Clinical trial NCT03879603: VRC 313: A Trivalent Virus-like Particle (VLP) Encephalitis Vaccine (WEVEE) in Healthy Adults
Official title: A Phase 1 Open Label, Dose-Escalation Clinical Trial to Evaluate the Safety and Immunogenicity of a Trivalent Virus-Like Particle (VLP) Encephalitis Vaccine, VRC-WEVVLP073-00-VP, in Healthy Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Venezuelan Equine Encephalitis
Western Equine Encephalitis
Eastern Equine Encephalitis
Alphavirus Infections
Keywords: Alphavirus
VEE
WEE
EEE
Vaccine
Virus-like particles
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2019-03-19
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Subjects were randomized into:

WEVEE vaccine alone (Group 1, Group 3, and Group 5) or, WEVEE vaccine mixed with alum (Group 2, Group 4, and Group 6, respectively).

The study started by randomizing subjects to get a dose of 6 mcg in Group 1 or Group 2. Safety data were reviewed after 2 weeks to make sure this vaccine dose had no safety concerns before subjects were randomized to get the next dose of 30 mcg in Group 3 or Group 4. Safety data were reviewed again to make sure the 30 mcg vaccine dose had no safety concerns before subjects were randomized to the 60 mcg dose in Group 5 or Group 6.

A total of 30 subjects were randomized among the 6 groups.
Primary purpose: PREVENTION

Brief summary: Western Equine Encephalitis Virus (WEEV), Eastern Equine Encephalitis Virus (EEEV), and Venezuelan Equine Encephalitis Virus (VEEV) are transmitted to humans by infected mosquitoes and can cause encephalitis (swelling of the brain) and other neurological manifestations, including fever, chills, discomfort, feeling sick, muscle pain and then headache, vomiting, restlessness, irritability, seizures, coma, and death.

Vaccines teach the body to prevent or fight an infection. When the body learns to fight an infection, this is called an immune response. Researchers developed a vaccine against Western, Eastern and Venezuelan equine encephalitis viruses to help the body make an immune response. There are no live or killed viruses in the vaccine, so you cannot get infected with any of these 3 viruses from getting the vaccine.

The experimental trivalent encephalitis vaccine, VRC-WEVVLP073-00-VP, is composed of Western equine encephalitis (WEE), Eastern equine encephalitis (EEE), and Venezuelan equine encephalitis (VEE) virus-like particles (VLP).

The purpose of this study is to test three doses (6 mcg, 30 mcg, and 60 mcg) of this experimental vaccine against Western, Eastern and Venezuelan equine encephalitis viruses.

Detailed description: This is a Phase 1, randomized, open-label, dose-escalation study to examine the safety, tolerability, and immune response of three doses (6 mcg, 30 mcg, and 60 mcg) of the WEVEE vaccine (VRC-WEVVLP073-00-VP) alone or with alum adjuvant (VRC-GENMIX083-AL-VP) in a 2-product administration regimen.

Eligible subjects were randomized to WEVEE alone (Groups 1, 3, and 5) or WEVEE plus alum (Groups 2, 4, and 6, respectively) in each dose group. No more than 1 subject was randomized and vaccinated per day for the first 3 subjects at each dose. If the 6 mcg dose of WEVEE was assessed as not showing safety concerns by a Protocol Safety Review Team (PSRT), randomization began for Groups 3 and 4 (30 mcg WEVEE without alum and with alum, respectively). In a second safety review conducted on the first 3 subjects to receive 30 mcg, if the 30 mcg dose of WEVEE was assessed as not showing safety concerns by the PSRT, randomization began for Groups 5 and 6 (60 mcg WEVEE without and with alum, respectively).

The product was administered in the upper arm muscle as an intramuscular (IM) injection via needle and syringe at Day 0 and 8 weeks later.

For all groups, solicited reactogenicity was evaluated using a 7-day diary card. Assessment of vaccine safety included clinical observation and monitoring of hematological and chemical parameters at clinical visits throughout the study.

Eligibility criteria: Inclusion Criteria:

A volunteer must have met all of the following criteria:

* Age 18 to 50 years
* Available for clinical follow-up through 36 weeks after randomization
* Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
* Able and willing to complete the informed consent process
* Willing to donate blood for sample storage to be used for future research
* In good general health, without clinically significant medical history, and has satisfactorily completed screening
* Physical examination and laboratory results without clinically significant findings within the 28 days prior to randomization

Laboratory Criteria within 28 days prior to randomization:

* Hemoglobin within institutional normal range or accompanied by Principal Investigator (PI) or designee approval
* White blood cell (WBC) and differential either within institutional normal range or accompanied by PI or designee approval
* Total lymphocyte count: ≥800 cells/mm3
* Platelets: 125,000-500,000/mm3
* Alanine aminotransferase (ALT): ≤ 1.25 x upper limit of normal range
* Serum creatinine: ≤1.1 x upper limit of normal
* Negative for HIV infection by an FDA-approved method of detection

Criteria applicable to women of childbearing potential:

* Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day of randomization before receiving the study product
* Agrees to use an effective method of birth control, if sexually active, from at least 21 days prior to randomization through the last study visit.

