Safety and Immunogenicity of a Self-Amplifying RNA Vaccine Against Crimean-Congo Hemorrhagic Fever

A Phase 1, Open Label, Dose-Escalation Study to Evaluate the Safety, Reactogenicity and Immunogenicity of a Nanoparticle Carrier-Formulated Self-Amplifying RNA Vaccine Against Crimean-Congo Hemorrhagic Fever (HDT-321) in Healthy Adults

The goal of this clinical trial is to assess the safety, tolerability and immunogenicity of three dosage levels, and a single or two-dose administration regimen, of the investigational HDT-321 product administered intra-muscularly. The main questions it aims to answer are:

• Is HDT-321 safe to use
• Does HDT-321 provide protection against Crimean-Congo hemorrhagic fever virus (CCHFV)

Researchers will record any adverse events and test blood samples to see if HDT-321 is safe and works to protect participants against Crimean-Congo hemorrhagic fever virus (CCHFV)

Participants will:

• Receive 1 or 2 doses of HDT-321
• Complete a memory aid and measurements for 7 days after receiving each dose of HDT-321
• Be followed throughout the study using phone calls and clinic visits to check for and record adverse events
• Provide blood samples at specific study visits

Study Overview

• Status: Recruiting
• Conditions: Crimean-Congo Hemorrhagic Fever; Vaccine
• Intervention / Treatment: Biological: 10 ug HDT 321; Biological: 25ug HDT-321; Biological: 50ug HDT-321

Detailed Description

This is an open-label, dose-escalation, first-in-human study to evaluate the safety, reactogenicity and immunogenicity of the investigational product HDT-321 in approximately 48 healthy adults aged 18-64 years.

Four groups of 12 participants at three dosage levels will be sequentially recruited in the study, starting with the lowest dose. Groups 1, 2 and 4 will receive 2 doses and group 3 will receive 1 dose of HDT-321.

Study progression and dose escalation will occur according to the following:

Group 1 (10 μg): Three sentinel participants will be initially enrolled and followed for 7 days post-first study injection for safety assessment by predetermined objective criteria. If none of the pre-defined halting rules are met, as confirmed by the Safety Review Team (SRT), enrollment of the remaining participants of the group will proceed. In addition, available safety data for 7 days post-second study injection will be evaluated in the sentinel group prior to administering the second injection of the remaining participants of Group 1. Available safety data for 7 days post-first study injection of all participants will be reviewed by the SRT. If none of the pre-defined halting rules are met and no safety concerns have been identified, enrollment of Group 2 participants will proceed.

Group 2 (25 μg): In a similar fashion, three sentinel participants will be initially enrolled and followed for 7 days post-first study injection for safety assessment by predetermined objective criteria. If none of the pre-defined halting rules are met, as confirmed by the SRT, enrollment of the remaining participants of the group will proceed. In addition, available safety data for 7 days post second study injection will be evaluated in the sentinel group prior to administering the second injection of the remaining participants of Group 2. Available safety data for 7 days post-first study injection of all Group 1 and 2 participants along with any available post-second injection from Group 1 participants will be reviewed by the SRT. If none of the pre-defined halting rules are met and no safety concerns have been identified, enrollment of Groups 3 and 4 participants will proceed.

Groups 3 and 4 (50 μg): the same procedure with initial enrollment of three sentinel participants will be followed as outlined above, prior to enrollment of the remaining participants of Group 3 and all of Group 4. In addition, the available data 7 days post-first injection of the entire Group 3 and 4 along with available post-second injection data from Group 1 and 2 will be reviewed prior to administering the second dose of Group 4 participants.

Blood samples will be collected from all participants in the study. Participants in groups 1, 2 and 4 will provide samples at screening and 8 additional visits. Participants in group 3 will provide samples at screening and 7 additional visits.

Participants will be requested to attend a combination of in person clinic visits and phone calls. Participants in groups 1, 2 and 4 will have 2 phone calls and 10 in-clinic visits. Two of the clinic visits will include administration of HDT-321 via IM injections. Participants in cohort 3 will have 1 phone call and 9 in-clinic visits. One of the clinic visits will include administration of HDT-321 via IM injection.

