The coronavirus disease 2019 (COVID-19) pandemic has been caused by the rapid outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pandemic has devastated lives and livelihoods and continues to be on an uncertain trajectory. Scientists have been working tirelessly to prevent future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus.
Study: Isolation and comparative analysis of antibodies that broadly neutralize sarbecoviruses. Image Credit: MattLphotography/Shutterstock
In a new study published on the bioRxiv* preprint server, scientists identified a human monoclonal antibody (mAb), which successfully neutralized or bound all sarbecoviruses tested in vitro. This monoclonal antibody was also protected against SARS-CoV-2 and SARS-CoV in vivo.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
The continued threat of zoonotic spillovers presents the need to develop interventions that could combat animal coronaviruses with pandemic potential. Many anti-SARS-CoV-2 mAbs have been characterized, and some of them have been reported to possess broadly neutralizing activity against SARS-CoV-2 and other sarbecoviruses, a viral subgenus containing both SARS-CoV-2 and SARS-CoV. These mAbs could serve as a therapeutic agent against current and future pandemics.
In the current study, scientists reported the isolation of three mAbs, broadly capable of neutralizing sarbecoviruses. In addition, they describe virological and structural findings from a comprehensive comparative analysis of these mAbs. The current study results could aid the development of pan-sarbecovirus antibodies and vaccines.
A new study
For this study, scientists screened sera from convalescent COVID-19 individuals. Serum from two patients potently neutralized all SARS-CoV-2 variants tested as well as SARS-CoV, albeit weakly. The next step was to sort for B.1.351 spike trimer-specific memory B cells from the blood of both patients. Subsequently, by single-cell RNA-sequencing, researchers determined the paired heavy and light chain sequences of each mAb. A total of 58 mAbs were isolated and characterized.
Key findings
10-40, 10-28, and 11-11 are three mAbs that were found to bind to SARS-CoV-2 spikes of D614G and B.1.351 as well as SARS-CoV. All the antibodies recognized epitopes within the receptor-binding domain (RBD) and hindered the soluble human ACE2 receptor binding to the spike. The light chains of 10-40, 10-28, and 11-11 were derived from IGLV6- 104 57*01, IGKV1-39*01, and IGLV1-40*01, respectively, and they showed low levels of somatic hypermutation.
Researchers compared the virus-neutralizing potency and breadth of 10-40, 10-28, and 11-11 to other RBD-directed mAbs with known activity against other sarbecoviruses. All mAbs, except CR3022, showed breadth by neutralizing all SARS-CoV-2 strains, and ADG2 was most potent. 10-28, 11-11, 2-36, and COVA1-16 exhibited lower potencies. ADG-2, 10-40, S2X259, and DH1047 showed decent neutralizing activity against authentic SARS-CoV.
Further, 10-40 and DH1047 neutralized all sarbecoviruses examined, while 11-11, S2X259, and ADG-2 were weak in neutralizing at least one of the viruses in the panel. None of the antibodies neutralized the Middle East respiratory syndrome virus (MERS). 10-40, 10-28, and S2H97 bound all RBD proteins derived from six sarbecoviruses, while this was not the case for DH1047. Overall, it was concluded that 10-40 can neutralize or bind every sarbecovirus that was studied. It also appeared to be the RBD-directed mAb with the most breadth against sarbecoviruses known to date.
The antibody-spike interactions for 10-40, 10-28, and 11-11 were subsequently, studied and their epitopes were also visualized at high resolution. The 10-40 crystal structure resolution revealed recognition of an epitope that is highly conserved among sarbecoviruses on the inner face of RBD. The 10-28 crystal structure antibody-RBD side-chain interactions were well defined at 3.2 Å resolution. All three antibodies recognized a region on the inner side of RBD, hidden in the RBD-down conformation of the spike.
Lastly, the in vivo protective efficacy of 10-40 was analyzed by challenging wild-type mice with a mouse-adapted SARS-CoV-2 strain, MA 10, the RBD mutations of which did not strongly affect the neutralizing activity of 10-40 in vitro. 10-40 appeared to be active in vivo against both SARS-CoV-2 and SARS-CoV.
Conclusion
Sarbecoviruses have caused two major outbreaks in humans in the past two decades, which means that we should prepare for the possibility of a similar future epidemic/pandemic. A pan-sarbecovirus neutralizing mAb and/or vaccine could be useful interventions to contain such outbreaks.
Scientists identified a human mAb, 10-40, that should fit this purpose in the current study. While RBD-directed mAbs that neutralize sarbecoviruses have been reported, 10-40 showed the most breadth. 10-40 was also observed to neutralize or bind all sarbecoviruses tested and showed promising potency against SARS-CoV-2 in vitro and in vivo. Despite being isolated from a COVID-19 patient, scientists observed that, interestingly, its potency against other sarbecoviruses was even better, and this is indeed promising news.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Study reveals how SARS-CoV-2 hijacks lung cells to drive COVID-19 severity