A Study to Assess the Safety and Immunogenicity of a New Influenza Vaccine Candidate MVA-NP+M1 in Healthy Adults
This is an open label phase I study, to assess the safety of a novel influenza vaccine, MVA-NP+M1. All volunteers recruited will be healthy. Twelve volunteers will be administered with a single dose of 5 x 10^7 pfu of MVA-NP+M1 via the Intradermal (ID) route (group 1). Sixteen volunteers will receive Intramuscular (IM) MVA-NP+M1. The first 8 volunteers will be administered a single dose of 5 x 10^7 pfu of MVA-NP+M1 followed by a further eight receiving 2.5 x 10^8 pfu of MVA-NP+M1 (group 2). The 3rd group will be split into 3 groups of 10 volunteers in the age ranges 50-59, 60-69 and 70 and above and administered intramuscularly with a single dose of 1.5 x 10^8 pfu of MVA-NP+M1. Safety data will be collected. The secondary aim of this study will be to assess the cellular immune responses generated by each dose.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||A Phase I Study to Assess the Safety and Immunogenicity of a New Influenza Vaccine Candidate MVA-NP+M1 in Healthy Adults|
- To assess the safety of a new influenza vaccine, MVA-NP+M1, when administered to healthy volunteers. [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
- To assess the cellular immune response generated by a new influenza vaccine, MVA-NP+M1, when administered as a single dose to healthy volunteers. [ Time Frame: 24 months ] [ Designated as safety issue: No ]
|Study Start Date:||August 2008|
|Study Completion Date:||November 2012|
|Primary Completion Date:||November 2012 (Final data collection date for primary outcome measure)|
Experimental: 1. MVA-NP+M1 ID
12 volunteers to receive MVA-NP+M1 via ID route
1. Intradermal injection at 5 x 10^7 pfu at day 0
Experimental: 2. MVA-NP+M1 IM
16 volunteers to receive MVA-NP+M1 via IM route
2.Intramuscular injection at 5 x 10^7 pfu/ml at day 0. Intramuscular injection at 2.5 x 10^8 pfu/ml at day 0
Experimental: 3. MVA-NP+M1 IM upper age group
30 volunteers to receive MVA-NP+M1 via IM route
3.Intramuscular injection at 1.5 x 10^8 pfu/ml at day 0
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.
|Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital|
|Oxford, Oxfordshire, United Kingdom, OX3 7LJ|
|Principal Investigator:||Adrian VS Hill, D.Phil FRCP||University of Oxford|