Clinical trial NCT05110911: Does Repeat Influenza Vaccination Constrain Influenza Immune Responses and Protection
Official title: Does Repeat Influenza Vaccination Constrain Influenza Immune Responses and Protection
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Influenza, Human
SARS-CoV-2 Infection
Keywords: Vaccine Response Impaired
Influenza, Human
Health Personnel
Influenza Vaccines
SARS-CoV-2 Infection
Immunologic Memory
Vaccination
Lead sponsor: University of Melbourne
Sponsor class: OTHER
Collaborators: name: The University of Queensland
name: Sydney Children's Hospitals Network
name: The Alfred
name: University of Adelaide
name: The University of Western Australia
name: London School of Hygiene and Tropical Medicine
name: University of Newcastle, Australia
First posted: 2021-11-08
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Healthcare workers (including staff, honorary staff, students and volunteers) from six participating hospitals (or healthcare services) who are eligible for the hospitals' free vaccination programmes, at the time of recruitment.

Brief summary: The objectives of this study are to understand the long-term consequences of repeated annual influenza vaccination among healthcare workers (HCWs) and to use statistical and mathematical modelling to elucidate the immunological processes that underlie vaccination responses and their implications for vaccination effectiveness. These objectives will be achieved by pursuing three specific aims:

1. To study the immunogenicity and effectiveness of influenza vaccination by prior vaccination experience
2. To characterize immunological profiles associated with vaccination and infection
3. To evaluate the impact of immunity on vaccination effectiveness.

Under Aim 1, a cohort of hospital workers will be recruited and followed for up to 4 years to assess their pre- and post-vaccination and post-season antibody responses, and their risk of influenza infection. These outcomes will be compared by vaccination experience, classified as frequently vaccinated (received ≥3 vaccines in the past 5 years), infrequently vaccinated (\<3 vaccinations in past 5 years), vaccinated once, vaccine naïve and unvaccinated.

In Aim 2, intensive cellular and serological assessments will be conducted to dissect the influenza HA-reactive B cell and antibody response, and build antibody landscapes that typify the different vaccination groups.

In Aim 3, the data generated in Aims 1 and 2 will be used to develop a mathematical model that considers prior infection, vaccination history, antibody kinetics, and antigenic distance to understand the effects of repeated vaccination on vaccine effectiveness.

Completion of the proposed research will provide evidence to inform decisions about continued support for influenza vaccination programs among HCWs and general policies for annual influenza vaccination, as well as much needed clarity about the effects of repeated vaccination.

In March-April 2020 pursuant to the SARS-CoV-2 global pandemic an administrative supplement added a SARS-CoV-2 protocol addendum for follow-up of COVID-19 infections amongst our HCW participant cohort.

The following objectives were added:

1. To estimate risk factors and correlates of protection for SARS-CoV-2 infection amongst HCW
2. To characterize viral kinetics and within-host viral dynamics of SARS-CoV-2 infecting HCW
3. To characterize immunological profiles following infection by SARS-CoV-2
4. To characterize immunological profiles following vaccination for SARS-CoV-2.

Detailed description: Over 140 million Americans are among the more than 500 million people who receive influenza vaccines annually. An important subgroup are healthcare workers (HCWs) for whom vaccination is recommended, and sometimes mandated, to protect themselves and vulnerable patients from influenza infection. However, there have been no large, long term studies of HCWs to support the effectiveness of these policies. HCWs are now a highly vaccinated population, the effects of which are also poorly understood. Mounting evidence suggests antibody responses to vaccination can be attenuated with repeated vaccination, which is corroborated by reports of poor vaccine effectiveness among the repeatedly vaccinated. Thus, there is a compelling need to directly evaluate HCW vaccination programs. The long term goal is to improve the efficient and effective use of influenza vaccines.

The specific objectives of this study are to understand the long-term consequences of repeated annual influenza vaccination among HCWs and to use statistical and mathematical modeling to elucidate the immunological processes that underlie vaccination responses and their implications for vaccination effectiveness. These objectives will be achieved by pursuing three specific aims:

1. To study the immunogenicity and effectiveness of influenza vaccination by prior vaccination experience
2. To characterize immunological profiles associated with vaccination and infection
3. To evaluate the impact of immunity on vaccination effectiveness.

Under Aim 1, a cohort of hospital workers will be recruited and followed for up to 4 years to assess their pre- and post-vaccination and post-season antibody responses, and their risk of influenza infection. These outcomes will be compared by vaccination experience, classified as frequently vaccinated (received ≥3 vaccines in the past 5 years), infrequently vaccinated (\<3 vaccinations in past 5 years), vaccinated once, vaccine naïve and unvaccinated.

