Targeted isolation of diverse human protective broadly neutralizing antibodies against SARS-like viruses

Abstract

The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.

Both COVID-19 infection and vaccination induce high-affinity cross-clade responses to SARS-CoV-2 variants

“…On the other hand, our findings describing the antibody response of pre-omicron convalescent or post-vaccination sera to the SARS-CoV-2 omicron variant are congruent with those found by others with other methods (see e.g. (He et al, 2022)), including viral neutralization and clinical observations.…”

Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques

“…Different presentations of S-protein in the vaccines, particularly the mRNA-based vaccines, induce relatively high serum nAb responses in most individuals that appear to strongly target epitopes that overlap the angiotensin converting enzyme 2 (ACE2) receptor binding site (RBS) in the receptor binding domain (RBD) (1,(5)(6)(7)(8)(9). Infection with SARS-CoV-2 produces more variable nAb responses, but again, there is a strong targeting of the RBD and the RBS (1,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Broadly Neutralizing Antibodies to SARS-CoV-2 Provide Novel Insights Into the Neutralization of Variants and Other Human Coronaviruses

“…This suggests that understanding the structural basis of bnAbs mediated neutralization mechanism of immune evading viruses can provide blueprints to guide structural-based therapeutics and vaccine design by employing affinity maturation through directed evolution, CDRH3 swapping and Reverse Vaccinology 2.0 approaches, respectively ( Burton, 2017 ; Kadam et al., 2017 ; Traboulsi et al., 2021 ; Zhao et al., 2021 ; Zupancic et al., 2021 ). Moreover, RBD mAbs from hybrid immune individuals dominantly target class III and IV epitopes with potent broad sarbecoviruses neutralizing potential ( He et al., 2022 ; Muecksch et al., 2022 ). These SARS-CoV-2 bnAbs exhibit unique immunogenetic features like presence of ‘YYDRxG’ motif in their CDRH3 region, enrichment of IGHV3-30, IGHV1-46, IGHV1-69 germline V-genes, IGHD2-15 and IGHD3-22 germline D-genes, moderately higher somatic hypermutation (SHM) >5% ( He et al., 2022 ; Muecksch et al., 2022 ).…”

“…Moreover, RBD mAbs from hybrid immune individuals dominantly target class III and IV epitopes with potent broad sarbecoviruses neutralizing potential ( He et al., 2022 ; Muecksch et al., 2022 ). These SARS-CoV-2 bnAbs exhibit unique immunogenetic features like presence of ‘YYDRxG’ motif in their CDRH3 region, enrichment of IGHV3-30, IGHV1-46, IGHV1-69 germline V-genes, IGHD2-15 and IGHD3-22 germline D-genes, moderately higher somatic hypermutation (SHM) >5% ( He et al., 2022 ; Muecksch et al., 2022 ). On the other hand, nAbs targeting NTD have not been ideal for clinical use development due to recurring mutations in the epitopes they target, resulting in lower effectiveness against the majority of the VOCs and VOIs ( Hastie et al., 2021 ).…”