Vaccination with Recombinant Parainfluenza Virus 5 Expressing Neuraminidase Protects against Homologous and Heterologous Influenza Virus Challenge

Abstract

Seasonal human influenza virus continues to cause morbidity and mortality annually, and highly pathogenic avian influenza (HPAI) viruses along with other emerging influenza viruses continue to pose pandemic threats. Vaccination is considered the most effective measure for controlling influenza; however, current strategies rely on a precise vaccine match with currently circulating virus strains for efficacy, requiring constant surveillance and regular development of matched vaccines. Current vaccines focus on eliciting specific antibody responses against the hemagglutinin (HA) surface glycoprotein; however, the diversity of HAs across species and antigenic drift of circulating strains enable the evasion of virus-inhibiting antibody responses, resulting in vaccine failure. The neuraminidase (NA) surface glycoprotein, while diverse, has a conserved enzymatic site and presents an appealing target for priming broadly effective antibody responses. Here we show that vaccination with parainfluenza virus 5 (PIV5), a promising live viral vector expressing NA from avian (H5N1) or pandemic (H1N1) influenza virus, elicited NA-specific antibody and T cell responses, which conferred protection against homologous and heterologous influenza virus challenges. Vaccination with PIV5-N1 NA provided cross-protection against challenge with a heterosubtypic (H3N2) virus. Experiments using antibody transfer indicate that antibodies to NA have an important role in protection. These findings indicate that PIV5 expressing NA may be effective as a broadly protective vaccine against seasonal influenza and emerging pandemic threats.IMPORTANCE Seasonal influenza viruses cause considerable morbidity and mortality annually, while emerging viruses pose potential pandemic threats. Currently licensed influenza virus vaccines rely on the antigenic match of hemagglutinin (HA) for vaccine strain selection, and most vaccines rely on HA inhibition titers to determine efficacy, despite the growing awareness of the contribution of neuraminidase (NA) to influenza virus vaccine efficacy. Although NA is immunologically subdominant to HA, and clinical studies have shown variable NA responses to vaccination, in this study, we show that vaccination with a parainfluenza virus 5 recombinant vaccine candidate expressing NA (PIV5-NA) from a pandemic influenza (pdmH1N1) virus or highly pathogenic avian influenza (H5N1) virus elicits robust, cross-reactive protection from influenza virus infection in two animal models. New vaccination strategies incorporating NA, including PIV5-NA, could improve seasonal influenza virus vaccine efficacy and provide protection against emerging influenza viruses.KEYWORDS influenza, vaccine, neuraminidase, parainfluenza virus 5, highly pathogenic avian influenza virus

Single-Dose, Intranasal Immunization with Recombinant Parainfluenza Virus 5 Expressing Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Spike Protein Protects Mice from Fatal MERS-CoV Infection

“…Perhaps virus transmission from camels to humans can be blocked, with concomitant immunization of high-risk human populations, as proposed by CEPI (The Coalition for Epidemic Preparedness Innovations) and WHO. As a vaccine vector, PIV5 has been effective in mice, cotton rats, hamsters, guinea pigs, ferrets, dogs, and nonhuman primates (25,(46)(47)(48)(49). It will be worthwhile to test PIV5-MERS-S in camels in the future.…”

A chimeric influenza hemagglutinin delivered by parainfluenza virus 5 vector induces broadly protective immunity against genetically divergent influenza a H1 viruses in swine

“…It will be interesting to evaluate a combination of PIV5-113 and PIV5-NP as a candidate vaccine to increase the breadth of protection. Previously, we have tested PIV5-based candidate vaccines in mice, hamsters, guinea pigs, ferrets, dogs, and monkeys and found that PIV5-based candidate vaccines are effective in those animals ( 33 , [36] , [37] , [38] , 52 , [70] , [71] , [72] , [73] , [74] , [75] ). Importantly, this is the first report showing the efficacy of PIV5 as a vector for swine vaccine development.…”

Parainfluenza virus 5–vectored vaccines against human and animal infectious diseases

“…Therefore, PIV5 viruses expressing NA of avian (H5N1) or pandemic (H1N1) influenza viruses were investigated. The results show that they can confer protection against homologous and heterologous influenza virus challenge in mice . In the case of PIV5 expressing NA of H5N1, two vaccine doses even conferred sterilizing immunity against H5N1 infection in mice.…”

“…In the case of PIV5 expressing NA of H5N1, two vaccine doses even conferred sterilizing immunity against H5N1 infection in mice. Both vaccines were also able to reduce clinical signs of disease and influenza virus shedding in ferrets. This study indicates that PIV5 expressing NA has the potential to be exploited as a universal influenza vaccine.…”