A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination

Abstract

The SARS CoV-2 pandemic has killed millions of people. This viral infection can also result in substantial morbidity, including respiratory insufficiency and neurological manifestations, such as loss of smell and psychiatric diseases. Most SARS CoV-2 vaccines are based on the spike antigen, and although they have shown extraordinary efficacy at preventing severe lung disease and death, they do not always confer sterilizing immune protection. We performed studies in K18-hACE2 mice to evaluate whether the efficacy of SARS CoV-2 vaccines could be augmented by incorporating nucleocapsid as a vaccine antigen. We vaccinated mice with adenovirus-based vaccines encoding spike antigen alone, nucleocapsid antigen alone, or combined spike and nucleocapsid antigens. Mice were then challenged intranasally with SARS CoV-2, and acute viral loads were quantified at a proximal site of infection (lung) and a distal site of infection (brain). Interestingly, the spike-based vaccine conferred acute protection in the lung, but not in the brain. The spike-based vaccine conferred acute protection in the brain only if combined with the nucleocapsid-based vaccine. These findings suggest that nucleocapsid-specific immunity is important for the distal control of SARS CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.

Single cell phototransfection of mRNAs encoding SARS-CoV2 spike and nucleocapsid into human astrocytes results in RNA dependent translation interference

“…Generating an immune response to the Nuc protein may prove effective against multiple SARS-CoV-2 strains, and when used in concert with Spike may elicit a synergistic response. This has been shown in preclinical studies using LNP delivery of both Spike and Nuc mRNAs (Class et al, 2021;Dangi et al, 2021). This is not surprising as among the most successful vaccines are those using either inactivated or attenuated viruses where much of virus structure remains intact providing more immunogens in a seemingly more natural context.…”

“…In the case of viral infection, the impact of expression of the mRNAs encoded by the viral genome can be assessed by introducing these mRNAs into the recipient cell in user-defined abundances. Coexpression of multiple exogenous RNAs in individual cells has been performed previously but with little concern about the relative levels of RNA transfection and subsequent protein expression (Class et al, 2021;Brouwer et al, 2021). For example, addition of multiple mRNAs has been used to induce the conversion of differentiated cells into induced pluripotent stem cells.…”