Safety and Immunogenicity of the Dengue Virus Vaccine TV005 (TetraVax-DV TV005) in Healthy Adults, Adolescents, and Children in Dhaka, Bangladesh

Phase II, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Immunogenicity of the Recombinant Live Attenuated Tetravalent Dengue Virus Vaccine Admixture TV005 (TetraVax-DV TV005) in Healthy Adults, Adolescents, and Children in Dhaka, Bangladesh

The purpose of this study is to evaluate the safety and immunogenicity of the recombinant live attenuated tetravalent dengue virus vaccine admixture TV005 (TetraVax-DV T005) in healthy adults, adolescents, and children in Dhaka, Bangladesh.

Dengue viruses (DENV) are the leading arboviral infection globally, with over 2 billion people at risk of infection worldwide. The first dengue fever outbreak in Bangladesh occurred in 2000, and since then, dengue fever has had a continued presence throughout Bangladesh. This study will evaluate the safety and immunogenicity of the recombinant live attenuated tetravalent dengue virus vaccine admixture TV005 (TetraVax-DV T005) in healthy adults, adolescents, and children in Dhaka, Bangladesh.

The study will enroll four cohorts of participants: adults, adolescents, children, and young children. Study researchers will evaluate study data for each cohort before enrolling the subsequent cohort.

Participants will be randomly assigned to receive either TV005 vaccine or placebo at study entry (Day 0). Additional study visits will occur on Days 7, 14, 28, 56, 180, 360, 720, and 1080. Study visits will include blood collection, physical examinations, and clinical assessments. Participants will record and monitor their temperature and symptoms until Day 14. Study staff will contact participants daily until Day 14; after Day 14, study staff will contact participants weekly (and after Day 180, monthly) throughout the study for follow-up health monitoring.

Inclusion Criteria:

• Healthy males or females (non-pregnant or lactating) between the ages of 12 months and 50 years at the time of enrollment into the study.
• Reside in Mirpur Wards 2, 3, or 5 (or other Wards within Mirpur as designated by the PI if needed to reach enrollment targets) at the time of screening.
• Study participants and/or their parents/guardians/legally acceptable or authorized representatives (LARs) who the Investigator believes can and will comply with the requirements of the protocol (e.g., return for follow-up visits).
• Good general health as determined by physical examination, laboratory screening, and review of medical history.
• If the participant is greater than or equal to 18 years of age, an informed consent form signed and dated by the study participant (and by an independent witness if required by local regulations). If the study participant is a minor, an assent form (for participants age 11-17 years) and informed consent form signed and dated by the participant's properly identified parent(s) or legally acceptable representative. If a participant is less than 11 years of age, the participant's parent(s) or legally acceptable representative will consent by signing the consent form for minor participants.
• If the participant is female, she must not be pregnant or planning to become pregnant up to 28 days post vaccination. Female participants under the age of 18 will be enrolled, if they have not yet reached menarche. Females 18 years of age or older, must be properly using a method of pregnancy prevention that is known to be highly effective per the PI. Reliable methods of contraception include: hormonal birth control, condoms with spermicide, diaphragm with spermicide, surgical sterilization, intrauterine device, and abstinence (greater than or equal to 6 months since last sexual encounter). For female study participants who are 18 years of age or older pregnancy testing will occur at screening and again before vaccination and they must have a negative pregnancy test prior to vaccination. Additionally, they will receive counselling on the importance of effective contraception during the 30 days prior to vaccination and continuing up to Day 28. Counselling will occur at their screening visit, on all clinic visit days up to Day 28. Female participants 18 years of age and older will be subject to pregnancy testing on the Study Day 28 and 56 visits. If female participants under the age of 18 that have not yet reached menarche prior to enrollment, reach menarche during the study, they will continue to be enrolled and followed-up through the entire three year follow-up period.

