Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.

Summary paragraph Influenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health 1 . Here we show that computationally designed, two-component nanoparticle immunogens 2 induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in an ordered array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens co-displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited antibody responses against vaccine-matched strains that were equivalent or superior to commercial QIV, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved HA stem. The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens make them attractive candidates for a supraseasonal influenza vaccine candidates with potential to replace conventional seasonal vaccines 3 .

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...