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

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

doi:10.1038/s41541-019-0114-8

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.

Highlights

As we commemorate the 100 years since the 1918 influenza pandemic, the threat of a potential new pandemic remains with influenza viruses undergoing antigenic drift and shift
highly pathogenic avian influenza (HPAI) A(H5N1) and A(H5N8) viruses from genetic clades that reductions in titers and higher Geometric mean titers (GMTs) ratios when comparing caused human infections and animal outbreaks in recent years responses to heterologous clade versus those to the vaccine were selected to evaluate the breadth of the antibody responses viruses (Fig. 1c, d)
The US Food and Drug Administration (FDA) accelerated vaccines based on older viruses that emerged over a decade ago. approval vaccine licensure criteria requires that based on hemagglutination inhibition (HI) titers, Ferret antisera generated against vaccine viruses A/Turkey and A/ Indo exhibited ≥4 fold reduction against most of the contemporthe lower limits of 95% confidence intervals (CI) for Seroprotection Rate (SPR) are ≥70% and Seroconversion rate (SCR) are ≥40% for healthy adults.[14]

Summary

Introduction

As we commemorate the 100 years since the 1918 influenza pandemic, the threat of a potential new pandemic remains with influenza viruses undergoing antigenic drift and shift. Since the identification of human infections with the highly pathogenic avian influenza (HPAI) A(H5N1) viruses over two decades ago, these viruses have become endemic in poultry and wild birds in many countries. They continue to cause sporadic human infections with high disease severity and high mortality (≥50% fatality).

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