Clinical Trial of HIV Vaccine Combinations in Healthy Men and Women

Study Overview
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Brief Summary
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This is a randomised two-part Phase I study which will explore the impact of different boosting options (MVA-CN54 and recombinant CN54gp140 protein) for oral Adenovirus serotype 4 vector prime expressing HIV-1 CN54 envelope (Ad4-EnvCN54) designed to optimize systemic and mucosal antibody responses. Part 1 is exploratory and designed to select conditions capable of promoting enhanced systemic and mucosal B cell responses in a limited number of participants. Part 2 is dependent upon Part 1 and is designed to study groups selected on performance in part 1 in an expanded number of subjects. Data from both stages will be combined for safety and immunological analyses.

Official Title
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A Phase I Single-Blind Randomised Trial Investigating Immunisation Strategies Using Ad4-EnvCN54, MVA-CN54 and CN54gp140/MPLA Combinations in Order to Maximise Antibody Responses to Human Immunodeficiency Virus

Conditions
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Human Immunodeficiency Virus

Intervention / Treatment
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* Biological: Ad4-EnvCN54
* Biological: MVA-CN54
* Biological: CN54gp140/MPLA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged between 18 and 50 years on the day of screening BMI between 18-30 Seronegative for Adenovirus 4 serum neutralising antibodies Available for follow-up for the duration of the study Willing and able to give written informed consent At low risk of HIV infection and willing to remain so for the duration of the study defined as: no history of injecting drug use in the previous ten years no gonorrhoea or syphilis in the last six months no high risk partner (e.g. injecting drug use, HIV positive partner) either currently or within the past six months no unprotected anal or vaginal intercourse in the last six months, outside a relationship with a regular partner known to be HIV negative Willing to undergo HIV testing Willing to undergo a STI screen for chlamydia, gonorrhoea and syphilis Must agree to require male sexual partner to use condoms, from at least 14 days before the first vaccination until at least 4 months after the last If heterosexually active female capable of becoming pregnant, must (in addition to requiring male partner to use condoms) agree to use hormonal contraception, or to complete abstinence, from at least 30 days before the first vaccination until at least 4 months after the last. [Note: Acceptable hormonal contraception is combined (estrogen and progestogen containing) or progestogen-only hormonal contraception associated with inhibition of ovulation. Complete abstinence can be used, when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, lactational amenorrhoea method, and IUD/IUS are not acceptable methods of contraception.] If sexually active male, must agree to use condoms from the day of first vaccination until at least 4 months after the last. [Note: Additional use of an effective method of contraception is recommended for any non-pregnant female partner over the same period.] Agree to abstain from donating blood, eggs or sperm from the day of first vaccination until at least 3 months after the end of their participation in the trial Registered with a GP for at least the past month Entered and clearance obtained from The Overvolunteering Prevention System (TOPS) database Exclusion Criteria: Are pregnant or breast feeding, or living with anyone under the age of 5 years old or over 75 years old Have close contact with an immunocompromised individual thought to be at clinical risk from Adenovirus infection Clinically relevant abnormality on history or examination including: Liver disease with inadequate hepatic function Any skin condition which may interfere with the trial assessment of the injection sites Haematological, metabolic, gastrointestinal or cardio-pulmonary disorders Uncontrolled infection; autoimmune disease, immunodeficiency Known hypersensitivity to any component of the vaccine formulations used in this trial, or have severe or multiple allergies to drugs or pharmaceutical agents History of severe local or general reaction to vaccination defined as Local: extensive, indurated redness and swelling involving most of the antero-lateral thigh or the arm, not resolving within 72 hours General: fever ≥39.5oC within 48 hours; anaphylaxis; bronchospasm; laryngeal oedema; collapse; convulsions or encephalopathy within 72 hours Receipt of live attenuated