A Study to Assess Safety, Tolerability and Immunogenicity of the Live Attenuated hRSV Vaccine rBCG-N-hRSV

Study Overview
=================
Brief Summary
-----------------
Human respiratory syncytial virus (hRSV) is the main cause of lower respiratory tract infection in children under one year of age. This study will evaluate the safety, tolerability and immunogenicity of a recombinant Mycobacterium bovis BCG vaccine that expresses the human Respiratory Syncytial Virus Nucleoprotein (N), in adult males (18 to 50 years of age).

Detailed Description
-----------------
hRSV is the main cause of infections in the lower respiratory tract, causing pneumonia, bronchiolitis and alveolitis in children younger than two years old. The infection is associated with the development of recurrent obstructive episodes in children with genetic predisposition. These hRSV infections also cause a high number of hospitalizations during the winter season. At Pontificia Universidad Católica de Chile, a vaccine has been developed to prevent hRSV infection, which is the conventional Bacillus Calmette Guerin (BCG) vaccine modified to recombinantly express the Nucleoprotein of hRSV (rBCG-N-hRSV). This vaccine has proven to be safe and immunogenic in different animal models, both in Chile and the USA. Doses of this vaccine have been manufactured under Current Good Manufacturing Practices (cGMP) conditions in USA, which are suitable to be tested in humans. Due to the unique immunogenic and safety characteristics observed in animal models used to test the efficacy of the rBCG-N-hRSV vaccine prototype, this clinical study will evaluate safety, tolerability and immunogenicity of the immunogenic cGMP formulation in healthy adults. Main objective: To characterize the safety and tolerability of escalating doses of the rBCG-N-hRSV vaccine, including doses of 5x10^3, 5x10^4 and 1x10^5 CFU (1%, 10% and 100% of the total dose) in healthy adult males of 18 to 50 years of age. Secondary objectives: To characterize the immune response against the Nucleoprotein of the hRSV in the previously stated escalating doses in the rBCG-N-hRSV. To characterize the immune response against the Mycobacterium in the previously stated escalating doses in the rBCG-N-hRSV. Study design: It corresponds to a phase I study, double blind (participant and personnel of the study) for the immunization of the tested vaccine or the control vaccine (Conventional BCG) within each cohort, to be performed in healthy adult males of 18 to 50 years of age. After a full clinical and laboratory evaluation to discard diseases, immunodeficiencies and latent tuberculosis infection, the participants will be enrolled into three cohorts in a open and successive manner. Within each cohort, they will be randomly and in a blind-manner assigned to receive the tested vaccine (rBCG-N-hRSV) or the control vaccine (conventional BCG). Cohort A: 6 participants vaccinated with 5x10^3 CFU of the rBCG-N-hRSV (1/100 part of the full dose) and 2 participants vaccinated with the conventional BCG (full dose). Cohort B: 6 participants vaccinated with 5x10^4 CFU of the rBCG-N-hRSV (1/10 part of the full dose) and 2 participants vaccinated with the conventional BCG (full dose). Cohort C: 6 participants vaccinated with 1x10^5 CFU of the rBCG-N-hRSV (full dose) and 2 participants vaccinated with the conventional BCG (full dose). Each cohort will be completed within two weeks, followed by a period of 4 weeks of follow-up, in which the security data will be evaluated by a Data and Safety Monitoring Board (DSMB), who will determinate whether, according to the previously defined parameters, the escalation to the next cohort is possible, the cohort must be repeated, or whether the study must be stopped. The DSMB is constituted by 5 physician experts in microbiology, virology/vaccinology and tuberculosis, with a wide national recognition, affiliated to institutions different from the sponsoring institution. Number of participants: A minimum of 24 subjects, 8 by cohort. 18 participants will receive the tested vaccine and 6 will receive the control vaccine. Main variables: Safety and tolerability. Evaluation of reactogenicity (Local and systemic Adverse Events-AE) Evaluation of laboratory AE Serious AE Evaluation of the presence of the vaccine in body fluids Secondary variables: Immunogenicity Evaluation of the immune response against M. bovis BCG. Evaluation of the immune response against hRSV-N.

Official Title
-----------------
A Double Blind, Controlled by Conventional BCG, Dose-escalation Phase I Study, to Evaluate Safety, Tolerability and Immunogenicity of a Mycobacterium Bovis BCG (Bacillus Calmette-Guérin) Vaccine, 1331 Danish Strain, Live Attenuated and Recombinant for the Expression of Human Respiratory Syncytial Virus Nucleoprotein (N) in Healthy Males Within 18 and 50 Years of Age

