Safety and Immunogenicity of a Novel Intranasal Influenza Vaccine (NasoVAX): A Phase 2 Randomized, Controlled Trial

Abstract

Annual influenza vaccination greatly reduces morbidity and mortality, but effectiveness remains sub-optimal. Weaknesses of current vaccines include low effectiveness against mismatched strains, lack of mucosal and other effective tissue-resident immune responses, weak cellular immune responses, and insufficiently durable immune responses. The safety and immunogenicity of NasoVAX, a monovalent intranasal influenza vaccine based on a replication-deficient adenovirus type 5 platform, were evaluated in a placebo-controlled single ascending-dose study. Sixty healthy adults (18–49 years) received a single intranasal dose of 1×109 viral particles (vp), 1 × 1010 vp, or 1 × 1011 vp of NasoVAX or placebo. NasoVAX was well-tolerated and elicited robust influenza-specific systemic and mucosal immune responses. The highest NasoVAX dose and the approved Fluzone® influenza vaccine elicited comparable hemagglutination inhibition (HAI) geometric mean titers (152.8 vs. 293.4) and microneutralization (MN) geometric mean titers (142.5 vs. 162.8), with NasoVAX HAI titers maintained more than 1-year on average following a single dose. Hemagglutinin-specific T cells responses were also documented in peripheral mononuclear cell (PBMC) preparations. Consistent with the intranasal route of administration, NasoVAX elicited antigen-specific mucosal IgA responses in the nasopharyngeal cavity with an increase of approximately 2-fold over baseline GMT at the mid- and high-doses. In summary, NasoVAX appeared safe and elicited a broad immune response, including humoral, cellular, and mucosal immunity, with no impact of baseline anti-adenovirus antibody at the most immunogenic dose.

Evaluation of Cell-Based and Surrogate SARS-CoV-2 Neutralization Assays

“…In addition to lower safety requirements than assays using replication-competent SARS-CoV-2, pseudotyped virus assays are well positioned for HTS testing of antibody responses elicited by natural infection, vaccination, and now, critically, to new viral variants of concern (VOC), as reported for other viruses ( 60 – 62 ). One limitation of the current study was that only two strains, Wuhan and D614G, were tested.…”

Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge

“…Conversely, nasal administration of replication-deficient human Ad5-vectored vaccines, such as AdCOVID, mimic natural infection of respiratory viruses and stimulate strong protective immunity, both systemically and mucosally, while maintaining an established clinical safety profile [ 47 , 48 , 49 , 50 , 51 ]. Intranasal vaccination stimulates mucosal IgA antibodies, providing a first line of defense at the point of respiratory pathogen inoculation [ 52 ], which correlates well with protection from respiratory infections such as influenza [ 53 , 54 , 55 ]. Numerous studies have demonstrated the ability of intranasally administered vaccines to block transmission of influenza between infected and naïve cage-mates [ 56 , 57 ].…”

Protective mucosal immunity against SARS-CoV-2 after heterologous systemic RNA-mucosal adenoviral vector immunization

“…In face of the encouraging results from the mixed vaccine regimens using RNA vaccine first followed by adenoviral vector vaccines [59][60][61][62] , it might be worthy to utilize an intranasal application for the viral vector boost immunization. This atraumatic, non-invasive application might also reduce the systemic side effects reported for the viral vector vaccines 79,80 .…”