Elsevier

Vaccine

Volume 26, Issue 33, 5 August 2008, Pages 4160-4167
Vaccine

Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults

https://doi.org/10.1016/j.vaccine.2008.05.077Get rights and content

Abstract

Objective

The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains.

Methods

In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5 μg or 15 μg H5 haemagglutinin (HA) vaccine ± AlPO4 adjuvant (phase I trial; N = 400) or two doses of 30 μg or 45 μg H5 HA with AlPO4 adjuvant (phase II trial; N = 400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation.

Findings

All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30 μg or 45 μg H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (≥1:20) persistence up to 6 months post-vaccination. The 7.5 and 15 μg formulations (±adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains.

Interpretation

Two doses of prototype 30 μg or 45 μg aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains [ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; Funding: CSL Limited, Australia].

Introduction

Pathogenic avian influenza A (H5N1) viruses are leading candidates for the next influenza pandemic. These viruses have spread to an unprecedented number of countries causing severe disease in poultry and associated zoonotic infections in humans with a high fatality rate [1]. Although H5N1 viruses have not yet demonstrated sustained person-to-person transmission, there is a concerted global effort to develop prototype pandemic vaccines based on currently circulating H5N1 strains.

To provide a rapid response to an emergent H5 pandemic and to facilitate the speed of clinical development and regulatory approval, it is desirable that prototype pandemic vaccine development be based closely on current licensed manufacturing processes for influenza vaccines [2] and on the use of adjuvants with an extensive safety record. Several prototype vaccines based on clade 1 H5N1 virus strains (A/Vietnam/1194/2004 and A/Vietnam/1203/2004) have been evaluated in adults [3], [4], [5], [6]. Findings from these studies confirm that at least two doses of vaccine are required to elicit an immune response in naïve populations.

Given the diversity of circulating H5 strains and the rapid evolution of influenza A viruses, prototype pandemic vaccines that confer protection against a number of circulating H5N1 viruses will maximise the protection achieved in a vaccinated population. Although existing prototype vaccines are based on the clade 1 strains [3], [4], [5], [6] genetically distinct clade 2 strains are responsible for the most recent human avian influenza infections [7]. The objective of this study was to evaluate prototype inactivated split-virus A/Vietnam/1194/2004 vaccine formulations in healthy adult populations. In addition, the ability of a 6-month booster vaccine to enhance immunogenicity and the cross-reactivity of immune responses to two diverse clade 2 H5N1 viruses was assessed.

Section snippets

Study design

We report results from two prospective, observational, multicentre trials that were conducted within Australia to assess the safety, tolerability and immunogenicity of: (i) 7.5 and 15 μg H5 haemagglutinin (HA) with or without AlPO4 adjuvant (phase I trial, ClinicalTrials.gov identifier: NCT00136331); and (ii) 30 μg or 45 μg H5 HA with AlPO4 adjuvant (phase II trial, ClinicalTrials.gov identifier: NCT00320346). The phase I trial was conducted from October 2005 to July 2006 at: (i) the Murdoch

Participant distribution and demographic data

A total of 400 participants were enrolled in each trial and randomised to each group within each trial (Fig. 1, Table 1). All enrolled participants were included in the safety populations. Over 98% (787/800) of participants completed the primary vaccination course, including the Day 42 follow-up visit. Of the 13 participants (from both trials) who did not complete the primary vaccination course, only one withdrew because of an AE (mild muscle ache and fatigue). Of the 271 participants who

Discussion

This study helps define the potential dosage regimen for a prototype H5N1 pandemic vaccine in healthy adult populations and provides new data demonstrating that inactivated, split-virus, clade 1, H5N1 vaccines, with or without adjuvant, elicit modest levels of cross-reactive MN antibodies to currently circulating variant H5N1 strains.

Immune responses in the phase I trial with the 7.5 and 15 μg HA formulations (with or without adjuvant) were comparable to those previously observed with similar

Acknowledgments

The data reported here were presented, in part, at the VIII International Symposium on Respiratory Viral Infections, Hawaii, March 16–19, 2006; the 3rd WHO Meeting on Evaluation of Pandemic Influenza Vaccines in Clinical Trials, WHO/HQ, Geneva, February 15–16, 2007 and the Options for the Control of Influenza VI Conference, Toronto Canada, June 17–23, 2007.

The authors would like to extend their thanks to the participants, investigators and personnel at each study site. Specifically, the authors

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