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

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

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.

Study Overview

• Status: Completed
• Conditions: RNA Virus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; Zika Virus Infection; Zika Virus; Flaviviral Diseases
• Intervention / Treatment: Biological: VRC-ZKADNA090-00-VP; Other: VRC-PBSPLA043-00-VP

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 2428
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • MG
    • Belo Horizonte, MG, Brazil, 30130-100
      • Hospital das Clinicas da Universidade Federal de Minas Gerais
  • SP
    • São Paulo, SP, Brazil, 05403-010
      • Centro de Pesquisas Clínicas Do Instituto Central Do Hospital Das Clínicas Da FMUSP
• Colombia
  • Atlantico
    • Barranquilla, Atlantico, Colombia, 080020
      • Clinica de la Costa Ltda
  • Santander
    • Bucaramanga, Santander, Colombia, 680003
      • Centro de Atencion y Diagnostico de Enfermedades Infecciosas
• Costa Rica
  • Los Yoses
    • San José, Los Yoses, Costa Rica
      • CCIM Costa Rican Center Center of Medical Research, Sociedad Anonima
• Ecuador
  • Guayas
    • Guayaquil, Guayas, Ecuador, 090506
      • AGA Clinical Centro de Investigaciones
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Hospital Civil Fray Antonio Alcalde
• Panama
  • San Miguelito Province
    • Panamá, San Miguelito Province, Panama
      • Instituto Conmemorativo Gorgas
• Peru
  • Lima, Peru, 15081
    • Unidad de Ensayos (UNIDEC) del Policlinico Universidad Nacional Mayor de San Marcos
  • Maynas/Loreto
    • Iquitos, Maynas/Loreto, Peru, 16001
      • Asociacion Civil Selva Amazonica
• Puerto Rico
  • Ponce, Puerto Rico, 00716
    • Ponce Medical School Foundation Inc./CAIMED Center
  • San Juan, Puerto Rico, 00927
    • Fundacion de Investigacion de Diego
  • San Juan, Puerto Rico, 00935
    • San Juan Hospital Research Unit
  • San Juan, Puerto Rico, 00936-5067
    • Puerto Rico Clinical and Translational Research Consortium
• United States
  • Florida
    • Miami, Florida, United States, 33143
      • QPS-Miami Research Associates
  • Texas
    • Edinburg, Texas, United States, 78539
      • Doctors Hospital at Renaissance
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A, Group 1: VRC-ZKADNA090-00-VP (4 mg), 2 injections; Zika virus wildtype (ZIKVwt) DNA vaccine (VRC-ZKADNA090-00-VP), in 2 limbs (both arms) on Day 0, Day 28 (+/-7 days), and Day 56 (-7/+14 days); 4 mg of vaccine administered intramuscularly (IM) by a needle-free injection device	Biological: VRC-ZKADNA090-00-VP; VRC-ZKADNA090-00-VP is composed of a single closed-circular DNA plasmid (VRC 5283) that encodes with wild type (wt) precursor transmembrane M (prM) and envelope (E) proteins from the H/PF/2013 strain of ZIKV
Experimental: Part A, Group 2: VRC-ZKADNA090-00-VP (4 mg), 4 injections; ZIKVwt DNA vaccine (VRC-ZKADNA090-00-VP), in 4 limbs (both arms and legs) on Day 0, Day 28 (+/-7 days), and Day 56 (-7/+14 days); 4 mg of vaccine administered IM by a needle-free injection device	Biological: VRC-ZKADNA090-00-VP; VRC-ZKADNA090-00-VP is composed of a single closed-circular DNA plasmid (VRC 5283) that encodes with wild type (wt) precursor transmembrane M (prM) and envelope (E) proteins from the H/PF/2013 strain of ZIKV
Experimental: Part A, Group 3: VRC-ZKADNA090-00-VP (8 mg), 4 injections; ZIKVwt DNA vaccine (VRC-ZKADNA090-00-VP), in 4 limbs (both arms and legs) on Day 0, Day 28 (+/-7 days), and Day 56 (-7/+14 days); 8 mg of vaccine administered IM by a needle-free injection device	Biological: VRC-ZKADNA090-00-VP; VRC-ZKADNA090-00-VP is composed of a single closed-circular DNA plasmid (VRC 5283) that encodes with wild type (wt) precursor transmembrane M (prM) and envelope (E) proteins from the H/PF/2013 strain of ZIKV
Experimental: Part B, Group 4: VRC-ZKADNA090-00-VP (4 mg), 2 injections; ZIKVwt DNA vaccine (VRC-ZKADNA090-00-VP), in 2 limbs (both arms) on Day 0, Day 28 (+/-7 days), and Day 56 (-7/+14 days); 4 mg of vaccine administered IM by a needle-free injection device	Biological: VRC-ZKADNA090-00-VP; VRC-ZKADNA090-00-VP is composed of a single closed-circular DNA plasmid (VRC 5283) that encodes with wild type (wt) precursor transmembrane M (prM) and envelope (E) proteins from the H/PF/2013 strain of ZIKV
Placebo Comparator: Part B, Group 5: Placebo (VRC-PBSPLA043-00-VP), 2 injections; Sterile phosphate-buffered saline (PBS) (VRC-PBSPLA043-00-VP), the placebo, in 2 limbs (both arms) on Day 0, Day 28 (+/-7 days), and Day 56 (-7/+14 days); 1 mL of placebo administered IM by a needle-free injection device	Other: VRC-PBSPLA043-00-VP; A sterile phosphate-buffered saline (PBS) prepared for human administration as a placebo; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting Local Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)	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).	7 days after each product administration
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)	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).	7 days after each product administration
Number of Participants With Abnormal Laboratory Measures of Safety (Part A)	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.	Day 0 after first product administration through Day 112
Number of Participants With Abnormal Laboratory Measures of Safety (Part B)	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.	Day 0 after first product administration through Day 308
Number of Participants With Serious Adverse Events (SAEs) Following Product Administration (Part A)	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.	Day 0 through Day 224
Number of Participants With Serious Adverse Events (SAEs) Following Product Administration (Part B)	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.	Day 0 through Day 672
Number of Participants With New Chronic Medical Conditions Following Product Administration (Part A)	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.	Day 0 through Day 224
Number of Participants With New Chronic Medical Conditions Following Product Administration (Part B)	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.	Day 0 through Day 672
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Product Administration (Part A and Part 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.	Day 0 through the one month visit that follows the last product administration (Visit 05), 84 days for both Parts A and B
Number of Participants With Virologically Confirmed Cases of ZIKV (Part B Only)	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.	Day 0 through Day 672

