Clinical trial NCT01676402: Seasonal Influenza HA DNA With Trivalent Inactivated Vaccine (TIV) Administered ID or IM in Healthy Adults 18-70 Years
Official title: Open-Label, Randomized Phase 1b Study of the Safety & Immunogenicity of Investigational Seasonal Influenza DNA Vaccine Followed by TIV Administered Intradermally (ID) or Intramuscularly (IM) in Healthy Adults 18-70 Years
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Influenza
Keywords: Influenza A (H1)
Influenza A (H3)
Influenza B
DNA Vaccine
Trivalent Inactivated Vaccine (TIV)
Healthy Adults
Intradermal (ID)
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: The Emmes Company, LLC
First posted: 2012-08-30
Enrollment: 316
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a Phase Ib study in healthy adults (18-70 years) to evaluate the safety, tolerability, and immunogenicity of same season and sequential season vaccination schedules consisting of the 2012/2013 seasonal influenza DNA vaccine (HA DNA) and licensed trivalent influenza vaccine (TIV) administered intradermally (ID) or intramuscularly (IM). The hypothesis is that evaluation of these investigational schedules will inform development of novel influenza vaccine strategies that may offer improved and cross-protective immunity against antigenically diverse influenza strains.

Detailed description: Vaccines are an effective way to prevent influenza infection. Each year the World Health Organization (WHO) and the U.S FDA recommend the influenza strains to include in the seasonal influenza vaccines. The licensed seasonal influenza vaccines are directed against 3 influenza virus strains: an influenza A H1N1, an influenza A H3N2, and an influenza B. The currently approved vaccines depend upon labor-intensive methods that limit manufacturing speed and capacity. Influenza vaccines that can be more rapidly produced and that induce stronger, broader and more persistent immune responses are a recognized public health need.

In this protocol we propose to use DNA vaccine antigen delivery to induce immune responses against native hemagglutinin (HA) structures prior to boosting with licensed TIV ID or with TIV IM.

The study will allow evaluation of the safety and immunogenicity of same season and sequential season vaccination schedules. The same season regimens (2012/13 prime and boost with a 14 week interval) consist of HA DNA prime with TIV ID boost -- or -- HA DNA prime with TIV IM boost. The active comparator for these schedules are TIV ID or TIV IM alone because a single dose of TIV is the standard for adult influenza vaccination within a single season. The sequential season regimens (2012/13 prime and 2013/14 boost) consist of concurrent administration (in different arms) of HA DNA and TIV ID prime with TIV ID boost -- or -- HA DNA and TIV IM prime with TIV IM boost. The active comparator for these regimens will be TIV ID followed by TIV ID boost -- or -- TIV IM followed by TIV IM boost, administered sequential seasons consistent with as typical pattern of use for these licensed vaccines. Evaluation of the investigational schedules and active comparator schedules will inform development of novel influenza vaccine strategies that may offer improved and cross-protective immunity against diverse influenza strains.

Eligibility criteria: Inclusion Criteria:

A subject must meet all of the following criteria:

* Healthy adults, 18 to 70 years old; volunteers who will be older than 64 during the 2013/2014 influenza season will not be enrolled after 11/16/2012.
* Available for clinical follow-up
* Able and willing to complete the informed consent process
* Willing to donate blood for sample storage to be used for future research
* Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) ≤40 within the 70 days prior to enrollment
* Has not yet received the current year (2012/13) influenza vaccine prior to enrollment and agrees to receive seasonal influenza vaccines during study participation only from the study site

Laboratory Criteria within 70 days prior to enrollment:

* Hemoglobin within institutional normal limits
* White blood cells either within institutional normal range or accompanied by site physician approval as consistent with healthy adult status
* Platelets = 125,000 - 500,000/mm3
* Alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
* Serum creatinine ≤ 1 x ULN based on site institutional normal range

Criteria applicable to women of childbearing potential:

* Negative human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day of enrollment
* Agree to use an effective means of birth control from 21 days prior to enrollment through 3 weeks after the second study vaccination

Exclusion Criteria:

A subject will be excluded if one or more of the following conditions apply:

Women Specific:

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

Subject has received any of the following substances:

* More than 10 days of systemic immunosuppressive medications or cytotoxic medications within the 12 weeks prior to enrollment or any within the 14 days prior to enrollment
* Blood products within 16 weeks prior to enrollment
* Immunoglobulin within 8 weeks prior to enrollment
* Investigational research agents within 28 days (4 weeks) prior to enrollment or planning to receive investigational products while on the study.
* Allergy treatment with antigen injections, unless on maintenance schedule and allergy shots could be staggered with the study vaccinations, within 14 days (2 weeks) prior to enrollment
* Current anti-tuberculosis (TB) prophylaxis or therapy

