Evaluation of the Protective Efficacy of TV003 or Previous Zika Infection Against Infection With ZIKV-SJRP Challenge Compared to DENV and ZIKV-naïve Controls Against Infection With ZIKV-SJRP Challenge

This study is an open label with 2 study arms. Arm 1 will evaluate the protective efficacy of TV003 against ZIKV challenge. Arm 1 will include infectivity controls who will receive PlasmaLyte (the TV003 diluent) and the treatment assignment will be blinded to reduce bias in the assessment of adverse events. The PlasmaLyte recipients will serve as infectivity controls to ensure the potency of the ZIKV challenge. The treatment assignment of the infectivity controls may be unblinded as early as 28 days after receipt of TV003/PlasmaLyte if they are needed for ZIKV-challenge of volunteers in Arm 2 and may be challenged earlier than the TV003 cohort. Arm 2 will evaluate the protective efficacy of previous ZIKV infection against subsequent ZIKV challenge. Both arms will be compared to historical controls who previously received ZIKV infection. Infectivity controls will not be included in the efficacy analysis.

This study will include 16 flavivirus-naïve subjects for Arm 1. Twelve subjects will receive the live attenuated dengue vaccine candidate TV003 at Study Day 0 and 4 subjects will receive PlasmaLyte at Study Day 0. These subjects will be randomized in blocks of 4 (3 TV003:1 PlasmaLyte). At Study Day 180, Arm 1 subjects will receive the controlled human infection strain of ZIKV SJRP/2016-184 as a challenge virus. These subjects will include those volunteers who received TV003 and at least 1 of the infectivity controls who received PlasmaLyte. Subjects in Arm 1 will be followed for approximately 52 weeks (approximately 360 days) from the time of vaccination.

Ten subjects who had a ZIKV infection, either from a previous ZIKV controlled human infection study where they had received either ZIKV SJRP/2016-184 or ZIKV Nicaragua/2016 or were excluded during screening for previous studies as having ZIKV infection, will be enrolled as a group in Arm 2. Subjects enrolled in Arm 2 will be challenged with the ZIKV SJRP/2016-184 challenge virus separately from TV003 recipients. At least 1 of the PlasmaLyte recipients enrolled in Arm 1 on Day 0 will be included in this group to receive ZIKV SJRP/2016-184 as an infectivity control. Arm 2 subjects will be followed after ZIKV challenge for approximately 26 weeks (approximately 180 days). Subjects will be screened for eligibility up to 60 days prior to vaccination on Study Day 0.

Inclusion criteria

• Adults between 18 and 40 years of age, inclusive.
• Good general health as determined by physical examination, laboratory screening, and review of medical history.
• Available for the duration of the study, approximately 52 weeks.
• Willingness to participate in the study as evidenced by signing the informed consent document.
• Must be able to complete the informed consent process and comprehension assessment independently and without assistance.
• Subjects assigned male at birth: Willingness to use barrier contraception during cervico-vaginal, anal, and oral intercourse from Study Day 0 through 90 days post ZIKV challenge (in accordance with CDC guidance).
• Subjects assigned female at birth: Willingness to use barrier contraception during cervico-vaginal, anal, and oral intercourse from Study Day 0 through 56 days post ZIKV challenge (in accordance with CDC guidance).
• Subjects of childbearing potential must be willing to use effective contraception through 56 days post-ZIKV challenge, in accordance with CDC guidance. Reliable methods of contraception include hormonal birth control* (implantable, hormonal patch, hormonal vaginal ring, oral contraception, Depo-Provera injection, etc.), surgical sterilization (hysterectomy, tubal ligation, or tubal coil at least 3 months prior to inoculation with TV003/PlasmaLyte and/or ZIKV challenge), and intrauterine device. All subjects assigned female at birth will be considered having child-bearing potential except for those with post-menopausal status documented as at least 1 year since last menstrual period, those assigned female at birth who have sex with partners assigned female at birth (exclusively) and have no intention of conceiving a child during the study, and for the vaccination phase of the study only, participants who practice abstinence (≥ 6 months with no sexual contact). Subjects who are not considered to be of childbearing potential will not be required to use contraception other than barrier contraception for the purpose of reducing potential transmission.

• Volunteers on hormonal birth control must not be on medications or other agents that decrease the effectiveness of hormonal birth control.

Inclusion criteria

for Challenge with ZIKV SJRP/2016-184:

• Currently enrolled in the study.
• Good general health as determined by physical examination and review of medical history.
• Available for the duration of the study, which is approximately 26 weeks after challenge.
• If the challenge portion of the study is expected to begin from March 16-October 30, subject is willing to reside in the inpatient unit for 6 days (or longer for safety if necessary) following receipt of ZIKV.
• Willingness to participate in the study as evidenced by signing the informed consent document.
• Female assigned at birth only: Female assigned at birth subjects of childbearing potential should be willing to use highly effective contraception for the duration of the trial. Reliable methods of contraception include hormonal birth control, surgical sterilization, and intrauterine device. All female assigned at birth subjects will be considered as having childbearing potential in this phase of the study, except for those who have had a hysterectomy, tubal ligation, or tubal coil (at least 3 months prior to vaccination), or who are considered to be post-menopausal, as documented by at least 1 year since last menstrual period.

