Systemic administration of an HIV-1 broadly neutralizing dimeric IgA yields mucosal secretory IgA and virus neutralization

Abstract

We investigated the mucosal distribution and neutralization potency of rhesus recombinant versions of the HIV-specific, broadly neutralizing antibody b12 (RhB12) following intravenous administration to lactating rhesus monkeys. IgG and dimeric IgA (dIgA) administration resulted in high plasma concentrations of broadly neutralizing antibody (bnAb), but the monomeric IgA (mIgA) was rapidly cleared from the systemic compartment. Interestingly, differences in the distribution of the RhB12 isoform were observed between the mucosal compartments. The peak concentration of RhB12 IgG was higher than dIgA in saliva, rectal, and vaginal secretions, but the bnAb concentration in milk was one to two logs higher after dIgA administration than with IgG or mIgA infusion. Neutralization was observed in plasma of all animals, but only those infused with RhB12 dIgA showed moderate levels of virus neutralization in milk. Remarkably, virus-specific secretory IgA was detected in mucosal compartments following dIgA administration. The high milk RhB12 dIgA concentration suggests that passive immunization with dIgA could be more effective than IgG to inhibit virus in breast milk.

Figure 1. Timeline of RhB12 IgG, mIgA, dIgA passive immunization. Lactating rhesus monkeys were immunized intravenously with B12 IgG, mIgA or dIgA

Plasma, milk and mucosal secretions were collected before infusion, and post infusion (1h, 6h, 24h, 72h, 1week, and then weekly for 7 weeks).

Figure 2. Passive immunization with RhB12 dIgA yields higher magnitude binding antibodies in milk than RhB12 mIgA or IgG infusion

The time to peak B12 mAb level in plasma was similar following B12 IgG, mIgA and dIgA infusion, but the peak plasma mIgA was lower than for IgG or dIgA (A). In milk mIgA peaked earlier (1-6h) than IgG (24-72h) or dIgA (6-24h). Even though the amount of mIgA infused was three times that of dIgA, the peak level of dIgA in milk was 1 to 2 fold higher and was more durable than that of mIgA (B). Dash line represents positivity cutoff calculated as three standard deviations above the average concentration measured at time 0. (0.042 days correspond to 1hour and 0.25 days to 6 hours)

Figure 3. Differences in the kinetics of B12 mAb in mucosal compartments following RhB12 IgG, mIgA, dIgA systemic infusion

The ratio of HIV-1 Env-specific to total IgG/IgA antibody was higher for IgG than mIgA/dIgA in rectal (A), saliva (B) and vaginal (C) secretions whereas the ratio Env-specific to total IgG/IgA was higher for dIgA in milk (D). Lines represent median. 0.042 days correspond to 1hour and 0.25 days correspond to 6 hours.

Figure 4. Detection of RhB12 sIgA in mucosal compartments following systemic RhB12 dIgA passive immunization

At the peak RhB12 level, Env-specific sIgA was detected in all mucosal compartments: rectal (A), saliva (B), vagina (C), milk (D), with lower sIgA (gray bar) /dIgA (black bar) in milk than in other mucosal compartments.

Figure 5. Tier 1 HIV 1 neutralization by plasma of RhB12 passively immunized monkeys

The peak neutralization activity achieved in plasma was higher following Rh B12 IgG infusion (A) than b12 mIgA (B). Plasma neutralization following RhB12 dIgA infusion is high at peak but short-lived (C). 0.042 days correspond to 1hour and 0.25 days correspond to 6 hours.