SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity and kinetics of the antibody response mounted against this novel virus are not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and non-structural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike.

Functional importance of the D614G mutation in the SARS-CoV-2 spike protein

“…Experimental data pertaining to neutralization of S(G614) and S(D614) pseudoviruses have been reported in abundance. The majority of experiments demonstrate similar neutralization of both S(D614) and S(G614) PVs by antibodies or patient antisera directed against one or the other S protein variant [ 28 , 35 , 51 , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] ], while in some cases S(G614) exhibited greater susceptibility to neutralization [ 51 , 57 ]. Similar neutralization or greater susceptibility of the S(G614) variant have been reproduced with live SARS-CoV-2 as well [ 47 , 48 ].…”

Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS–CoV–2 Spike

“…The magnitude of the neutralizing antibody response, which is thought to be important for protection from re-infection and/or disease, has been associated with disease severity. Specifically, those with most severe disease typically develop the strongest antibody response whereas those experiencing mild disease, or who are asymptomatic, can have lower levels of neutralizing activity detectable in their sera (Guthmiller et al, 2021; Laing et al, 2020b; Legros et al, 2021; Rees-Spear et al, 2021; Seow et al, 2020; Zohar et al, 2020). Antibodies targeting RBD have been suggested to account for >90% of neutralizing activity in convalescent sera (Greaney et al, 2020; Piccoli et al, 2020) and several neutralizing epitopes on RBD that are targeted by highly potent monoclonal antibodies have been molecularly characterized (Barnes et al, 2020; Brouwer et al, 2020; Piccoli et al, 2020; Pinto et al, 2020; Rogers et al, 2020; Tortorici et al, 2020; Wang et al, 2020; Wu et al, 2020).…”

Distinct B cell subsets give rise to antigen-specific antibody responses against SARS-CoV-2

“…Previous studies from our group and others have suggested serum antibody titers correlate with sex, SARS-CoV-2 severity, and age 6,14,23 . We therefore investigated the frequencies of SARS-CoV-2-reactive B cells to assess whether reactivity toward particular SARS-CoV-2 antigens correlated with clinical parameters.…”

“…Despite these advances, there have been no mAbs isolated against other immunogenic targets of SARS-CoV-2, including the internal nucleoprotein (NP) and open reading frame (ORF) proteins 7 and 8, which have been suggested to induce antibody responses and immunomodulatory effects in humans [8][9][10][11][12] . Moreover, the properties and frequencies of B cell subsets targeting distinct SARS-CoV-2 antigens remain poorly understood, and are likely shaped by clinical features such as age and disease severity 6,13,14 . To address these knowledge gaps, we comprehensively characterized the SARS-CoV-2-specific B cell repertoire in convalescent COVID-19 patients and generated mAbs against the spike, ORF8, and NP proteins.…”