Tuberculosis
Conditions
Keywords
Healthy Participants, Healthy Individuals, Tuberculosis, Vaccine
Brief summary
This Phase 1, randomized, double-blind, placebo-controlled study will evaluate the safety, tolerability, and immune responses of the investigational HCMV-TB vaccine candidate VIR-1778 in adults in overall good health without HIV who are cytomegalovirus (CMV) seropositive. Participants will receive two doses of either VIR-1778 or placebo administered 12 weeks apart. The study will assess the safety of VIR-1778, its ability to induce immune responses against Mycobacterium tuberculosis (TB) antigens, and the presence of vaccine-derived virus in blood, saliva, and urine. The study is based on the hypothesis that VIR-1778 will be safe and well tolerated and will induce CD4+ and CD8+ T-cell responses against TB antigens. Approximately 116 participants will be enrolled.
Interventions
BIOLOGICALVIR-1778 (5 × 10^5 ffu)
Live attenuated human cytomegalovirus (HCMV)-vectored tuberculosis (TB) vaccine candidate expressing seven Mycobacterium tuberculosis antigens (TB7Ag). Administered as a 1 mL subcutaneous injection in the deltoid at Week 0 and Week 12.
BIOLOGICALVIR-1778 (5 × 10^6 ffu)
Live attenuated human cytomegalovirus (HCMV)-vectored tuberculosis (TB) vaccine candidate expressing seven Mycobacterium tuberculosis antigens (TB7Ag). Administered as a 1 mL subcutaneous injection in the deltoid at Week 0 and Week 12.
OTHERHT Diluent Placebo
HT buffer placebo containing 20 mM histidine and 10% trehalose-dihydrate without active vaccine. Administered as a 1 mL subcutaneous injection in the deltoid at Week 0 and Week 12.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
General and Demographic Criteria 1. At least 18 years old at screening and up to 55 years old on day of enrollment. 2. Access to a participating HVTN CRS and willingness to be followed for the planned duration of the study. 3. Demonstrates an understanding of the study and is able and willing to provide informed consent. 4. Agrees not to enroll in another study of an investigational agent during participation in the trial. If a potential participant is already enrolled in another clinical trial, approvals are required prior to enrollment into HVTN 606. 5. In good general health according to the clinical judgment of the site investigator. 6. Physical examination and laboratory results without clinically significant findings that would interfere with assessment of safety or reactogenicity in the clinical judgment of the site investigator. 7. Willing to not donate blood, sperm, or other tissues until after the last required protocol clinic visit. 8. CMV seropositive. 9. Systolic blood pressure of 90 to \< 140 mmHg and diastolic blood pressure of 50 to \< 90 mmHg at screening visit. The average blood pressure between the screening visit and the enrollment visit must be below 140 mmHg systolic and 90 mmHg diastolic. A single measurement ≥ 160 systolic mmHg or 100 mmHg diastolic during the current study evaluation is exclusionary. 10. Male volunteers with partners of pregnancy potential must agree to have their partners use contraception through the end of the study (does not include long-term follow-up). 11. For Part A only: Women who are not of pregnancy potential or male volunteers. Any individual may be enrolled if they are not of pregnancy potential. 12. For Part B only: Women volunteers who are of pregnancy potential must * Be willing to use an approved method of highly effective contraception from 14 days before enrollment through the end of the study * Refrain from egg donation and in vitro fertilization from the time of study product administration through the end of the study * Have negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test at screening (ie, prior to randomization) and prior to study product administration on the day of study product administration. Women who are NOT of pregnancy potential due to having undergone hysterectomy or salpingectomy or tubal ligation or bilateral oophorectomy (verified by medical records) are not required to undergo pregnancy testing. * Also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit 13. Willingness to receive HIV and TB test results. 14. Hemogram/complete blood count (CBC) • Hemoglobin: ≥ 11.0 g/dL for women, ≥ 13.0 g/dL for men Note: If receiving exogenous hormones for more than 6 consecutive months with dosing equivalent to parenteral testosterone ≥1000 mg every 12 weeks or estradiol valerate ≥2 mg/week, determine hemoglobin eligibility based on the exogenous hormone reported. 15. White blood cell count = 2,500 to 12,000 cells/mm3 (WBC over 12,000/mm3 is not exclusionary if further evaluation shows general good health and if approval is granted). • Platelets = 125,000 to 550,000 cells/mm3. 