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

Virus Diseases Clinical Trial

— DNA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03110770
• Other study ID #: VRC 705
• Status: Completed
• Phase: Phase 2
• Start date: March 29, 2017
• Est. completion date: October 4, 2019

Study information

• Verified date: January 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2428
• Est. completion date: October 4, 2019
• Est. primary completion date: October 4, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 15 Years to 35 Years

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Flaviviral Diseases
• Flaviviridae Infections
• Flavivirus Infections
• Infections
• RNA Virus Infections
• Virus Diseases
• Zika Virus
• Zika Virus Infection

Intervention

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

Other:
• VRC-PBSPLA043-00-VP
A sterile phosphate-buffered saline (PBS) prepared for human administration as a placebo

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Brazil,  Colombia,  Costa Rica,  Ecuador,  Mexico,  Panama,  Peru,  Puerto Rico, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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