Exclusion Criteria:

• Pregnant or lactating female or female planning to become pregnant within 28 days of receiving an investigational product or planning to discontinue abstinence or contraceptive precautions within 28 days of receiving an investigational product. Menstruating females under the age of 18 will be excluded from being enrolled.
• Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, renal, autoimmune, hematologic, or endocrine disease or functional defect, as determined by history, physical examination, or screening tests.
• History of any neurological, psychiatric, or behavioural disorder or seizures, with the exception of a single febrile seizure in childhood.
• Self-reported or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months, or long-term systemic corticosteroid therapy (prednisone or equivalent, greater than or equal to 0.5 mg/kg/day or 20 mg/day, for more than 2 consecutive weeks within the past 3 months). Inhaled and topical steroids are allowed.
• Having a height-for-age z-score (HAZ) or weight-for-age z-score (WAZ) of less than or equal to 3 for children under the age of two. Severe malnutrition as observed by the study physician for all study participants ages 2 years old and older.
• Hepatitis C virus (HCV) infection by screening and confirmatory assays (screening in adults and adolescents only), or hepatitis B virus (HBV) infection, by hepatitis B surface antigen (HBsAg) screening (all participants) or, unwilling to allow HCV (adults and adolescents only) and HBV testing.
• Screening laboratory values of Grade 1 or above for absolute neutrophil count (ANC), alanine transaminase (ALT), or platelet count, as defined in this protocol.
• For children under 5 years of age, screening laboratory values of Grade 1 or above for Haemoglobin.
• History of allergic reaction likely to be exacerbated by any component of the vaccine; any history of a severe allergic reaction or anaphylaxis.
• Current alcohol abuse or drug addiction that might interfere with the ability to comply with trial procedures.
• Any other condition that in the opinion of the Investigator would jeopardize the safety or rights of a participant participating in the trial or would render the participant unable to comply with the protocol.
• Planned administration of any vaccine from 30 days prior to receipt of the study vaccine and ending 30 days after; with the exceptions of standard infant and child Expanded Program on Immunization (EPI) inactivated vaccines and the inactivated influenza vaccine or the inactivated rabies vaccine (without administration of immunoglobulin) administered to adults or children.
• Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding receipt of study vaccine/placebo or planned use at any time during the study period or history of having received any investigational dengue vaccine at any previous time.
• Current participation in any clinical or investigational study.
• Administration of immunoglobulins and/or blood products within 90 days preceding the dose or planned administration at any time during the study period, which might interfere with assessment of the immune response.
• A planned or anticipated move to a location that will prohibit full participation in the trial for the three year duration.
• Potential adult volunteers or parents of potential child volunteers, who do not have easy access to a fixed or mobile telephone.
• Any participant that resides in a household with an individual previously enrolled in an older age cohort in this study. Only one participant from each household will be enrolled.
• Any participant identified as a site employee of the Investigator or study clinic, with direct involvement in the proposed study or other studies under the direction of that Investigator or study clinic, as well as any immediate family member (such as husband, wife and their children, adopted or natural) of the clinic employees or the Investigator.

Elimination Criteria During the Study:

The following criteria should be checked at each visit subsequent to the first visit. If any become applicable during the study, it will not require withdrawal of the participant from the study but may determine a participant's evaluability in the per-protocol (PP) analysis. The participant will continue to be evaluated for safety purposes at the regularly scheduled visits. See the protocol for definition of study cohorts to be evaluated.

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine/placebo during the study period.
• Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs during the study period. For corticosteroids, this will mean prednisone, or equivalent, greater than or equal to 0.5 mg/kg/day. Inhaled and topical steroids are allowed.
• Administration of a licensed vaccine during the period starting from 30 days before dose of vaccine/placebo and ending 30 days after, with the exception of standard infant and childhood EPI "inactivated" vaccinations.
• Administration of immunoglobulins and/or any blood products during the study period.
• Pregnancy within the 28 days after investigational product administration.