Channels • 2022 • Volume 6 • Number 2 Page 15 with the fact that the immune responses were similar in the monkeys compared to in the human participants, and that Ad26/Ad26 HD gp140 regimen appeared to be among the most immunogenic within the aforementioned ELISAs, that Barouch et al. determined the Ad26/Ad26 HD gp140 regimen to be the most optimal for further clinical testing in a phase 2 trial. Thus, the lack of statistical significances in the ELISAs seems to be overshadowed by the findings of the concurrent macaque study that demonstrated the effectiveness of the Ad26/Ad26 HD gp140 regimen against actual viral challenge - though, of course, it still isn’t entirely known how accurate the macaque model represents humans (Barouch et al., 2018). Thus, with this evaluation of this overarching study’s results completed, it should be asked whether or not this study supports the idea of advancing an Ad26 viral vector/gp140 subunit vaccine regimen into further clinical trials. As seems obvious based on the preceding paragraph, especially considering the fact that Barouch et al. determined that the Ad26/Ad26 HD gp140 was appropriate for phase 2 clinical testing, it does appear that Barouch et al.’s study helps to answer whether or not an Ad26vectored/gp140 subunit vaccine regimen can induce sufficient immune correlates of protection to warrant further trial testing - particularly by answering that, yes, it can. Specifically, this study demonstrated that an Ad26-vectored/gp140 subunit regimen can induce immune correlates in the first place; it also showed that one of those regimens is also effective in providing protection to macaques (one of the closest animal models to humans for HIV-1 infection) against a very similar virus to HIV-1. Therefore, the selected, optimal regimen from this study demonstrates all of the currently predicted hallmarks of a potentially successful universal HIV-1 vaccine (including, very importantly, being safe and well tolerated - thereby fulfilling the key goal of passing initial safety assessments of a phase 1/2a trial). There are, however, important questions still left unanswered from this study. For example, there is still the uncertainty as to whether or not it’s appropriate to predict the protective ability of a vaccine regimen in humans based upon the protective ability of that same vaccine in nonhuman primates (Barouch et al., 2019). Another question that this study also doesn’t answer is whether it’s the quantity or the quality of the IgG1/IgG3 and/or Fc-mediated effector function responses that matters more in preventing the acquisition of HIV-1. If it’s the quality of these immune correlates that matter more than quantity of correlates produced, then predicting whether or not an HIV-1 vaccine is effective in an individual may have more to do with underlying genetics, such as SNPs (single nucleotide polymorphisms) in Fc-receptor genes (Su et al., 2019), then it does with the titers of IgG Abs or magnitudes of Fc-mediated effector functions produced in clinical trials. Another question that this study leaves open-ended, is what effects increasing the valency of the viral vector would have on the immunogenicity of the vaccine. Fortunately, however, it is this question that is answered in the following study. The second study that will be discussed in this review, was published in late 2020 and details the observations/data collected from another phase 1/2a vaccine trial (called TRAVERSE) conducted by Baden et al. Interestingly, Dr. Dan H. Barouch, the lead investigator from the previous APPROACH study, is also credited as being one of the
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