Influenza HA Ferritin Vaccine, Alone or in Prime-Boost Regimens With an Influenza DNA Vaccine in Healthy Adults

VRC 316: A Phase I Open-Label Clinical Trial To Evaluate Dose, Safety, Tolerability, And Immunogenicity Of An Influenza HA Ferritin Vaccine, Alone Or In Prime-Boost Regimens With An Influenza DNA Vaccine In Healthy Adults

Background:

Influenza, or "flu", is a very common infectious respiratory disease. Researchers want to develop a vaccine against flu. Vaccines teach the body to fight or prevent an infection. When the body learns to fight an infection, this is called an immune response. In this study, researchers want to test two new vaccines to help the body make an immune response to flu.

Subjects received the vaccine injections in the upper arm muscle. One vaccine, the influenza HA Ferritin vaccine (HA-F A/Sing), was given to all subjects with a needle injection. The other vaccine, influenza DNA vaccine (DNA A/Sing), was given to subjects in Group 3 by a needle-free device that uses high pressure to push the vaccine through the skin and into the muscle.

Objective:

To test the safety and side effects of two new vaccines for prevention of H2 influenza (flu).

Eligibility:

Part I: Healthy adults ages 18-47 born after 1969.

Part II: Healthy adults ages 18-70, but not born in 1966-1969.

Design:

Volunteers were tested for eligibility in a separate screening protocol.

In Part I, all subjects received injections of HA Ferritin vaccine. These subjects were not expected to have H2N2 exposure based on their age and when H2N2 last circulated in the population. Five subjects in Group 1 received one injection of 20 mcg dose vaccine at Day 0 to test if it is safe. Then, five additional subjects in Group 2 received a total of two injections of a 60 mcg dose on Day 0 and 16 weeks later.

In Part II, responses were evaluated from adults born before 1966 who may have prior potential exposure to H2N2 influenza as well as adults similar to those enrolled in Part I who are not expected to have H2N2 exposure. Also, Part II compared responses to 2 different vaccine regimens. Group 3 subjects received a DNA influenza vaccine prime at Day 0 and the HA Ferritin vaccine boost 16 weeks later. Group 4 subjects received the HA Ferritin vaccine 2 times, on Day 0 and 16 weeks later.

Study Design: This is a Phase I open-label, dose escalation study to evaluate the dose, safety, tolerability, and immunogenicity of VRC-FLUNPF081-00-VP (HA-F A/Sing) vaccine alone or in prime-boost regimens with VRC-FLUDNA082-00-VP (DNA A/Sing) vaccine. The hypotheses are that VRC-FLUNPF081-00-VP and VRC-FLUDNA082-00-VP vaccines are safe, well-tolerated, and induce an immune response to the H2 antigen. The primary objectives are to evaluate the safety and tolerability of two different doses of the HA-F A/Sing vaccine alone and in prime-boost regimens in healthy adults. Secondary objectives are related to the evaluation of the immunogenicity of the HA-F A/Sing and DNA A/Sing vaccines in prime-boost regimens.

Study Products: The investigational HA-F A/Sing vaccine, developed by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), is composed of Helicobacter pylori non-haem ferritin with an influenza virus H2 hemagglutinin (HA) insert to form a nanoparticle displaying eight HA trimers from A/Singapore/1/57 (H2N2) influenza.

The investigational DNA A/Sing vaccine, developed by the VRC, NIAID, is composed of a single closed-circular DNA plasmid that encodes the H2 protein of A/Singapore/1/57 influenza.

Subjects: Up to 80 healthy adults ages 18-70 were enrolled; adults born between 1966 and 1969 were excluded from the trial.

Study Plan: Vaccines were administered intramuscularly (IM) in the deltoid muscle. This study has two parts:

Part I evaluated the safety, tolerability, and immunogenicity of 1 or 2 doses of the HA-F A/Sing vaccine in a dose-escalation design. In Group 1, five subjects received a 20 mcg dose of the HA-F A/Sing vaccine via needle and syringe on Day 0. If this dose was assessed as safe and well tolerated, enrollment began for Group 2. In Group 2, five subjects received the higher 60 mcg dose of the HA-F A/Sing vaccine via needle and syringe on Day 0 and Week 16. If this higher dose was assessed as safe, enrollment began for Part II.

