Structural basis for broad coronavirus neutralization

Abstract

our coronaviruses mainly associated with common cold-like symptoms are endemic in humans, namely OC43, HKU1, NL63 and 229E, while three highly pathogenic zoonotic coronaviruses have emerged in the past two decades, leading to epidemics and a pandemic. Severe acute respiratory syndrome coronavirus (SARS-CoV) was discovered in Guangdong Province in China in 2002 and spread to five continents through air travel routes, infecting 8,098 people and causing 774 deaths. No cases were reported after 2004 1,2 . In 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in the Arabian Peninsula, where it still circulates. It was exported to 27 countries, infecting a total of 2,494 individuals and claiming 858 lives as of January 2020 according to the World Health Organization 3 . A recent study further suggested that undetected zoonotic MERS-CoV transmissions are currently occurring in Africa 4 . A novel coronavirus, named SARS-CoV-2, was associated with an outbreak of severe pneumonia in Hubei Province, China, at the end of 2019 and has since infected over 121 million people and claimed more than 2.6 million lives worldwide during the ongoing COVID-19 pandemic 5,6 .SARS-CoV and SARS-CoV-2 probably originated in bats 5,7-10 , with masked palm civets and racoon dogs acting as intermediate amplifying and transmitting hosts for SARS-CoV [11][12][13] . Although MERS-CoV was also suggested to have originated in bats, repeated zoonotic transmissions occurred from dromedary camels 14,15 . The identification of numerous coronaviruses in bats, including viruses related to SARS-CoV-2, SARS-CoV and MERS-CoV, along with evidence of spillovers of SARS-CoV-like viruses to humans, strongly indicates that future coronavirus emergence events will continue to occur 5,[7][8][9][10][16][17][18][19][20] .The coronavirus spike (S) glycoprotein mediates entry into host cells and comprises two functional subunits mediating attachment to host receptors (S 1 subunit) and membrane fusion (S 2 subunit) [21][22][23][24][25][26][27] . As the S homotrimer is prominently exposed at the viral surface and is the main target of neutralizing antibodies (Abs), it is a focus of therapeutic and vaccine design efforts 28 . We previously showed that the SARS-CoV-2 receptor-binding domain (RBD, part of the S 1 subunit) is immunodominant, comprises multiple distinct antigenic sites, and is the target of 90% of the neutralizing activity present in COVID-19 convalescent plasma 29 . Accordingly, monoclonal Abs (mAbs) with potent neutralizing activity have been identified against the SARS-CoV-2, SARS-CoV and MERS-CoV RBDs and shown to protect against viral challenge in vivo [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] . The isolation of S309 from an individual recovered from SARS-CoV, which neutralizes SARS-CoV-2 and SARS-CoV through recognition of a conserved RBD epitope, demonstrated that potent neutralizing mAbs could inhibit β-coronaviruses belonging to different lineage B (sarbecovirus) clades 31 . An optimized version of S...

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

“…4c). Our panel therefore extends prior observations 4,5,32,38 to highlight a general tradeoff between sarbecovirus breadth and potency of SARS-CoV-2 neutralization (Fig. 4e).…”

“…Though S2H97-like antibodies are rare in polyclonal sera, the protective capacity and exceptional breadth of S2H97 indicates that pan-sarbecovirus vaccines could seek to improve responses to this epitope by unmasking this and other cryptic broadly neutralizing epitopes 5,37,41 . Broader cross-reactivity among betacoronavirus lineages including MERS and OC43 has been reported for antibodies that bind the spike S2 domain 32,38,42 . Though S2H97 breadth does not extend beyond sarbecoviruses, its discovery expands our view of what can be achieved via a potent RBD-directed antibody response.…”

High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

“…Antibodies targeting the receptor binding domain (RBD) of the spike protein are thought to dominate the neutralizing activity of convalescent or vaccine recipient plasma 1 , and include the most potent neutralizing antibodies cloned from convalescent individuals 2–6 . However, additional SARS-CoV-2 neutralizing antibody targets include the N-terminal domain (NTD) and the fusion machinery 3,5,7–9 , and the full spectrum of epitopes targeted by neutralizing antibodies in convalescent or vaccine recipient plasma has not been defined. Circulating SARS-CoV-2 variants of concern (VOC) or variants of interest (VOI) encode spike amino acid substitutions 10–13 , some of which confer resistance individual human monoclonal antibodies but have variable, typically modest, effects on neutralization by polyclonal plasma antibodies 1,4,13–17 .…”

Identification of Human SARS-CoV-2 Monoclonal Antibodies from Convalescent Patients Using EBV Immortalization

“…The other 10% of neutralizing mAbs recognize the N-terminal domain (NTD) or the stalk regions of S1 or S2 [ 32 , 33 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. Some neutralizing antibodies may interfere with RBD or spike protein conformational changes upon ACE2 binding or with the S fusion machinery [ 48 , 49 ]. In addition, the induction of protein S1 shedding has been linked to neutralization potency [ 46 , 47 ].…”

“…Although the two mAbs identified here do not show neutralization activity in vitro, they may nonetheless be useful for diagnostic or other purposes, such as studies on the emerging variants of SARS-CoV-2 or other β coronaviruses [ 49 ]. Worth noting is that the role of antibodies in controlling viral infections is complex.…”