Synthetic Influenza vaccine (FLU-v) stimulates cell mediated immunity in a double-blind, randomised, placebo-controlled Phase I trial☆
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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Cited by (75)
The race toward a universal influenza vaccine: Front runners and the future directions
2023, Antiviral ResearchUniversal influenza vaccine technologies and recombinant virosome production
2022, Methods in MicrobiologyCitation Excerpt :Another example is FLU-v, a vaccine developed by PepTcell (SEEK, United Kingdom) which comprises a peptide with sequences from NP, M1 and M2 proteins. Similarly, it has been evaluated in several clinical trials and the results were fairly promising (Table 1), showing that FLU-v could stimulate cell-mediated immunity, as well as reduce symptoms and the shedding of viruses from vaccinated individuals (Pleguezuelos, Dille, et al., 2020; Pleguezuelos, James, et al., 2020; Pleguezuelos et al., 2012, 2015; ). There are also other recombinant vaccines that have been designed and tested in animals.
Peptides to combat viral infectious diseases
2020, PeptidesCitation Excerpt :Equimolar combination of four peptides (M1: DLEALMEWLKTRPILSPLTKGILGFVFTLTVP, NPA: DLIFLARSALILRGSVAHKSC, NPB: PGIADIEDLTLLARSMVVVRP, and M2: IIGILHLILWILDRLFFKCIYRLF) were tested in clinical trials and the safety and efficacy were reported. This suggested that FLU-v-like peptides activate the T cell arm of immune response and have potential as vaccines [163,164,190]. Multimeric-001 (M-001) is another peptide vaccine that has met its primary endpoint in phase II.
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ClinicalTrials.gov Identifier NCT01181336.