Preprint Article Version 1 This version is not peer-reviewed

Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

Version 1 : Received: 20 December 2018 / Approved: 27 December 2018 / Online: 27 December 2018 (10:14:21 CET)

How to cite: Isakova-Sivak, I.; Matyushenko, V.; Kotomina, T.; Kiseleva, I.; Krutikova, E.; Donina, S.; Rekstin, A.; Larionova, N.; Sivak, K.; Muzhikyan, A.; Katelnikova, A.; Rudenko, L. Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge. Preprints 2018, 2018120317 (doi: 10.20944/preprints201812.0317.v1). Isakova-Sivak, I.; Matyushenko, V.; Kotomina, T.; Kiseleva, I.; Krutikova, E.; Donina, S.; Rekstin, A.; Larionova, N.; Sivak, K.; Muzhikyan, A.; Katelnikova, A.; Rudenko, L. Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge. Preprints 2018, 2018120317 (doi: 10.20944/preprints201812.0317.v1).

Abstract

The development of universal influenza vaccines, i.e. vaccines that can provide broad protection against seasonal and potentially pandemic influenza viruses, has been a priority for more than 20 years. Several approaches have been proposed that redirect the adaptive immune responses from immunodominant hypervariable regions to low-immunogenic but highly conserved regions of viral proteins. Here we induced broadly reactive anti-hemagglutinin (HA) stalk antibody by sequential immunizations with live attenuated influenza vaccines (LAIVs) expressing chimeric HA (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. In addition, the source of the viral nucleoprotein (NP) of the LAIV strains was changed from A/Leningrad/17 master donor virus (MDV) to wild-type (WT) H1N1pdm09 virus, in order to induce CD8 T-cell immune responses more relevant to current infections. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Naïve ferrets were immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) > cHA LAIVs (NP-MDV) > LAIVs (NP-MDV). This ferret study showed that prototype universal LAIVs that combine the two approaches of inducing anti-HA stalk antibody and more relevant CD8 T-cell immune responses are highly promising candidates for further clinical development.

Subject Areas

universal influenza vaccine; chimeric hemagglutinin; nucleoprotein; live attenuated influenza vaccine; sequential immunization; ferret model

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