Protocol-defined solicited local and systemic AEs will be collected for 7 days following each study injection via memory aid. Other AEs will be collected for 28 days following each study injection. SAEs, AESIs, MAAEs and NOCDs will be collected from the first study injection through their entire study participation.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: James Keary; Phone Number: 206-567-8230; Email: james.keary@hdt.bio
• Study Contact Backup: Name: Aude Frevol; Phone Number: 206-704-5705; Email: aude.frevol@hdt.bio

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Flourish Research San Antonio (Clinical Trials of Texas)
      • Contact: Barbara Corral, DNP; Phone Number: 151 210-949-0122; Email: BCorral@flourishresearch.com
      • Contact: Jessie Williams; Phone Number: 179 210-949-0122; Email: jwilliams@flourishresearch.com
      • Principal Investigator: Douglas Denham, MD
      • Sub-Investigator: Barbara Corral, DNP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Males and non-pregnant females 18 to 64 years of age at the time of signing the ICF.
2. Body mass index (BMI) 17 to 35 inclusive at screening.
3. Considered by the PI or designee to be in good general health as determined by medical history, physical examination, vital sign measurements*, and clinical laboratory assessments conducted no more than 30 days prior to the first study injection administration.
4. Screening laboratory values within the laboratory reference ranges or considered non-clinically significant (NCS) if within Grade 1 severity on the toxicity grading scale.
5. Negative human immunodeficiency virus (HIV) 1/2 antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibody.
6. Women of childbearing potential must agree to use or have practiced true abstinence or use at least one acceptable primary form of contraception3 for at least 30 days prior to the first injection and for 60 days after the last injection. Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the day of and prior to each study injection.
7. Able to understand and comply with planned study procedures and willing to be available for all study required procedures, visits, and telephone calls for the duration of the study.
8. Provide written informed consent before initiation of any study procedures.
9. Willing to abstain from donating whole blood or blood derivatives 30 days prior to screening and for the duration of the study.
10. Willing to refrain from receiving any licensed vaccine within 28 days prior to and after scheduled study injections.

Exclusion Criteria:

1. Any medical disease or condition that, in the opinion of the participating site PI or appropriate sub-investigator, precludes study participation. Including Acute, subacute, intermittent, or chronic medical diseases or conditions that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of the trial. Significant respiratory disease (COPD) requiring daily medications, asthma that is not well controlled, significant cardiovascular disease, history of myocarditis or pericarditis, myocardial infarction, coronary artery bypass surgery or stent placement, or uncontrolled cardiac arrhythmia, Neurological or neurodevelopmental conditions, ongoing malignancy or recent diagnosis of malignancy in the last five years excluding basal cell and squamous cell carcinoma of the skin, blood dyscrasias or significant disorder of coagulation, chronic liver disease, including fatty liver, autoimmune disease, including localized or history of psoriasis or hypothyroidism without a defined non-autoimmune cause and Immunodeficiency of any cause.
2. Abnormal screening electrocardiogram (ECG)
3. History of hypersensitivity or severe reactions to previous vaccinations
4. History of hypersensitivity or severe reactions to products known to contain polyethylene glycol (PEG).
5. Allergy to antibiotics structurally similar to kanamycin (including but not limited to neomycin, streptomycin, tobramycin, and gentamycin).
6. Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immunemodifying drugs within 6 months prior to the first study injection (for corticosteroids: prednisone ≥20 mg/day or equivalent). Intra-articular, inhaled, nasal, and topical steroids are allowed.
7. Received immunoglobulins or any blood products within 60 days prior to enrollment/Day 1.
8. Donated blood products within 30 days prior to enrollment/Day 1.
9. Received an investigational or non-registered medicinal product within 30 days prior to screening.
10. Currently enrolled, or plan to participate, in another clinical trial with an investigational agent to be received during the study period.
11. Received or plans to receive any non-study vaccine within 28 days before and after each study injection.
12. Febrile illness*, as determined by the participating site PI or appropriate sub-investigator, with or without fever (oral temperature ≥38.0°C/100.4°F), within 24 hours prior to each study injection.
13. Current heavy smoking/vaping (defined as 1 pack or more of cigarettes a day or vaping equivalent*). *1-2 mL of 20 mg/mL of nicotine salt
14. Known or suspected alcohol or illicit drug abuse within the past 12 months prior to Study Day 1.
15. Breastfeeding or plans to breastfeed from the time of the first vaccination through 60 days after the last study injection.
16. Participants unlikely to cooperate with the requirements of the study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Group 1 will include 12 participants who will receive a 10 ug two dose schedule of HDT-321 at day 1 and day 29.	Biological: 10 ug HDT 321; HDT-321 Investigational Vaccine (a Nanoparticle Carrier-Formulated self-amplifying RNA encoding the NP of CCHFV)
Experimental: Group 2; Group 2 will include 12 participants who will receive a 25 ug, two dose schedule of HDT-321 at day 1 and day 29.	Biological: 25ug HDT-321; HDT-321 Investigational Vaccine (a Nanoparticle Carrier-Formulated self-amplifying RNA encoding the NP of CCHFV)
Experimental: Group 3; Group 3 will include 12 participants who will receive a 50 ug one dose schedule of HDT-321 at day 1.	Biological: 50ug HDT-321; HDT-321 Investigational Vaccine (a Nanoparticle Carrier-Formulated self-amplifying RNA encoding the NP of CCHFV)
Experimental: Group 4; Group 4 will include 12 participants who will receive a 50 ug two dose schedule of HDT-321 at day 1 and day 29.	Biological: 50ug HDT-321; HDT-321 Investigational Vaccine (a Nanoparticle Carrier-Formulated self-amplifying RNA encoding the NP of CCHFV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Solicited local and systemic adverse events (AEs)	Frequency and grade of solicited local and systemic AEs during the 7-day follow-up period after each study injection (i.e. the day of administration and 6 subsequent days).	Day 1-7 post administration
Unsolicited study product related adverse events	Frequency and grade of unsolicited study product related AEs reported during the 28-day follow-up period after each study injection.	Day 1-28 post administration
Laboratory abnormalities	Occurrence of laboratory abnormalities at 7 days post injection visit (increased or decreased outside normal ranges, as determined by the FDA Guidance for Industry Toxicity Grading Scale for Healthy Adults Enrolled in Preventive Vaccine Clinical Trials, 2007)	Day 1-7 post administration
Serious AEs, AEs of Special Interest, Medically Attended AEs, and New-Onset of Chronic Diseases	Frequency and grade of Serious AEs (SAEs), AEs of Special Interest (AESIs), Medically-Attended AEs (MAAEs), and New-Onset of Chronic Diseases (NOCDs) during the duration of participation in the study.	Day 1 to end of study participation (Day 394)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunogenicity of HDT-321	Evaluate the immunogenicity of HDT-321 as measured by IgG ELISA to the CCHFV NP measured 28 and 56 days after each injection. Using geometric mean titers (GMTs) of circulating antibodies against CCHFV NP through Day 57 along with seroconversion rate for anti-NP antibody through Day 57.	Day 1 to Day 57

