Humoral and cell-mediated immune responses to H5N1 plant-made virus-like particle vaccine are differentially impacted by alum and GLA-SE adjuvants in a Phase 2 clinical trial

Stéphane Pillet,Sonia Trépanier,Jan Ter Meulen,Bader Yassine-Diab,Nathalie Landry,Brian J Ward,Jean-François Poulin,Éric Aubin

doi:10.1038/s41541-017-0043-3

Abstract

The hemagglutinination inhibition (HI) response remains the gold standard used for the licensure of influenza vaccines. However, cell-mediated immunity (CMI) deserves more attention, especially when evaluating H5N1 influenza vaccines that tend to induce poor HI response. In this study, we measured the humoral response (HI) and CMI (flow cytometry) during a Phase II dose-ranging clinical trial (NCT01991561). Subjects received two intramuscular doses, 21 days apart, of plant-derived virus-like particles (VLP) presenting the A/Indonesia/05/2005 H5N1 influenza hemagglutinin protein (H5) at the surface of the VLP (H5VLP). The vaccine was co-administrated with Alhydrogel® or with a glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). We demonstrated that low doses (3.75 or 7.5 μg H5VLP) of GLA-SE-adjuvanted vaccines induced HI responses that met criteria for licensure at both antigen doses tested. Alhydrogel adjuvanted vaccines induced readily detectable HI response that however failed to meet licensure criteria at any of three doses (10, 15 and 20 μg) tested. The H5VLP also induced a sustained (up to 6 months) polyfunctional and cross-reactive HA-specific CD4+ T cell response in all vaccinated groups. Interestingly, the frequency of central memory Th1-primed precursor cells before the boost significantly correlated with HI titers 21 days after the boost. The ability of the low dose GLA-SE-adjuvanted H5VLP to elicit both humoral response and a sustained cross-reactive CMI in healthy adults is very attractive and could result in significant dose-sparing in a pandemic situation.

Highlights

Since the first recorded direct bird-to-human transmission of highly pathogenic avian influenza H5N1 in Hong Kong in 1997, these viruses have spread to several countries causing widespread death and illness in domestic and migratory birds as well as human infections and fatalities
Gender was well distributed between groups with a slightly higher proportion of woman who received 7.5 μg of H5 VLP vaccine (H5VLP) combined with glucopyranosyl lipid adjuvantstable emulsion (GLA-SE; 7.5 μg H5VLP + GLA group)
The alum-adjuvanted groups induced hemagglutinination inhibition (HI) higher antibody titers than previously reported for a plant-produced recombinant H5 not self-assembling into a VLP16, and were similar or slightly higher than what we previously observed for the Virus-like particle (VLP) vaccine[6,14] and what was observed for an alum-adjuvantedinactivated split virion vaccine.[17]

Summary

Introduction

Since the first recorded direct bird-to-human transmission of highly pathogenic avian influenza H5N1 in Hong Kong in 1997, these viruses have spread to several countries causing widespread death and illness in domestic and migratory birds as well as human infections and fatalities. Latest outbreaks highlighted the overall needs to improve the manufacturing capacity of influenza vaccine worldwide.[2] manufacturing capacity of vaccines against H5N1 viruses is limited due to the lethality of those highly pathogenic viruses to the embryonated eggs, which remains the most common producing system for influenza vaccine.[3] Virus-like particle (VLP) expressing influenza antigenic protein can overcome most of the current pitfalls associated with traditional egg-based technologies, especially the plant-made VLP.[4,5,6,7,8] Immunogenicity of influenza vaccines was historically evaluated regarding the antibody response, which remains the essential criteria for licensure. We reported the short and long-term antibody responses and the CMI induced by two doses of a plantmade H5 VLP vaccine (H5VLP) adjuvanted with Alum-based (Alhydrogel®, Brenntag, QC) or with the synthetic toll-like receptor 4 (TLR4) agonist glucopyranosyl lipid adjuvant (GLA) formulated in a stable emulsion (GLA-SE®, Immune Design Corp, WA) given 21 days apart to healthy adults during a Phase II clinical trial

Methods

Results

Conclusion