Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: Complete protection of rhesus monkeys from mucosal SHIV challenge

Abstract

Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1 + dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline.

Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

“…As the levels of anti-Env IgG but not those of anti-Env IgA in these secretions were associated with protection, our data suggest that nonneutralizing serum IgG (but not IgA) that transudates into vaginal tissues and secretions may play a significant role in preventing vaginal virus transmission. On the other hand, we postulate that even greater protection might perhaps be achieved if both mucosal IgA and serum IgG antibody responses can be induced (48).…”

Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk

“…Nevertheless, there is solid evidence that mucosal IgA could contribute to the prevention of HIV transmission. In a recent study, vaccine-elicited mucosal IgA responses were associated with protection against vaginal simian-human immunodeficiency virus (SHIV) challenge (14), and multiple investigations have demonstrated that passive rectal immunization with neutralizing dimeric IgA can protect from subsequent SHIV exposure (15,16). Similarly, we recently reported an association between a high magnitude of Env-specific IgA and low rates of breast milk HIV transmission (17).…”

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

“…This is an important question to address in future studies. An elegant study by Ruprecht et al showed that rectal administration of an anti-HIV V3 recombinant dimeric human IgA2 monoclonal antibody (MAb), combined with systemic administration of the parental IgG1 MAb, was able to completely protect adult macaques against rectal SHIV-1157ipEL challenge, whereas passive immunization with only IgG1 or dIgA2 protected only 0% and 17% of macaques, respectively (65).…”