In Aim 2, intensive cellular and serological assessments will be conducted to dissect the influenza HA-reactive B cell and antibody response, and build antibody landscapes that typify the different vaccination groups.

In Aim 3, the data generated in Aims 1 and 2 will be used to develop a mathematical model that considers prior infection, vaccination history, antibody kinetics, and antigenic distance to understand the effects of repeated vaccination on vaccine effectiveness. This approach is innovative because it will provide insights into the effect of complex immunological dynamics on infection outcomes, thereby representing a novel departure from previous studies, which have ignored these difficult-to-measure processes. Completion of the proposed research will provide evidence to inform decisions about continued support for influenza vaccination programs among HCWs and general policies for annual influenza vaccination, as well as much needed clarity about the effects of repeated vaccination.

In March-April 2020 pursuant to the SARS-CoV-2 global pandemic an administrative supplement added a SARS-CoV-2 protocol addendum for follow-up of COVID-19 infections amongst our HCW participant cohort.

The following objectives were added under the supplement IRB application:

1. To estimate risk factors and correlates of protection for SARS-CoV-2 infection amongst HCW
2. To characterize viral kinetics and within-host viral dynamics of SARS-CoV-2 infecting HCW
3. To characterize immunological profiles following infection by SARS-CoV-2
4. To characterize immunological profiles following vaccination for SARS-CoV-2.

Eligibility criteria: Inclusion Criteria:

Eligible participants will be recruited from 1 of 6 participating hospitals and will meet the following criteria:

* Personnel (including staff, honorary staff, students and volunteers) located at a participating hospital or healthcare service at the time of recruitment who would be eligible for the hospital's free vaccination programme
* Be aged ≥18 years old and ≤60 years old;
* Have a mobile phone that can receive and send SMS messages;
* Willing and able to provide blood samples;
* Available for follow-up over the next 7 months;
* Able and willing to complete the informed consent process.

There are no restrictions on the type of healthcare worker (HCW) that can be recruited into the study in terms of their job role. HCWs can be any hospital staff, including clinical, research, administrative and support staff.

Exclusion Criteria:

* Immunosuppressive treatment (including systemic corticosteroids) within the past 6 months;
* Personnel for whom vaccination is contraindicated at the time of recruitment.

