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

Many efforts are now underway to develop vaccines based on stabilized soluble trimeric forms of the S protein ectodomain (Wrapp et al., 2020) . It is at this moment unclear whether these S-protein trimers, RBDs, or some parallel or serial combination thereof, will make better antigens. Recent studies suggest that neutralization activity of patient sera correlates with its RBD recognition, and that most neutralizing antibodies bind the RBD (To et al., 2020). It is possible that the remainder of the S protein presents non-neutralizing epitopes that are more immunogenic than the RBD, and thus the RBD by itself may elicit antisera that are more neutralizing. However, other antibody effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement fixation, are more efficiently activated when multiple antibodies bind their target simultaneously, and these non-neutralizing activities can play important roles in viral control. If these activities contribute significantly to SARS-CoV-2 prevention, the S-protein trimer may make a better antigen than the RBD. Alternatively, an optimized combination of both antigens may focus . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.10.036418 doi: bioRxiv preprint the immune response to a critical neutralizing epitope while also promoting more efficient antibody effector functions. A trimer-prime, RBD-boost strategy may even be necessary. (Luo et al., 2018; Wang et al., 2016; Yip et al., 2016) , and SARS-CoV-1 ADE has been observed by several groups in cell culture studies (Jaume et al., 2011; Liu et al., 2019; Wan et al., 2020; Wang et al., 2014; Yang et al., 2005; Yip et al., 2014) . ADE is more obvious in feline coronavirus, where it results in a shift in tropism and increase in disease severity (Huisman et al., 1998; Huisman et al., 2009; Weiss and Scott, 1981) . Although ADE could theoretically be mediated by multiple mechanisms, the standard paradigm is provided by flaviviruses, most notably by dengue virus (Takada and Kawaoka, 2003) . It is well appreciated that a second dengue virus infection with a different serotype can result in a hemorrhagic fever. In addition, a dengue-virus vaccine was reported to increase hospitalizations of vaccinees after their first dengue-virus exposure (Flipse and Smit, 2015; Tsai et al., 2017) . In both cases, the underlying mechanism is presumed to be enhanced Fc-receptor-mediated internalization of virions bound to antibodies.