HIV-1-neutralizing antibody induced by simian adenovirus- and poxvirus MVA-vectored BG505 native-like envelope trimers

Abstract

Rabbits and monkeys immunized with HIV type 1 (HIV-1) native-like BG505 SOSIP.664 (BG505s) glycoprotein trimers are known to induce antibodies that can neutralize the autologous tier-2 virus. Here, we assessed the induction of HIV-1 trimer binding and neutralizing antibody (nAb) titres when BG505s trimers were also delivered by non-replicating simian (chimpanzee) adenovirus and non-replicating poxvirus modified vaccinia virus Ankara (MVA) vaccine vectors. First, we showed that approximately two-thirds and one-third of the trimers secreted from the ChAdOx1.BG505s (C) and MVA.BG505s (M) vaccine-infected cells, respectively, were cleaved and in a native-like conformation. Rabbits were immunized intramuscularly with these vaccine vectors and in some cases boosted with ISCOMA-TRIX™-adjuvanted BG505s protein trimer (P), using CCC, MMM, PPP, CPP, MPP and CMP vaccine regimens. We found that the peak trimer-binding antibody and tier-1A and autologous tier-2 nAb responses induced by the CC, CM, PPP, CPP, MPP and CMP regimens were comparable, although only PPP induced autologous tier-2 nAbs in all the immunized animals. Three animals developed weak heterologous tier-2 nAbs. These results demonstrate that ChAdOx1 and MVA vectors are useful delivery modalities for not only Tcell, but also antibody vaccine development.

Strategies for inducing effective neutralizing antibody responses against HIV-1

“…These antibody titres also declined faster after immunization for the protein-only group. However, the homologous protein regimen induced more robust Tier 2 NAb titres than the ones that included ChAdOx1 and MVA [269].…”

“…Nonetheless, heterologous combinations of chimpanzee adenovirus Oxford 1 (ChAdOx1) [264] and modified vaccinia Ankara (MVA) [265] viral vectors have shown a good safety and immunogenicity profile [266][267][268]. Capucci et al showed that a sequential regimen of ChAdOx1, MVA and soluble BG505 SOSIP trimer protein induced similar binding-antibody titres to the protein-only regimen, while only the sequential regimen induced cytotoxic T cell responses [269]. These antibody titres also declined faster after immunization for the protein-only group.…”

Antibody Responses Elicited by Immunization with BG505 Trimer Immune Complexes

“…Reagents. BG505 SOSIP.664 trimers were expressed in CHO cells and purified as described previously (2). Rabbit MAbs 11A, 11B, and 12A were transiently expressed, affinity purified, and checked for purity and integrity as described previously (15).…”

“…on the native HIV-1 trimer (1). Toward that end, the BG505 SOSIP.664 envelope (Env) glycoprotein trimer has been used in multiple animal immunization studies (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The BG505 Env glycoprotein lacks N-glycosylation sites at positions 241 and 289 (7,8).…”

Virus-Like-Vaccines against HIV

“…While these constructs have clearly solidified our knowledge of the challenges faced in HIV vaccine design, they have provided no clear path forward. Indeed, the focus on obtaining tier 2 virus neutralization may be detrimental, as this draws resources and focus from DNA and virus vectored regimens that, while not able to yield the same consistency in autologous tier 2 neutralization, can provide broader binding antibody responses [ 45 ]. Currently, the only inducible mechanism of protection we know of with some certainty is that protection against HIV acquisition can be elicited by broadly cross-reacting antibodies [ 46 ].…”