LAUSR

Since the discovery that a retrovirus, human immunodeficiency virus type one (HIV-1), causes the acquired immune deficiency syndrome (AIDS), more than 77 million people have become infected with HIV and 37 million have died over the last 40 years [1]. Therapeutic breakthroughs in the form of antiretroviral drugs have ensured the increased survival of adults and children living with HIV, have led to major in-roads for preventing paediatric HIV infection and produced strategies to deploy antiretrovirals to prevent sexual transmission. Despite these scientific advancements, the HIV pandemic is not under control and continues to devastate the lives of millions of people around the world. The lack of an HIV vaccine underscores the complexity of the immune evasion strategies utilized by HIV. Underlying challenges that scientists face in their endeavour to find a vaccine include the lack of a model for natural immunity, a virus that mutates rapidly, and the inability of the human species to self-cure HIV and hence define a correlate of protection against naturally occurring HIV infection. HIV vaccine development has become a process of stepwise learning of how to make a vaccine that induces an immune response that is markedly better than the human immune response to HIV. Insights into these processes have occurred when efficacy trials of candidate vaccines have taken place. Scientific advancements, innovation, political will, coupled with the substantial financial investment will continue to be critical in our path to find a vaccine against this virus that is among the biggest killers in history. To date only one HIV vaccine trial has demonstrated modest efficacy. The RV144 study conducted in Thailand investigated a heterologous prime/boost vaccine regimen consisting of ALVAC HIV (vcp1572) plus AIDSVAX B/E gp120 [2]. With a demonstrated vaccine efficacy of 31.2%, the mechanism of protection was thought to be via non-neutralizing immune responses from several functional antibody assays such as antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) [3]. In addition, IgG antibodies that recognize the V2 loop in the HIV envelope gp120 appeared to correlate with a reduced acquisition. These findings stood in contrast to traditional vaccine development, which relies on eliciting high levels of broadly neutralizing antibodies as the major mechanism of protection most recently exemplified by the high rate of success of COVID-19 vaccines [4-7]. Vaccines against SARS-CoV-2 elicit high levels of neutralizing antibody and high-grade efficacy with a reasonable correlation between the level of neutralizing antibodies and increasing efficacy. In 2014, the HIV Vaccine Trials Network (HVTN) outlined a strategy to execute a series of large-scale efficacy trials that would define the approach needed for a successful HIV vaccine. This strategy was broken into two frameworks: the first to determine whether broadly protective antibodies could reduce HIV acquisition, that is could a vaccine regimen that elicited high levels of non-neutralizing antibodies be developed that would enhance the protective efficacy beyond that seen in RV144; and second, to discern whether neutralizing antibodies could actually prevent acquisition. As no vaccine as yet has been able to elicit anything but strain-specific neutralization, the neutralizing antibody approach was to use the passive infusion of broadly neutralizing antibodies brought on by the revolution of B-cell engineering and cloning to evaluate whether high levels of monoclonal antibodies could reduce HIV acquisition. Between 2015 and 2019, the HVTN initiated five largescale efficacy trials: three in sub-Saharan Africa and two in North and South America. Three were directed at stimulating non-neutralizing antibodies and one set of integrated trials evaluated the passive infusion of the monoclonal antibody VRC01 in the antibody-mediated prevention (AMP) trials. The past 12 months have started to bring in the results of these trials. The earliest returns from non-neutralizing antibodies have been disappointing. HVTN 702, which was built upon the regimen of RV144, was stopped in January 2020 for lack of efficacy. HVTN 702 was based upon the same regimen used in RV144 except adapted to the subtype C region. Despite evidence of high levels of binding antibodies, ADCP and ADCC activity, no efficacy was noted [8]. The one deficiency Gray GE and Corey L Journal of the International AIDS Society 2021, 24:e25749 http://onlinelibrary.wiley.com/doi/10.1002/jia2.25749/full | https://doi.org/10.1002/jia2.25749