Consequences of the B Cell Response: Protection versus Enhancement
Several studies have demonstrated that high virus-specific antibody titers to SARS-CoV-2 are correlated with greater neutralization of virus in vitro and are inversely correlated with viral load in patients (Figure 4) (Okba et al., 2020, Wölfel et al., 2020, Zhao et al., 2020a). Despite these indications of a successful neutralizing response in the majority of individuals, higher titers are also associated with more severe clinical cases (Li et al., 2020b, Okba et al., 2020, Zhao et al., 2020a, Zhou et al., 2020a), suggesting that a robust antibody response alone is insufficient to avoid severe disease (Figure 4).
This was also observed in the previous SARS-CoV-1 epidemic, where neutralizing titers were found to be significantly higher in deceased patients compared to patients who had recovered (Zhang et al., 2006). This has led to concerns that antibody responses to these viruses may contribute to pulmonary pathology via antibody-dependent enhancement (ADE) (Figure 4). This phenomenon is observed when non-neutralizing virus-specific IgG facilitate entry of virus particles into Fc-receptor (FcR) expressing cells, particularly macrophages and monocytes, leading to inflammatory activation of these cells (Taylor et al., 2015). A study in SARS-CoV-1-infected rhesus macaques found that anti-S IgG contributed to severe acute lung injury (ALI) and massive accumulation of monocytes and macrophages in the lung (Liu et al., 2019). Furthermore, serum containing anti-S Ig from SARS-CoV-1 patients enhanced the infection of SARS-CoV-1 in human monocyte-derived macrophages in vitro (Yip et al., 2014). ADE was also reported with a monoclonal antibody isolated from a patient with MERS-CoV (Wan et al., 2020c). Somewhat reassuringly, there was no evidence of ADE mediated by sera from rats vaccinated with SARS-CoV-2 RBD in vitro (Quinlan et al., 2020) nor in macaques immunized with an inactivated SARS-CoV-2 vaccine candidate (Gao et al., 2020c).
As of now, there is no evidence that naturally developed antibodies toward SARS-CoV-2 contribute to the pathological features observed in COVID-19. However, this possibility should be considered when it comes to experimental design and development of therapeutic strategies. Importantly, in all of the descriptions of ADE as it relates to CoV, the FcR was necessary to trigger the antibody-mediated pathology. High-dose intravenous immunoglobulin (IVIg), which may blunt ADE, has been trialed in COVID-19 patients (Cao et al., 2020b, Shao et al., 2020), but further studies are needed to determine the extent to which IVIg is safe or beneficial in SARS-CoV-2 infection. Vaccine trials will need to consider the possibility of antibody-driven pathology upon antigen rechallenge; strategies using F(ab) fragments or engineered Fc monoclonal antibodies may prove particularly beneficial in this setting (Amanat and Krammer, 2020).