Conditions
-----------------
Respiratory Syncytial Virus Infections

Intervention / Treatment
-----------------
* Biological: rBCG-N-hRSV 1/100
* Biological: rBCG-N-hRSV 1/10
* Biological: rBCG-N-hRSV full dose
* Biological: Conventional BCG full dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Chilean male within 18 and 50 years old. To have accepted his voluntary participation through the sign of the informed consent. To be in good health, according to the medical history, physical examination and normal laboratory tests. To be vaccinated with BCG once or twice during his life. Exclusion Criteria: Symptoms or diagnosis suggesting some systemic disease including renal, liver, cardiovascular or pulmonary impairment, immunodeficiency, autoimmune disease, malignancies, psychiatric or other conditions that can interfere on the interpretation of the results or compromise the health of the participants. Body mass index lower than 19 and higher that 30 kg/m2 and/or weight under 50 kg. Not being able to attend all the study visits (face-to-face and call phones) or not follow the specified instructions (fasting, not doing intense physical exercise during the previous 24 hours to the visits and 72 hours post-vaccine). Signs of latent or active infectious diseases by Mycobacterium tuberculosis (TB): QuantiFERON-TB positive test or Chest X-ray suggesting Tuberculosis (TBC). Positive screening for Human Immunodeficiency Virus (HIV), Hepatitis B superficial antigen (HBsAG) and anti-Hepatitis C Virus (HCV). Evidence of primary or secondary immunodeficiency, determined by history, physical test and levels of serum immunoglobulins and lymphocytes sub-populations at the screening. Use of immunosuppressors during the last 6 months previous to the visit. Use of inhaled corticosteroids during the last year or with antecedents of bronchial hyper-reactivity. Antecedents of intradomiciliary contact with subjects with Tuberculosis or other mycobacteria, even when he/she is under treatment. Antecedents of substance abuse (drugs or alcohol), according to DSM IV (See footnote*) Occurrence of any serious adverse event associated to the previous BCG vaccination. History of severe allergic reaction or anaphylaxis to vaccines History of severe infections (use of IV antibiotics, opportunist, latent TBC, herpes zoster) during six months previous to the visit. Not use or rejection to the use of contraceptives during the whole study (See footnote**). Administration of Immunoglobulins or blood-derived products during the six months previous to the visit or the planning of its use during the study. Eczema at the vaccination site (deltoid zone). Antecedents of keloid scar. Being vaccinated with BCG during the last 10 years. History of being vaccinated with BCG three or more times or the presence of three BCG scars. Using other investigational products during the 30 days previous to the study. Administration of any vaccine during the 8 weeks previous to the recruitment. Planned administration of any other different vaccine 30 days after the vaccination with the rBCG-N-hRSV. Acute illness symptoms and/or feverish symptoms at the time or during the last seven days previous to the recruitment (fever defined as an oral or axillary temperature of >38ºC). (*) Substance abuse (drugs or alcohol): Maladaptive pattern of substance abuse that leads to a deterioration or clinical significant discomfort, expressed by one or more associated problems, during a time of twelve months, in one of the four vitals areas: inability to achieve main obligations; consume in dangerous situations, such as driving a vehicle; legal problems; consume despite the social and interpersonal difficulties associated. (**) Given the remote possibility of negative effects produced by the vaccination in the sperm, the recruitment will be performed only to volunteers that are not planning of conceiving a child during the study duration. In each visit, the abstinence fulfillment will be checked or the use of effective contraceptive. Eligibility criteria: The eligibility of the volunteers will be performed if they fulfill the inclusion criteria and fulfill none of the mentioned exclusion criteria, also presenting all the normal screening study. All the volunteers must sign the Informed consent approved by the Ethic Committee of the Facultad de Medicina of the Pontificia Universidad Católica de Chile, before starting the first screening visit.

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

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional BCG full dose<br>Participants will receive one full dose of the Conventional BCG vaccine administered as an intradermal injection at study entry. | Biological: Conventional BCG full dose<br>* 2x10^5 colony forming units (CFU) of conventional BCG will be administered as an intradermal injection.<br>|
| Experimental: rBCG-N-hRSV 1/100 dose<br>Participants will receive one 1/100 dose of the rBCG-N-hRSV vaccine administered as an intradermal injection at study entry. | Biological: rBCG-N-hRSV 1/100<br>* 5x10^3 colony forming units (CFU) of rBCG-N-hRSV will be administered as an intradermal injection.<br>|
| Experimental: rBCG-N-hRSV 1/10 dose<br>Participants will receive one 1/10 dose of the rBCG-N-hRSV vaccine administered as an intradermal injection at study entry. | Biological: rBCG-N-hRSV 1/10<br>* 5x10^4 colony forming units (CFU) of rBCG-N-hRSV will be administered as an intradermal injection.<br>|
| Experimental: rBCG-N-hRSV full dose<br>Participants will receive one full dose of the rBCG-N-hRSV vaccine administered as an intradermal injection at study entry. | Biological: rBCG-N-hRSV full dose<br>* 1x10^5 colony forming units (CFU) of rBCG-N-hRSV will be administered as an intradermal injection.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Required Adverse Events Grade II, III, and IV, Laboratory Adverse Events Grade II, III, and IV, and Severe Considered Adverse Events Related to the Vaccine. | To determine the safety of the rBCG-N-hRSV by evaluating the number of vaccinated participants with adverse events (AEs) due to the vaccination. Among these AEs, the following will be measured: Number of subjects with required AEs grade II, III, and IV, laboratory AEs grade II, III, and IV, and severe AEs (SAEs) considered related to the vaccine. Required AEs included pain, induration, pustule, fever, headache, myalgia, and diarrhea, among others. AEs were collected by self-report on diary cards, study visits, and study phone calls. Laboratory AEs included hematological and biochemical parameters, such as blood counts, transaminases, cholesterol, creatine phosphokinase, and urine analyses, among others. SAEs were defined as any untoward medical occurrence that resulted in death; was life-threatening; required hospitalization; or resulted in disability, among others. Grade 4 laboratory AEs were also considered SAEs. | Up to 180 days post-vaccination (A total of 11 months and 6 days for the whole study) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
human Respiratory Syncytial Virus, Phase I, Recombinant BCG vaccine