VRC 705: A Phase 2/2B, Randomized Trial to Evaluate the Safety, Immunogenicity and Efficacy of a Zika Virus DNA Vaccine in Healthy Adults and Adolescents
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 2,428
- 试验地点
- 32
- 主要终点
- Number of Participants Reporting Local Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Part A was open-label. For Part A, the participant, investigator and outcome assessor knew what the participant received.
Part B injections were prepared by an unblinded site pharmacist or designee who was not involved in any participant assessments and did not discuss randomizations with study clinicians. Participants, study personnel, site data entry personnel, and laboratory personnel performing immunologic assays were blinded to the treatment assignment of all product administrations. The investigational new drug (IND) Sponsor unblinded treatment assignments for Part B at the end of the study.
入排标准
- 年龄范围
- 15 Years 至 35 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •A participant must meet all of the following criteria:
- •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
- •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
排除标准
- •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
结局指标
主要结局
Number of Participants Reporting Local Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)
时间窗: 7 days after each product administration
Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)
时间窗: 7 days after each product administration
Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after each study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than once at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA Guidance - September 2007).
Number of Participants With Abnormal Laboratory Measures of Safety (Part B)
时间窗: Day 0 after first product administration through Day 308
Any abnormal laboratory results recorded as unsolicited AEs are summarized. Safety laboratory parameters included: alanine aminotransferase (ALT), white blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Laboratory safety evaluations were scheduled at baseline and weeks 4, 8, 16, and 44. Institutional laboratory normals as well as the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007 were used.
Number of Participants With Serious Adverse Events (SAEs) Following Product Administration (Part B)
时间窗: Day 0 through Day 672
Any SAEs recorded from receipt of first study product administration through the last expected study visit at Day 672 are summarized. The relationship between a SAE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol.
Number of Participants With Virologically Confirmed Cases of ZIKV (Part B Only)
时间窗: Day 0 through Day 672
Virologically confirmed Zika infection, irrespective of symptoms, by polymerase chain reaction (PCR) in blood or in urine were recorded from receipt of first study product administration through the last expected study visit.
Number of Participants With Abnormal Laboratory Measures of Safety (Part A)
时间窗: Day 0 after first product administration through Day 112
Any abnormal laboratory results recorded as unsolicited AEs are summarized. Safety laboratory parameters included: alanine aminotransferase (ALT), white blood cells (WBC), red blood cells (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Laboratory safety evaluations were scheduled at baseline and weeks 4, 6, 8, 10, 12, and 16. Institutional laboratory normals as well as the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007 were used.
Number of Participants With Serious Adverse Events (SAEs) Following Product Administration (Part A)
时间窗: Day 0 through Day 224
Any SAEs recorded from receipt of first study product administration through the last expected study visit at Day 224 are summarized. The relationship between a SAE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol.
Number of Participants With New Chronic Medical Conditions Following Product Administration (Part B)
时间窗: Day 0 through Day 672
New onset chronic medical conditions were reported from receipt of first study product administration through the last expected study visit at Day 672.The relationship between a chronic medical condition and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol.
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Product Administration (Part A and Part B)
时间窗: Day 0 through the one month visit that follows the last product administration (Visit 05), 84 days for both Parts A and B
Unsolicited AEs and attribution assessments were recorded in the study database from receipt of the first study product administration through the one month visit that followed the last study product administration (Visit 05), 84 days for both Parts A and B for participants who received all three study product administrations. If a participant received the first and second product administrations but not the third, then the time frame was through 56 days (Visit 04). If a participant only received the first product administration but not the second or third, then the time frame was through 28 days (Visit 03). The relationship between an AE and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.
Number of Participants With New Chronic Medical Conditions Following Product Administration (Part A)
时间窗: Day 0 through Day 224
New onset chronic medical conditions were reported from receipt of first study product administration through the last expected study visit at Day 224.The relationship between a chronic medical condition and the study product was assessed by the investigator on the basis of his or her clinical judgment and the definitions outlined in the protocol.
次要结局
- Number of Participants With Positive Response to Zika Antigen-specific Neutralizing Antibody (Part A)(Day 0 to 28 days after the third product administration)
- Number of Participants With Subclinical Cases of ZIKV (Part B Only)(Day 0 through Day 672)
- Zika Antigen-specific Neutralizing Antibody Geometric Mean Titer (GMT) - (Part A)(Day 0 to 28 days after the third product administration)
- Number of Participants With Positive Response to Zika Antigen-specific Neutralizing Antibody (Part B)(Day 0 to 28 days after the third product administration)
- Zika Antigen-specific Neutralizing Antibody Geometric Mean Titer (GMT) - (Part B)(Day 0 to 28 days after the third product administration)