16. Chemistry panel: * Alanine aminotransferase (ALT) \< 1.25 × upper limit of institutional reference range * Aspartate aminotransferase (AST) (\< 1.25 × upper limit of normal (ULN)) based on institutional normal range * Serum creatinine ≤ 1.1 × ULN based on institutional normal range * Direct bilirubin levels \< 7.7 mic mol/L (0.45mg/dL) and total bilirubin \< 22.5 mic mol/L (1.3 mg/dL) (volunteers known to have Gilbert's Syndrome with an abnormal total bilirubin are not excluded) * Gamma-glutamyl transferase (GGT) \< 1.1 × ULN based on institutional normal range 17. Negative HIV-1 and -2 blood test by one of the following options: * Negative European Conformity (CE)-marked or FDA-approved enzyme immunoassay (EIA) or chemiluminescent microparticle immunoassay (CMIA) or * Negative results on 2 different brands of HIV rapid tests (one of which must be CE-marked or FDA-approved) Note: For participants with vaccine-induced seropositivity (VISP) from previous HIV vaccine study product(s), a negative result from a HVTN HIV diagnostics testing laboratory within 14 days prior to enrollment. 18. Negative hepatitis B surface antigen (HBsAg). 19. Negative anti-hepatitis C virus antibodies (anti-HCV), or negative HCV nucleic acid test if the anti-HCV is positive. 20. All volunteers must use condoms for the duration of the study . ALL volunteers regardless of sex, reproductive status, or sex of partner(s) must use condoms as a barrier method to mitigate against potential VIR-1778 transmission to their partner(s) (in the event that shedding occurs).
Exclusion criteria
1. Known significant exposure to TB in the 2 years prior to enrollment, as determined by the site investigator based on potential participant report and available medical records. Note: Significant exposure is defined as close contact with a person who has active TB and has not completed TB treatment. Close contact is defined as sleeping in the same contiguous house/dwelling, and/or working or socializing in close proximity in an enclosed space frequently (eg, several times a week). 2. History of prior active TB disease, as determined by the site investigator based on participant report and available medical, laboratory, or radiographic records. 3. Current anti-TB prophylaxis or therapy. 4. Evidence of active TB disease as determined by the site investigator. 5. Blood products or immunoglobulin within 16 weeks prior to enrollment; receipt of immunoglobulin within 16 weeks prior to enrollment requires approval. 6. Pregnant or breastfeeding. 7. Receipt of investigational research agents with a half-life of 7 or fewer days within 4 weeks prior to enrollment. If a potential participant has received investigational agents with a half-life of more than 7 days (or unknown half-life) within the past year, approval is required for enrollment. 8. Use of (val)acyclovir, (val)ganciclovir, letermovir, foscarnet, or another antiviral with anti-CMV activity within 30 days prior to the first vaccination. Chronic or suppressive use of (val)acyclovir is not permitted. Short-term use (defined as less than 10 days) of (val)acyclovir is permitted at standard doses provided there have been no more than 2 courses of (val)acyclovir over the last 6 months. Topical use is not exclusionary. 9. Investigational TB vaccine(s) or CMV-based vaccine received in prior vaccine trials or BCG vaccination outside infancy. For volunteers who have received control/placebo in a TB vaccine trial, eligibility will be determined on a case-by-case basis. 10. Investigational non-TB vaccine(s) or non-CMV vaccine received within the last 1 year in a prior vaccine trial. Exceptions may be made for vaccines that have subsequently undergone licensure by the FDA or by the national regulatory authority where the volunteer is enrolling. For volunteers who have received control/placebo in an experimental vaccine trial, eligibility will be determined on a case-by-case basis. For volunteers who have received an experimental vaccine(s) greater than 1 year ago, eligibility for enrollment will be determined on a case-by-case basis. 11. Receipt of any of the following within 4 weeks prior to enrollment: * Live replicating vaccine * Any mRNA-based vaccine with FDA licensure, FDA EUA, or WHO EUL * ACAM2000 vaccine \> 28 days prior with a vaccination scab still present 12. Receipt of any vaccines that are not covered in the exclusion criterion #10 within 14 days prior to enrollment. Please note this includes replication-incompetent vaccines such as the Jynneos vaccine for the prevention of mpox (formerly known as monkeypox) disease. 