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.

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.

No abstract

Given a graph G, a k-total difference labeling of the graph is a total labeling f from the set of edges and vertices to the set {1, 2, • • • k} satisfying that for any edge {u, v}, fis the minimum k such that there is a k-total difference labeling of G in which no two adjacent labels are identical. We extend prior work on total difference labeling by improving the upper bound on χ td (Kn) and also by proving results concerning infinite regular graphs.By a k-vertex labeling of a graph, we mean a function f from the vertices to the positive integers {1, 2, • • • k} for some k. Similarly, by a k-edge labeling of a graph, we mean a function f from the edges to {1, 2, • • • k} for some k. A k-total labeling is a function f from the set of edges and vertices to {1, 2, • • • k} for some k. A k-vertex labeling is said to be proper if no two adjacent vertices share the same label. Similarly, a k-edge labeling is proper if no two edges that share a vertex share a label. A proper k-total labeling is a k-total labeling such that its corresponding k-edge labeling is proper, its corresponding k-vertex labeling is proper, and no edge has the same label as either of its vertices.Ranjan Rohatgi and Yufei Zhang introduced the idea of a total difference labeling of a graph [4].Given a graph G, a k-total difference labeling of the graph is a total labeling f from the set of edges and vertices to the set {1, 2, • • • k} satisfying that for any edge {u, v}, fRecall that a total labeling of a graph is a labeling of both the edges and vertices of a graph. In general, f is a function from the union of the edge set and vertex set of G (denoted by E(G) and V (G), respectively) to the set {1, 2, • • • , k}. We will concern ourselves with proper total difference labelings. In a proper k-total difference labeling, f is a function from V (G) ∪ E(G) to the set {1, 2, • • • , k} that satisfies the following properties:

No abstract