Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif.
| العنوان: | Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif. |
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| المؤلفون: | Hauser BM, Sangesland M, Lam EC, Denis KJS, Feldman J, Yousif AS, Caradonna TM, Kannegieter T, Balazs AB, Lingwood D, Schmidt AG |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2021 Jun 29. Date of Electronic Publication: 2021 Jun 29. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. In mice, we find that a cocktail of these homotrimeric sarbecovirus RBDs elicits antibodies to conserved viral epitopes outside of the ACE2 receptor binding motif (RBM). Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. We further show that a substantial fraction of the neutralizing antibodies elicited after vaccination in humans also engages non-RBM epitopes on the RBD. Collectively, our results suggest a strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine. Author Summary: Immunity to SARS-CoV-2 in the human population will be widespread due to natural infection and vaccination. However, another novel coronavirus will likely emerge in the future and may cause a subsequent pandemic. Humoral responses induced by SARS-CoV-2 infection and vaccination provide limited protection against even closely related coronaviruses. We show immunization with a cocktail of trimeric coronavirus receptor binding domains induces a neutralizing antibody response that is broadened to related coronaviruses with pandemic potential. Importantly, this broadening occurs in context of an initial imprinted SARS-CoV-2 spike immunization showing that preexisting immunity can be expanded to recognize other related coronaviruses. Our immunogens focused the serum antibody response to conserved epitopes on the receptor binding domain outside of the ACE2 receptor binding motif; this contrasts with current SARS-CoV-2 therapeutic antibodies, which predominantly target the receptor binding motif. |
| معلومات مُعتمدة: | T32 AI007245 United States AI NIAID NIH HHS; F30 AI160908 United States AI NIAID NIH HHS; R01 AI146779 United States AI NIAID NIH HHS; DP2 DA040254 United States DA NIDA NIH HHS; T32 GM008313 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20201217 Latest Revision: 20220716 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC7743097 |
| DOI: | 10.1101/2020.12.07.415216 |
| PMID: | 33330872 |
| قاعدة البيانات: | MEDLINE |
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