vaccine within 60 days or other vaccine within 30 days of enrolment Receipt of an experimental vaccines containing HIV antigens, Ad4 and MVA-C products at any time in the past Receipt of blood products or immunoglobin within 4 months of screening, or drugs that suppress the immune system, such as steroids (including inhaled steroids, excluding topical steroids unless applied to the upper arm), in the preceding 3 months Participating in another trial of a medicinal product, completed less than 30 days prior to enrolment HIV 1 or 2 positive or indeterminate on screening Positive for antibodies to hepatitis B surface antigen, hepatitis C antibody or serology indicating active syphilis requiring treatment Clinically significant positive reaction in antinuclear antibody screen or clinically significant immunoglobulin (IgA, IgG or IgM) values Grade 1 or above clinically significant routine laboratory parameters Unable to read and/or speak English to a fluency level adequate for the full comprehension of procedures required in participation and consent Women with a history of toxic shock syndrome Women using an intrauterine device for contraception (as incompatible with softcup sampling) Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data Unlikely to comply with protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>Month 0: oral placebo Month 3: oral placebo + I.M. CN54gp140/MPLA + I.M. placebo Month 6: oral placebo + I.M. CN54gp140/MPLA + I.M. placebo | Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Experimental: Group B<br>Month 0: Ad4-EnvCN54 Month 3: oral placebo + I.M. CN54gp140/MPLA + I.M. placebo Month 6: oral placebo + I.M. CN54gp140/MPLA + I.M. placebo | Biological: Ad4-EnvCN54<br>* Live, replication-competent adenovirus 4 vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Experimental: Group C<br>Month 0: Ad4-EnvCN54 Month 3: Ad4-EnvCN54 + I.M. CN54gp140/MPLA + I.M. placebo Month 6: oral placebo + I.M. CN54gp140/MPLA + I.M. placebo | Biological: Ad4-EnvCN54<br>* Live, replication-competent adenovirus 4 vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Experimental: Group D<br>Month 0: Ad4-EnvCN54 Month 3: Ad4-EnvCN54 + I.M. CN54gp140/MPLA + I.M. placebo Month 6: Ad4-EnvCN54 + I.M. CN54gp140/MPLA + I.M. placebo | Biological: Ad4-EnvCN54<br>* Live, replication-competent adenovirus 4 vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Active Comparator: Group E<br>Month 0: oral placebo Month 3: oral placebo + I.M. CN54gp140/MPLA + I.M. MVA-CN54 Month 6: oral placebo + I.M. CN54gp140/MPLA + I.M. MVA-CN54 | Biological: MVA-CN54<br>* Live, non-replicating modified vaccinia Ankara vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Experimental: Group F<br>Month 0: Ad4-EnvCN54 Month 3: oral placebo + I.M. CN54gp140/MPLA + I.M. MVA-CN54 Month 6: oral placebo + I.M. CN54gp140/MPLA + I.M. MVA-CN54 | Biological: Ad4-EnvCN54<br>* Live, replication-competent adenovirus 4 vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: MVA-CN54<br>* Live, non-replicating modified vaccinia Ankara vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Experimental: Group G<br>Month 0: Ad4-EnvCN54 Month 3: Ad4-EnvCN54 + I.M. CN54gp140/MPLA + I.M. MVA-CN54 Month 6: oral placebo + I.M. CN54gp140/MPLA + I.M. MVA-CN54 | Biological: Ad4-EnvCN54<br>* Live, replication-competent adenovirus 4 vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: MVA-CN54<br>* Live, non-replicating modified vaccinia Ankara vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|
| Experimental: Group H<br>Month 0: Ad4-EnvCN54 Month 3: Ad4-EnvCN54 + I.M. CN54gp140/MPLA + I.M. MVA-CN54 Month 6: Ad4-EnvCN54 + I.M. CN54gp140/MPLA + I.M. MVA-CN54 | Biological: Ad4-EnvCN54<br>* Live, replication-competent adenovirus 4 vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: MVA-CN54<br>* Live, non-replicating modified vaccinia Ankara vector, engineered to express the envelope glycoprotein of HIV-1 isolate 97CN54<br>Biological: CN54gp140/MPLA<br>* Recombinant glycoprotein of HIV-1 isolate 97CN54, with liposomal monophosphoryl lipid A adjuvant<br>* Other names: CN54-M;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mucosal antigen-specific antibodies measured by binding ELISA | Frequency of mucosal binding antibodies to HIV CN54gp140 antigen | At two weeks after the final immunisation | 
| Adverse events | Frequency of adverse events | Up to twenty-four weeks after the final immunisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum and mucosal antigen-specific antibodies measured by binding ELISA | Frequency of serum and mucosal binding antibodies to HIV CN54gp140 antigen | Up to twenty-four weeks after the final immunisation |