13. Initiation of Ag-based immunotherapy for allergies within the previous year (stable immunotherapy is not exclusionary); inclusion of participants who initiated immunotherapy within the previous year requires PSRT approval. 14. Congenital or acquired immunodeficiency, including systemic medication use likely to impair immune response to vaccine in the opinion of the site investigator, such as glucocorticoid use, ≥ prednisone 10 mg/day within 3 months prior to enrollment. 15. Autoimmune disease, current or history of (not exclusionary: mild, well-controlled psoriasis). 16. Asthma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of solicited local reactogenicity | Through 14 days after each study vaccination | Incidence and severity of solicited local reactogenicity following receipt of study vaccine. |
| Incidence of solicited systemic reactogenicity | Through 14 days after each study vaccination | Incidence and severity of solicited systemic reactogenicity following receipt of study vaccine. |
| Incidence of adverse events (AEs) | Through 52 weeks after last receipt of study product | Incidence of adverse events following receipt of study product. |
| Incidence of serious adverse events (SAEs) | Through 52 weeks after last receipt of study product | Incidence of serious adverse events. |
| Incidence of medically attended adverse events (MAAEs) | Through 52 weeks after last receipt of study product | Incidence of medically attended adverse events. |
| Incidence of adverse events leading to early participant withdrawal or permanent discontinuation | Through 52 weeks after last receipt of study product | Incidence of adverse events resulting in early participant withdrawal or permanent discontinuation of study product |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of insert-specific CD4 T-cell responses | Up to 8 weeks after the first vaccination and up to 52 weeks after the second vaccination | Frequency (percentages of T cells responding) of CD4 T-cell responses to the VIR-1778-derived TB7Ag fusion protein above baseline, as measured by intracellular cytokine staining (ICS) and flow cytometry. |
| Functional parameters of insert-specific CD4 T-cell responses to synthetic TB peptides | Up to 8 weeks after the first vaccination and up to 52 weeks after the second vaccination | Functional profile (cell surface markers, cytokines, or functional markers) of insert-specific CD4 T-cell responses to the VIR-1778-derived TB7Ag fusion protein measured by intracellular cytokine staining (ICS) and flow cytometry. |
| Phenotypic profile (markers of memory phenotype) of insert-specific CD4 T-cell responses | Up to 8 weeks after the first vaccination and up to 52 weeks after the second vaccination | Phenotypic profile (markers of memory phenotype) of insert-specific CD4 T-cell responses to the VIR-1778-derived TB7Ag fusion protein measured by flow cytometry |
| Frequency of insert-specific CD8 T-cell responses | Up to 8 weeks after the first vaccination and up to 52 weeks after the second vaccination | Frequency (percentages of T cells responding) of insert-specific CD8 T-cell responses to the VIR-1778-derived TB7Ag fusion protein above baseline, as measured by intracellular cytokine staining (ICS) and flow cytometry. |
| Functional parameters of insert-specific CD8 T-cell responses to synthetic TB peptides | Up to 8 weeks after the first vaccination and up to 52 weeks after the second vaccination | Functional profile (cell surface markers, cytokines, or functional markers) of insert-specific CD8 T-cell responses to the VIR-1778-derived TB7Ag fusion protein measured by intracellular cytokine staining (ICS) and flow cytometry. |
| Phenotypic profile (markers of memory phenotype) of insert-specific CD8 T-cell responses | Up to 8 weeks after the first vaccination and up to 52 weeks after the second vaccination | Phenotypic profile (markers of memory phenotype) of insert-specific CD8 T-cell responses to the VIR-1778-derived TB7Ag fusion protein measured by flow cytometry. |
| Number of participants with VIR-1778 vector shedding in in plasma | Through 52 weeks after the second vaccination | Detection of VIR-1778 in plasma measured by quantitative polymerase chain reaction (qPCR). |
| Number of participants with VIR-1778 vector shedding in saliva | Through 52 weeks after the second vaccination | Detection of VIR-1778 in saliva measured by quantitative polymerase chain reaction (qPCR). |
| Number of participants with VIR-1778 vector shedding in urine | Through 52 weeks after the second vaccination | Detection of VIR-1778 in urine measured by quantitative polymerase chain reaction (qPCR). |
Countries
Peru
Outcome results
None listed