Data shown are geometric means??SD from six samples. the initial immunization. NHPs immunized with a single dose of CF501/RBD-Fc produced high titers of nAbs. The immunized macaques also exhibited durable humoral and cellular GW806742X immune responses and showed remarkably reduced viral load in the upper and lower airways upon SARS-CoV-2 challenge even at 108 days post the final immunization. Thus, CF501/RBD-Fc can be further developed as a novel pan-sarbecovirus vaccine to combat current and future outbreaks of sarbecovirus diseases. Subject terms: Innate immunity, Immunology, Molecular biology Introduction Global public health is usually constantly threatened by emerging viruses.1 Coronaviruses, especially sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe acute respiratory syndrome coronavirus (SARS-CoV), have respectively caused two global health crises within the past 20 years.2C4 In particular, the ongoing global pandemic of coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 infection has resulted in Sox18 more than 270 million confirmed cases and 5.3 million deaths (https://www.who.int/). The emergence of SARS-CoV-2 variants of concern (VOCs), including B.1.1.7 (Alpha),5 B.1.351 (Beta),6 P.1 (Gamma)7 and B.1.617.2 (Delta),8 and variants of interest (VOIs), such as B.1.427 (Epsilon), P.2 (Zeta), B.1.525 (Eta), B.1.526 (Iota), B.1.617.1 (Kappa), and C.37 (Lambda) (https://www.who.int/), has posed a serious challenge for the development of COVID-19 vaccines. These VOCs have shown increased transmissibility, infectivity, and resistance to humoral responses induced by some COVID-19 vaccines.8C13 With the worldwide spread of SARS-CoV-2 and increased immune pressure, more variants are expected to emerge in the near future. Furthermore, numerous SARS-related coronaviruses (SARSr-CoVs) identified from bats, such as WIV1, Rs3367, and RsSHC014, represent potential threats to humans since they can utilize human angiotensin-converting enzyme 2 (ACE2) as their common receptor to enter and replicate in primary airway epithelial cells.14C16 Similar to SARS-CoV, which infects humans through intermediate animal hosts, these bat SARSr-CoVs may also break the species barrier to infect an intermediate animal host, and then humans.14,17,18 Thus, the constant emergence of SARS-CoV-2 variants and the high pandemic potential of SARSr-CoVs underscore the need for the development of pan-sarbecovirus or universal coronavirus vaccines.19 Recent studies revealed that only one amino acid mutation, such as E484K in the spike (S) protein of SARS-CoV-2, confers resistance to the neutralization activity of convalescent or immune sera.9 So far, SARS-CoV-2 has shown relatively few variants. In comparison, other sarbecoviruses, such as SARS-CoV, share low homology (~76% amino acid identity for the S protein) with SARS-CoV-2,20 which substantially increases the difficulty of developing pan-sarbecovirus GW806742X vaccines. Moreover, neutralizing antibody (nAb) titers against SARS-CoV-2 and its variants gradually decrease only a few months after vaccination with current COVID-19 vaccines.21,22 Therefore, how to induce potent and durable protective immunity against the currently circulating SARS-CoV-2 variants, future SARS-CoV-2 variants, and SARSr-CoVs, is now the challenge confronting vaccine developers. Subunit vaccines are the most commonly used vaccines because of their excellent safety profiles and efficacy.23C27 Therefore, the development of safe and effective COVID-19 subunit vaccines is GW806742X expected to play a significant role in controlling the COVID-19 pandemic. Currently, most COVID-19 subunit vaccines target mainly the spike (S) protein or receptor-binding domain name (RBD). Especially, the RBD contains multiple neutralizing epitopes, and 90% neutralization was induced by the RBD in COVID-19 convalescent sera.28C30 Moreover, RBD-immunized mice or nonhuman primates (NHPs) exhibited protection against SARS-CoV-2 challenge.25,31,32 Most importantly, several RBD-binding monoclonal antibodies (mAbs), such as A23-58.1, B1-182.1, and A19-61.1 exhibit great potency against all VOCs and VOIs.33 Besides, S309,34 DH1047,35 BG10-19,36 S2X259,37 XG014,38,39 ADI5568920 and ADG-2, 40 have been reported to show cross-neutralizing activity against SARS-CoV-2 and SARS-CoV, providing proof-of-concept for the development of a pan-sarbecovirus vaccine GW806742X that uses RBD as an immunogen. However, we previously found that the SARS-CoV-2 RBD-Fc protein formulated with Freunds adjuvant induced only a very limited cross-nAb response.25 Thus, the induction of cross-nAbs has become an obstacle hindering the development of pan-sarbecovirus vaccines. Adjuvants are essential components of subunit vaccines by promoting potent and persistent.