The SARS-CoV-2 receptor-binding domain elicits a potent neutralizing response without antibody-dependent enhancement

Brian D Quinlan; Huihui Mou; Lizhou Zhang; Yan Gao; Wenhui He; Amrita Ojha; Mark S Parcells; Guangxiang Luo; Wenhui Li; Guocai Zhong; Hyeryun Choe; Michael Farzan

Because the S protein is the dominant protein exposed on the virion, and because its activity can be impeded with antibodies, it is likely the major target of any SARS-CoV-2 vaccine. Soluble trimeric S proteins, including those stabilized through various mechanisms, have been tested as SARS-CoV-1 vaccines, and similar approaches are now being taken against SARS-CoV-2 (Chen et al., 2005; Walls et al., 2020; Wrapp et al., 2020) . Another approach, immunizing with the RBD alone, has been shown to raise potent neutralizing antibodies against SARS-CoV-1 in rodents (He et al., 2006; He et al., 2004) . Although the RBD presents fewer epitopes than the S-protein trimer, this approach may have key advantages. The RBD is easier to produce, and is less likely to elicit antibodies against poorly neutralizing but more immunogenic epitopes. In addition, antibodydependent enhancement (ADE) contributes to the pathogenicity of feline coronaviruses (Huisman et al., 2009; Olsen et al., 1992; Weiss and Scott, 1981) , and has been raised as a concern for vaccines against SARS-CoV-1 (Jaume et al., 2012; Liu et al., 2019; Luo et al., 2018; Wan et al., 2020; Wang et al., 2016; Wang et al., 2014; Yang et al., 2005; Yip et al., 2016) 3. ADE contributes to the pathology of other viral diseases, notably those caused by flaviviruses, and in those cases, non-neutralizing antibodies promote more efficient ADE than those which also neutralize (Dejnirattisai et al., 2010; Halstead and O'Rourke, 1977; Takada and Kawaoka, 2003) . Thus the RBD-elicited antibodies may mediate ADE less efficiently than those recognizing other S-protein epitopes because they are more likely to be neutralizing.