Despite remarkable progress in the development and authorization of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a need to validate vaccine platforms for broader application. The current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity in the nasal compartment, which is the first barrier that SARS-CoV-2 virus breaches before dissemination to the lung. We report the development of an intranasal subunit vaccine that uses lyophilized spike protein and liposomal STING agonist as an adjuvant. This vaccine induces systemic neutralizing antibodies, IgA in the lung and nasal compartments, and T-cell responses in the lung of mice. Single-cell RNA sequencing confirmed the coordinated activation of T/B-cell responses in a germinal center-like manner within the nasal-associated lymphoid tissues, confirming its role as an inductive site to enable durable immunity. The ability to elicit immunity in the respiratory tract can prevent the establishment of infection in individuals and prevent disease transmission.Mucosal vaccination can stimulate both systemic and mucosal immunity and has the advantage of being a non-invasive procedure suitable for immunization of large populations. However, mucosal vaccination is

No abstract

Respiratory viral infections, especially Influenza (endemic) or SARS-CoV-2 (pandemic since 2020), cause morbidity and mortality worldwide. Despite remarkable progress in the development and deployment of vaccines, they are clearly impacted by the rapid emergence of viral variants. The development of an off-the-shelf, effective, safe, and low-cost drug for prophylaxis against respiratory viral infections is a major unmet medical need. Here, we developed NanoSTING, a liposomally encapsulated formulation of the endogenous STING agonist, cGAMP, to function as an immunoantiviral. NanoSTING rapidly activates the body's innate immune system to facilitate a broad-spectrum antiviral response against SARS-CoV-2 and influenza variants in hamsters and mice. We demonstrate that a single intranasal dose of NanoSTING can: (1) treat infections throughout the respiratory system and minimize clinical symptoms, (2) protect against highly pathogenic strains of SARS-CoV-2 (alpha and delta), (3) provide durable protection against reinfection from the same strains without the need for retreatment, (4) prevent transmission of the highly infectious SARS-CoV-2 Omicron strain, and (5) provide protection against both oseltamivir-sensitive and resistant strains of influenza. Mechanistically, administration of NanoSTING rapidly upregulated interferon-stimulated and antiviral pathways in both the nasal turbinates and lung. Our results support using NanoSTING as a thermostable, immunoantiviral with broad-spectrum antiviral properties making it appealing as a therapeutic for prophylactic or early post-exposure treatment.

Immunization programs against SARS-CoV-2 with commercial intramuscular (IM) vaccines prevent disease but not infections. The continued evolution of variants of concern (VOC) like Delta and Omicron has increased infections even in countries with high vaccination coverage. This is due to commercial vaccines being unable to prevent viral infection in the upper airways and exclusively targeting the spike (S) protein that is subject to continuous evolution facilitating immune escape. Here we report a multi-antigen, intranasal vaccine, NanoSTING-NS that yields sterilizing immunity and leads to the rapid and complete elimination of viral loads in both the lungs and the nostrils upon viral challenge with SARS-CoV-2 VOC. We formulated vaccines with the S and nucleocapsid (N) proteins individually to demonstrate that immune responses against S are sufficient to prevent disease whereas combination immune responses against both proteins prevents viral replication in the nasal compartment. Studies with the highly infectious Omicron VOC showed that even in vaccine-naive animals, a single dose of NanoSTING-NS significantly reduced transmission. These observations have two implications: (1) mucosal multi-antigen vaccines present a pathway to preventing transmission and ending the pandemic, and (2) an explanation for why hybrid immunity in humans is superior to vaccine-mediated immunity by current IM vaccines.