Immunogenicity in Rabbits of HIV-1 SOSIP Trimers from Clades A, B, and C, Given Individually, Sequentially, or in Combination

Abstract

Recombinant soluble HIV-1 envelope glycoprotein (Env) SOSIP trimers are a design platform for inducing broadly neutralizing antibodies (bNAbs) by vaccination. To date, these and alternative designs of native-like trimers, given singly or in pairs, have not induced bNAbs in test animals such as rabbits or macaques. Here, we have evaluated whether trivalent and tetravalent combinations of SOSIP trimers from clades A, B, and C, delivered simultaneously or sequentially, induce better neutralizing antibody responses in rabbits than when given alone. None of the tested formulations led to the induction of bNAbs. We found that BG505 clade A trimers dominated the autologous NAb responses induced by combinations, which probably relates to the presence of immunodominant glycan holes on the BG505 trimer. Furthermore, autologous NAb responses to all individual trimers were reduced when they were delivered in combinations compared with when delivered alone, suggesting that immunogen interference had occurred. Finally, in a sequential regimen, a heterologous clade C trimer cross-boosted NAb responses that were primed by earlier immunizations with clade A and B trimers. Taken together, these findings should allow us to improve the design of immunization regimens based on native-like HIV-1 Env trimers.IMPORTANCE A successful HIV-1 vaccine most probably requires a trimeric envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and therefore the only target for neutralizing antibodies. Native-like Env trimers can induce strain-specific neutralizing antibodies but not yet broadly neutralizing antibodies. To try to broaden the antibody response, we immunized rabbits with soluble native-like Env trimers from three different clades using monovalent, multivalent, and sequential regimens. We found that the neutralizing antibody response against each immunogen was reduced when the immunogens were delivered in combination or sequentially compared to the monovalent regimen. In contrast, when the Env trimers from different clades were delivered sequentially, the neutralizing antibody response could be cross-boosted. Although the combination of native-like Env trimers from different clades did not induce broadly neutralizing antibodies, the results provide clues on how to use native-like trimers in vaccination experiments.

Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

“…We observed that immunization with a combination of immunogens in a cocktail formulation or in sequence did not induce bNAbs, but merely autologous NAb responses. Furthermore, the autologous NAb responses were prominent against the most immundominant trimer of the cocktail [69]. Thus, the immune response shows narrow specificity, similar to what has been reported for influenza vaccines [74].…”

“…One strategy to counteract the immunogenicity of the BG505 specific glycan hole would be to immunize with trimers that contain glycans at positions N241 and N289. Previous studies have shown that immunizations with trimers based on isolates with a denser glycan shield (AMC008 and ZM197M) induced a broader heterologous NAb response compared to trimers from isolates with large holes in the glycan shield (BG505 and B41), which supports the pursuit of this strategy [69].…”

“…To increase neutralization breadth, we have explored the use of cocktail and sequential regimens [17,69]. We observed that immunization with a combination of immunogens in a cocktail formulation or in sequence did not induce bNAbs, but merely autologous NAb responses.…”

Vaccine-induced protection from homologous Tier 2 simian-human immunodeficiency virus challenge in nonhuman primates

“…449 In conclusion, we provide evidence that protein immunization with native-like Env 450 trimers can induce potent and protective nAb titers in the SHIV/macaque model. Thus, 451 nAb-mediated protection from Tier 2 virus challenge is not limited to bnAbs, which are 452 generally focused to a single site of vulnerability and have a defined effector-function 453 profile, but can also be accomplished by polyclonal autologous nAb responses of 454 sufficient magnitude and specificity, which comprise a broad range of neutralizing and 455 non-neutralizing antibody lineages to various, often overlapping epitopes that interact in 456 both synergistic or competitive ways (Klasse et al, 2018;Pauthner et al, 2017;Sanders 457 et al, 2015;Torrents de la Peña et al, 2018). The protective nAb titer threshold against 458 the homologous challenge virus that we determined is in rough accord with passive 459 antibody transfer studies and provides a benchmark for comparison with upcoming 460 antibody protection studies against HIV in humans (www.ampstudy.org).…”

“…NAb specificities to the N355-region were observed in BG505 SOSIP immunized rabbits 256 (Klasse et al, 2018), and were detected in week 0 plasma of animal 12-137 using electron 257 microscopy based serum mapping ( Figure S3C) (Bianchi et al, 2018). We could further 258…”