Influenza Clinical Trial
Official title:
A Phase IIA Study to Assess the Safety and Efficacy of a New Influenza Candidate Vaccine MVA-NP+M1 In Healthy Adults
This is a Phase IIa open label, non placebo controlled, non-randomised controlled challenge
study. The primary objective of this study is to assess the safety of a new influenza
vaccine, MVA-NP+M1, when administered as a single dose to healthy volunteers.
Initially two volunteers will be vaccinated and challenged with Influenza, followed by
vaccination of a further 12 volunteers and an Influenza challenge of those 12 along with 12
non-vaccinated controls.
Antibodies against the external proteins of influenza can prevent the virus from infecting
cells and either prevent infection or limit the spread of infection. However the surface
proteins are highly variable and there is little antibody cross-reactivity between variants.
Once a cell has been infected with the virus, it is then vulnerable to T cell attack
resulting in the destruction of infected cells so that no more virus can be produced and the
infection is controlled. There is evidence from clinical trials of influenza challenge, and
animal models that T cell responses can protect in the absence of antibodies. Additionally,
since T cells can recognise the highly conserved internal proteins of influenza,
cross-subtype protection can be achieved.
Seasonal influenza infection results in a T cell response to the virus which can protect
against subsequent infection. However over the course of a few years these responses decline
below protective levels. The new vaccine being tested in this study is designed to boost
these T cell responses back to protective levels. Even responses that may be too low to be
reliably quantified by currently available assays may still be boosted to high levels by a
single dose of recombinant MVA. Since the internal proteins vary little between influenza
subtypes, this could result in a 'universal' vaccine against influenza A. If the need to
continually reformulate the vaccine in response to mutations in the viral coat proteins can
be removed, the universal vaccine could be produced in large amounts and used more widely
than the existing seasonal 'flu vaccines, thus protecting the population against currently
circulating viruses and new virus types that are at present only found in avian species.
There is very little polymorphism of NP and M1 between influenza A isolates. NP is 92%
identical between H3N2 and H1N1 strains, and 91% identical between H3N2 and H5N1 strains. M1
is 95% identical between H3N2 and H1N1 strains, and 93% identical between H3N2 and H5N1
strains. This low level of variation appears to allow strong T cell cross-reactivity.
MVA is a highly attenuated strain of vaccinia virus that is unable to replicate efficiently
in human cell lines and most mammalian cells. Viral replication is blocked at a late stage
of virion assembly, so, importantly, viral and recombinant protein synthesis is unimpaired.
This means that MVA is an efficient single round expression vector, incapable of causing
infection in mammals. Replication-deficient recombinant MVA has been seen as an
exceptionally safe viral vector. This safety in man is consistent with the avirulence of MVA
in animal models, where recombinant MVAs have also been shown to be protectively immunogenic
as vaccines against viral diseases and cancer. Importantly for a vaccine which may
eventually be used in a large proportion of the population, recombinant MVAs expressing HIV
antigens have been shown to be safe and immunogenic in HIV-infected subjects.
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Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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