Clinical trial NCT03110770: VRC 705: A Zika Virus DNA Vaccine in Healthy Adults and Adolescents
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Zika Virus
Zika Virus Infection
Virus Diseases
Flavivirus Infections
Flaviviral Diseases
Flaviviridae Infections
RNA Virus Infections
Keywords: Flavivirus
Zika
Vaccine
Physiological Effects of Drugs
Immunologic Factors
Virus-like Particles
Zika vaccine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2017-04-12
Enrollment: 2428
Sex: ALL
Minimum age (years): 15
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part A participants (n=90) were randomized to study groups at a 1:1:1 ratio to receive a 4 mg or 8 mg dose of vaccine split between 2 or 4 injections. In Part B, participants (n=2338) 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 number of injections in Part B was determined by preliminary data from the Phase 1 trial and from Part A.
Primary purpose: PREVENTION

Brief 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.

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.

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

Primary outcomes:
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)
timeFrame: 7 days after each product administration
measure: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms for 7 Days After Each Product Administration (Part A and Part B)
timeFrame: 7 days after each product administration
measure: Number of Participants With Abnormal Laboratory Measures of Safety (Part A)
timeFrame: Day 0 after first product administration through Day 112
measure: Number of Participants With Abnormal Laboratory Measures of Safety (Part B)
timeFrame: Day 0 after first product administration through Day 308
measure: Number of Participants With Serious Adverse Events (SAEs) Following Product Administration (Part A)
timeFrame: Day 0 through Day 224
measure: Number of Participants With Serious Adverse Events (SAEs) Following Product Administration (Part B)
timeFrame: Day 0 through Day 672
measure: Number of Participants With New Chronic Medical Conditions Following Product Administration (Part A)
timeFrame: Day 0 through Day 224
measure: Number of Participants With New Chronic Medical Conditions Following Product Administration (Part B)
timeFrame: Day 0 through Day 672
measure: Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Product Administration (Part A and Part B)
timeFrame: Day 0 through the one month visit that follows the last product administration (Visit 05), 84 days for both Parts A and B
measure: Number of Participants With Virologically Confirmed Cases of ZIKV (Part B Only)
timeFrame: Day 0 through Day 672
Secondary outcomes:
measure: Zika Antigen-specific Neutralizing Antibody Geometric Mean Titer (GMT) - (Part A)
timeFrame: Day 0 to 28 days after the third product administration
measure: Number of Participants With Positive Response to Zika Antigen-specific Neutralizing Antibody (Part A)
timeFrame: Day 0 to 28 days after the third product administration
measure: Number of Participants With Subclinical Cases of ZIKV (Part B Only)
timeFrame: Day 0 through Day 672
measure: Zika Antigen-specific Neutralizing Antibody Geometric Mean Titer (GMT) - (Part B)
timeFrame: Day 0 to 28 days after the third product administration
measure: Number of Participants With Positive Response to Zika Antigen-specific Neutralizing Antibody (Part B)
timeFrame: Day 0 to 28 days after the third product administration
Other outcomes:
Locations:
city: Miami
country: United States
facility: QPS-Miami Research Associates
state: Florida
city: Edinburg
country: United States
facility: Doctors Hospital at Renaissance
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Belo Horizonte
country: Brazil
facility: Hospital Das Clinicas Da Universidade Federal de Minas Gerais
state: MG
city: São Paulo
country: Brazil
facility: Centro de Pesquisas Clínicas Do Instituto Central Do Hospital Das Clínicas Da FMUSP
state: SP
city: Barranquilla
country: Colombia
facility: Clinica de la Costa Ltda
state: Atlantico
city: Bucaramanga
country: Colombia
facility: Centro de Atencion y Diagnostico de Enfermedades Infecciosas
state: Santander
city: San José
country: Costa Rica
facility: CCIM Costa Rican Center Center of Medical Research, Sociedad Anonima
state: Los Yoses
city: Guayaquil
country: Ecuador
facility: AGA Clinical Centro de Investigaciones
state: Guayas
city: Guadalajara
country: Mexico
facility: Hospital Civil Fray Antonio Alcalde
state: Jalisco
city: Panamá
country: Panama
facility: Instituto Conmemorativo Gorgas
state: San Miguelito Province
city: Iquitos
country: Peru
facility: Asociacion Civil Selva Amazonica
state: Maynas/Loreto
city: Lima
country: Peru
facility: Unidad de Ensayos (UNIDEC) del Policlinico Universidad Nacional Mayor de San Marcos
city: Ponce
country: Puerto Rico
facility: Ponce Medical School Foundation Inc./CAIMED Center
city: San Juan
country: Puerto Rico
facility: Fundación de Investigación de Diego
city: San Juan
country: Puerto Rico
facility: San Juan Hospital Research Unit
city: San Juan
country: Puerto Rico
facility: Puerto Rico Clinical and Translational Research Consortium
Study officials:
affiliation: VRC, NIAID, NIH
name: Julie Ledgerwood, DO
role: STUDY_CHAIR
References:
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.
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.
citation: 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.
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.