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Subclinical Cases of ZIKV (Part B Only)	Virologically confirmed cases of Zika infection without clinical signs or symptoms were recorded from receipt of first study product administration through the last expected study visit by PCR virus detection in blood of participants at regularly defined intervals. Subclinical cases of ZIKV infection were identified by retrospective PCR.	Day 0 through Day 672
Zika Antigen-specific Neutralizing Antibody Geometric Mean Titer (GMT) - (Part A)	Antibody response as measured by ZIKV neutralization antibody (NAb) assay. Neutralizing activity is reported as the dilution of sera required to neutralize eighty percent of infection events (EC80).	Day 0 to 28 days after the third product administration
Number of Participants With Positive Response to Zika Antigen-specific Neutralizing Antibody (Part A)	A participant was a responder or met the threshold of a positive response if the post vaccination anti-ZIKV antibody titer was 30 or greater.	Day 0 to 28 days after the third product administration
Zika Antigen-specific Neutralizing Antibody Geometric Mean Titer (GMT) - (Part B)	Antibody response as measured by ZIKV neutralization antibody (NAb) assay. Neutralizing activity is reported as the dilution of sera required to neutralize fifty percent of infection events (EC50).	Day 0 to 28 days after the third product administration
Number of Participants With Positive Response to Zika Antigen-specific Neutralizing Antibody (Part B)	A participant is a responder or met the threshold of a positive response if the post vaccination anti-ZIKV antibody titer was 30 or greater.	Day 0 to 28 days after the third product administration