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory immunogenicity of HDT-321	Evaluate antibody subclass response as measured by IgG1, IgG2, IgG3, and IgG4 ELISA to the CCHFV NP. Using geometric mean titers (GMT) of antigen-specific IgG1, IgG2, IgG3, and IgG4.	Day 1 to end of study participation (Day 394)
Exploratory immunogenicity of HDT-321	Evaluate the immunogenicity of HDT-321 as measured by IgG ELISA to the CCHFV NP measured after Day 57. Using geometric mean titers (GMTs) of circulating antibodies against CCHFV NP and seroconversion rate for anti-NP antibody.	Day 57 to the end of study participation (Day 394)
Exploratory Immunogenicity of HDT-321	Evaluate the immunogenicity of HDT-321 vaccine as measured by IgG ELISA to the CCHFV NP from other strains. Using geometric mean titers (GMT) of strain-specific, antigen-specific IgG.	Day 1 to end of study participation (Day 394)
Exploratory immunogenicity of HDT-321	evaluate the immunogenicity as measured by IgM and IgA ELISA to the CCHFV NP. Using geometric mean titers (GMT) of antigen-specific IgM and IgA	Day 1 to end of study participation (Day 394)
Exploratory immunogenicity of HDT-321	evaluate B cell and T cell responses to CCHFV NP as percentages. Using the diversity of the cellular responses by assessing cells expressing interferon gamma (IFN-γ), interleukin 2 (IL-2), tumor necrosis factor (TNF), and other markers. as well as rate of antigen-specific cell-mediated immune responses for T cells expressing IFN-γ.	Day 1 to end of study participation (Day 394)

Collaborators and Investigators

• Sponsor: HDT Bio
• Collaborators: The University of Texas Medical Branch, Galveston; Clinical Trials of Texas, Inc.; Technical Resources International, Inc. (TRI); DFNet Research Inc.; BioAgilytix Labs, LLC; Quest Laboratories
• Investigators: Study Director: Malcolm Duthie, PhD, HDT Bio

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: January 16, 2025
• First Submitted That Met QC Criteria: January 23, 2025
• First Posted (Actual): January 29, 2025

Study Record Updates

• Last Update Posted (Actual): July 28, 2025
• Last Update Submitted That Met QC Criteria: July 23, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Vaccine; Healthy; Female; Male; Preventative; 18-64
• Additional Relevant MeSH Terms: Vector Borne Diseases; Infections; RNA Virus Infections; Virus Diseases; Arbovirus Infections; Tick-Borne Diseases; Body Temperature Changes; Bunyaviridae Infections; Fever; Hemorrhagic Fevers, Viral; Hemorrhagic Fever, Crimean
• Other Study ID Numbers: HDT-321-001; W15QKN-16-9-1002 / 23-86397-01 (Other Grant/Funding Number: Medical CBRN Defense Consortium (MCDC))

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
• product manufactured in and exported from the U.S.: No