Relationship between Vaccine-Induced Antibody Capture of Infectious Virus and Infection Outcomes following Repeated Low-Dose Rectal Challenges with Simian Immunodeficiency Virus SIVmac251

Abstract

Antibodies are known to enhance in vitro infection by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). We measured the ability of antibodies induced by ALVAC-SIV/gp120 vaccination, given with alum or MF59 adjuvant, to capture infectious SIVmac251 and determined the association between capture and infection outcomes following lowdose, repeated rectal challenge of rhesus macaques. We found that capture correlated with the number of transmitted/founder (T/F) variants that established infection, such that animals whose plasma captured more virus were infected with a higher number of T/F strains. Capture also correlated with results of Env binding assays, indicating that greater immunogenicity resulted in greater capture. Although vaccination elicited negligible neutralizing activity against the challenge strain (50% inhibitory dilutions of >1/80 in all cases), animals with low capture and whose plasma, at a fixed dilution, inhibited a higher fraction of virus were infected at a lower rate than animals with high capture and low neutralization (P ‫؍‬ 0.039); only animals with the low capture/high neutralization response profile were protected compared with unvaccinated control animals (P ‫؍‬ 0.026). In a sieve analysis, high capture and low capture were distinguishable on the basis of polymorphisms in the V1 loop of Env at amino acids 144 and 145. Our results indicate that vaccine-induced antibody that binds to and captures infectious virus but does not inhibit its infectivity may enhance the likelihood of infection following rectal challenge with SIVmac251. Higher immunogenicity resulting in better antibody capture but similar anti-infectivity may not improve vaccine efficacy. IMPORTANCEVaccines generally prevent viral infections by eliciting antibodies that inhibit virus infectivity. However, antibodies, including those induced by vaccination, have the potential to enhance, rather than prevent infection. We measured the ability of vaccineinduced antibodies to capture infectious simian immunodeficiency virus (SIV) and explored the relationship between virus capture and infection outcomes. We found that capture correlated with the number of SIV variants that established infection, such that animals whose plasma captured more virus were infected with a higher number of unique strains. In addition, animals whose sera had high capture but weak anti-infectivity activity were infected at a higher rate than were animals with low capture and stronger anti-infectivity activity. These results suggest that vaccines that induce antibodies that bind to and capture infectious virus but do not inhibit virus infectivity will not be effective in preventing infection. Human and nonhuman primate studies have provided evidence that vaccines designed to prevent human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infections might, at times, increase the risk of infection (1). Such a deleterious effect can be apparent in the overall analysis of vaccine efficacy or from analyses of su...

Antibody-Dependent Cellular Phagocytosis in Antiviral Immune Responses

“…Since monocytes and macrophages can be infected with HIV-1, one theory is that antibody-mediated phagocytosis may have caused increased viral infection of these phagocytes. More specifically, enhancement may have been due solely to weakly or non-neutralizing antibodies that remain capable of engaging but not neutralizing HIV-1 virus (151). However, it is notable that no enhancement of infection in the vaccine arm was observed in the VAX003 and VAX004 clinical trials, both of which elicited high levels of non-neutralizing antibodies (152, 153).…”

Passive and active antibody studies in primates to inform HIV vaccines

“…The partial protection by F240 is intriguing and complicates interpreting results of the study. One possibility based on in vitro analysis, was the greater ability of F240 compared to b6 and b12 to capture infectious virions although recently this characteristic has not held up as advantageous [57]. The mechanisms behind F240 protection are unknown, but it was hypothesized that even though functionally inactive, the gp41 “stump” epitope recognized by F240 on otherwise infectious virions provided a footing for Fc receptor mediated mechanisms that decreased infectivity of the virus inoculum.…”

“…V2 specific antibodies appeared important but there were other important signals of protection, including induction of Env-dependent intestinal lymphoid cells. However, antibodies from MF59-adjuvanted ALVAC/gp120 vaccinated NHPs captured more infectious virus than the alum group, resulting in a higher number of T/F strains [57]. Thus understanding the relative importance of neutralizing and capture antibodies in mucosal acquisition models remains a key goal of adjuvant and antigen design for HIV vaccines.…”

Reappraising the Value of HIV-1 Vaccine Correlates of Protection Analyses

“…Nonetheless, the reported differences between alum and MF59 adjuvants in whether they aid protective responses do not readily conform with some other findings. For example, MF59 induces stronger virion-capturing antibody responses than alum ( 110 ), but virion capture has been linked to both protective and infection-enhancing net effects ( 37 , 66 , 110 – 112 ) ( Table 2 ), and alum is less effective than MF59 in supporting the induction of serum antibody responses to Env immunogens, including the anti-V2 IgG response, a reported CoP candidate ( 15 , 16 ).…”