A Study to Assess the Safety and Immunogenicity of a New Influenza Vaccine Candidate MVA-NP+M1 in Healthy Adults

• ClinicalTrials.gov Identifier: NCT00942071
• Recruitment Status: Completed
• First Posted: July 20, 2009
• Last Update Posted: November 29, 2012
• Sponsor: University of Oxford
• Collaborator: Wellcome Trust
• Information provided by (Responsible Party): University of Oxford

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Influenza	Biological: MVA-NP+M1	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 58 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: August 2008
• Actual Primary Completion Date: November 2012
• Actual Study Completion Date: November 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1. MVA-NP+M1 ID; 12 volunteers to receive MVA-NP+M1 via ID route	Biological: MVA-NP+M1; 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	Biological: MVA-NP+M1; 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	Biological: MVA-NP+M1; 3.Intramuscular injection at 1.5 x 10^8 pfu/ml at day 0

Outcome Measures

Primary Outcome Measures :

1. To assess the safety of a new influenza vaccine, MVA-NP+M1, when administered to healthy volunteers. [ Time Frame: 24 months ]

Secondary Outcome Measures :

1. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy adult aged 18 or over, no upper age limit
• Resident in or near Oxford for the duration of the vaccination study
• Able and willing (in the Investigators' opinions) to comply with all study requirements
• Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner
• For females, a negative pregnancy test on the day of vaccination and agreement to practice effective contraception for the duration of the study.
• Agreement to refrain from blood donation during the course of the study
• Written informed consent

Exclusion Criteria:

• Participation in another research study involving an investigational product in the 30 days preceding enrolment, or planned use during the study period
• Prior receipt of a recombinant MVA vaccine
• Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate
• Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed)
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g. egg products
• Any history of anaphylaxis in reaction to vaccination
• History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
• History of serious psychiatric condition
• Any chronic illness requiring ongoing or awaiting hospital specialist supervision, other than minor surgical procedures and follow up of surgery over 6 months prior to screening.
• Suspected or known current injecting drug or alcohol abuse (as defined by an alcohol intake of greater than 42 units every week)
• Seropositive for hepatitis B surface antigen (HBsAg)
• Seropositive for hepatitis C virus (antibodies to HCV)
• For females, pregnancy, lactation or willingness/intention to become pregnant during the study
• Any other significant disease, disorder or finding, which, in the opinion of the Investigators, may either put the volunteer at risk because of participation in the study, or may influence the result of the study, or the volunteer's ability to participate in the study.
• Any clinically significant abnormal finding on screening biochemistry or haematology blood tests or urinalysis, as determined by the investigators.

Contacts and Locations

Locations

United Kingdom

Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital

Oxford, Oxfordshire, United Kingdom, OX3 7LJ

Sponsors and Collaborators

University of Oxford

Wellcome Trust

Investigators

• Principal Investigator: Adrian VS Hill, D.Phil FRCP; University of Oxford

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Antrobus RD, Lillie PJ, Berthoud TK, Spencer AJ, McLaren JE, Ladell K, Lambe T, Milicic A, Price DA, Hill AV, Gilbert SC. A T cell-inducing influenza vaccine for the elderly: safety and immunogenicity of MVA-NP+M1 in adults aged over 50 years. PLoS One. 2012;7(10):e48322. doi: 10.1371/journal.pone.0048322. Epub 2012 Oct 31.

• Responsible Party: University of Oxford
• ClinicalTrials.gov Identifier: NCT00942071
• Other Study ID Numbers: Flu001
• First Posted: July 20, 2009
• Last Update Posted: November 29, 2012
• Last Verified: November 2012

Keywords provided by University of Oxford:

Influenza; Vaccine

Additional relevant MeSH terms:

Influenza, Human; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases