DCVC H1 HA mRNA Vaccine for Flu

Recruiting in Palo Alto (17 mi)

+1 other location

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Immunosuppressants, Corticosteroids, Chemotherapy, others

Disqualifiers: Immunosuppressive conditions, Neoplastic disease, Psychiatric illness, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This is a Phase 1, single-site, comparator-controlled, dosage-escalating study of an intramuscularly administered mRNA-LNP vaccine encoding for DCVC H1 HA in up to 50 adult volunteers aged 18 to 49 years, inclusive. This study is designed to assess the safety and immunogenicity of two doses of DCVC H1 HA mRNA vaccine administered 28 days apart. Eligible participants will be sequentially enrolled into dosage escalation groups (10 mcg, 25 mcg, and 50 mcg). A separate group of 10 participants will receive one dose of the licensed quadrivalent influenza vaccine (IIV4). Enrollment of participants into the IIV4 group is limited to when the vaccine is available for a given year. Concurrent enrollment of the IIV4 group and any pre-specified study product group or groups may present logistical challenges due to the availability of the IIV4 vaccine and may preclude enrollment of all study participants prior to the subsequent off-season. Participants receiving IIV4 will be followed for safety but only their immune responses will be compared to those of participants receiving DCVC H1 HA mRNA vaccine. Dosing of DCVC H1 HA mRNA vaccine will commence at the lowest dose (10 mcg) and only escalate to the next highest dose if safety concerns are not identified. For each DCVC H1 HA mRNA vaccine dosing group, the first two participants enrolled will be considered the sentinel subgroup. After the two participants in the Low Dose sentinel subgroup are enrolled and given their first vaccination, enrollment and subsequent vaccinations in that dosing group will then be stopped until Day 3. This review will be conducted by a Safety Review Committee (SRC). If no halting criteria are met, the SRC will allow administration of the second dose for the sentinel subgroup and continued enrollment of the remaining 8 Low Dose Group participants (expanded subgroup) to complete enrollment of 10 participants. In order for a timely receipt of a second dose of study product on Day 29, SRC review and approval must occur prior to Study Day 28 for the first sentinel participant in the Low Dose Group. After the Low Dose Group enrollment is completed and both doses have been administered, enrollment will be stopped pending SRC review. After all participants in the Low Dose Group have completed the Day 36 visit, the SRC will review the clinical laboratory, reactogenicity, and adverse event information through the Day 36 visit for all Low Dose Group participants that received two doses. Approval by the SRC will allow dose escalation and initiation of enrollment of the Medium Dose Group sentinel subgroup. The Medium and High Dose sentinel and expanded groups will be enrolled as described above for the Low Dose sentinel and expanded groups, respectively, with the High Dose expanded subgroup enrolling up to 18 individuals. The primary objective of this study is to assess the safety of two doses of DCVC H1 HA mRNA Vaccine administered intramuscularly in healthy adults (18-49 yrs) at dosage levels of 10 mcg, 25 mcg, and 50 mcg.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, certain medications like corticosteroids and high-dose inhaled steroids should not be taken within 30 days before the study vaccination. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the DCVC H1 HA mRNA vaccine for flu?

The research does not provide direct evidence about the effectiveness of the DCVC H1 HA mRNA vaccine for flu, but it does suggest that influenza vaccination in general can lower the risk of certain heart-related issues in patients with chronic obstructive pulmonary disease (COPD). This implies that flu vaccines may have broader health benefits beyond just preventing the flu.

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How is the DCVC H1 HA mRNA vaccine different from other flu treatments?

The DCVC H1 HA mRNA vaccine is unique because it uses a lipid nanoparticle-encapsulated mRNA platform to encode a consensus hemagglutinin (HA) sequence, aiming to provide broad protection against various H1N1 influenza strains, unlike traditional vaccines that target specific strains and may not be as effective due to viral mutations.

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Eligibility Criteria

Healthy adults aged 18-49 with stable blood pressure, not pregnant or breastfeeding, and without significant health conditions can join. They must agree to use contraception and avoid sperm donation for specified periods around vaccination. Exclusions include drug abuse, liver disease, immune disorders, recent corticosteroid use, severe reactions to vaccines, certain heart conditions, psychiatric hospitalization within the past 5 years.

Inclusion Criteria

I can follow the study's procedures and attend all visits.

I agree not to donate sperm and to use contraception for 90 days after my last vaccine dose.

Must agree to collection of venous blood and nasal absorption specimens per protocol and enrollment in DMID 19-0025 biorepository protocol for use of residual blood specimens

Exclusion Criteria

I have had Guillain-Barré Syndrome in the past.

Has a positive urine toxicology screen

I have a history of heart inflammation.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of DCVC H1 HA mRNA vaccine administered 28 days apart

4 weeks

2 visits (in-person)

Safety Evaluation

Safety Review Committee evaluates safety data to determine dose escalation

1 week

Follow-up

Participants are monitored for safety and immunogenicity after treatment

4 weeks

1 visit (in-person)

Participant Groups

The trial is testing a new mRNA vaccine (DCVC H1 HA) against H1N1 influenza in healthy adults. Participants will receive varying doses (10 mcg up to an optimal dose determined by safety outcomes) compared with a standard quadrivalent flu vaccine. The study aims to find the safest effective dose.

Group I: Arm 3 Experimental Treatment 2 Interventions

Healthy adults, 18 to 49 years of age will receive 50 mcg of DCVC H1 HA mRNA vaccine administered intramuscularly to the upper arm/deltoid at days 1 and 29. A safety evaluation will occur to ensure the safety data support proceeding to the optimal dose group. N = 20

Group II: Arm 2 Experimental Treatment 2 Interventions

Healthy adults, 18 to 49 years of age will receive 25 mcg of DCVC H1 HA mRNA vaccine administered intramuscularly to the upper arm/deltoid at days 1 and 29. A dose escalation safety evaluation will occur to ensure the safety data support proceeding to the higher dose group. N = 10

Group III: Arm 1 Experimental Treatment 2 Interventions

Healthy adults, 18 to 49 years of age will receive 10 mcg of DCVC H1 HA mRNA Vaccine administered intramuscularly to the upper arm/deltoid at days 1 and 29. A dose escalation safety evaluation will occur to ensure the safety data support proceeding to the higher dose group. N = 10

Group IV: Arm 4 Active Control 3 Interventions

Healthy adults, 18 to 49 years of age will receive 60 mcg of Licensed quadrivalent inactivated influenza vaccine (IIV4), Fluzone Quadrivalent, administered intramuscularly to the upper arm/deltoid once. N = 10

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Iowa Hospitals & Clinics - Department of Internal Medicine Iowa City, IA

University of Iowa - Infectious Disease Clinic Iowa City, IA

Who Is Running the Clinical Trial?

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

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Controlled clinical comparative evaluation of fluticasone powder inhalation versus flunisolide dose aerosol in patients with mild to moderate asthma]. [2021] A 6 week randomised, multicentre parallel group study compared the efficacy and safety of fluticasone propionate (FP) dry powder inhaler 2 x 250 micrograms/d and flunisolide (FLUN) metered dose inhaler 2 x 500 micrograms/d. 169 patients with mild to moderate asthma (FEV1/VC > or = 60% predicted) participated. The final clinical judgement resulted from the change in FEV1 and symptom intensity (measured by the oxygen cost diagram = OCD). 79% of the patients in the FP group showed improvement or partial improvement, compared to 57% in the flunisolide group (p = 0.02). The results indicate a greater efficacy of FP concerning the intensity of dyspnea, cough and symptoms at night (p = 0.03). During the treatment period morning and evening PEF improved in both groups; in 81% of the FP patients and 71% of the FLUN patients. 50% of all patients had a FEV1 below 2.5 l/s. The greater efficacy of FP was especially found in patients with lower FEV1. In both treatment groups drug safety was judged good or excellent by most patients. The results of this 6 week study indicate a greater efficacy (FEV1 and symptoms) of FP 2 x 250 micrograms/d versus FLUN 2 x 500 micrograms/d. The study confirms that there is at least a 2:1 ratio in efficacy comparing FP with FLUN in asthma patients.

2. United States pubmed.ncbi.nlm.nih.gov

A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. [2019] We found Cop 1 to be effective and relatively safe in a previous (exacerbating-remitting) clinical trial. This current trial involves 106 chronic-progressive patients. The major end point, confirmed progression of 1.0 or 1.5 units (depending on baseline disability) on the Kurtzke Expanded Disability Status Scale, was observed in nine (17.6%) treated and 14 (25.5%) control patients. The differences between the overall survival curves were not significant. Progression rates at 12 and 24 months were higher for the placebo group (p = 0.088) with 2-year probabilities of progressing of 20.4% for Cop 1 and 29.5% for placebo. We found a significant difference at 24 months between placebo and Cop 1 at one but not the other center. Two-year progression rates for two secondary end points, unconfirmed progression, and progression of 0.5 EDSS units, (p = 0.03) are significant.

3. Switzerland pubmed.ncbi.nlm.nih.gov

Influenza Vaccination and the Risk of Ventricular Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease: A Population-Based Longitudinal Study. [2021] Backgrounds: Influenza vaccination could decrease the risk of major cardiac events in patients with chronic obstructive pulmonary disease (COPD). However, the effects of the vaccine on decreasing the risk of ventricular arrhythmia (VA) development in such patients remain unclear. Methods: We retrospectively analyzed the data of 18,658 patients with COPD (≥55 years old) from the National Health Insurance Research Database from January 1, 2001, to December 31, 2012. After a 1:1 propensity score matching by the year of diagnosis, we divided the patients into vaccinated and unvaccinated groups. Time-varying Cox proportional hazards regression was applied to assess the time to event hazards of influenza vaccination exposure. Results: The risk of VA occurrence was significantly lower in the vaccinated group during influenza season and all seasons [adjusted hazard ratio (aHR): 0.62, 95% CI: 0.41-0.95; aHR: 0.69, 95% CI: 0.44-1.08; and aHR: 0.65, 95% CI: 0.48-0.89, in the influenza season, non-influenza season, and all seasons, respectively]. Among patients with CHA2DS2-VASc scores (conditions and characteristics included congestive heart failure, hypertension, diabetes, stroke, vascular disease, age, and sex) of 2-3, receiving one time and two to three times of influenza vaccination were associated with lower risk of VA occurrence in all seasons (aHR: 0.28, 95% CI: 0.10-0.80; aHR: 0.27, 95% CI: 0.10-0.68, respectively). Among patients without stroke, peripheral vascular disease, and diabetes, a lower risk of VA occurrence after receiving one and two to three times vaccination was observed in all seasons. Among patients with a history of asthma and patients without a history of heart failure, ischemic heart disease, angina hypertension, or renal failure, a significantly lower risk of VA occurrence was observed after the first time of vaccination in all seasons. Conclusions: Influenza vaccination may be associated with lower risks of VA among patients with COPD aged 55-74. Further investigation is still needed to resolve this clinical question.

4. Switzerland pubmed.ncbi.nlm.nih.gov

Hypercapnic ventilation response in patients with lung disease: improved accuracy by correcting for ventilation ability. [2018] The hypercapnic ventilation response (HCVR) is positively correlated with forced expired volume in 1 s (FEV1). Therefore, subjects of small stature or patients with lung disease have low values for HCVR. However, indexing the HCVR for the subject's predicted maximal voluntary ventilation (MVV) results in a corrected HCVR (CHCVR) which is not dependent on FEV1 in normal subjects [Respiration 1993;60:197-202]. We hypothesized that the CHCVR would also be useful in assessing chemosensitivity in patients with poor lung function. To obtain the predicted MVV, we used the linear regression for FEV1 vs. measured MVV obtained from 411 patients with a wide range of FEV1 values (MVV = 31.2 x FEV1 + 11.8, r = 0.90, p

5. United States pubmed.ncbi.nlm.nih.gov

Single-Inhaler Triple Therapy and Health-Related Quality of Life in COPD: The IMPACT Study. [2022] The phase 3 InforMing the PAthway of COPD (chronic obstructive pulmonary disease) Treatment (IMPACT) trial, single-inhaler therapy with fluticasone furoate (FF) 100 μg, umeclidinium (UMEC) 62.5 μg, and vilanterol (VI) 25 μg demonstrated a reduction in the rate of moderate or severe exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This article reports additional evidence of improvements in symptoms and health-related quality of life (HRQoL) with FF/UMEC/VI compared with either FF/VI or UMEC/VI from the IMPACT study.

6. United States pubmed.ncbi.nlm.nih.gov

Development of an mRNA vaccine against a panel of heterologous H1N1 seasonal influenza viruses using a consensus hemagglutinin sequence. [2023] Seasonal influenza, causes hundreds of thousands of deaths annually, posing a severe threat to human health. Currently available influenza vaccines are targeted only at specific strains or conserved epitopes; however, these vaccines are not completely efficacious because influenza viruses can undergo mutation during circulation, leading to antigenic mismatch between recommended strains and circulating strains and elusion from the immune system. Therefore, developing an influenza vaccine that is quick, effective, and broadly protective has become crucial, and the integral part of hemagglutinin (HA) remains an ideal target for vaccine development. This study developed a lipid nanoparticle-encapsulated nucleoside-modified mRNA vaccine (mRNA-LNPs) encoding a consensus full-length HA sequence (H1c) and evaluated its protective efficacy and immunogenicity through in vitro and in vivo assays. Following two intramuscular immunizations (2, 10 µg, or 20 µg) at a 3-week interval in BALB/c mice, H1c-mRNA-LNP vaccine induced strong antibodies as shown in the hemagglutination-inhibition test and protective neutralizing antibodies against numerous heterologous H1N1 influenza viruses as shown in the microneutralization assay. Additionally, both Th1- and Th2-biased cellular immune responses were elicited, with the Th1-biased response being stronger. Two doses of the H1c-mRNA-LNP vaccine could neutralize a panel of heterologous H1N1 influenza viruses and could confer protection in mice. Taken together, these findings suggest that the H1c-mRNA-LNP vaccine encoding a consensus full-length HA is a feasible strategy for developing a cross-protective vaccine against a panel of heterologous H1N1 influenza viruses.

