ArticlesEfficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trial
Introduction
Seasonal influenza has a substantial annual global impact, accounting for an estimated 1 billion illnesses worldwide and more than 600 000 life-years lost in the USA alone.1 Present vaccine approaches have limited efficacy, with the most recent reports estimating protection against illness of 40–60% in adults.2, 3 In situations in which animals are exposed to a newly arisen influenza strain against which they have no protective neutralising antibodies, cross-reactive T cells against conserved internal antigens of influenza have been shown to be associated with limiting viral shedding and reduced duration of symptoms.4, 5, 6, 7, 8, 9 In human influenza challenge studies, protection against symptoms and viral replication has been associated with the magnitude of the influenza-specific CD4 T-cell response.10 During the 2009 influenza A H1N1 pandemic, individuals with documented influenza in the previous season were less likely to become ill, despite an absence of cross-reactive antibodies.11 In the prospective Flu Watch study and in previous trials, the two influenza proteins most commonly recognised by T cells were virus nucleoprotein (NP) and matrix protein 1 (M1), and the quartile with the highest previous T-cell responses was less likely to develop influenza.12 NP and M1 have little polymorphism between influenza A strains, which appears to allow strong T-cell cross-reactivity.13 Thus, a vaccine against influenza that induces protective T-cell responses against conserved internal antigens might provide lasting immunity against human seasonal influenza and other subtypes with pandemic potential.6, 9, 14, 15, 16
Recombinant viral-vectored vaccines have been used in humans to induce a high magnitude of CD4 and CD8 T-cell responses to a wide range of antigens in large numbers of patients. One such vector is modified vaccinia Ankara (MVA), which has been used to generate strong T-cell responses to HIV-1,17, 18 tuberculosis,19 hepatitis C virus,20 influenza,13 and melanoma.21 MVA-NP+M1 is a replication-deficient vector expressing the NP and M1 antigens from an H3N2 strain.13 Studies have shown that vaccination with MVA-NP+M1 results in an increase in influenza-specific cross-reactive effector T cells that secrete interferon γ (IFNγ), which were maintained at higher levels for longer than a year.13, 22 These increases were similar to that associated with decreased influenza infection in a natural history study, although different assay methods were used.12 In a small phase 2a human challenge study, MVA-NP+M1-vaccinated individuals experimentally challenged with live influenza tended to show less severe symptoms and shorter duration of viral shedding than control participants.23 These and other studies demonstrated the safety of MVA-NP+M1 in both young and older adults when used alone and in combination with licensed inactivated seasonal influenza vaccine.24, 25, 26, 27
On the basis of these findings, we designed a trial to test the hypothesis that MVA-NP+M1 would provide added benefit to seasonal vaccination.
Section snippets
Study design and participants
FLU009 was a phase 2b, randomised, placebo-controlled, double-blind trial conducted at eight outpatient clinical trial sites in Queensland, New South Wales, Victoria, and South Australia (appendix p 6). The study was planned to be run over two consecutive influenza seasons (exact dates determined by the Australian National Notifiable Diseases Surveillance System). Participants were adults aged 18 years or older who had received the 2019 QIV (either Sanofi FluQuadri [Paris, France] or Seqirus
Results
The conditional power calculated at the interim analysis (presented to the data monitoring committee on Jan 20, 2020) indicated that, if continued for a second influenza season, the chance of a statistically significant outcome was low (<20%) in showing that the overall 2-year incidence of laboratory-confirmed influenza with MVA-NP+M1 would be lower than in the placebo group. Therefore, the data monitoring committee recommended stopping the trial for futility based on predefined criteria, and
Discussion
Ample pre-existing data support the T-cell hypothesis in influenza—ie, that inducing an increase in cross-reacting T cells can improve outcomes, detected as a reduction in either viral load or overall symptom magnitude and duration.9 Improvements in these outcomes should be detectable in field efficacy studies, which rely on symptom-based sampling during the influenza season. In this study, a vaccine that induced both CD4 and CD8 T-cell responses to the conserved influenza A internal proteins
Data sharing
The protocol and statistical analysis plan have been published online. De-identified and anonymous data and tables, listings, and figures will be made available immediately for all reasonable requests after contacting the corresponding author and citing the research plan and intended use.
Declaration of interests
TGE, EE-V, LB, and CE are employees of Vaccitech. KR is a paid consultant to Vaccitech. SG is a founder and holds stock in Vaccitech and is named on the MVA-NP+M1 patent. All other authors declare no competing interests.
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