Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

Abstract

The emerging SARS-CoV-2 variants of concern (VOC) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

A live attenuated vaccine confers superior mucosal and systemic immunity to SARS-CoV-2 variants

“…We find that specifically this live attenuated vaccine elicits superior protection from SARS-CoV-2 infection especially at mucosal sites of virus entry. This stands in agreement with previous preclinical COVID-19 vaccine studies using intranasal administration of LAV, protein-based or virus-vectored spike vaccines showing high efficacy in animal models (29) and induction of mucosal immunity (54)(55)(56)(57)(58)(59)(60). Our observations on improved immunity induced by heterologous immunization with an intramuscular mRNA vaccine followed by an intranasal sCPD9 boost are in line with recent studies that combine systemic priming followed by an intranasal boost with adenovirus vector vaccines (61,62).…”

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

“…The respiratory tract is the site of invasion and primary site of replication and disease manifestation for SARS-CoV-2 and its variants. Several studies investigating viral vector and protein-based vaccines have demonstrated that superior mucosal immunity can be achieved through direct antigen presentation across the mucosal surface of the lung (59)(60)(61)(62). Mucosal vaccination strategies have been shown to improve upon systemic vaccination through the induction of tissue resident memory T and B cells, which can rapidly respond to viral invasion into the respiratory tract (31,63).…”

Dealing with a mucosal viral pandemic: lessons from COVID-19 vaccines

“…The nasal administration of a lentivirus vector containing the SARS-CoV-2 Spike protein protected mice from SARS-CoV-2 infection thanks to an IgA response 103 . An adenoviral-vectored trivalent vaccine expressing the Spike protein but also nucleocapsid and RdRp antigens was found to induce local and systemic antibodies and lung tissue-resident T lymphocytes in mice 4 to 8 weeks post-immunization 104 . Humoral responses obtained after intranasal administration of this vaccine were superior compared to intramuscular immunization and induced protective mucosal immunity against ancestral and variant (Alpha, Beta) strains of SARS-CoV-2.…”