Primary outcomes:
measure: Seropositivity post-vaccination (influenza vaccine)
timeFrame: Post-vaccination blood draws are at 14-21 days post vaccination. Collected each year 2020-2023 post annual influenza vaccination.
measure: Seropositivity post-season (influenza vaccine)
timeFrame: End of the season blood draws are in October or November each year, at the conclusion of Australia's annual influenza season. Vaccination usually occurs in April or May. Collected each year 2020-2023 post annual influenza season.
measure: Fold-rise in geometric mean antibody titre (GMT) pre- to post-vaccination
timeFrame: Changes from day 0 to day 14-21 post influenza vaccination. Collected each year 2020-2023 pre and post annual influenza vaccination.
measure: Fold-change in geometric mean antibody titre (GMT) post-vaccination to post-season
timeFrame: Changes from day 14-21 to post-season. Influenza season in Australia is approximately May to November. Pre-vaccination to post-season is approximately April or May to October or November each year. Collected each year 2020-2023.
measure: Seroconversion fraction post-vaccination
timeFrame: Changes from day 0 to day 14-21 post influenza vaccination. Collected each year 2020-2023 pre and post annual influenza vaccination.
Secondary outcomes:
measure: Healthcare workers (HCWs) PCR-positive for influenza at the end of each season
timeFrame: Influenza season in Australia is approximately May to November. Follow up for PCR-positives from approximately April/May to October/November each year from 2020-2023.
measure: Influenza attack rate at the end of each season
timeFrame: Person-time at risk, during influenza season. Influenza season in Australia is approximately May to November. Follow up for PCR-positives from approximately April/May to October/November each year from 2020-2023.
measure: Vaccine efficacy (VE)
timeFrame: Person-time at risk, during influenza season. Influenza season in Australia is approximately May to November. Follow up for PCR-positives from approximately April/May to October/November each year from 2020-2023.
measure: Duration of illness (influenza)
timeFrame: Days ill, during influenza season. Influenza season in Australia is approximately May to November. Follow up for PCR-positives from approximately April/May to October/November each year from 2020-2023.
measure: Haemagglutinin (HA) antibody landscapes for vaccine-naïve and highly-vaccinated healthcare workers (HCWs)
timeFrame: Bloods on day 0, day 7, day 14-21 post influenza vaccination and end of season. Collected each year 2020-2023 pre and post annual influenza vaccination and end of influenza season.
measure: Haemagglutinin (HA) antibody landscapes for infected versus uninfected healthcare workers (HCWs)
timeFrame: Bloods on day 7 and day 14-21 post influenza infection. Collected each year 2020-2023 along with pre and post annual influenza vaccination and end of influenza season bloods.
measure: Enumeration of cells
timeFrame: Bloods on day 0 and day 14-21 post influenza vaccination and post infection. The key indicator is the frequency of these B cells on day 14 post-vaccination relative to pre-vaccination frequencies. Collected each year 2020-2023.
measure: B cells
timeFrame: Blood draws on day 7 post influenza vaccination and post infection. Collected each year 2020-2023.
measure: Quantify biological mechanisms that shape the antibody response
timeFrame: Bloods on day 0, day 7, day 14-21 post influenza vaccination, day 7, day 14-21 post infection and end of season. Collected each year 2020-2023.
measure: Estimate protective titres
timeFrame: Bloods on day 0, day 7, day 14-21 post influenza vaccination, day 7, day 14-21 post infection and end of season. Collected each year 2020-2023.
measure: Optimal influenza vaccination strategy for healthcare workers (HCWs) under different vaccine availability
timeFrame: Bloods on day 0, day 7, day 14-21 post influenza vaccination, day 7, day 14-21 post infection and end of season. Collected each year 2020-2023.
measure: Estimated SARS-CoV-2 attack rates among symptomatic and asymptomatic healthcare workers (HCWs)
timeFrame: Follow-up period 2020-2023.
measure: Case-hospitalization risk
timeFrame: Follow-up period 2020-2023.
measure: Risk factors for asymptomatic, mild and severe SARS-CoV-2 infection
timeFrame: Follow-up period 2020-2023.
measure: Estimated SARS-CoV-2 antibody titre associated with protection
timeFrame: Follow-up period 2020-2023.
measure: Estimated SARS-CoV-2 antibody kinetics over time
timeFrame: Bloods on day 3, day 7, day 14-21, day 30 post infection and end of season. Daily swabs during symptomatic infection to two days post resolution of symptoms. Follow-up period 2020-2023.
measure: Identification of key behavioural drivers of transmission
timeFrame: Follow-up period 2020-2023.
measure: Estimated duration of viral shedding and viral load in SARS-CoV-2 infection over time
timeFrame: During symptomatic infection to two days post resolution of symptoms. Follow-up period 2020-2023.
measure: Enumeration of SARS-CoV-2-reactive B and T cells and identification of dominant epitopes
timeFrame: Bloods on day 3, day 7, day 14-21, day 30 post infection and end of season. Follow-up period 2020-2023.
measure: Gene expression
timeFrame: Changes from day 0 to day 7 post vaccination. Follow-up period 2020-2023.
measure: Enumeration of SARS-CoV-2-reactive B and T cells induced by each vaccine formulation
timeFrame: Specific B and T cells detected at day 14-21 post vaccine schedule completion versus day 0. Follow-up period 2020-2023.
measure: Seroconversion of SARS-CoV-2 serum antibody titres induced by each vaccine formulation
timeFrame: At day 14-21 post vaccine schedule completion. Follow-up period 2020-2023.
measure: Fold changes in innate immune cells and in vaccine specific B and T cells
timeFrame: Vaccine specific B and T cells detected at day 14-21 post vaccine schedule completion versus day 0. Follow-up period 2020-2023.
measure: Comparison of antibody (and B and T cell) responses induced against COVID-19 and influenza vaccines among participants who received COVID-19 versus influenza vaccine first or who were co-administered both vaccines.
timeFrame: Antibody levels will be correlated with fold changes in innate immune cells and in vaccine specific B and T cells detected at day 14-21 post vaccine schedule completion versus day 0. Follow-up period 2020-2023.
Other outcomes:
Locations:
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Nedlands
country: Australia
facility: Perth Children's Hospital
state: Western Australia
Study officials:
affiliation: University of Melbourne
name: Sheena Sullivan, MPH, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Melbourne
name: Annette Fox, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: London School of Hygiene and Tropical Medicine
name: Adam Kucharski, MMath, PhD
role: PRINCIPAL_INVESTIGATOR
References: