Elsevier

Vaccine

Volume 30, Issue 31, 29 June 2012, Pages 4655-4660
Vaccine

Synthetic Influenza vaccine (FLU-v) stimulates cell mediated immunity in a double-blind, randomised, placebo-controlled Phase I trial

https://doi.org/10.1016/j.vaccine.2012.04.089Get rights and content

Abstract

Objectives

Current Influenza vaccines elicit antibody mediated prophylactic immunity targeted to viral capsid antigens. Despite their global use these vaccines must be administered yearly to the population, cannot be manufactured until the circulating viral strain(s) have been identified and have limited efficacy. A need remains for Influenza vaccines addressing these issues and here we report the results of a Phase Ib trial of a novel synthetic Influenza vaccine (FLU-v) targeting T cell responses to NP, M1 and M2.

Methods

Forty-eight healthy males aged 18–40 were recruited for this single-centre, randomised, double blind study. Volunteers received one single low (250 μg) or high (500 μg) dose of FLU-v, either alone or adjuvanted. Safety, tolerability and basic immunogenicity (IgG and IFN-γ responses) parameters were assessed pre-vaccination and for 21 days post-vaccination.

Results

FLU-v was found to be safe and well tolerated with no vaccine associated severe adverse events. Dose-dependent IFN-γ responses >2-fold the pre-vaccination level were detected in 80% and 100% of volunteers receiving, respectively, the low and high dose adjuvanted FLU-v formulations. No formulation tested induced any significant FLU-v antibody response.

Conclusion

FLU-v is safe and induces a vaccine-specific cellular immunity. Cellular immune responses are historically known to control and mitigate infection and illness during natural infection.

Highlights

► Synthetic FLU-v vaccine targets conserved immunoreactive regions in NP, M1 and M2. ► Phase I trial: One dose of FLU-v, either 250 or 500 μg, with or without adjuvant. ► FLU-v is safe and well tolerated. No vaccine associated severe adverse events. ► Low and high dose adjuvanted FLU-v formulations induce strong cellular immunity. ► FLU-v formulations do not induce significant vaccine-specific antibody responses.

Introduction

Influenza causes yearly epidemics associated with significant morbidity and economic loss [1] as well as increased mortality in some groups (e.g. elderly) [2]. Occasionally, it also causes pandemics characterised by high infection and mortality rates. The Spanish Flu pandemic of 1918 affected one-third of the world population (i.e. 500 million) and caused over 40 million fatalities [3].

For over 50 years, Influenza public health programs have relied on vaccines that elicit neutralising antibodies to Haemagglutinin (HA) and Neuraminidase (NA). These prophylactic vaccines have, however, three major shortcomings. Firstly, the high variability of HA and NA means that one vaccine cannot provide universal protection against all Influenza strains. As new variants of the virus emerge every year, vaccine preparations must be updated and populations re-vaccinated. Secondly, mass manufacturing of HA/NA-based Influenza vaccines can only start once the circulating pathogenic strain(s) is identified. This results in a delay of 6 months or more between an Influenza outbreak and a vaccine being available [4]. Finally, the efficacy of HA/NA-based vaccines is limited. A recent report [5] suggests their efficacy rate is only 59% in 18–64 year olds, falling to 35% in those over 65 years of age.

Much research has been carried out on novel Influenza vaccine candidates that totally or partially address the above described shortcomings of current vaccines (reviewed in [6] and [7]). Most of them continue to target antibody immunity to viral antigens (e.g. HA, NA, M2e), whilst a few target cellular immune responses to a different range of antigens (e.g. NP, M1, M2).

Influenza-specific CD8+ T-cell responses are a feature on natural infection [8] and we and others [9], [10], [11], [12], [13] have shown that a CD8+ T-cell response can, in the absence of neutralising antibodies, protect mice against lethal challenge with homotypic and heterotypic Influenza strains. In our case [9], this protective response was induced following immunisation with an equimolar admixture of synthetic polypeptides covering conserved immunogenic regions in M1, M2, NP and PB1. We now describe the results of a first-in-man Phase I clinical trial of a novel Influenza candidate, FLU-v, based on those synthetic polypeptides.

Section snippets

Study population

FLU-v was assessed in a randomised, double blind single-centre study (Quintiles Drug Research Unit at Guy's Hospital). Volunteers were enrolled if at screening they were males aged 18–40 years with Body Mass Index (BMI) 18.5–28.5 kg/m2, no clinically significant abnormal findings (i.e. physical examination, electrocardiogram (ECG), medical history or laboratory results) and non-users or low-users (i.e. ≤10 cigarettes per day) of tobacco-products.

Vaccine description

FLU-v is a sterile equimolar mixture of four

Recruitment and safety

Forty-eight volunteers were enrolled in this study (April’10 to July’10). Trial profile and baseline clinical and demographic data are reported in Fig. 1.

For the non-adjuvanted FLU-v formulations, nine individuals (90%) receiving the low dose (LD group) reported 24 AEs, whilst eight individuals (80%) receiving the high dose (HD group) reported 38 AEs. For the adjuvanted FLU-v formulations, nine individuals (90%) receiving the low dose (LDA group) reported 25 AEs, whilst 10 individuals (100%)

Conclusions

This is a first-in-man evaluation of a synthetically manufactured vaccine (FLU-v) incorporating conserved immunogenic regions identified in NP, M1 and M2 proteins of Influenza.

Being an exploratory study, volunteers received two different non-optimised vaccine doses (250 or 500 μg), delivered in a single vaccination either alone or with an adjuvant.

Vaccination with FLU-v did not cause major AEs. The vast majority were mild and the most common of them, pain at the site of injection, was consistent

Acknowledgements

We are grateful to the volunteers in this study as well as to Prof. T.G.K. Mant and the rest of the Quintiles team (UK) for carrying out the clinical interventions described in this manuscript.

Olga Pleguezuelos, Stuart Robinson, Gregory Stoloff and Wilson Caparrós-Wanderley developed the vaccine, managed the clinical trial and wrote and reviewed the manuscript. This study was fully sponsored by SEEK (Peptcell Ltd), a privately owned biopharmaceutical company. All authors are employees of the

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