Defining the root cause of reduced H1N1 live attenuated influenza vaccine effectiveness: low viral fitness leads to inter-strain competition

Oliver Dibben,Jonathan Crowe,Katarzyna E Schewe,Shaun Cooper,Laura Hill,Helen Bright

doi:10.1038/s41541-021-00300-z

Oliver Dibben, Jonathan Crowe + Show 4 more

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https://doi.org/10.1038/s41541-021-00300-z

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Journal: npj Vaccines	Publication Date: Mar 12, 2021
Citations: 13	License type: open-access

Affiliation: AstraZeneca (United Kingdom)

Abstract

In the 2013–14 and 2015–16 influenza seasons, reduced vaccine effectiveness (VE) was observed for the H1N1 component of the FluMist quadrivalent live attenuated influenza vaccine (QLAIV) in the USA, leading to loss of Advisory Committee on Immunization Practices recommendation. Here we demonstrate in ferrets that 2015–16A/H1N1pdm09 vaccine strain A/Bolivia/559/2013 (A/BOL13) is outcompeted in trivalent (TLAIV) and QLAIV formulations, leading to reduced protection from wild-type challenge. While monovalent (MLAIV) A/BOL13 provided significant protection from wild-type virus shedding and fever at doses as low as 3.0 log10 fluorescent focus units (FFU), it failed to provide a similar level of protection in TLAIV or QLAIV formulation, even at a 6.0 log10 FFU dose. Conversely, clinically effective H1N1 strain A/New Caledonia/20/1999 provided significant protection in MLAIV, TLAIV, and QLAIV formulations. In conclusion, reduced A/BOL13 replicative fitness rendered it susceptible to inter-strain competition in QLAIV, contributing to its reduced VE in the 2015–16 season.

Highlights

FluMist/Fluenz® is an intranasal live attenuated influenza vaccine (LAIV), with vaccine virus replication occurring in the epithelia of the upper respiratory tract, resulting in generation of both humoral and cell-mediated immune responses[1,2,3].In the 2013–14 influenza vaccine season, the influenza A pandemic 2009 H1N1 (A/H1N1pdm09) component of quadrivalent LAIV (QLAIV) was found to have low vaccine effectiveness (VE)in the USA4,5
Recent studies showed that A/BOL13 possessed HA thermal and pH stability profiles comparable with historic, clinically effective LAIV strains[9], suggesting that factors other than HA stability were contributing to the reduced A/H1N1pdm[09] VE
We further demonstrated that the reduced fitness of A/BOL13 was replicated in vivo, with decreased levels of monovalent LAIV (MLAIV) shedding in ferrets relative to A/New Caledonia/20/1999 (A/NC99)

Summary

Introduction

FluMist/Fluenz® is an intranasal live attenuated influenza vaccine (LAIV), with vaccine virus replication occurring in the epithelia of the upper respiratory tract, resulting in generation of both humoral and cell-mediated immune responses[1,2,3].In the 2013–14 influenza vaccine season, the influenza A pandemic 2009 H1N1 (A/H1N1pdm09) component of quadrivalent LAIV (QLAIV) was found to have low vaccine effectiveness (VE)in the USA4,5. In the 2013–14 influenza vaccine season, the influenza A pandemic 2009 H1N1 (A/H1N1pdm09) component of quadrivalent LAIV (QLAIV) was found to have low vaccine effectiveness (VE). The initial hypothesized root cause for this low VE was low thermostability of the hemagglutinin (HA) protein of the. A/H1N1pdm[09] strain, A/California/07/2009 (A/CA09)[6,7]. A/CA09 was subsequently replaced with a more thermostable strain, A/. A/BOL13 demonstrated mainly low–moderate effectiveness in the 2015–16 season[5], with high VE (65%) only seen in a single study[8]. Recent studies showed that A/BOL13 possessed HA thermal and pH stability profiles comparable with historic, clinically effective LAIV strains[9], suggesting that factors other than HA stability were contributing to the reduced A/H1N1pdm[09] VE

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