Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy Volunteers

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT02385123

Collaborator

(none)

Enrollment

Location

Arm

Actual Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open label, single arm, study of longitudinal immunologic responses to influenza vaccine in healthy adult subjects. This study will enroll males and non-pregnant females, 18-49 years old. The subjects will be screened at enrollment with a history and physical exam and laboratory testing to ensure they are healthy enough to participate. Qualifying subjects will be vaccinated with an FDA approved seasonal inactivated influenza vaccine (IIV) according to the package insert. The study will enroll 10 healthy volunteers per vaccination season in years 1, 2, and 4; as well as 20 healthy volunteers per vaccination season in years 5 and 6 of this study, for a total enrollment of 70 subjects. The primary objective of the study is to characterize HA-specific plasmablasts and memory B cells after influenza vaccination.

Condition or Disease	Intervention/Treatment	Phase
Influenza Influenza Immunisation	Biological: Influenza Virus Vaccine Inactivated	Phase 4

Detailed Description

This is an open label, single arm, study of longitudinal immunologic responses to influenza vaccine in healthy adult subjects. This study will enroll males and non-pregnant females, 18-49 years old. The study duration is 6 years and participant duration of 180 days. The subjects will be screened at enrollment with a history and physical exam and laboratory testing to ensure they are healthy enough to participate. Qualifying subjects will be vaccinated with an FDA approved seasonal inactivated influenza vaccine (IIV) according to the package insert. Approximately 450 ml of blood will be collected for the research assays during the course of the study. Specifically, 16 ml will be collected for screening; 48ml will be collected at enrollment; 96ml will be collected at visit days 7 and 14; and 64 ml will be collected at 28, 90, and 180 days post vaccination. The study will enroll 10 healthy volunteers per vaccination season in years 1, 2, and 4; as well as 20 healthy volunteers per vaccination season in years 5 and 6 of this study, for a total enrollment of 70 subjects. Individuals who complete the study will be given the option to re-enroll in subsequent years as long as they continue to meet all inclusion/exclusion criteria. Re-enrolling subjects will be re-consented, given new subject identifiers, and counted towards the enrollment number goal for each year of participation. Due to the COVID-19 pandemic, all non-essential research was halted in mid-March 2020. New enrollments were placed on hold for this study. The primary objective of the study is to characterize HA-specific plasmablasts and memory B cells after influenza vaccination and the secondary objective is to investigate the longevity of humoral immunity to influenza virus in humans.

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Evaluation of Human Immune Responses to Influenza Virus Vaccination in Healthy Volunteers

Actual Study Start Date :

Apr 1, 2015

Actual Primary Completion Date :

Dec 6, 2019

Actual Study Completion Date :

Dec 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Seasonal flu vaccine 0.5 ml of seasonal inactivated influenza vaccine (IIV) will be administered intramuscularly (IM) on day 0 of each study season. The study will enroll 10 subjects each season, in years 1, 2, 4 ,5, and 6 of the study for a total of n=50.	Biological: Influenza Virus Vaccine Inactivated A synthetic vaccine consisting of three inactivated influenza viruses: two different influenza type A strains and one influenza type B strain. Trivalent influenza vaccine is formulated annually, based on influenza strains projected to be prevalent in the upcoming flu season.

Arm

Intervention/Treatment

Experimental: Seasonal flu vaccine

0.5 ml of seasonal inactivated influenza vaccine (IIV) will be administered intramuscularly (IM) on day 0 of each study season. The study will enroll 10 subjects each season, in years 1, 2, 4 ,5, and 6 of the study for a total of n=50.

Biological: Influenza Virus Vaccine Inactivated

A synthetic vaccine consisting of three inactivated influenza viruses: two different influenza type A strains and one influenza type B strain. Trivalent influenza vaccine is formulated annually, based on influenza strains projected to be prevalent in the upcoming flu season.

Outcome Measures

Primary Outcome Measures

Percentage of subjects achieving seroconversion (pre-vaccination Hemagglutination Inhibition (HI) titer < 1:10 and a post-vaccination HI titer > 1:40 or a pre-vaccination HI titer > 1:10 and a minimum four-fold rise in post-vaccination HI antibody titer) [Day 28]
Percentage of subjects achieving seroconversion (pre-vaccination Hemagglutination Inhibition (HI) titer < 1:10 and a post-vaccination HI titer > 1:40 or pre-vaccination HI titer > 1:10 and a minimum four-fold rise in post-vaccination HI antibody titer) [Day 0]

