Channels • 2022 • Volume 6 • Number 2 Page 21 There are a couple of avenues that should be investigated based on some of the shortcomings of the APPROACH and TRAVERSE studies. First, based on the fact that the accuracy of the macaque model for HIV-1 infection in humans is still uncertain (Barouch et al., 2018), it is crucial that scientists elucidate how accurately the protective efficacy of an Ad26 vector/subunit HIV-1 vaccine in humans can be predicted based on that same vaccine’s protection against infection in rhesus macaques. Fortunately, the ongoing Imbokodo and MOSAICO trials, which are aimed at testing the protective efficacy of TRAVERSE’s tetravalent regimen in humans, will likely provide critical data for helping to answer this issue. Once the results from the Imbokodo and MOSAICO trials are published, the protective efficacy of the utilized regimen could be readily compared to the protective efficacy of that same regimen in rhesus monkeys. Another avenue of research that should be undertaken is regarding the uncertainty of whether the quantity or quality of the elicited immune correlates of protection is more vital in fighting HIV-1 infection. It appears that the TRAVERSE study was more concerned with the quantity aspect of the immune correlates rather than the quality - paying particular attention towards the fact that the tetravalent regimen was eliciting higher titers of Fc mediating Abs and higher ADCP scores (Baden et al., 2020). However, focusing entirely on the quantity of elicited immune correlates may negatively affect the overall vaccine development process - especially if future research discovers that it is the greater coordination of elicited immune responses that is more critical than greater quantities/concentrations of immune correlates. If a vaccine candidate is capable of both eliciting greater magnitudes of immune correlates, as well as greater (more effective) cooperation between the elicited immune correlates, then a more favorable middle-ground would be reached in satisfying both the quantity and quality aspects of the elicited immune correlates of protection. One way that researchers could emphasize the quality aspect more, is by checking correlation coefficient values between immune correlates (such as between ADCP and ADCC) that are elicited during future trials, rather than simply looking at the magnitudes (scores and titers) of immune correlates of protection. Finally, one last avenue of further research that should be explored would investigate whether or not repeatedly using an Ad26 vector builds up a sufficient immune memory against the vector to negatively impact its ability to deliver its transgenic cargo. As discussed in the introduction, previous research has demonstrated that, even in the presence of an Ad26-specific immune response, Ad26 vectors are still successful in eliciting effective immune responses against the immunogen expressed by the Ad26 vector (Baden et al., 2013). What is unclear, however, is how long the Ad26 vector is capable of effectively delivering its cargo in the presence of increasing Ad26-specific immune responses. If, for example, the prophylactic HIV-1 vaccine regimen would need to become more of a yearly vaccination (similar to how the influenza vaccine currently is), there is no reliable data to strongly suggest that the Ad26 vector-based vaccine would remain effective for long. Thus, research into this subject could have beneficial long-term implications.
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