Dose Escalation, Open-Label Clinical Trial to Evaluate Safety, Tolerability and Immunogenicity of a Nipah Virus (NiV) mRNA Vaccine, mRNA-1215, in Healthy Adults

National Institute of Allergy and Infectious Diseases (NIAID)40 enrolled

Overview

Background: Nipah virus (NiV) is transmitted from animals to humans, from humans to humans, and through contaminated food. Infected people may have a cough and trouble breathing. Some people may develop serious symptoms, such as brain infection and inflammation, that can lead to death. There are no drugs or vaccines to treat or prevent NiV infection. Objective: To test the safety of an experimental vaccine (mRNA-1215) for NiV. Researchers will also evaluate how participants bodies respond to the vaccine. Eligibility: Healthy, nonpregnant adults aged 18 to 60 years. Design: Participants visited the NIH clinic 13 to 15 times over 14 to 16 months. Participants received 2 doses of the experimental vaccine at 1 month apart. The vaccine was given as a shot into the muscle of the upper arm. Participants stayed in the clinic at least 30 minutes after each vaccination. Participants were given a diary card and a thermometer. They recorded their temperature and any other reactogenicity symptoms for 7 days after each vaccination. During each follow-up visit, 3 to 14 tubes of blood were drawn for research. Some participants underwent an optional procedure called apheresis. A needle is placed into a vein in each arm. Blood is removed through one needle. The blood passed through a machine that separates some of the blood cells. The rest of the blood is returned to the body through another needle. The mRNA-1215 vaccine cannot cause NiV infection.

Design: This Phase I, dose escalation, open label clinical trial was the first study of mRNA-1215 in healthy adults to evaluate the safety, tolerability, and immunogenicity of a Nipah virus (NiV) mRNA vaccine. The hypotheses were that the vaccine would be safe, tolerable, and would elicit an immune response in healthy adults. Study Product: The investigational mRNA-1215 vaccine is a lipid nanoparticle dispersion containing mRNA that encodes for a secreted prefusion stabilized F component covalently linked to a G monomer (PreF/G) of a NiV Malaysian 1999 strain with a trimerization domain resulting in secretion of a trimer of heterodimers. mRNA-1215 was co-developed by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Disease (NIAID) and ModernaTX, Inc, and manufactured by ModernaTX. Participants: Healthy adults, 18 to 60 years of age. Plan: Participants were enrolled at the NIH Clinical Center and received mRNA-1215 via intramuscular (IM) injection by needle and syringe into the deltoid muscle. A dose escalation safety evaluation occurred to ensure the safety data support proceeding to the higher dose groups. The mRNA-1215 vaccine dose for Group 4 was selected based on interim analysis of safety and immunogenicity data from Groups 1-3. Participants were evaluated for safety and immune responses through clinical observation and blood collection for safety labs at specified timepoints throughout the study. The study schema was as follows: Study Schema Group Participants Dose/Route Day 0 Week 4 1. 10 25 mcg IM X X 2. 10 50 mcg IM X X 3. 10 100 mcg IM X X 4. 10 10 mcg IM X X Total \*\*40 \*\*Enrollment of up to 50 subjects was permitted in case additional evaluations were required for safety or immunogenicity. Duration: Participants were evaluated for safety and immune responses throughout the study for 52 weeks following the second vaccine dose.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

* INCLUSION CRITERIA: A volunteer must meet all of the following criteria: 1. Healthy adults between the ages of 18-60 years inclusive. 2. Based on history and physical examination, in good general health and without history of any of the conditions listed in the exclusion criteria. 3. Able and willing to complete the informed consent process. 4. Available for clinic visits for 52 weeks after last product administration. 5. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. 6. Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) of 18 to 35 within the 56 days prior to enrollment. Laboratory Criteria within 56 days before enrollment: 7. White blood cells (WBC) and differential within institutional normal range or accompanied by the site Principal Investigator (PI) or designee approval. 8. Total lymphocyte count \>= 800 cells/microL. 9. Platelets = 125,000 - 500,000 cells/microL. 10. Hemoglobin within institutional normal range or accompanied by the PI or designee approval. 11. Alanine aminotransferase (ALT) \<= 1.25 X institutional upper limit of normal (ULN). 12. Aspartate aminotransferase (AST) \<= 1.25 X institutional ULN. 13. Alkaline phosphatase (ALP) \<1.1 X institutional ULN. 14. Total bilirubin within institutional normal range or accompanied by the PI or designee approval. 15. Serum creatinine \<= 1.1 X institutional ULN. 16. Negative for HIV infection by an FDA-approved method of detection Criteria applicable to women of childbearing potential: 17. Negative beta-human chorionic gonadotropin (Beta-HCG) pregnancy test (urine or serum) on the day of enrollment. 18. Agrees to use an effective means of birth control from at least 21 days prior to enrollment through the end of the study. EXCLUSION CRITERIA: A volunteer will be excluded if one or more of the following conditions apply: 1. Breast-feeding or planning to become pregnant during the study. 2. More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 4 weeks prior to enrollment or any within the 14 days prior to enrollment. 3. Blood products within 16 weeks prior to enrollment. 4. Any vaccine, including COVID-19 vaccines, received within 4 weeks prior to enrollment. 5. Investigational research agents within 4 weeks prior to enrollment or planning to receive investigational products while on the study 6. Current allergy treatment with allergen immunotherapy with antigen injections, unless on maintenance schedule. 7. Current anti-TB prophylaxis or therapy. 8. Known immediate hypersensitivity to any component of the study product, including polyethylene glycol (PEG). 9. Confirmed past NiV infection, prior residence in (\>6 months), or planned travel for any length of time during the study to countries where NiV infection is endemic, eg. Bangladesh, India, Philippines. Volunteer has a history of any of the following clinically significant conditions: 10. Serious reactions to vaccines that preclude receipt of the study vaccination, including allergic reaction (anaphylaxis, urticaria or allergic reaction requiring medical intervention) to SARS-CoV-2 mRNA vaccines, as determined by the investigator 11. History of myocarditis and/or pericarditis 12. Hereditary angioedema, acquired angioedema, or idiopathic forms of angioedema 13. Asthma that is not well controlled 14. Diabetes mellitus (type I or II), with the exception of gestational diabetes 15. Thyroid disease that is not well controlled 16. Idiopathic urticaria within the past year 17. Autoimmune disease or immunodeficiency 18. Hypertension that is not well controlled 19. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws 20. Malignancy that is active or history of malignancy that is likely to recur during the period of the study 21. Seizure disorder other than 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures that have not required treatment within the last 3 years. 22. Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen 23. Guillain-Barre Syndrome 24. Any medical, psychiatric, social condition, occupational reason or other responsibility that, in the judgment of the investigator, is a contraindication to protocol participation or impairs a subject s ability to give informed consent, including but not limited to clinically significant forms of: infectious diseases, drug or alcohol abuse, autoimmune diseases, psychiatric disorders, or heart disease.