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

* Contraindication to receiving an FDA-approved seasonal influenza vaccination
* Serious reactions to vaccines that preclude receipt of study vaccinations, as determined by the site investigator
* Hereditary angioedema (HAE), acquired angioedema (AAE), or idiopathic forms of angioedema
* Asthma that is severe, unstable or required emergent care, urgent care, hospitalization or intubation during the previous two years or that is expected to require the use of oral, intravenous or high dose inhaled corticosteroids
* Diabetes mellitus type I
* Thyroid disease that is not well-controlled
* Generalized idiopathic urticaria within the 1 year prior to enrollment
* Hypertension that is not well controlled
* 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, or use of blood thinners such as Coumadin or Plavix®
* Malignancy that is active or treated malignancy for which there is not reasonable assurance of sustained cure or malignancy that is likely to recur during the period of the study
* Seizure disorder other than: 1) febrile seizures, 2) seizures secondary to alcohol withdrawal more than 3 years ago, or 3) seizures for which no treatment has been required within the 3 years prior to enrollment
* Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen
* Guillain-Barré Syndrome
* Psychiatric condition that precludes compliance with the protocol; past or present psychoses; disorder requiring lithium; or within 5 years prior to enrollment, a history of suicide plan or attempt
* Any medical, psychiatric, or other condition that, in the judgment of the investigator, is a contraindication to protocol participation or impairs ability to give informed consent

Primary outcomes:
measure: Incidence of solicited adverse events after the first injection
timeFrame: Day 0 to Day 7
measure: Incidence of solicited adverse events after the second injection
timeFrame: Day of injection to 7 days after second injection
measure: Incidence of unsolicited adverse events of any severity 28 days after the first injection
timeFrame: Day 0 to Day 28
measure: Incidence of unsolicited adverse events of any severity for 28 days after the second injection
timeFrame: Day of injection to 28 days after injection
measure: Incidence of serious adverse events or new chronic medical conditions through 24 weeks after the 2nd injection
timeFrame: Day 0 to 24 weeks after second injection
measure: Number of subjects with influenza or influenza-like illnesses (ILI)
timeFrame: Day 0 to 24 weeks after second injection
measure: Mean change from baseline in safety laboratory measures
timeFrame: Day 21
measure: Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2)
timeFrame: Day 119
measure: Proportion of subjects with seroconversion for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4)
timeFrame: Day 21
measure: Geometric Mean HAI Titer for each of the 2012/13 influenza vaccine strains (Group 1 and Group 2)
timeFrame: Day 119
measure: Geometric Mean HAI titer for each of the 2012/13 influenza vaccine strains (Group 3 and Group 4)
timeFrame: 3 weeks after completion of the HA DNA prime, Day 21
Secondary outcomes:
measure: Seroconversion for each of the 2012/13 and 2013/14 influenza vaccine strains
timeFrame: 3 weeks after each study injection
measure: Geometric Mean HAI Titer for each of the 2012/13 and 2013/14 influenza vaccine strains
timeFrame: 3 weeks after each study injection
measure: Proportion of subjects with four-fold rise from baseline for each of the 2012/13 and 2013/14 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies
timeFrame: 3 weeks after each study injection
measure: Geometric Mean neutralization titer of 2012/13 and 2013/14 influenza vaccine strain-specific H1, H3, and B neutralizing antibodies
timeFrame: 3 weeks after each study injection
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Saint Louis
country: United States
facility: Saint Louis University - Doisy Research Center
state: Missouri
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Chief, Clinical Trials Core Vaccine Research Center, NIAID, NIH
name: Barney S Graham, M.D., Ph.D.
role: STUDY_DIRECTOR
affiliation: Deputy Chief, Clinical Trials Core Vaccine Research Center, NIAID, NIH
name: Julie Ledgerwood, DO
role: STUDY_CHAIR
References:
citation: Ledgerwood JE, Wei CJ, Hu Z, Gordon IJ, Enama ME, Hendel CS, McTamney PM, Pearce MB, Yassine HM, Boyington JC, Bailer R, Tumpey TM, Koup RA, Mascola JR, Nabel GJ, Graham BS; VRC 306 Study Team. DNA priming and influenza vaccine immunogenicity: two phase 1 open label randomised clinical trials. Lancet Infect Dis. 2011 Dec;11(12):916-24. doi: 10.1016/S1473-3099(11)70240-7. Epub 2011 Oct 3.
citation: Ledgerwood JE, Graham BS. DNA vaccines: a safe and efficient platform technology for responding to emerging infectious diseases. Hum Vaccin. 2009 Sep;5(9):623-6. doi: 10.4161/hv.8627. No abstract available.
citation: Carter C, Houser KV, Yamshchikov GV, Bellamy AR, May J, Enama ME, Sarwar U, Larkin B, Bailer RT, Koup R, Chen GL, Patel SM, Winokur P, Belshe R, Dekker CL, Graham BS, Ledgerwood JE; VRC 703 study team. Safety and immunogenicity of investigational seasonal influenza hemagglutinin DNA vaccine followed by trivalent inactivated vaccine administered intradermally or intramuscularly in healthy adults: An open-label randomized phase 1 clinical trial. PLoS One. 2019 Sep 18;14(9):e0222178. doi: 10.1371/journal.pone.0222178. eCollection 2019.