Exclusion Criteria:

A volunteer was excluded if one or more of the following conditions applied:

Female-Specific Criteria

• Breast-feeding or planning to become pregnant while participating in the study

Volunteer received any of the following:

* More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to randomization or any within the 14 days prior to randomization
* Blood products within 16 weeks prior to randomization
* Immunoglobulin within 8 weeks prior to randomization
* Prior vaccinations with an investigational alphavirus vaccine
* Investigational research agents within 4 weeks prior to randomization or planning to receive investigational products while on study
* Live attenuated vaccines within 4 weeks prior to randomization
* Inactivated vaccines within 2 weeks prior initial study vaccine administration unless approved by the PI
* Current anti-tuberculosis (TB) prophylaxis or therapy

Volunteer has a history of any of the following clinically significant conditions:

* A history of confirmed or suspected viral encephalitis infection
* Serious reactions to vaccines that preclude receipt of study vaccinations as determined by the investigator
* Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema
* Asthma that is not well controlled
* Diabetes mellitus (type I or type II) with the exception of gestational diabetes
* Thyroid disease that is not well controlled
* Hypertension that is not well controlled
* Evidence of autoimmune disease or immunodeficiency
* Idiopathic urticaria within the last year
* Malignancy that is active or history of malignancy that is likely to recur during the study
* Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with intramuscular (IM) product administration or blood draws
* Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures or treatment for a seizure disorder within the last 3 years
* Asplenia, functional asplenia or any condition resulting in absence or removal of the spleen
* Psychiatric condition that precludes compliance with the protocol; past or present psychoses; or within 5 years prior to randomization, a history of suicide plan or attempt
* Any other chronic or clinically significant medical, psychiatric or social condition that, in the judgement of the investigator is a contraindication to protocol participation or impairs a volunteer's ability to give informed consent.

Primary outcomes:
measure: Number of Subjects Reporting Local Reactogenicity Signs and Symptoms For 7 Days After Each Product Administration
timeFrame: 7 days after each product administration, at approximately Week 1 and Week 9
measure: Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms For 7 Days After Each Product Administration
timeFrame: 7 days after each product administration, at approximately Week 1 and Week 9
measure: Number of Subjects With Abnormal Laboratory Measures of Safety
timeFrame: Day 0 through Day 252
measure: Number of Subjects With One or More Unsolicited Non-Serious Adverse Events (AEs)
timeFrame: Day 0 through 4 weeks of each study product administration, up to Week 12
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: Day 0 through Day 252
Secondary outcomes:
measure: Antigen-specific Neutralizing Antibody Geometric Mean Titers (GMTs) at 4 Weeks After the Last Product Administration of VRC-WEVVLP073-00-VP (WEVEE) Alone Or With Alum Adjuvant
timeFrame: 4 weeks after the last product administration, at Week 12
measure: Percentage of Positive Responders at 4 Weeks After the Last Product Administration of VRC-WEVVLP073-00-VP (WEVEE) Alone Or With Alum Adjuvant
timeFrame: 4 weeks after the last product administration, at Week 12
Other outcomes:
Locations:
city: Decatur
country: United States
facility: The Hope Clinic of the Emory Vaccine Center
state: Georgia
Study officials:
affiliation: VRC/NIAID/NIH
name: Julie E Ledgerwood, DO
role: STUDY_CHAIR
affiliation: VRC/NIAID/NIH
name: Grace Chen, MD
role: STUDY_CHAIR
References:
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citation: Akahata W, Yang ZY, Andersen H, Sun S, Holdaway HA, Kong WP, Lewis MG, Higgs S, Rossmann MG, Rao S, Nabel GJ. A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection. Nat Med. 2010 Mar;16(3):334-8. doi: 10.1038/nm.2105. Epub 2010 Jan 28.
citation: Coates EE, Edupuganti S, Chen GL, Happe M, Strom L, Widge A, Florez MB, Cox JH, Gordon I, Plummer S, Ola A, Yamshchikov G, Andrews C, Curate-Ingram S, Morgan P, Nagar S, Collins MH, Bray A, Nguyen T, Stein J, Case CL, Kaltovich F, Wycuff D, Liang CJ, Carlton K, Vazquez S, Mascola JR, Ledgerwood JE; VRC 313 Study Team. Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial. Lancet Infect Dis. 2022 Aug;22(8):1210-1220. doi: 10.1016/S1473-3099(22)00052-4. Epub 2022 May 11.