Smith Justin C, Arunachalam Prabhu S, Legere Traci H, Cavacini Lisa A, Hunter Eric, Pulendran Bali, Amara Rama R, Kozlowski Pamela A
Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94304, USA.
Vaccines (Basel). 2024 Dec 10;12(12):1386. doi: 10.3390/vaccines12121386.
A goal of mucosal human immunodeficiency virus type 1 (HIV-1) vaccines is to generate mucosal plasma cells producing polymeric IgA (pIgA)-neutralizing antibodies at sites of viral entry. However, vaccine immunogens capable of eliciting IgA neutralizing antibodies (nAbs) that recognize tier 2 viral isolates have not yet been identified.
To determine if stabilized native-like HIV-1 envelope (Env) trimers could generate IgA nAbs, we purified total IgA and IgG from the banked sera of six rhesus macaques that had been found in a previous study to develop serum nAbs after subcutaneous immunization with BG505.664 SOSIP and 3M-052 adjuvant, which is a TLR7/8 agonist. The neutralization of autologous tier 2 BG505 T332N pseudovirus by the IgA and IgG preparations was measured using the TZM-bl assay. Anti-SOSIP binding antibodies (bAbs) were measured by ELISA.
The IgG samples were found to have significantly greater levels of both nAb and bAb. However, after normalizing the nAb titer relative to the concentration of bAb, SOSIP-specific IgA purified from 2/6 animals was found to neutralize just as effectively as SOSIP-specific IgG, and in 3/6 animals, neutralization by the specific IgA was significantly greater. The more potent neutralization by IgA in these three animals was associated with a higher percentage of anti-SOSIP J chain-bound (polymeric) antibody.
The parenteral vaccination of nonhuman primates with BG505.664 SOSIP generates HIV-1 tier 2 IgA nAbs in serum, including SOSIP-specific polymeric IgA, which appears to neutralize more efficiently than monomeric IgA or IgG. Mucosal delivery of this SOSIP or other stable Env trimers could generate locally synthesized polymeric IgA nAbs in mucosal tissues and secretions.
黏膜型人类免疫缺陷病毒1型（HIV-1）疫苗的一个目标是在病毒进入部位产生分泌聚合型IgA（pIgA）中和抗体的黏膜浆细胞。然而，尚未鉴定出能够引发识别2级病毒分离株的IgA中和抗体（nAbs）的疫苗免疫原。
为了确定稳定的天然样HIV-1包膜（Env）三聚体是否能产生IgA nAbs，我们从6只恒河猴的储存血清中纯化了总IgA和IgG，这些恒河猴在先前的一项研究中被发现，在用BG505.664 SOSIP和3M-052佐剂（一种TLR7/8激动剂）进行皮下免疫后产生了血清nAbs。使用TZM-bl试验测量IgA和IgG制剂对自体2级BG505 T332N假病毒的中和作用。通过ELISA测量抗SOSIP结合抗体（bAbs）。
发现IgG样品的nAb和bAb水平均显著更高。然而，在将nAb效价相对于bAb浓度进行标准化后，发现从2/6只动物中纯化的SOSIP特异性IgA中和效果与SOSIP特异性IgG一样有效，在3/6只动物中，特异性IgA的中和作用显著更强。这三只动物中IgA更强的中和作用与更高比例的抗SOSIP J链结合（聚合）抗体相关。
用BG505.664 SOSIP对非人灵长类动物进行肠胃外疫苗接种可在血清中产生HIV-1 2级IgA nAbs，包括SOSIP特异性聚合型IgA，其似乎比单体IgA或IgG更有效地中和。这种SOSIP或其他稳定的Env三聚体的黏膜递送可在黏膜组织和分泌物中产生局部合成的聚合型IgA nAbs。
