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. 2018 Dec 3;13(12):e0208028.
doi: 10.1371/journal.pone.0208028. eCollection 2018.

Rationale for vaccination with trivalent or quadrivalent live attenuated influenza vaccines: Protective vaccine efficacy in the ferret model

Larisa Rudenko  1 , Irina Kiseleva  1 , Elena Krutikova  1 , Ekaterina Stepanova  1 , Andrey Rekstin  1 , Svetlana Donina  1 , Maria Pisareva  1 , Elena Grigorieva  1 , Kirill Kryshen  2 , Arman Muzhikyan  2 , Marina Makarova  2 , Erin Grace Sparrow  3 , Guido Torelli  3 , Marie-Paule Kieny  4
Affiliations

Rationale for vaccination with trivalent or quadrivalent live attenuated influenza vaccines: Protective vaccine efficacy in the ferret model

Larisa Rudenko et al. PLoS One. .

Abstract

Background and aim: The majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model.

Methods and results: Ferrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages.

Conclusions: In this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV.

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Conflict of interest statement

LR, IK, EK, ES, AR, SD, MP, EG, KK, AM, MM and MPK declare no conflict of interest. EGS and GT are employed by the study sponsor (World Health Organization, WHO). The founding sponsor, EGS and GT were involved in the design of the study, analyses of data and the decision to publish the results but were not involved in the collection or interpretation of data. The manuscript was reviewed by the study sponsor prior to submission. KK, AM and MM are employed by the commercial Institute of Preclinical Research Ltd, St Petersburg, Russia. However, this company was not the funding organization. Grant funding by WHO does not alter our adherence to all PLOS ONE policies on sharing data and materials. Participation of employees of commercial Institute of Preclinical Research Ltd, St Petersburg, Russia in this study does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Test groups of ferrets.
Fig 2
Fig 2. Body temperature of ferrets.
(a) after vaccination with T-LAIVs, Q-LAIV or PBS; (b) after challenge with WT B/Vic following by vaccination with T-LAIVs, Q-LAIV or PBS; (c) after challenge with WT B/Yam following by vaccination with T-LAIVs, Q-LAIV or PBS. *significantly different from non-vaccinated, non-challenged group (P1: Kruskal-Wallis ANOVA (all groups); P2: Mann-Whitney U test (vs. group 9)).
Fig 3
Fig 3. Detection of challenge virus in ferrets.
(a) detection of challenge virus by culturing test samples in embryonated eggs; (b) detection of challenge virus in test samples by quantative RT-PCR. P values (Mann-Whitney U test) are stated. T-LAIV (B/Vic) + WT B/Vic (group 1); T-LAIV (B/Vic) + WT B/Yam (group 2); T-LAIV (B/Yam) + WT B/Vic (group 3); T-LAIV (B/Yam) + WT B/Yam (group 4); Q-LAIV + WT B/Vic (group 5); Q-LAIV + WT B/Yam (group 6); WT B/Vic (control of challenge virus, group 7); WT B/Yam (control of challenge virus, group 8).
Fig 4
Fig 4. Histological view of the lungs.
Red arrows indicate inflammation; black arrows indicate presence of goblet cells. (a) Bronchus. Alcian blue, H&E x 200; (b). Alveolar tissue. Alcian blue, H&E x 400; (c) Bronchus. Alcian blue, H&E x 200; (d). Alveolar tissue. Alcian blue, H&E x 400.
See this image and copyright information in PMC

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