7. England pubmed.ncbi.nlm.nih.gov

Rational development of a combined mRNA vaccine against COVID-19 and influenza. [2023] As the world continues to experience the COVID-19 pandemic, seasonal influenza remain a cause of severe morbidity and mortality globally. Worse yet, coinfection with SARS-CoV-2 and influenza A virus (IAV) leads to more severe clinical outcomes. The development of a combined vaccine against both COVID-19 and influenza is thus of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we developed and characterized a novel mRNA vaccine encoding the HA antigen of influenza A (H1N1) virus, termed ARIAV. Then, ARIAV was combined with our COVID-19 mRNA vaccine ARCoV, which encodes the receptor-binding domain (RBD) of the SARS-CoV-2 S protein, to formulate the final combined vaccine, AR-CoV/IAV. Further characterization demonstrated that immunization with two doses of AR-CoV/IAV elicited robust protective antibodies as well as antigen-specific cellular immune responses against SARS-CoV-2 and IAV. More importantly, AR-CoV/IAV immunization protected mice from coinfection with IAV and the SARS-CoV-2 Alpha and Delta variants. Our results highlight the potential of the LNP-mRNA vaccine platform in preventing COVID-19 and influenza, as well as other respiratory diseases.

8. United States pubmed.ncbi.nlm.nih.gov

Development of a nucleoside-modified mRNA vaccine against clade 2.3.4.4b H5 highly pathogenic avian influenza virus. [2023] Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating at unprecedently high levels in wild and domestic birds and have the potential to adapt to humans. We generated an mRNA lipid nanoparticle (LNP) vaccine encoding the hemagglutinin (HA) glycoprotein from a clade 2.3.4.4b H5 isolate. We show that the vaccine is immunogenic in mice and ferrets and prevents morbidity and mortality of ferrets following 2.3.4.4b H5N1 challenge.

9. United States pubmed.ncbi.nlm.nih.gov

Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses. [2023] Combined vaccine formulations targeting not only hemagglutinin but also other influenza virus antigens could form the basis for a universal influenza virus vaccine that has the potential to elicit long-lasting, broadly cross-reactive immune responses. Lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) vaccines can be utilized to efficiently target multiple antigens with a single vaccine. Here, we assessed the immunogenicity and protective efficacy of nucleoside-modified mRNA-LNP vaccines that contain four influenza A group 2 virus antigens (hemagglutinin stalk, neuraminidase, matrix protein 2, and nucleoprotein) in mice. We found that all vaccine components induced antigen-specific cellular and humoral immune responses after administration of a single dose. While the monovalent formulations were not exclusively protective, the combined quadrivalent formulation protected mice from all challenge viruses, including a relevant H1N1 influenza virus group 1 strain, with minimal weight loss. Importantly, the combined vaccine protected from morbidity at a dose of 125 ng per antigen after a single vaccination in mice. With these findings, we confidently conclude that the nucleoside-modified mRNA-LNP platform can be used to elicit protection against a large panel of influenza viruses.

10. England pubmed.ncbi.nlm.nih.gov

Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. [2020] Currently available influenza virus vaccines have inadequate effectiveness and are reformulated annually due to viral antigenic drift. Thus, development of a vaccine that confers long-term protective immunity against antigenically distant influenza virus strains is urgently needed. The highly conserved influenza virus hemagglutinin (HA) stalk represents one of the potential targets of broadly protective/universal influenza virus vaccines. Here, we evaluate a potent broadly protective influenza virus vaccine candidate that uses nucleoside-modified and purified mRNA encoding full-length influenza virus HA formulated in lipid nanoparticles (LNPs). We demonstrate that immunization with HA mRNA-LNPs induces antibody responses against the HA stalk domain of influenza virus in mice, rabbits, and ferrets. The HA stalk-specific antibody response is associated with protection from homologous, heterologous, and heterosubtypic influenza virus infection in mice.