SARS-CoV-2 spike RBD and nucleocapsid encoding DNA vaccine elicits T cell and neutralising antibody responses that cross react with variants

Abstract

The efficacy of vaccines targeting SARS-CoV-2 is becoming apparent now that the mRNA and adenovirus vector vaccines that have been approved for emergency use are showing promise. However, the longevity of the protective immune response and its efficacy against emerging variants remains to be determined. To improve longevity and future protection against variants, we have designed a DNA vaccine encoding both the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) and its nucleocapsid (N) protein, the latter of which is highly conserved amongst beta coronaviruses. The vaccine elicits strong pro-inflammatory CD4 Th1 and CD8 T-cell responses to both proteins, with these responses being significantly enhanced by fusing the nucleocapsid sequence to a modified Fc domain. We have shown that the vaccine also stimulates high titre antibody responses to RBD which efficiently neutralise in both a pseudotype and live virus neutralisation assay and show cross reactivity with S proteins from the emerging variants Alpha (B.1.1.7) and Beta (B.1.351). This DNA platform can be easily adapted to target variant RBD and N proteins and we show that a vaccine variant encoding the B.1.351 RBD sequence stimulates cross-reactive humoral and T-cell immunity. These data support the translation of this DNA vaccine platform into the clinic, thereby offering a particular advantage for targeting emerging SARS-CoV-2 variants.

Immunogenicity and In Vivo Protective Effects of Recombinant Nucleocapsid-Based SARS-CoV-2 Vaccine Convacell®

“…Several lines of evidence indicate that the nucleocapsid (N) protein of SARS-CoV-2 may represent a possible target for vaccination against COVID-19. Vaccines targeting the N protein of the virus have been suggested as an intervention scenario alternative to approached targeting of the RBD-ACE2 binding [36,37,[42][43][44][45][46]61,62]. In particular, N protein is capable of inducing the creation of tissue memory cells (T RM cells) in lungs, which for years retain the ability to respond to the pathogen, stopping its spread at the very beginning of the infectious process [47].…”

“…It should also be mentioned that several other studies support the usefulness of vaccination with N-based SARS-CoV-2 vaccines. For example, there are studies suggesting that vaccination with N and S or RBD may increase anti-SARS-CoV-2 immunity [42][43][44]. It may therefore be envisioned that Convacell ® can be combined with other S-or RBD-targeting vaccines to increase the armamentarium of COVID-19 vaccines.…”

“…A recent study has demonstrated that N can appear on the surface of infected cells, indicating that it can be a target for antibody-dependent cellular cytotoxicity (ADCC) and for cytotoxic T-cells [41]. Furthermore, several studies indicate that vaccination with N in combination with S or RBD may increase anti-SARS-CoV-2 immunity [42][43][44]. Accordingly, researchers have started to investigate N as a candidate antigen for the development of a SARS-CoV-2 vaccine [45][46][47].…”