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Viruses. 2018 Mar 25;10(4). pii: E148. doi: 10.3390/v10040148.

Applying Unique Molecular Identifiers in Next Generation Sequencing Reveals a Constrained Viral Quasispecies Evolution under Cross-Reactive Antibody Pressure Targeting Long Alpha Helix of Hemagglutinin.

Author information

1
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. Nastasja.Hauck@gmx.de.
2
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. josiane.kirpach@lih.lu.
3
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. muesli.chrissy.kiefer@googlemail.com.
4
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. sophie.farinelle@lih.lu.
5
iQur Ltd., London NW1 0NH, UK. sophie.maucourant@touchlight.com.
6
iQur Ltd., London NW1 0NH, UK. stephen.morris@ucl.ac.uk.
7
iQur Ltd., London NW1 0NH, UK. william.rosenberg@iqur.com.
8
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. feng.he@lih.lu.
9
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. Claude.Muller@lih.lu.
10
Laboratoire national de santé, 1, rue Louis Rech, L-3555 Dudelange, Luxembourg. Claude.Muller@lih.lu.
11
Department of Infection and Immunity, Luxembourg Institute of Health, 29, rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. i-na.lu@clin.au.dk.

Abstract

To overcome yearly efforts and costs for the production of seasonal influenza vaccines, new approaches for the induction of broadly protective and long-lasting immune responses have been developed in the past decade. To warrant safety and efficacy of the emerging crossreactive vaccine candidates, it is critical to understand the evolution of influenza viruses in response to these new immune pressures. Here we applied unique molecular identifiers in next generation sequencing to analyze the evolution of influenza quasispecies under in vivo antibody pressure targeting the hemagglutinin (HA) long alpha helix (LAH). Our vaccine targeting LAH of hemagglutinin elicited significant seroconversion and protection against homologous and heterologous influenza virus strains in mice. The vaccine not only significantly reduced lung viral titers, but also induced a well-known bottleneck effect by decreasing virus diversity. In contrast to the classical bottleneck effect, here we showed a significant increase in the frequency of viruses with amino acid sequences identical to that of vaccine targeting LAH domain. No escape mutant emerged after vaccination. These results not only support the potential of a universal influenza vaccine targeting the conserved LAH domains, but also clearly demonstrate that the well-established bottleneck effect on viral quasispecies evolution does not necessarily generate escape mutants.

KEYWORDS:

bottleneck effect; immune pressure; immune selection; influenza; next generation sequencing; unique molecular identifiers; vaccine; virus evolution

PMID:
29587397
PMCID:
PMC5923442
DOI:
10.3390/v10040148
[Indexed for MEDLINE]
Free PMC Article

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