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Julie Ledgerwood, DO, VRC, NIAID, NIH

Publications and helpful links

General Publications

• Ledgerwood JE, Pierson TC, Hubka SA, Desai N, Rucker S, Gordon IJ, Enama ME, Nelson S, Nason M, Gu W, Bundrant N, Koup RA, Bailer RT, Mascola JR, Nabel GJ, Graham BS; VRC 303 Study Team. A West Nile virus DNA vaccine utilizing a modified promoter induces neutralizing antibody in younger and older healthy adults in a phase I clinical trial. J Infect Dis. 2011 May 15;203(10):1396-404. doi: 10.1093/infdis/jir054. Epub 2011 Mar 11.
• Martin JE, Pierson TC, Hubka S, Rucker S, Gordon IJ, Enama ME, Andrews CA, Xu Q, Davis BS, Nason M, Fay M, Koup RA, Roederer M, Bailer RT, Gomez PL, Mascola JR, Chang GJ, Nabel GJ, Graham BS. A West Nile virus DNA vaccine induces neutralizing antibody in healthy adults during a phase 1 clinical trial. J Infect Dis. 2007 Dec 15;196(12):1732-40. doi: 10.1086/523650.
• Dowd KA, Ko SY, Morabito KM, Yang ES, Pelc RS, DeMaso CR, Castilho LR, Abbink P, Boyd M, Nityanandam R, Gordon DN, Gallagher JR, Chen X, Todd JP, Tsybovsky Y, Harris A, Huang YS, Higgs S, Vanlandingham DL, Andersen H, Lewis MG, De La Barrera R, Eckels KH, Jarman RG, Nason MC, Barouch DH, Roederer M, Kong WP, Mascola JR, Pierson TC, Graham BS. Rapid development of a DNA vaccine for Zika virus. Science. 2016 Oct 14;354(6309):237-240. doi: 10.1126/science.aai9137. Epub 2016 Sep 22.
• Gaudinski MR, Houser KV, Morabito KM, Hu Z, Yamshchikov G, Rothwell RS, Berkowitz N, Mendoza F, Saunders JG, Novik L, Hendel CS, Holman LA, Gordon IJ, Cox JH, Edupuganti S, McArthur MA, Rouphael NG, Lyke KE, Cummings GE, Sitar S, Bailer RT, Foreman BM, Burgomaster K, Pelc RS, Gordon DN, DeMaso CR, Dowd KA, Laurencot C, Schwartz RM, Mascola JR, Graham BS, Pierson TC, Ledgerwood JE, Chen GL; VRC 319; VRC 320 study teams. Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials. Lancet. 2018 Feb 10;391(10120):552-562. doi: 10.1016/S0140-6736(17)33105-7. Epub 2017 Dec 5.

Helpful Links

• Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2017
• Primary Completion (Actual): October 4, 2019
• Study Completion (Actual): October 4, 2019

Study Registration Dates

• First Submitted: March 28, 2017
• First Submitted That Met QC Criteria: April 6, 2017
• First Posted (Actual): April 12, 2017

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Vaccine; Physiological Effects of Drugs; Immunologic Factors; Zika; Flavivirus; Virus-like Particles; Zika vaccine
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Arbovirus Infections; Vector Borne Diseases; Infections; Communicable Diseases; Virus Diseases; Zika Virus Infection; RNA Virus Infections; Flavivirus Infections; Flaviviridae Infections
• Other Study ID Numbers: VRC 705

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No