Comparative Study of the Temperature Sensitive, Cold Adapted and Attenuated Mutations Present in the Master Donor Viruses of the Two Commercial Human Live Attenuated Influenza Vaccines.

Laura Rodriguez,Stephen Dewhurst,Andrew Smith,Aitor Nogales,Emma C Reilly,Pilar Blanco-Lobo,Luis Martínez-Sobrido,Baek Kim,Tatsuya Maehigashi,David J Topham

doi:10.3390/v11100928

Laura Rodriguez, Stephen Dewhurst + Show 8 more

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https://doi.org/10.3390/v11100928

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Abstract

Influenza viruses cause annual, seasonal infection across the globe. Vaccination represents the most effective strategy to prevent such infections and/or to reduce viral disease. Two major types of influenza vaccines are approved for human use: inactivated influenza vaccines (IIVs) and live attenuated influenza vaccines (LAIVs). Two Master Donor Virus (MDV) backbones have been used to create LAIVs against influenza A virus (IAV): the United States (US) A/Ann Arbor/6/60 (AA) and the Russian A/Leningrad/134/17/57 (Len) H2N2 viruses. The mutations responsible for the temperature sensitive (ts), cold-adapted (ca) and attenuated (att) phenotypes of the two MDVs have been previously identified and genetically mapped. However, a direct comparison of the contribution of these residues to viral attenuation, immunogenicity and protection efficacy has not been conducted. Here, we compared the In vitro and in vivo phenotype of recombinant influenza A/Puerto Rico/8/34 H1N1 (PR8) viruses containing the ts, ca and att mutations of the US (PR8/AA) and the Russian (PR8/Len) MDVs. Our results show that PR8/Len is more attenuated in vivo than PR8/AA, although both viruses induced similar levels of humoral and cellular responses, and protection against homologous and heterologous viral challenges. Our findings support the feasibility of using a different virus backbone as MDV for the development of improved LAIVs for the prevention of IAV infections.

Highlights

In the United States (US), the Centers for Disease Control and Prevention (CDC) has estimated that influenza has caused between 9.3 and 49.0 million illnesses each year, since 2010- along with betweenViruses 2019, 11, 928; doi:10.3390/v11100928 www.mdpi.com/journal/viruses12,000 and 79,000 deaths annually [1]
Our results show that Puerto Rico/8/34 H1N1 (PR8) containing the mutations of the Russian Len Master Donor Virus (MDV) (PR8/Len) is more attenuated in vivo than the PR8 containing the mutations of the US Ann Arbor/6/60 (AA) MVD (PR8/AA)
In a previous work [35], we introduced four of the five mutations (NP already contains a G at position 34) responsible for the ts, ca and att phenotypes of the US AA MDV [32,33] into the PB2 (N265S) and PB1 (K391E, E581G and A661T) genes of PR8 to create a PR8 live attenuated influenza vaccines (LAIVs)

Summary

Introduction

In the United States (US), the Centers for Disease Control and Prevention (CDC) has estimated that influenza has caused between 9.3 and 49.0 million illnesses each year, since 2010- along with betweenViruses 2019, 11, 928; doi:10.3390/v11100928 www.mdpi.com/journal/viruses12,000 and 79,000 deaths annually [1]. Introduction of the mutations of the US AA MDV into the pandemic A/California/04/09 H1N1 virus (Cal/09) resulted in reduced ts and ca in vitro and limited attenuation in vivo [37,38,39]. These results suggest that the ts, ca and att phenotypes induced by the mutations of the US AA MDV are influenced by the virus backbone into which they are introduced. Both PR8/AA and PR8/Len induced similar levels of humoral and cellular responses and both induce protection against homologous (PR8, H1N1)

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