Outcomes

Primary Outcomes

Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Product Administration

Participants recorded the occurrence of solicited local symptoms on a diary card for 7 days after 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, modified from FDA Guidance - September 2007.

Time frame: 7 days after product administration

Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of Product Administration

Participants recorded the occurrence of solicited systemic symptoms on a diary card for 7 days after 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 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, modified from FDA Guidance - September 2007.

Time frame: 7 days after product administration

Number of Participants With Serious Adverse Events Following Product Administration

SAEs were recorded from receipt of product administration through the last study visit at Week 56. The relationship between a SAE and the study product was assessed by the investigator based on 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.

Time frame: Day 0 after product administration through Day 392, up to Week 56

Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Product Administration

Unsolicited AEs and attribution assessments were recorded in the study database from receipt of study product administration through the visit scheduled for 4 weeks after study product administration. At other time periods greater than 4 weeks after the study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator based on 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.

Time frame: Day 0 through 28 days post product administration, up to Week 4

Number of Participants With New Chronic Medical Conditions Following Product Administration

New chronic medical conditions that required ongoing medical management were recorded from receipt of study product administration through the last expected study visit through Day 392, up to Week 56. The relationship between a new chronic medical condition and the study product was assessed by the investigator based on 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

Time frame: Day 0 after product administration through Day 392, up to Week 56

Number of Participants With Adverse Events of Special Interest (AESI) Following Product Administration

An AESI is an AE (serious or nonserious) of scientific medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the investigator to the Sponsor is required.

Time frame: Day 0 after product administration through Day 392, up to Week 56

Number of Participants With Medically Attended Adverse Events (MAAEs) Following Product Administration

MAAEs are defined as adverse events leading to hospitalization, an emergency room visit or an otherwise unscheduled visit to or from medical personnel, for any reason.

Time frame: First vaccination to 6 months

Number of Participants With Abnormal Laboratory Measures of Safety Following Product Administration

Abnormal lab results recorded as unsolicited adverse events (AEs) are summarized\*. Safety lab parameters included pregnancy test, hematology and chemistry labs, and HIV Serology diagnostic test. Institutional lab normal ranges as well as Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials FDA Guidance, September 2007 were used.

Time frame: Day 0 after product administration through Day 392, up to Week 56

Secondary Outcomes

Geometric Mean NiV(M) Pre-F Binding Antibody Titer (GMTs) and 95% Confidence Intervals (CIs).

Vaccine-induced binding antibody titers against Pre-F antigen of Nipah virus Malaysia strain (NiV(M)) were measured by ELISA. The value of the antibody response was determined by obtaining half of the maximum effective concentration (EC50) titer from the optical density 450 nm curves for the function of the reciprocal dilution using a four-parameter logistic curve fit in Prism (version 10.2.2). NiV Pre-F EC50 titers were normalized using the World Health Organization (WHO)/National Institute for Biological Standards and Control (NIBSC) international standard (IS, NIBSC code 22/130) and are reported as group geometric mean titers (GMTs) and 95% confidence intervals (CIs) in international units per milliliter (IU/ml).

Time frame: Serum samples collected at baseline (Week 0) and at two weeks after the second product administration (Week 6).

Geometric Mean NiV(M) G Binding Antibody Titer (GMTs) and 95% Confidence Intervals (CIs).

Vaccine-induced binding antibody titers against G antigen of Nipah virus Malaysia strain (NiV(M)) were measured by ELISA. The value of the antibody response was determined by obtaining half of the maximum effective concentration (EC50) titer from the optical density 450 nm curves for the function of the reciprocal dilution using a four-parameter logistic curve fit in Prism (version 10.2.2). NiV G EC50 titers were normalized using the World Health Organization (WHO)/National Institute for Biological Standards and Control (NIBSC) international standard (IS, NIBSC code 22/130) and are reported as group geometric mean titers (GMTs) and 95% confidence intervals (CIs) in international units per milliliter (IU/ml).

Time frame: Serum samples collected at baseline (Week 0) and at two weeks after the second product administration (Week 6).

Dose Escalation, Open-Label Clinical Trial to Evaluate Safety, Tolerability and Immunogenicity of a Nipah Virus (NiV) mRNA Vaccine, mRNA-1215, in Healthy Adults

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes