HIV vaccine trial uncovers plausible mechanisms of protection

From the HVTN, Vaccine and Infectious Disease Division

Although development of an HIV vaccine is a global priority, to date no vaccine trial has elicited complete protective immunity. Despite failing to prevent HIV infection, a recent trial revealed potential antibody-mediated correlates of protection (CoP). However, further trials are necessary to confirm the CoP discovered by this single trial. To evaluate immune responses that can protect against HIV, Scott Neidich, Youyi Fong,  Peter Gilbert and Georgia Tomaras of the HIV Vaccine Trials Network (HVTN) in the Vaccine and Infectious Disease Division and Duke University used data and serum samples from a recent HVTN vaccine trial to gather CoP insight that could inform future vaccine design. They published this work in the Journal of Clinical Investigation.

The HVTN 505 trial tested the efficacy of a DNA/recombinant adenovirus serotype 5 (rAd5) HIV vaccine in men and transgendered persons who have sex with men in the United States. Although this vaccine trial lacked overall efficacy, a subsequent study (deCamp et al.) demonstrated through a viral sieve analysis that patients vaccinated in HVTN 505 who became infected contained HIV envelope (Env) sequences distant from those found in people who became infected in the unvaccinated group, suggesting that vaccination did influence viral acquisition. A humoral correlate of HIV risk CoR was identified, as anti-Env antibodies correlated with reduced HIV infection. Given these findings and results from previously published preclinical studies, the authors of the current study hypothesized that antibody-dependent cellular phagocytosis (ADCP)—a phenomenon where receptors on innate immune cells bind the Fc region on antibodies that are bound to pathogens, facilitating phagocytosis of the bound cell or pathogen—constitutes an important vaccine-mediated CoP for HIV.

Fc receptors (FcR) on innate immune cells such as macrophages are divided into different types that have unique binding patterns for antibody isotypes. FcgR bind IgG, the type of antibody previously shown to correlate with HIV protection. More specifically, FcgRIIa is associated with ADCP, so the authors focused on FcgR and its role in vaccine-mediated ADCP. The authors used an in vitro fluorescence assay to quantify ADCP activity in serum samples collected from HVTN 505 vaccinated and unvaccinated participants. Env IgG ADCP was detected in the majority of vaccinated participants, prompting the authors to ask if ADCP and FcgRIIa engagement are independent correlates of HIV risk. Regression analysis revealed that IgG ADCP and FcgR IIA responses to HIV Env were both inversely correlated with HIV infection risk, even when correcting for cell-mediated contributions. 

The interconnected mechanisms behind vaccine correlates of protection.
The interconnected mechanisms behind vaccine correlates of protection. Image provided by the HVTN.

Coauthors Raphael Gottardo and Chad Young  more closely interrogated the role of IgG3, a subclass of IgG,  that was previously shown to correlate with HIV risk in the RV144 trial. IgG3 was previously shown to have improved ADCP activity over IgG1. So, together the laboratory scientists and computational biologists quantified HIV-specific IgG3 rates in vaccinated individuals and found high IgG3 titers and that IgG3 breadth, or its ability to bind a wide range of HIV epitopes, correlated with decreased HIV risk. Having previously shown that IgA antibodies (a class of antibodies with distinct effector functions) in plasma were correlated with increased HIV risk, the authors then asked whether anti-Env IgA elicited by vaccination modified the IgG-mediated decreased HIV acquisition. They measured IgA in HVTN 505 participants’ serum and found that those with low-to-undetectable titers of IgA had the highest inverse correlation between ADCP and FcgRIIa and decreased HIV risk. This result supports the effect for circulating IgA that was reported in the RV144 trial and suggests that IgA may impede the protective effects of FcgRIIa-mediated ADCP, potentially by outcompeting IgG responses or that it is marker of some other response that was not measured. To examine the impact of all of the measured immune responses, Peter Gilbert and Brian Williamson utilized a machine learning approach called SuperLearner and found that the combination of antibody isotype, specificity and function with polyfunctional CD8 T cells were the best predictors of HIV-1 risk.  In those vaccinees who became infected, Holly Janes and team also found that the level of FcgRIIa binding impacted viral load setpoint in addition to HIV risk.

Finally, the authors sought to explore the effects of individual genetic diversity on the robustness of ADCP and FcgRIIa as CoP for HIV. Using blood collected during HVTN 505, Dan Geraghty’s laboratorysequenced FcR regions of vaccinated and unvaccinated participants and identified single-nucleotide polymorphisms (SNP) in the FcgRIIa gene. Shuying Li selected seven SNPs and analyzed how each affected the correlation between ADCP and FcgRIIa binding with HIV risk. While participants with a specific FcgRIIa SNP maintained the correlation between ADCP and HIV risk, those with another did not have an inverse correlation between ADCP and HIV risk, suggesting that FcgRIIa-mediated protective benefits are dependent on host genetics.

This work identified three antibody features (IgG3 breadth,  FcgRIIa binding, and phagocytosis) that inversely correlated with HIV risk Additionally, this research interrogated the potential mechanism underlying ADCP by further elucidating which isotype of antibody responses positively or negatively correlate with HIV risk. These results will inform future HIV research, as vaccines can be designed to specifically target IgG3 responses, and FcgRIIa ADCP effectiveness may be informed by individuals’ SNP profiles.  Senior and corresponding author, Georgia Tomaras (HVTN, Duke University) notes that “Our results identify that antibodies specifically higher IgG3 and Fc effector functions together with low IgA and in combination with polyfunctional CD8 T cells are important measures for guiding improved vaccination strategies.”

This work was supported by the NIAID, the NIH/NIAID Duke Center for AIDS Research, and the Bill and Melinda Gates Foundation.

UW/Fred Hutch Cancer Consortium members Daniel Geraghty, Larry Corey, Julie McElrath, Raphael Gottardo, and Peter Gilbert contributed to this work.

Neidich SD, Fong Y, Shuying SL, Geraghty DE, Williamson BD, Young WC, Goodman D, Seaton KE, Shen X, Sawant S, Zhang L, deCamp AC, Blette BS, Shao M, Yates NL, Feely F, Pyo CW, Ferrari G, HVTN 505 Team, Ian F, Karuna ST, Swann EM, Mascola JR, Graham BS, Hammer SM, Sobieszczyk ME, Corey L, Janes HE, McElrath MJ, Gottardo R, Gilbert PB, Tomaras GD. 2019. Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk. Journal of Clinical Investigation. 10.1172/JCI126391