TY - JOUR
T1 - High thermostability improves neutralizing antibody responses induced by native-like HIV-1 envelope trimers
AU - del Moral-Sánchez, Iván
AU - Russell, Rebecca A.
AU - Schermer, Edith E.
AU - Cottrell, Christopher A.
AU - Allen, Joel D.
AU - Torrents de la Peña, Alba
AU - LaBranche, Celia C.
AU - Kumar, Sanjeev
AU - Crispin, Max
AU - Ward, Andrew B.
AU - Montefiori, David C.
AU - Sattentau, Quentin J.
AU - Sliepen, Kwinten
AU - Sanders, Rogier W.
N1 - Funding Information: The authors thank Marit van Gils for donating the 10A monoclonal antibody; and Michel Nussenzweig, Hermann Katinger, Mark Connors, James Robinson, Dennis Burton, John Mascola, Peter Kwong, and William Olson for donating antibodies and reagents directly or through the NIH AIDS Research and Reference Reagent Program. We thank Dietmar Katinger and Ehsan Suleiman for providing the squalene emulsion adjuvant. This project has received funding from the European Union?s Horizon 2020 research and innovation program under grant agreement No. 681137 (to R.W.S., Q.S., and M.C.). This work was also supported by the U.S. National Institutes of Health Grant P01 AI110657 (to A.B.W. and R.W.S.) and NIAID Contract #HHSN27201100016C (to D.C.M.); by the International AIDS Vaccine Initiative (IAVI); by the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD), grants OPP1111923 and OPP1132237 (to R.W.S.) and OPP1115782 (A.B.W.); by the Aids Fonds Netherlands, Grant #2016019 (to R.W.S.); and by the Fondation Dormeur, Vaduz (to R.W.S.). R.W.S. is a recipient of a Vici grant from the Netherlands Organization for Scientific Research (NWO). We thank EMBO for the Short-Term Fellowship (STS-7814) awarded to S.K. The electron microscopy data were collected at Electron Microscopy Facility of The Scripps Research Institute. Funding Information: The authors thank Marit van Gils for donating the 10A monoclonal antibody; and Michel Nussenzweig, Hermann Katinger, Mark Connors, James Robinson, Dennis Burton, John Mascola, Peter Kwong, and William Olson for donating antibodies and reagents directly or through the NIH AIDS Research and Reference Reagent Program. We thank Dietmar Katinger and Ehsan Suleiman for providing the squalene emulsion adjuvant. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 681137 (to R.W.S., Q.S., and M.C.). This work was also supported by the U.S. National Institutes of Health Grant P01 AI110657 (to A.B.W. and R.W.S.) and NIAID Contract #HHSN27201100016C (to D.C.M.); by the International AIDS Vaccine Initiative (IAVI); by the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD), grants OPP1111923 and OPP1132237 (to R.W.S.) and OPP1115782 (A.B.W.); by the Aids Fonds Netherlands, Grant #2016019 (to R.W.S.); and by the Fondation Dormeur, Vaduz (to R.W.S.). R.W.S. is a recipient of a Vici grant from the Netherlands Organization for Scientific Research (NWO). We thank EMBO for the Short-Term Fellowship (STS-7814) awarded to S.K. The electron microscopy data were collected at Electron Microscopy Facility of The Scripps Research Institute. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Soluble HIV-1 envelope glycoprotein (Env) immunogens are a prime constituent of candidate vaccines designed to induce broadly neutralizing antibodies. Several lines of evidence suggest that enhancing Env immunogen thermostability can improve neutralizing antibody (NAb) responses. Here, we generated BG505 SOSIP.v9 trimers, which displayed virtually no reactivity with non-neutralizing antibodies and showed increased global and epitope thermostability, compared to previous BG505 SOSIP versions. Chemical crosslinking of BG505 SOSIP.v9 further increased the melting temperature to 91.3 °C, which is almost 25 °C higher than that of the prototype SOSIP.664 trimer. Next, we compared the immunogenicity of a palette of BG505-based SOSIP trimers with a gradient of thermostabilities in rabbits. We also included SOSIP.v9 proteins in which a strain-specific immunodominant epitope was masked by glycans to redirect the NAb response to other subdominant epitopes. We found that increased trimer thermostability correlated with increased potency and consistency of the autologous NAb response. Furthermore, glycan masking steered the NAb response to subdominant epitopes without decreasing the potency of the autologous NAb response. In summary, SOSIP.v9 trimers and their glycan masked versions represent an improved platform for HIV-1 Env based vaccination strategies.
AB - Soluble HIV-1 envelope glycoprotein (Env) immunogens are a prime constituent of candidate vaccines designed to induce broadly neutralizing antibodies. Several lines of evidence suggest that enhancing Env immunogen thermostability can improve neutralizing antibody (NAb) responses. Here, we generated BG505 SOSIP.v9 trimers, which displayed virtually no reactivity with non-neutralizing antibodies and showed increased global and epitope thermostability, compared to previous BG505 SOSIP versions. Chemical crosslinking of BG505 SOSIP.v9 further increased the melting temperature to 91.3 °C, which is almost 25 °C higher than that of the prototype SOSIP.664 trimer. Next, we compared the immunogenicity of a palette of BG505-based SOSIP trimers with a gradient of thermostabilities in rabbits. We also included SOSIP.v9 proteins in which a strain-specific immunodominant epitope was masked by glycans to redirect the NAb response to other subdominant epitopes. We found that increased trimer thermostability correlated with increased potency and consistency of the autologous NAb response. Furthermore, glycan masking steered the NAb response to subdominant epitopes without decreasing the potency of the autologous NAb response. In summary, SOSIP.v9 trimers and their glycan masked versions represent an improved platform for HIV-1 Env based vaccination strategies.
UR - http://www.scopus.com/inward/record.url?scp=85125664508&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41541-022-00446-4
DO - https://doi.org/10.1038/s41541-022-00446-4
M3 - Article
C2 - 35228534
SN - 1476-0584
VL - 7
JO - npj Vaccines
JF - npj Vaccines
IS - 1
M1 - 27
ER -