Safety and Immunogenicity of MVA.HIVconsv in HIV-1 Seropositive Adults on HAART

Study Overview
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Brief Summary
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In this study, the novel vaccine candidate, MVA.HIVconsv, will be tested for safety, tolerability and immunogenicity in HIV-1-seropositive subjects receiving effective antiretroviral therapy. MVA.HIVconsv will be tested as a single vaccine modality, as a prelude to testing in a heterologous viral vector boost regimen which will include a replication-defective simian adenovirus expressing the same immunogen.

Official Title
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HIV-CORE 001 - A Randomised Placebo-controlled Study to Evaluate the Safety and Immunogenicity of a Candidate HIV-1 Vaccine, MVA.HIVconsv, Delivered by Intramuscular Needle Injection to HIV-1 Seropositive Adult Subjects Receiving Antiretroviral Therapy (ART).

Conditions
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HIV-1

Intervention / Treatment
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* Biological: MVA.HIVconsv low dose
* Other: Placebo low dose
* Biological: MVA.HIVconsv high dose
* Other: Placebo high dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 18-60 years Confirmed HIV-1 seropositive Willing and able to give written informed consent for participation in the study Treated continuously with a combination of 3 or more antiretroviral agents for the preceding 12 months Willing and able to adhere to an effective ART regimen for the duration of the study (switching from current regimen is allowed if for reasons of tolerability or toxicity) CD4 cell count > 350 cells/μl at screening and at the preceding clinic visit Plasma viral load < 50 copies / ml at screening and at the preceding clinic visit No new AIDS-defining diagnosis or progression of HIV-related disease in the preceding 6/12 months Haematological and biochemical laboratory parameters as follows: Haemoglobin > 10g/dl Platelets > 100,000/μl ALT ≤ 2.5 x ULN Creatinine ≤ 1.3 x ULN Serology: negative for hepatitis B surface antigen OR HbsAg positive with HBV DNA < 1000 copies/ml; negative for hepatitis C antibodies OR confirmed clearance of HCV infection (spontaneous or following treatment); negative syphilis serology or documented adequate treatment of syphilis if positive EIA IgG or TPHA Available for follow up for duration of study (screening + 38 weeks) and willing to comply with the protocol requirements Women of child-bearing age must not be pregnant, planning a pregnancy or breast-feeding. Sexually active women must be willing to use an approved method of contraception from screening until 4 months after the third immunisation. Sexually active men in heterosexual relationships must be willing to use an approved method of contraception with their partners from screening until 4 months after the third immunisation. Exclusion Criteria: Confirmed HIV-2 seropositive Positive pregnancy test Participation in another clinical trial within 12 weeks of study entry History of autoimmune disease other than HIV-related auto-immune disease which has resolved with ART History or clinical manifestations of any physical or psychiatric disorder which could impair the subject's ability to complete the study History of anaphylaxis or severe adverse reaction to vaccines History of alcohol or drug dependency which could, in the opinion of the investigators, impair the subject's ability to complete the study Previous immunisation with a recombinant MVA vaccine Immunisation with any experimental immunogens within 6 months of study entry Receipt of blood products or immunoglobulins within 6 months of study entry Treatment for cancer or lymphoproliferative disease within 1 year of study entry Receipt of vaccines other than Hepatitis B vaccine within 2 weeks of study entry or planned receipt within 2 weeks of vaccination Any other prior therapy which, in the opinion of the investigators, would make the individual unsuitable for the study or influence the results of the study Current or recent use (within last 3 months) of interferon or systemic corticosteroids or other immunosuppressive agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose vaccinees<br>Individuals will receive three intramuscular injections of MVA.HIVconsv alone at a dose of 1x10^8 pfu. | Biological: MVA.HIVconsv low dose<br>* Three intramuscular injections of MVA.HIVconsv alone at a dose of 1x10^8 pfu at week 0, 4 and 12.<br>|
| Experimental: High dose vaccinees<br>Individuals will receive three intramuscular injections of MVA.HIVconsv alone at a dose of 4x10^8 pfu. | Biological: MVA.HIVconsv high dose<br>* Three intramuscular injections of MVA.HIVconsv alone at a dose of 4x10^8 pfu at week 0, 4 and 12.<br>|
| Placebo Comparator: Low dose placebo<br>Individuals will receive three intramuscular injections of low dose placebo | Other: Placebo low dose<br>* Three intramuscular injections of placebo alone (200ul) at week 0, 4 and 12.<br>|
| Placebo Comparator: High dose placebo<br>Individuals will receive three intramuscular injections of high dose placebo | Other: Placebo high dose<br>* Three intramuscular injections of placebo alone (800ul) at week 0, 4 and 12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of volunteers who develop a grade 3 or 4 local or systemic reactions |  | Actively collected data throughout the study until 6 months after the last vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A descriptive summary of grade 3 or 4 local and systemic events, including laboratory abnormalities |  | Actively collected data throughout the study until 6 months after the last vaccination | 
| A descriptive summary of serious adverse events, including laboratory abnormalities |  | Actively collected data throughout the study until 6 months after the last vaccination | 
| The proportion of volunteers who develop CD8+ T cell responses to a new HIV-1 epitope, as determined by IFN-γ ELISPOT assay |  | Screen (≤ day -28); Day 0; Day 14; Day 28; Day 42; Day 56; Day 84; Day 112; Day 182; Final visit (day 266 / early termination) | 
| The proportion of volunteers in whom the magnitude of CD8+ T cell responses to HIVconsv peptides increases by ≥ 3-fold, as determined by IFN-γ ELISPOT assay |  | Screen (≤ day -28); Day 0; Day 14; Day 28; Day 42; Day 56; Day 84; Day 112; Day 182; Final visit (day 266 / early termination) | 
| Evaluation of the effect of MVA.HIVconsv vaccinations on viral suppressive capacity of CD8+ T cells in vitro, using a novel flow cytometric assay |  | Screen (≤ day -28); Day 0; Day 14; Day 28; Day 42; Day 56; Day 84; Day 112; Day 182; Final visit (day 266 / early termination) | 
| Magnitude and phenotype, including but not limited to activation status, of HIV-1-specific CD8+ T cell populations identified by tetramer staining before and after vaccination, in selected volunteers with appropriate HLA class I alleles. |  | Screen (≤ day -28); Day 0; Day 14; Day 28; Day 42; Day 56; Day 84; Day 112; Day 182; Final visit (day 266 / early termination) | 
| PBMC will be stored for other exploratory assays to characterise vaccine-expanded T cell populations such as IL-10 secretion and CFSE proliferation assays. |  | Screen (≤ day -28); Day 0; Day 14; Day 28; Day 42; Day 56; Day 84; Day 112; Day 182; Final visit (day 266 / early termination) | 
| Serum and plasma will be stored for investigation of binding and neutralising antibodies to vaccinia and of pro-inflammatory cytokines. |  | Screen (≤ day -28); Day 0; Day 14; Day 28; Day 42; Day 56; Day 84; Day 112; Day 182; Final visit (day 266 / early termination) |