Secondary Outcome Measures

Endpoint IgG titers for serum antibody responses directed against the hemagglutinin (HA) head regions [Day 0]
Endpoint IgG titers for serum antibody responses directed against the hemagglutinin (HA) head regions [Day 180]
Endpoint IgG titers for serum antibody responses directed against the hemagglutinin (HA) head regions [Day 28]
Endpoint IgG titers for serum antibody responses directed against the hemagglutinin (HA) stem regions [Day 0]
Endpoint IgG titers for serum antibody responses directed against the hemagglutinin (HA) stem regions [Day 180]
Endpoint IgG titers for serum antibody responses directed against the hemagglutinin (HA) stem regions [Day 28]
Expression of human influenza-specific monoclonal antibodies from plasmablasts [Day 7]
Frequency of hemagglutinin (HA) head-specific IgG secreting memory B cells per total IgG secreting cells [Day 0]
Frequency of hemagglutinin (HA) head-specific IgG secreting memory B cells per total IgG secreting cells [Day 180]
Frequency of hemagglutinin (HA) head-specific IgG secreting memory B cells per total IgG secreting cells [Day 28]
Frequency of hemagglutinin (HA) stem-specific IgG secreting memory B cells per total IgG secreting cells [Day 0]
Frequency of hemagglutinin (HA) stem-specific IgG secreting memory B cells per total IgG secreting cells [Day 180]
Frequency of hemagglutinin (HA) stem-specific IgG secreting memory B cells per total IgG secreting cells [Day 28]
Function of human influenza- specific monoclonal antibodies assessed by virus neutralization assay [Day 7]
Function of human influenza-specific monoclonal antibodies assessed by Enzyme-Linked Immunosorbent Assay (ELISA) [Day 7]
Function of human influenza-specific monoclonal antibodies assessed by Hemagglutination Inhibition (HAI) assay [Day 7]
Influenza hemagglutinin head-specific memory B-cells level [Day 0]
Influenza hemagglutinin head-specific memory B-cells level [Day 180]
Influenza hemagglutinin head-specific memory B-cells level [Day 28]
Influenza hemagglutinin serum antibody level [Day 0]
Influenza hemagglutinin serum antibody level [Day 180]
Influenza hemagglutinin serum antibody level [Day 28]
Influenza hemagglutinin stem-specific memory B-cells level [Day 0]
Influenza hemagglutinin stem-specific memory B-cells level [Day 180]
Influenza hemagglutinin stem-specific memory B-cells level [Day 28]
Plasmablast responses against hemagglutinin (HA) head antigens assessed by direct ex vivo enzyme-linked immunospot (ELISPOT) [Day 7]
Plasmablast responses against hemagglutinin (HA) stem anitgens assessed by direct ex vivo enzyme-linked immunospot (ELISPOT) [Day 7]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 49 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Male or female subjects between 18 and 49 years of age, inclusive.
Subjects capable of providing written informed consent prior to initiation of any study procedures. Subjects able to understand and comply with planned study procedures and be available for all study visits.
Screening labs within normal limits per the local laboratory normal ranges or considered to be not clinically significant by the investigator. Normal laboratory ranges are as listed below:

A. Hematology:

Hemoglobin: Male- 12.9-16.1 gm/dL, Female- 11.4-14.4 gm/dL
White blood cells (WBC): Male- 4.2-9.2/uL, Female- 4-10/uL
Platelet count: 150-400/uL

B. Chemistries:

Kidney function:Glomerular filtration rate (GFR) > / = 60 mL/min/1.73 m^2;
Liver enzymes: Albumin > / = 3.5 g/dL; ALT <66 U/L; AST <62 U/L

Subjects who have not received the seasonal influenza vaccine in the current flu season and are not suspected to have had an influenza infection in the current flu season.
Female subjects of child bearing potential must have a negative urine pregnancy test at the screening visit, enrollment visit and all subsequent study visits longer than 14 days since the last pregnancy test.

Exclusion Criteria:

Known infection with HIV, HCV, or HBV. This information will be obtained verbally from the patient.
If female, active pregnancy or breast-feeding or plans to become pregnant during study participation.
Chronic medical conditions that cause immunodeficiency or that require medications which could alter immune function such as immunosuppressants and immunoenhancers.
Have any medical disease or condition that, in the opinion of the site principal investigator or appropriate sub-investigator, is a contraindication to study participation. This includes any chronic medical disease or condition, defined as persisting 3 months (defined as 90 days) or longer, 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 this study
Have an acute illness, as determined by the site principal investigator or appropriate sub-investigator, within 72 hours prior to study vaccination. An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site principal investigator or appropriate subinvestigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
Persons taking anticoagulants, long-term aspirin therapy, or long-term systemic steroids (greater than 3 months in the past 12 months and any within 30 days).
Have known hypersensitivity or allergy to eggs, egg or chicken protein, or other components of the study vaccine;
Have a known latex allergy;
Have a history of severe reactions following previous immunization with licensed influenza virus vaccines.
Have a history of Guillain-Barre syndrome.
Subjects who had or are suspected to have had an influenza infection in the current influenza season.
Subjects who, at screening, have abnormal vital signs and/or physical exam, including a temperature > / = 38.0 C, Systolic blood pressure < / = 90 or > / = 160 mmHg, pulse < / = 60 or > 110 beats per minute, new rash, signs of infection.
Subjects who have already received the seasonal influenza vaccine in the current influenza vaccination season.