Vaccine Pandemic Preparedness Through Airway Immunological Characterization

Study Overview
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Brief Summary
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The study aims to compare the effectiveness of live attenuated influenza vaccines (LAIV) and injected-inactivated vaccines (IIV) in healthy individuals aged 20-40. It will investigate cellular and humoral responses, identify immunological markers for targeted vaccine improvement, and establish a collaborative platform for accelerated immunological and clinical vaccine research.

Detailed Description
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There are several types of vaccines and the focus on the important role of vaccines in health has increased after the SARS-CoV-2 pandemic. Therefore, it is desired to investigate whether so-called 'live attenuated influenza vaccines' (LAIV) can prove more effective than the most frequently used 'injected-inactivated vaccines' (IIV). Several studies have previously compared the humoral and cellular response to LAIV and IIV and some of these have shown that LAIV elicits a more robust cellular response than intramuscularly administered vaccines. In the study, the immunological differences in cellular and humoral response following vaccination either intramuscularly or nasally will be characterized. The patient group will consist of healthy individuals between 20-40 years of age. It is further desired to identify immunological markers that vaccines can be directed against in order to improve the immunological response. Finally, a platform for collaboration on accelerated immunological and clinical vaccine research will be established. The study is a randomized, double-blind, placebo-controlled study. It is carried out in several locations and is Good Clinical Practice monitored.

Official Title
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In-depth Immunological Analysis of Airway Immunity Following Nasal Live Attenuated and Intramuscular Influenza Vaccine

Conditions
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Influenza, Human

Intervention / Treatment
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* Biological: Vaxigripetra
* Biological: Flumist


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have not received any influenza vaccines as per medical history and documented in The Danish Vaccine Registry(DDV) Exclusion Criteria: Laboratory-confirmed influenza infection during the past year documented by a positive PCR test in the Danish Microbiological database Total IgG levels < 6.1 g/L obtaining at screening visit Influenza specific IgA in upper quartile in mucosa. Upper quartile will be defined real time in the screening population Active smoker BMI > 35 Charlson (score > 0) Women of childbearing potential not using safe contraception, or who are pregnant, or breast-feeding Any allergies to components of or contraindication for Vaxigriptetra® or Flumist® Participants who have experienced severe adverse reactions to previous influenza vaccinations or components of the vaccines, including allergy to egg Use of immunosuppressive drugs1 within the past 6 months or who are currently using them Known immunodeficiency disorders [any diagnosis that would qualify to an ICD-10 diagnosis in the categories DD80-DD89 (except DD86) HIV, HBV, HCV laboatory confirm active infection at screening visit Have an acute illness, including an oral temperature ≥ 38°C, within 3 days prior to vaccination Have received any vaccines, including live-attenuated vaccines within 4 weeks before inclusion, or plan receipt of such vaccines within 30 days following the inclusion Any known malignant neoplasm within 5 years (except basal carcinoma of the skin). Severe mental illness or linguistic issues which significantly impedes cooperation Inability to provide written informed consent Previous medical history, evidence of an intercurrent illness or any condition that, in the opinion of the investigator, would interfere with evaluation of the study vaccine products or interpretation of subject safety or that may compromise the safety of the subject in the study.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2-arm randomized controlled, multicenter, parallel group intervention study in patients aged between 20-40 who have not received influenza vaccines as registered in The Danish Vaccine Registry(DDV). Participants will be randomly allocated to one of four treatment groups.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaxigripetra<br>This arm will receive 1 dose of 0.5 mL Vaxigripetra (intra-muscular injection) and 1 dose of 0.2 mL placebo (nasal, 1 spray in each nostril). | Biological: Vaxigripetra<br>* Tetravalent intramuscular vaccine. Mechanism of action: The vaccine induces an immune reaction involving antibody production.<br>|
| Experimental: Flumist<br>This arm will receive 1 dose of 0.5 mL placebo (intra-muscular injection) and 1 dose of 0.2 mL Flumist (nasal, 1 spray in each nostril). | Biological: Flumist<br>* Tetravalent live attenuated influenza vaccine administered as a nasal spray. Mechanism of action: Not fully understood according to the prescribing information, but may involve influenza-specific T-cells and antibodies (serum and mucosal).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antigen activated CD4+ T-lymphocytes | Cellular, measured at -14, day +7, day +28(+/-5 days) and day +90(+/- 5 days) | 3 months | 
| Rise in mucosal antibody response(IgG and IgA) | Humoral, number of participants with ≥ four-fold rise in mucosal antibody titer against each vaccine virus haemagglutinin antigens vaccine-specific antibody(IgG and IgA) titers in respiratory secretions measured using antibody titer at -14, day +7, day +28(+/- 5 days) and day 90(+/- 5 days) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukocyte cell subsets, incl. B- and T-cell subsets and activation patterns | Cellular, quantification and characterization of leukocyte cell subsets, incl T- and B-cell subsets and activation patterns, using highly standardized flowcytometry in combination with single cell RNAsequencing (scRNAseq) analysis coupled with single cell surface marker profiling (CITEseq or similar platform) for in-depth characterization of immune cell subsets measured at -14, day +7 day +28 (+/-5 days) and day +90 (+/-5 days) after vaccination. | 3 months | 
| Rise in antibody response(IgG) measured in serum | Humoral, Number of participants with ≥-four-fold rise in serum antibody titers against each vaccine virus haemagglutinin antigens vaccine-specific antibody (IgG) titers in serum measured using antibody titer measured measured at -14, day +7 day +28 (+/-5 days) and day +90 (+/-5 days) after vaccination. | 3 months |