Page 8 Adam • Evaluation of the Humoral/Fc-mediated Immune Responses… inclusion of only Env (HIV-1 envelope) antigens within a vaccine may only elicit a neutralizing antibody (NAb) response, whereas inclusion of antigens that are encoded by the Gag and Pol HIV-1 genes could also illicit more of a non-neutralizing Ab humoral response (Su et al., 2019). What’s remarkable, however, is the fact that debate over which immune responses should be targeted for elicitation by a vaccine has been continuing since the beginning of HIV-1 vaccine development. In fact, towards the beginning of HIV-1 vaccine development, there was an emphasis on attempting to elicit a predominantly humoral response to the vaccine in order to provide protective immunity against HIV-1 acquisition and construct populations of memory B-cells specific to HIV-1. However, as the years of research progressed, a new interest in attempting to elicit more of a cellular immune response (specifically be CTLs) came to the forefront of research; but this too began to fall out of favor after several failed research attempts to elicit CTL responses capable of effectively controlling HIV-1 infection. Though the subject of HIV-1 vaccine research began to seem rather bleak, in 2009, a groundbreaking study performed in Thailand, called the RV144 trial, was published and demonstrated that a viral vector (recombinant canarypox)/gp120 subunit combined vaccine regimen demonstrated moderate efficacy (estimated 60% at 12 months and 31.2% at 42 months) against HIV-1 acquisition in humans. To date, this RV144 vaccine regimen is the only vaccine/vaccine regimen that has demonstrated efficacy against HIV-1, and it naturally sparked a renewed hope in being able to develop a more effective HIV-1 vaccine focused on eliciting the immune responses that were correlated with reduced risk in the RV144 trial (Ng’uni et al., 2020; Zolla-Pazner & Gilbert, 2019; Haynes et al., 2012). The importance of this RV144 trial, and the influence it has wielded upon successive HIV-1 vaccine studies, cannot be overstated. Just a cursory read-through of only a few research articles having to do with HIV-1 vaccine development (ones published since 2009) will demonstrate repeated references to this study, and it is this RV144 study that has proven instrumental to the two vaccine studies that will follow later in this paper. Before moving forwards, however, it would be helpful to briefly describe the findings of the RV144 trial that have influenced much of the more recent research into development of a vaccine. Lessons from the RV144 HIV Vaccine Trial The first critical finding from RV144, was the fact that it appeared IgG Abs, specific to the V1V2 region of the gp120 subunits, were inversely correlated with risk of HIV-1 infection, while IgA Abs specific to other gp120/gp41 epitopes were positively correlated with infection risk - leading to the hypothesis that the IgA Abs were possibly competing with the IgG Abs when binding to HIV-1 particles. The RV144 study also showed that Fc-mediated effector functions, specifically ADCC (Antibody-dependent cellular cytotoxicity), was also inversely correlated with HIV-1 infection risk. Since, therefore, IgG Abs (in particular, IgG1 and IgG3) were known to mediate effector functions like ADCC, it was suggested, based on
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