Sublingual Immunization with a Live Attenuated Influenza A Virus Lacking the Nonstructural Protein 1 Induces Broad Protective Immunity in Mice

Abstract

The nonstructural protein 1 (NS1) of influenza A virus (IAV) enables the virus to disarm the host cell type 1 IFN defense system. Mutation or deletion of the NS1 gene leads to attenuation of the virus and enhances host antiviral response making such live-attenuated influenza viruses attractive vaccine candidates. Sublingual (SL) immunization with live influenza virus has been found to be safe and effective for inducing protective immune responses in mucosal and systemic compartments. Here we demonstrate that SL immunization with NS1 deleted IAV (DeltaNS1 H1N1 or DeltaNS1 H5N1) induced protection against challenge with homologous as well as heterosubtypic influenza viruses. Protection was comparable with that induced by intranasal (IN) immunization and was associated with high levels of virus-specific antibodies (Abs). SL immunization with DeltaNS1 virus induced broad Ab responses in mucosal and systemic compartments and stimulated immune cells in mucosa-associated and systemic lymphoid organs. Thus, SL immunization with DeltaNS1 offers a novel potential vaccination strategy for the control of influenza outbreaks including pandemics.

Buccal and sublingual vaccine delivery

“…Similarly, sublingual administration of live-attenuated virus lacking the non-structural protein 1 (DeltaNS1) was as protective against influenza virus challenges in mice as intranasal immunization. Sublingual immunization with these DeltaNS1 viruses induced high levels of virus-specific antibodies and stimulated immune cells in mucosaassociated and systemic lymphoid organs [27]. Moreover, the vaccine was well tolerated and did not induce bodyweight loss in sublingually vaccinated mice.…”

Mucosal vaccine delivery: Current state and a pediatric perspective

“…Mucosal vaccines delivered through the oral cavity can be classified into live attenuated microbes (wild type virus, recombinant virus & bacteria) [183–185], inactivated viruses [186], and subunit vaccines [187]. Microbe-based vaccines are able to induce broad-spectrum immunity sublingually unlike the subunit vaccines, for which poor antigen-specific immune responses are observed.…”

Sublingual Delivery of Vaccines for the Induction of Mucosal Immunity

“…An ideal vaccine against an infectious pathogen should prime the host for induction of pathogen-specific memory immune responses at the appropriate mucosal compartments, thereby, preventing the entry and/or replication of the invading pathogen at the site of infection. Previous studies have established that mucosal vaccination can efficiently stimulate the local mucosal immunity and the broadly functional systemic immunity and suggested that mucosal vaccine delivery may be a proficient method to induce pathogen-specific secretory antibody responses as well as cytotoxic T lymphocyte (CTL) responses at the target mucosal tissues (2)(3)(4)(5)(6)(7)(8). Accordingly, these studies also have reported that mucosal vaccination is highly effective in conferring protection against various mucosal pathogens.…”

“…However, studies have reported that influenza vaccination efficacy is closely correlated to the immune responses induced within the respiratory mucosa, and parenteral vaccines being used presently have been shown to be inefficient in stimulating immune responses at the respiratory mucosa (10). In recent years, a number of studies have explored the potential of sublingual immunization in eliciting desired immune responses against various potential vaccine components which includes soluble protein antigens, virus-like particles, and inactivated or live-attenuated viruses (3)(4)(5)(6)(7)(8)11,12). These studies have successfully demonstrated the safety and efficacy of sublingual immunization in inducing antigen-specific systemic and mucosal immune responses and protection against pathogen challenges.…”