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 of the antibody response mounted against this novel virus is 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 nonstructural 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. IMPORTANCE With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein. Subjects who mounted a larger response against the spike also mounted antibody responses against other viral antigens, including the nucleocapsid protein and ORF8. Additionally, this study reveals that subjects with more severe disease mount a larger memory B cell response against the spike. These data suggest that subjects with more severe COVID-19 disease are likely better protected from reinfection with SARS-CoV-2.

Assessment of S1-, S2-, and NCP-Specific IgM, IgA, and IgG Antibody Kinetics in Acute SARS-CoV-2 Infection by a Microarray and Twelve Other Immunoassays

“…On one hand, more robust IgA antibody responses have already been described in clinically more severe CoVID-19 cases, possibly indicating higher levels of virus replication in the respiratory tract ( 36 , 37 ). On the other hand, comprehensive B-cell analyses revealed a strong humoral response against the spike protein in severely ill individuals, but NCP-specific responses even exceeded those against S ( 38 ). Further studies with higher patient numbers are needed and underway to comprehensively clarify the correlation of antibody levels of different immunoglobulin classes and against variable viral proteins with the clinical severity of CoVID-19.…”

Passive Immunity Should and Will Work for COVID-19 for Some Patients

“…The D614G mutation in the S protein did not associate with neutralization escape [39,63,73]. [150,151].…”

“…The Spike (S) protein is a dominant immunoreactive protein and has several recognized regions, including the receptor binding domain [33][34][35][36][37][38][39]. Other recognized antigens commonly include Nucleocapsid (N), Membrane (M), orf3a, orf6, orf8, orf10, and Nsp5 (Mpro or 3CLpro) (Figure 1) [36,37,[39][40][41][42][43][44]. The latter may or may not include structural proteins of intact virus and may arise as proteins derived during the processes of infection.…”

“…Neutralization antibodies may decline although maturation in Fc effector functions may persist [66]. Key antibody responses are followed by memory B cell persistence [28,39,48,49,57,65,66,78,102,107]. Likewise, T cell recognition lasts well after declining humoral immunity markers [23,57,67].…”

“…Likewise, T cell recognition lasts well after declining humoral immunity markers [23,57,67]. The memory B potential increases with severity of infection [39]. Some groups have found a degree of anti-S2 subunit and anti-N IgG reactivity in infection-naïve individuals [45,107].…”