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. 2019 May 29:4:22.
doi: 10.1038/s41541-019-0114-8. eCollection 2019.

Heterologous prime-boost with A(H5N1) pandemic influenza vaccines induces broader cross-clade antibody responses than homologous prime-boost

Min Z Levine  1 , Crystal Holiday  1 , Stacie Jefferson  1 , F Liaini Gross  1   2 , Feng Liu  1 , Sheng Li  3   4 , Damien Friel  5 , Philippe Boutet  5 , Bruce L Innis  6   7 , Corey P Mallett  6 , Terrence M Tumpey  1 , James Stevens  1 , Jacqueline M Katz  1
Affiliations

Heterologous prime-boost with A(H5N1) pandemic influenza vaccines induces broader cross-clade antibody responses than homologous prime-boost

Min Z Levine et al. NPJ Vaccines. .

Abstract

Highly pathogenic avian influenza (HPAI) A(H5Nx) viruses continue to pose a pandemic threat. US national vaccine stockpiles are a cornerstone of the influenza pandemic preparedness plans. However, continual genetic and antigenic divergence of A(H5Nx) viruses requires the development of effective vaccination strategies using stockpiled vaccines and adjuvants for pandemic preparedness. Human sera collected from healthy adults who received either homologous (2 doses of a AS03A-adjuvanted A/turkey/Turkey/1/2005, A/Turkey), or heterologous (primed with AS03A-adjuvanted A/Indonesia/5/2005, A/Indo, followed by A/Turkey boost) prime-boost vaccination regimens were analyzed by hemagglutination inhibition and microneutralization assays against 8 wild-type HPAI A(H5Nx) viruses from 6 genetic clades. Molecular, structural and antigenic features of the A(H5Nx) viruses that could influence the cross-clade antibody responses were also explored. Compared with homologous prime-boost vaccinations, priming with a clade 2.1.3.2 antigen (A/Indo) followed by one booster dose of a clade 2.2.1 antigen (A/Turkey) administered 18 months apart did not compromise the antibody responses to the booster vaccine (A/Turkey), it also broadened the cross-clade antibody responses to several antigenically drifted variants from 6 heterologous clades, including an antigenically distant A(H5N8) virus (A/gyrfalcon/Washington/410886/2014, clade 2.3.4.4) that caused recent outbreaks in US poultry. The magnitude and breadth of the cross-clade antibody responses against emerging HPAI A(H5Nx) viruses are associated with genetic, structural and antigenic differences from the vaccine viruses and enhanced by the inclusion of an adjuvant. Heterologous prime-boost vaccination with AS03A adjuvanted vaccine offers a vaccination strategy to use existing stockpiled vaccines for pandemic preparedness against new emerging HPAI A(H5Nx) viruses.

Keywords: Diseases; Immunology; Influenza virus; Medical research.

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Conflict of interest statement

Competing interestsThe following interests are relevant to the submitted work. D.F., P.B., B.L.I, and C.P.M are, or were at the time of the studies, employees of the GSK group of companies. D.F., P.B., and C.P.M. report ownership of GSK shares and/or restricted GSK shares. B.L.I. and C.P.M. are listed as an inventor on patents owned by the GSK group of companies. M. Z. L. C.H., S.J., F.L.G, F.L, T.M.T., J.S., and J.M.K. are employees of CDC; at the time of the study, S.L. was an employee of BARDA.

Figures

Fig. 1
Fig. 1
HI and MN antibody responses post homologous and heterologous prime-boost vaccination. a Geometric mean titers (GMTs) of the HI antibody responses from each of the 3 study groups post vaccination, b GMTs of neutralizing antibody responses of each of the 3 study groups post vaccination. c HI GMT ratios against A/Turkey; d MN GMT ratios against A/Turkey. Error bars indicate 95% confidence intervals (CI) of HI and MN responses from each group (N = 35 per group). Groups that achieved statistical difference in responses were indicated by: *p < 0.05, **p < 0.01, ***p < 0.001. A/tk/TK/05 (A/turkey/Turkey/1/2005), A/ID/5/05 (A/Indonesia/5/2005), A/VN/1194/04/(A/Vietnam/1194/2004), A/ID/12379/12 (A/Indonesia/NIHRD-12379/2012), A/EG/N04915/14 (A/Egypt/N04915/2014), A/dk/BD/19097/13 (A/duck/Bangladesh/19097/2013), A/dk/VN/1584/12 (A/duck/Vietnam/NCVD-1584/2012), A/gf/410886/14 (A/gyrfalcon/Washington/410886/2014)
Fig. 2
Fig. 2
Structure-based sequence alignment of A(H5Nx) viruses used in the study. The locations equivalent to H1 and H3 antigenic sites are labeled with the antigenic site designation (Sa [1], Sb [2], Ca [3], or Cb [4] for H1 antigenic sites and A (red), B (yellow), C (green), D (aqua), or E (pink) for H3 antigenic sites. Glycosylation motifs (NXT/S) are boxed. Accession numbers: A/Indonesia/5/2005 (Genbank EF541394.1), A/turkey/Turkey/1/2005 (Genbank EF619980.1), A/Vietnam/1194/2004 (Genbank EF541402.1) A/Egypt/N04915/2014 (GISAID EPI_ISL_262572), A/duck/Bangladesh/19097/2013 (Genbank KF715205.1), A/gyrfalcon/Washington /410886/2014 (Genbank EPI569390). A/Indonesia/NIHRD-12379/2012 (GISAID EPI442759); and A/duck/Vietnam/NCVD-1584/2012 (EPI424977)
Fig. 3
Fig. 3
Structural models of hemagglutinin from A(H5Nx) viruses used in the study. Antigenic sites A and B (H3 equivalent) are colored as electrostatic surface, red indicates acidic and blue indicates basic. Sites A (AS-A) and B (AS-B) are the major antigenic sites surrounding the receptor binding site (RBS). Change in glycosylation side chain at position 154 and 140 are labeled
See this image and copyright information in PMC

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