Strain-Dependent Impact of G and SH Deletions Provide New Insights for Live-Attenuated HMPV Vaccine Development.

Julia Dubois,Thomas Julien,Christian Couture,Olus Uyar,Marie-Christine Venable,Guy Boivin,Manuel Rosa-Calatrava,Marie-Hélène Cavanagh,Claire Nicolas De Lamballerie,Sophie Lavigne,Julie Carbonneau,Andrés Pizzorno,Blandine Padey,Aurélien Traversier,Olivier Terrier,Bruno Lina,Marie-Ève Hamelin

doi:10.3390/vaccines7040164

Abstract

Human metapneumovirus (HMPV) is a major pediatric respiratory pathogen with currently no specific treatment or licensed vaccine. Different strategies to prevent this infection have been evaluated, including live-attenuated vaccines (LAV) based on SH and/or G protein deletions. This approach showed promising outcomes but has not been evaluated further using different viral strains. In that regard, we previously showed that different HMPV strains harbor distinct in vitro fusogenic and in vivo pathogenic phenotypes, possibly influencing the selection of vaccine strains. In this study, we investigated the putative contribution of the low conserved SH or G accessory proteins in such strain-dependent phenotypes and generated recombinant wild type (WT) and SH- or G-deleted viruses derived from two different patient-derived HMPV strains, A1/C-85473 and B2/CAN98-75. The ΔSH and ΔG deletions led to different strain-specific phenotypes in both LLC-MK2 cell and reconstituted human airway epithelium models. More interestingly, the ΔG-85473 and especially ΔSH-C-85473 recombinant viruses conferred significant protection against HMPV challenge and induced immunogenicity against a heterologous strain. In conclusion, our results show that the viral genetic backbone should be considered in the design of live-attenuated HMPV vaccines, and that a SH-deleted virus based on the A1/C-85473 HMPV strain could be a promising LAV candidate as it is both attenuated and protective in mice while being efficiently produced in a cell-based system.

Highlights

Human metapneumovirus (HMPV) is a worldwide cause of acute respiratory tract infections (ARTI) among children, the elderly and immunocompromised individuals [1,2]
B2/CAN98-75 strains and the “attachment” role attributed to the G protein, we further evaluated the specific impact of the G and SH gene deletions on the binding and the entry of the rHMPV to LLC-MK2 cells (Figure 2)
We further investigated the properties of ∆G- and ∆SH-viruses by using reconstituted human airway epithelium (HAE) as a more physiological model of respiratory infection

Summary

Introduction

Human metapneumovirus (HMPV) is a worldwide cause of acute respiratory tract infections (ARTI) among children, the elderly and immunocompromised individuals [1,2]. HMPV infections share many features with those of the human respiratory syncytial virus (HRSV), belonging to the Pneumoviridae family [3,4]. While several HRSV vaccine candidates have already entered clinical trials [5], some HMPV candidates have shown the potential to progress towards clinical evaluation stages [6]. LAV have shown the potential to elicit both humoral and mucosal immunity and mimic natural viral replication routes, and they are considered as highly suitable for HMPV pediatric immunization strategies [8]

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Results

Discussion

Conclusion