Influenza, Vaccine Virus Shedding
Conditions
Keywords
influenza, vaccine, virus, antibody, cytokine, respiratory
Brief summary
Intranasal live attenuated influenza vaccine (LAIV; trade name FluMist/Fluenz-Tetra, manufactured by AstraZeneca/Medimmune) is the standard influenza vaccine given to children aged 2-17 years of age in the UK. It is also licensed to be given to adults up to the age of 49 years in the USA. The systems biology of the human blood response to influenza vaccines has been studied in great detail, but there is a paramount need to study innate and specific, soluble and cellular immune responses at the nasal mucosal site of influenza infection. In this way this study aims to determine correlates of efficacy and vaccine take in serum and nasal mucosal lining fluid (MLF).
Detailed description
This study will collect serial samples prior to vaccination and at intervals up to day 28 post-vaccination to establish the kinetics of the nasal mucosal and blood systemic response to LAIV in young adults aged 18-30 years (n=40). In the nose the investigators will measure viral load, soluble mediators of inflammation and antibodies (humoral immunity) in mucosal lining fluid; while cellular immune responses and serology will be assessed in blood samples. Investigators at Imperial College London (ICL) have been involved in the development of novel methods of non-invasive precision mucosal sampling, including absorption of MLF from the nose by nasosorption. The investigators have also developed assays for influenza-specific IgA by ELISA, and aim to compare this assay against a repertoire of serological assays in patients after LAIV administration. The study will precisely assess mucosal and systemic immune responses to the LAIV nasal vaccine. The primary endpoint will be based on nasal mucosal levels of IgA and IgG antibodies to the 4 constituent viral subtypes in LAIV: measured by ELISA and multiplex immunoassay (Mesoscale Diagnostics) and expressed as seroconversion rates, geometric mean titre (GMT) changes, and geometric mean fold rises (GMFR). The secondary endpoints will be: (1) haemagglutination inhibition (HAI) assay titres measured in serum and the nose, (2) influenza pseudotype neutralisation by antibodies in serum and the nose, (3) nasal cytokine and chemokine levels as measured by immunoassay and (4) nasal viral load quantified by qPCR. It is thought that the immune response to LAIV in an individual is mediated by a combination of mucosal and systemic factors, involving innate and specific mechanisms that have different kinetics, and various cell types. By understanding the molecular and cellular basis of the nasal mucosal response to LAIV, the investigators hope to identify key molecular signatures and biomarkers associated with LAIV responses, and to assess protective pathways that could be stimulated by novel vaccines. The nasal vaccine challenge model could be used to test other new vaccines, and proceed to rational development of improved vaccines for influenza and other diseases. Furthermore nasal mucosal methods could be used in the clinic to identify subjects who have responded poorly to vaccines, or to assess vaccine efficacy in large populations.
Interventions
BIOLOGICALLive attenuated influenza vaccine
Vaccination with live attenuated influenza vaccine (LAIV)
OTHERVehicle control
Vehicle control nasal challenge
Sponsors
Imperial College Healthcare NHS Trust
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
* Capacity to provide written informed consent * Aged 18-30 years (inclusive) * Fluent English speaker
Exclusion criteria
* Current involvement in another study unless observational or in follow-up phase (non-interventional) * Received any influenza vaccine over the last 2 years * Egg allergy * Previous significant adverse reaction to any vaccination/immunisation * Current regular (daily) smoker * Pregnant * Any medication that may affect the immune system (e.g. steroids) * Taking regular acetylsalicylic acid (aspirin) * Unable to give informed consent * Current acute severe febrile illness * Taking long term antibiotics * Clinically diagnosed influenza in the last 2 years * Any long-term health problem with heart disease, lung disease (including asthma), kidney disease, neurologic disease, liver disease, metabolic disease (e.g. diabetes) or anemia or another blood disorder * Use of drugs for the treatment of rheumatoid arthritis, Crohn's disease, or psoriasis or anticancer drugs; or radiation treatments * History of Guillain-Barre syndrome * Live with or expect to have close contact with a person whose immune system is severely compromised and who must be in protective isolation (e.g., an isolation room of a bone marrow transplant unit) * Received any other vaccinations in the past 4 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Shedding Each Vaccine Virus Measured by qPCR of Nasosorption Samples | 1-7 days post vaccination | Vaccine virus shedding in nasosorption samples collected between 1-7 days post-vaccination and quantified using multiplex qPCR assay measures in the LAIV vaccine recipient cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With >2-fold Rise in Mucosal and/or Serum Antibody Titre Against Each Vaccine Virus Haemagglutinin Antigens | 28 days post vaccination | Vaccine specific antibody (IgG and IgA) titres in serum and/or respiratory secretions (nasosorption and nasal wash) measured using endpoint titre and arbitrary unit level immunoassay measurements of samples collected from the n=40 LAIV vaccine recipient arm. |
Countries
United Kingdom
Participant flow
Pre-assignment details
No significant events occur after participant enrollment but prior to assignment to a study arm. Participants were not randomised for assignment to LAIV or Mucosal immune stability arms, but were assigned based on their having responded to different enrollment advertisements.
Participants by arm
| Arm | Count |
|---|---|
| Live Attenuated Influenza Vaccine Participants receiving live attenuated influenza vaccine (LAIV) were initially screened per the study protocol to ensure that inclusion and exclusion criteria were complete. Participants were then invited to the vaccination arm of the study, where n=40 participants received LAIV and completed 5 study visits each over the course of 28 days. | 40 |
| Mucosal Immune Stability Cohort In the placebo/vehicle challenge 'Mucosal immune stability' arm, a further n=8 participants attended for a single visit at which repeat nasal samples were collected to match the LAIV arm. | 8 |
| Total | 48 |
Baseline characteristics
| Characteristic | Live Attenuated Influenza Vaccine | Mucosal Immune Stability Cohort | Total |
|---|---|---|---|
| Age, Continuous | 22 years | 23 years | 22 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 8 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 30 Participants | 5 Participants | 35 Participants |
| Sex: Female, Male Male | 10 Participants | 3 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 8 |
| other Total, other adverse events | 0 / 40 | 0 / 8 |
| serious Total, serious adverse events | 0 / 40 | 0 / 8 |
Outcome results
Primary
Number of Participants Shedding Each Vaccine Virus Measured by qPCR of Nasosorption Samples
Vaccine virus shedding in nasosorption samples collected between 1-7 days post-vaccination and quantified using multiplex qPCR assay measures in the LAIV vaccine recipient cohort.
Time frame: 1-7 days post vaccination
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Live Attenuated Influenza Vaccine | Number of Participants Shedding Each Vaccine Virus Measured by qPCR of Nasosorption Samples | 31 participants |
Secondary
Number of Participants With >2-fold Rise in Mucosal and/or Serum Antibody Titre Against Each Vaccine Virus Haemagglutinin Antigens
Vaccine specific antibody (IgG and IgA) titres in serum and/or respiratory secretions (nasosorption and nasal wash) measured using endpoint titre and arbitrary unit level immunoassay measurements of samples collected from the n=40 LAIV vaccine recipient arm.
Time frame: 28 days post vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Live Attenuated Influenza Vaccine | Number of Participants With >2-fold Rise in Mucosal and/or Serum Antibody Titre Against Each Vaccine Virus Haemagglutinin Antigens | 28 Participants |