Abstract
Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.
Highlights
The influenza A virus (IAV) belongs to the Orthomyxoviridae family of enveloped viruses, which contain an eight-segmented, negative-sense, single-stranded RNA genome [1]
We have shown that IAV PA-X and non-structural protein 1 (NS1) proteins can affect viral pathogenicity and the safety and immunogenicity of a pH1N1 Live Attenuated Influenza Vaccine (LAIV) candidate [18]
Human 293T cells were co-transfected with pCAGGS plasmids expressing the green fluorescent protein (GFP) or Gaussia luciferase (Gluc), along with pDZ plasmids that were either empty (E), contained the WT PA from the master donor virus (MDV) A/AA/6/60 LAIV (PAWT + ), or a mutant PA that has an altered frameshift (PAMT − )
Summary
The influenza A virus (IAV) belongs to the Orthomyxoviridae family of enveloped viruses, which contain an eight-segmented, negative-sense, single-stranded RNA genome [1]. According to the antigenic properties of the hemagglutinin (HA; H1–H18) and neuraminidase (NA; N1–N11) viral surface glycoproteins, IAVs are classified in subtypes with 18 HA and 11 NA subtypes currently circulating [2]. IAV is responsible for seasonal epidemics that cause mild to severe respiratory illness or even death, representing a threat worldwide to public health. Vaccination is considered the most effective approach to protect against seasonal influenza infections. Despite worldwide vaccination plans, seasonal influenza is still responsible for 1 billion infections, causing 3–5 million cases of severe disease, and between 290,000 and 650,000 deaths annually, according to the World Health Organization (WHO) and the Center for Disease Control (CDC) [3]. Seasonal IAVs circulating in humans include the H3N2 and the H1N1 subtypes [4]. Due Pathogens 2020, 9, 86; doi:10.3390/pathogens9020086 www.mdpi.com/journal/pathogens
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