Nucleocapsid-specific humoral responses improve the control of SARS-CoV-2

Abstract

SummaryThe spike protein of SARS-CoV-2 is a critical antigen present in all approved SARS-CoV-2 vaccines. This surface viral protein is also the target for all monoclonal antibody therapies, but it is unclear whether antibodies targeting other viral proteins can also improve protection against COVID-19. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice. On the next day, the recipient mice were challenged intranasally with SARS-CoV-2 to evaluate whether nucleocapsid-specific humoral responses affect viral control. Interestingly, mice that received nucleocapsid-specific sera exhibited enhanced control of a SARS-CoV-2 infection. These findings provide the first demonstration that humoral responses specific to an internal coronavirus protein can help clear infection, warranting the inclusion of other viral antigens in next-generation SARS-CoV-2 vaccines and providing a rationale for the clinical evaluation of nucleocapsid-specific monoclonals to treat COVID-19.HighlightsA SARS-CoV-2 nucleocapsid vaccine elicits robust nucleocapsid-specific antibody responses.This nucleocapsid vaccine generates memory B cells (MBC).Nucleocapsid-specific humoral responses do not prevent SARS-CoV-2 infection.Nucleocapsid-specific humoral responses help control a SARS-CoV-2 infection.

The Nucleocapsid Protein Of SARS-CoV-2, Combined With ODN-39M, Is A Potential Component For An Intranasal Bivalent Pancorona Vaccine

“…Dangi et al, 2021, also evidenced that combining spike and nucleocapsid vaccine formulations improve distal protection in brain (Dangi et al, 2021). These authors even demonstrated the protective role of anti-N Abs, proven by passive transfer experiments (Dangi et al, 2022).…”

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…Most antigenic sites where variants capable of immune evasion emerge are enriched in IDRs [ 2 , 219 ] and can compromise effectiveness of neutralizing antibodies generated by vaccines [ 220 ]. Approximately 51% of experimentally determined IDRs in SARS-CoV-2 are located in the N protein [ 2 ], and not surprisingly, sera from mice immunized with nucleocapsid-based vaccines may enhance control of SARS-CoV-2 infections [ 221 ]. Even though human coronaviruses are not distinguished for possessing abundant IDRs—~7.3% in the NL63 proteome compared to 77.3% in that of the Avian carcinoma virus [ 202 ]—and the SARS-CoV-2 proteome exhibits an extremely high level of structural order with only a few functionally relevant proteins displaying IDRs [ 217 ], an extensive examination of the dark proteome of this virus revealed that almost the entire SARS-CoV-2 virus contain molecular recognition features that are important sites for intrinsic disorder-based protein–protein interactions [ 222 ].…”

Vaccine-induced spike- and nucleocapsid-specific cellular responses maintain potent cross-reactivity to SARS-CoV-2 Delta and Omicron variants

“…In addition, vaccine-induced N-specific immune responses have been associated with S-independent protective immunity in animal models (Afkhami et al, 2022;Dangi et al, 2021;Matchett et al, 2021). Recent studies have also shown that N-specific non-NAb promotes antibody-dependent cellular cytotoxicity and other Fcreceptor-mediated functions and can result in the control of SARS-CoV-2 infection (Dangi et al, 2021(Dangi et al, , 2022Fielding et al, 2021;Yewdell et al, 2021). These discoveries suggest that the inclusion of N into a COVID-19 vaccine formulation may be important for the induction of T cell responses, and in addition for the stimulation of non-NAb responses.…”