result in increased T cell breadth. One possibility could be that, since T cell recognizing specific epitopes are extremely rare in people who have not previously been exposed to them, delivering the vaccine at multiple sites may increase the chance of recognition of that epitope by its corresponding T cell. As Dr. Miner put it, “’hitting’ many regional lymph nodes might give a better immune response.” Additionally, increasing the number of vaccine sites might also increase the ability for cells to present the epitopes to T cells, as there might be competition for loading onto antigen-presenting cells. With a standard vaccination approach, a select few peptides with a stronger capability of binding may win out, even if these are not as useful for effective CTL responses. The research team is also interested to see whether a prime-boost strategy, where the initial vaccination (prime) is followed by a secondary vaccination at a later time point (boost), may further increase CTL responses or protective outcomes. Altogether, this study provided a new piece of the puzzle in how to design an effective HIV vaccine, yet they recognize that “it is unlikely that a 4-limb vaccination strategy will be logistically practical going forward in the clinic”, Dr. Miner stated, “but perhaps a 2-limb strategy may be feasible.” Dr. Miner concluded with the acknowledgment that this work was a successful collaboration among many Clinical, Data and Laboratory centers, adding that “it truly takes a village to conduct even a phase 1 study”. Hopefully all their hard work will one day cumulate in the first effective HIV vaccine, which would undoubtedly be a monumental achievement.
This research was funded by the National Institute of Allergy and Infectious Diseases.
Fred Hutch/University of Washington/Seattle Children’s Cancer Center Consortium members Drs. Steven De Rosa, James Kublin and Juliana McElrath contributed to this work.
Miner MD, deCamp A, Grunenberg N, De Rosa SC, Fiore-Gartland A, Bar K, Spearman P, Allen M, Yu PC, Manso B, Frahm N, Kalams S, Baden L, Keefer MC, Scott HM, Novak R, Van Tieu H, Tomaras GD, Kublin JG, McElrath MJ, Corey L, Frank I; HVTN 085 Study Team. Polytopic fractional delivery of an HIV vaccine alters cellular responses and results in increased epitope breadth in a phase 1 randomized trial. EBioMedicine. 2024 Feb;100:104987. doi: 10.1016/j.ebiom.2024.104987. Epub 2024 Feb 1. PMID: 38306894; PMCID: PMC10847480.
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Source: Fred Hutch Cancer Centerhttps://www.fredhutch.org/en/news/spotlight/2024/03/a-shot-for-every-limb--how-splitting-up-the-hiv-may-increase-imm.html
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