VRC 705: A Zika Virus DNA Vaccine in Healthy Adults and Adolescents

This was a multicenter, randomized study to evaluate the safety, immunogenicity, and efficacy of VRC-ZKADNA090-00-VP (Zika virus wildtype DNA vaccine) or placebo. In Part A, the primary objective was to evaluate the safety and tolerability of the vaccine in different vaccination regimens. In Part B, the primary objectives were to evaluate the safety and efficacy of the vaccine compared to placebo.

This was a multicenter, randomized study to evaluate safety, immunogenicity, and efficacy of a 3-dose vaccination regimen with the Zika virus wildtype (ZIKVwt) DNA vaccine (VRC-ZKADNA090-00-VP) or placebo (VRC-PBSPLA043-00-VP). The placebo was a sterile phosphate-buffered saline (PBS). The hypotheses were that the ZIKVwt DNA vaccine would be safe and would elicit a ZIKV-specific immune response.

Participants received study product intramuscularly (IM) in the limbs as specified by the group assignment by PharmaJet needle-free device. In Part A, 90 participants were randomized to vaccine at a 1:1:1 ratio to receive a 4 mg dose split between 2 injections, 4 mg dose split between 4 injections or 8 mg dose split between 4 injections. In Part B, 2338 participants were randomized to vaccine or placebo in a 1:1 ratio to receive a 4 mg (1 mL) dose of vaccine or 1 mL of placebo split between 2 injections. The vaccine dose and administration plan for Part B was selected based on Part A and Phase 1 data.

Vaccine safety and tolerability were assessed by monitoring of clinical and laboratory parameters throughout the study. Solicited reactogenicity symptoms were collected for 7 days after each product administration. The study schedule included clinic visits with safety and immunogenicity blood samples collected at particular time points.

Vaccine efficacy was evaluated in Part B by comparing incidence of virologic ZIKV cases between vaccine and placebo groups. During the study, when participants exhibited any possible symptom of ZIKV infection, they were evaluated by blood and urine ZIKV polymerase chain reaction (PCR). Stored blood samples were also assessed retrospectively by ZIKV PCR to identify possible asymptomatic cases. A Data and Safety Monitoring Board (DSMB) oversaw the study.

Eligibility Criteria:
Inclusion Criteria:

A participant must meet all of the following criteria:

Part A:

* 18 to 35 years of age
* Available for clinical follow-up through Study Week 32
* Accessible injection sites on each limb as follows: 1 injection site in the deltoid muscle of each arm and 1 injection site in the vastus lateralis muscle of each anterolateral thigh

Part B:

* 15 to 35 years of age
* Available for clinical follow-up through Study Week 96
* Accessible injection sites on the deltoid muscle of each arm. Injection in the vastus lateralis muscle of the anterolateral thighs may have been allowed with IND Sponsor approval if an injection site on each deltoid muscle was not available.

Part A and B:

* Able to provide proof of identity to the satisfaction of the clinician completing the enrollment process
* Able and willing to complete the informed consent/assent process
* Able and willing to complete the Assessment of Understanding and to verbalize understanding of all questions answered incorrectly prior to signing consent/assent
* Willing to donate blood and urine to be stored and used for future research
* In good general health without clinically significant medical history
* Physical examination and laboratory results without clinically significant findings within the 56 days prior to randomization
* Weight \>30 kilograms (kg)
* Agree not to receive any licensed or investigational flavivirus vaccines through 4 weeks after last product administration

Laboratory Criteria within 56 days prior to randomization:

* Hemoglobin within site institutional normal limits
* Absolute neutrophil count (ANC) within site institutional normal limits
* Total lymphocyte count ≥800 cells/mm\^3
* Platelets = 125,000-510,000 cells/mm\^3
* Alanine aminotransferase (ALT) ≤1.5 x upper limit of normal (ULN) based on site institutional normal range for respective age group
* Serum creatinine ≤1.2 x ULN based on site institutional normal range for respective age group
* Negative result on a human immunodeficiency virus (HIV) test that meets local standards for identification of HIV infection

Criteria applicable to women and adolescents of childbearing potential:

* Negative result on a human chorionic gonadotropin pregnancy test (urine or serum) on day of randomization before receiving study product
* Agree to use effective means of birth control from at least 21 days before randomization through 12 weeks after the last product administration

Criteria applicable to adolescents:

* Capability of the parent/guardian of the minor to understand and comply with planned study procedures
* Capability of the minor and their parent/guardian to provide informed consent/assent

Exclusion Criteria:

Criteria applicable to women and adolescents of childbearing potential:

• Breast-feeding or planning to become pregnant while participating through 12 weeks after the last product administration

Participant has received any of the following:

* More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to randomization
* Any systemic immunosuppressive medications or cytotoxic medications within the 14 days prior to randomization
* Blood products within 16 weeks prior to randomization
* Immunoglobulin within 8 weeks prior to randomization
* Investigational research agents within 4 weeks prior to randomization or planning to receive investigational products while on the study
* Any vaccination within 2 weeks prior to randomization
* Any live attenuated vaccination within 4 weeks prior to randomization
* Current anti-tuberculosis (TB) prophylaxis or therapy

Participant has any of the following:

* Confirmed history of ZIKV infection (as reported by participant)
* Serious reactions to vaccines
* Chronic angioedema or chronic urticaria
* Asthma that is not well-controlled
* Diabetes mellitus (type I or II)
* Clinically significant autoimmune disease or immunodeficiency
* Hypertension that is not well-controlled
* Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions)
* Significant bruising or bleeding difficulties with IM injections or blood draws
* Malignancy that is active or history of a malignancy that is likely to recur during the period of the study
* Seizure or treatment for a seizure disorder within the last 3 years
* Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen
* History of Guillain-Barré Syndrome
* Psychiatric condition that may preclude compliance with the protocol; past or present psychoses; or a history of suicide plan or attempt within 5 years prior to randomization
* Any medical psychiatric, or social condition that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a participant's ability to give informed consent