Part II evaluated the safety, tolerability, and immunogenicity of HA-F A/Sing vaccine in prime-boost regimens. Subjects were stratified by age and randomized equally into Groups 3 and Group 4. In Group 3, subjects received DNA A/Sing vaccine via a PharmaJet Needle-Free Injector on Day 0 and HA-F A/Sing vaccine via needle and syringe on Week 16. In Group 4, subjects received HA-F A/Sing vaccine via needle and syringe on Day 0 and Week 16.

For Group 1, the protocol required about 8 clinic visits and 1 telephone follow up contact after the injection.

For Group 2, Group 3 and Group 4, the protocol required about 10 clinic visits and 2 telephone follow-up contacts after each injection.

For all Groups, solicited reactogenicity were 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.

Study Duration: Subjects were evaluated for 40 weeks following the first vaccine administration.

INCLUSION CRITERIA:

A subject must meet all of the following criteria:

• Healthy subjects aged 18-70 (excluding subjects born between 1966-1969)
• Based on history and examination, must be in good general health and without history of any of the conditions listed in the exclusion criteria
• Received at least one licensed current seasonal influenza vaccine from 2014 to the present
• Able and willing to complete the informed consent process
• Available for clinic visits for 40 weeks after enrollment
• Willing to have blood samples collected, stored indefinitely, and used for research purposes
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
• Physical examination and laboratory results without clinically significant findings and a Body Mass Index (BMI) less than or equal to 40 within the 84 days before enrollment

Laboratory Criteria within 84 days before enrollment:

• White blood cells (WBC) and differential either within institutional normal range or accompanied by the site Principal Investigator (PI) or designee approval
• Total lymphocyte count greater than or equal to 800 cells/mm^3
• Platelets = 125,000 - 500,000/mm^3
• Hemoglobin within institutional normal range
• Serum iron either within institutional normal range or accompanied by the site PI or designee approval
• Alanine aminotransferase (ALT) less than or equal to 1.25 times institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) less than or equal to 1.25 times institutional ULN
• Alkaline phosphatase (ALP) less than or equal to 1.1 times institutional ULN
• Total bilirubin within institutional ULN
• Serum creatinine less than or equal to 1.1 times institutional ULN
• Negative for HIV infection by an FDA approved method of detection

Criteria applicable to women of childbearing potential:

• Negative beta-human chorionic gonadotropin (Beta-HCG) pregnancy test (urine or serum) on the day of enrollment
• 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 subject will be excluded if one or more of the following conditions apply:

- Breast-feeding or planning to become pregnant during the study.

Subject has received any of the following substances:

• 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
• Blood products within 16 weeks prior to enrollment
• Live attenuated vaccines within 4 weeks prior to enrollment
• Inactivated vaccines within 2 weeks prior to enrollment.
• Investigational research agents within 4 weeks prior to enrollment or planning to receive investigational products while on the study
• Current allergy treatment with allergen immunotherapy with antigen injections, unless on maintenance schedule
• Current anti-tuberculosis (TB) prophylaxis or therapy
• Previous H2 influenza investigational vaccine
• Receipt of a licensed influenza vaccine within 6 weeks before trial enrollment

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

• 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 II), with the exception of gestational diabetes
• Thyroid disease that is not well controlled
• Idiopathic urticaria within the past year
• Evidence of autoimmune disease or immunodeficiency
• 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
• Malignancy that is active or history of 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 that have not required treatment within the last 3 years
• Asplenia, functional asplenia or any condition resulting in the absence or removal of the spleen
• Guillain-Barre Syndrome
• Psychiatric condition that precludes compliance with the protocol; past or present psychoses; or within 5 years prior to enrollment, a history of suicide plan or attempt
• 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.