Additional Inclusion Criteria for Arm 2 Subjects with a Previous History of ZIKV Infection Only:

-History or serologic evidence of previous ZIKV or identified as an infectivity control.

Exclusion criteria

• Currently pregnant, as determined by positive beta-human choriogonadotropin (b-hCG) test, breast-feeding, planning to become pregnant during the 12-month duration of the study or planning to donate eggs through 56 days post ZIKV challenge. A careful detailed reproductive and contraception use history will be obtained and the subject will be excluded if the history or clinical record raises concerns related to pregnancy prevention.
• Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease by history, physical examination, and/or laboratory studies.
• Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and cooperate with the requirements of the study protocol.
• Evidence of recent opiate use based on urine toxicology screen.
• Screening laboratory values of Grade 1 or above for absolute neutrophil count (ANC), ALT, and serum creatinine, as defined in this protocol.
• Any other condition that in the opinion of the investigator would jeopardize the safety or rights of a subject participating in the trial or would render the subject unable to comply with the protocol.
• Any significant alcohol or drug abuse in the past 12 months which has caused medical, occupational, or family problems, as indicated by subject history.
• History of a severe allergic reaction or anaphylaxis.
• Severe asthma (emergency room visit or hospitalization within the last 6 months).
• HIV infection, by screening and confirmatory assays.
• Hepatitis C virus (HCV) infection, by screening and confirmatory assays.
• Hepatitis B virus (HBV) infection, by Hepatitis B surface antigen (HBsAg) screening.
• History of Guillain-Barré syndrome (GBS).
• History of seizure disease or peripheral neuropathy.
• History of any neuroinflammatory disorder, i.e., Bell's Palsy, transverse myelitis.
• Any known immunodeficiency syndrome, including that caused by malignancy.
• Use of anticoagulant medications, (use of antiplatelet medication such as aspirin or non-steroidal anti-inflammatory medication is permitted and will not exclude a subject from enrollment).
• Use of corticosteroids (excluding topical, inhaled, or nasal) or immunosuppressive drugs within 28 days prior to or following vaccination. Immunosuppressive dose of corticosteroids is defined as ≥10 mg prednisone equivalent per day for ≥14 days.
• Receipt of a live vaccine within 28 days or an inactivated or subprotein vaccine within the 14 days prior to vaccination or anticipated receipt of any vaccine during the 28 days following vaccination with the exception of the inactivated influenza vaccine and COVID 19 vaccines either licensed or under EUA which can be given at any time, however all effort will be made to avoid giving influenza and COVID-19 vaccines within the above windows.
• Asplenia.
• Receipt of blood products within the past 6 months, including transfusions or immunoglobulin or anticipated receipt of any blood products or immunoglobulin during the 28 days following vaccination.
• Anticipated receipt of any investigational agent in the 28 days before or after vaccination.
• Subject has definite plans to travel to a ZIKV endemic or dengue endemic area during the study.
• Previous hypersensitivity to any study product component.
• Refusal to allow storage of specimens for future research.
• Subject is a JHU student currently enrolled in a coursework, an internship, or clinical hours where the supervisor or instructor of record is employed by the Center.
• Subject is faculty or staff currently employed by the Center.

Additional Exclusion Criteria for TV003/PlasmaLyte Group Only:

• History or serologic evidence of previous ZIKV, dengue virus infection, yellow fever virus, St. Louis encephalitis virus, or West Nile virus.
• Previous receipt of a flavivirus vaccine (licensed or experimental).

Exclusion criteria

for ZIKV SJRP/2016-184:

• Female assigned at birth only: Currently pregnant, as determined by positive B- HCG test, or breast-feeding.
• Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, or renal disease based on history, physical examination, and/or laboratory studies.
• Any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of a subject participating in the trial, or would render the subject unable to comply with the protocol.
• History of a severe allergic reaction or anaphylaxis.
• Any known immunodeficiency syndrome.
• HIV infection, by screening and confirmatory assays (performed within 14 days of ZIKV challenge).
• Hepatitis C virus (HCV) infection, by screening and confirmatory assays.
• Hepatitis B virus (HBV) infection, by Hepatitis B surface antigen (HBsAg) screening.
• Current use of anticoagulant medications (this does not include anti-platelet medication such as aspirin or non-steroidal anti-inflammatory medications).
• Use of corticosteroids (excluding topical, inhaled, or nasal) or immunosuppressive drugs within 28 days prior to or following challenge. An immunosuppressive dose of corticosteroids is defined as ≥ 10 mg of a prednisone equivalent per day for ≥14 days.
• Receipt of a live vaccine within 28 days or an inactivated or subprotein vaccine within the 14 days prior to inoculation or anticipated receipt of any vaccine during the 28 days following inoculation with the exception of the inactivated influenza vaccine and COVID-19 vaccines either licensed or under EUA which can be given at any time, however all effort will be made to avoid giving influenza and COVID-19 vaccines within the above windows.
• Asplenia.
• Receipt of blood products within the past 6 months, including transfusions or immunoglobulin, or anticipated receipt of any blood products or immunoglobulin during the 28 days following challenge.
• Anticipated receipt of any other investigational agent in the 28 days before or after challenge.
• Definite plans to travel to a dengue-endemic area during the remainder of the study.