MCMV-based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination

Xiaoyan Zheng,Federico Bertoglio,Michael Hust,Carlos A. Guzmán ,Thomas Ebensen,M. Zeeshan Chaudhry,Ofer Mandelboim,Stephan Ludwig,Stefan Pöhlmann,Luka Čičin-Šain,Dunja Bruder,Adriana Tomić,Stipan Jonjić,Astrid Krmpotić,Julia D. Boehme ,Kathrin Eschke,Yotam Bar-On,Yeonsu Kim,Martin Messerle,Linda Brunotte,Markus Hoffmann

doi:10.1038/s41423-021-00814-5

Abstract

Global pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) are well-known viruses with a zoonotic origin that have caused global pandemics with severe consequences on human health and economies
Pseudotyped virus neutralization could be Generation of recombinant murine CMV (MCMV) expressing influenza assessed for only one time point due to historical reasons
Hemagglutinin or the SARS-CoV-2 S protein We recently showed that MCMVIVL, a recombinant MCMV vaccine we tested the dynamics of serum neutralization capacity using a bona fide SARS-CoV-2 isolate

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) are well-known viruses with a zoonotic origin that have caused global pandemics with severe consequences on human health and economies. Influenza pandemics have resulted in global disruptions, such as the H1N1 Spanish flu in 1918, the H3N2 Hong Kong flu in 1968 and the H1N1dpm swine flu in 2009, and resulted in rapid global spread of this respiratory disease In addition to these influenza pandemics, seasonal influenza epidemics regularly cause elevated morbidity and mortality in the colder seasons. Both IAV and SARS CoV-2 may cause mild to severe respiratory illnesses and pose a particular threat to at-risk groups, such as elderly people or people with pre-existing medical conditions Both of these respiratory viruses depend on a viral surface protein for attachment and entry into host cells. SARS-CoV-2 S and IAV HA are the main antigenic targets in vaccine formulations against these viruses

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Conclusion