Immunogenicity of Alternative Annual Influenza Vaccination Strategies in Older Adults in Hong Kong (PIVOT)

Immunogenicity of Alternative Annual Influenza Vaccination Strategies in Older Adults in Hong Kong - a Randomized Controlled Trial

This study allows to evaluate the strength and duration of immune responses between annual receipt of standard inactivated vaccine and alternative potent vaccines, including annual receipt of adjuvanted inactivated vaccine, annual receipt of high-dose inactivated vaccine, annual receipt of recombinant HA vaccine, and the alternate combinations of the former three vaccines over four years, for identifying improved vaccination strategies for influenza vaccination in older adults in a location experiencing a subtropical pattern in influenza activity.

Study Overview

• Status: Active, not recruiting
• Conditions: Influenza, Human
• Intervention / Treatment: Biological: Standard inactivated influenza vaccine (NH formulation); Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); Biological: High-dose inactivated influenza vaccine (NH formulation); Biological: Recombinant hemagglutinin inactivated influenza vaccine (NH formulation)

Detailed Description

Background: The typical vaccination strategy of annual administration with inactivated trivalent influenza vaccine (TIV) or quadrivalent influenza vaccine (QIV) may provide suboptimal protection to older adults in a location with prolonged periods of influenza activity because of the weaker immune response of older adults to vaccination and because of post-vaccination waning in protection over the course of a year. We hypothesize that in a subtropical or tropical location with prolonged circulation of influenza viruses, the higher antibody titers over years achieved after receipt of annual high-dose vaccine, MF59-adjuvanted vaccine or recombinant haemagglutinin (HA) vaccine, or different vaccination strategies of their combinations with or without the standard vaccine, might lead to greater protection than annual receipt of standard vaccines.

Aim: To test the immune profiles over time of older adults following different influenza vaccination strategies.

Design and subjects: Initially a 4-year immunogenicity study with a randomized controlled design among 2200 older adults aged 65-82 years. We will enroll participants who are willing to receive annual influenza vaccination from the general community including community centres and day-care centres. Eligible individuals will be randomly allocated to ten intervention groups (i.e. annual standard QIV, annual MF59-adjuvanted TIV, annual high-dose TIV, annual recombinant-HA QIV, and six combinations of their alternate annual use) consisting of four rounds of vaccination before each winter influenza season and followed up for 4 years. For each round of vaccination, blood samples for immunological tests will be collected before vaccination and 30 and 182 days after vaccination in all participants, and also at 7, 91 and 273 days after vaccination in a subset of 10% of the participants. Acute illnesses among participants will be monitored by active surveillance efforts during influenza seasons. The vaccine formulation in each round of vaccination will be updated for each season according to WHO recommendations.

Study extension: In years 5-8, all participants will receive the recombinant-HA QIV once per year before each winter influenza season, and their receipt of COVID-19 vaccines will also be recorded. Samples will be collected at the same timepoints to monitor immune responses to influenza vaccination and how responses are affected by prior vaccination history.

Main outcome measures: Antibody titers measured by haemagglutination-inhibition assays, which is an established correlate of protection, in addition to other measurements on humoral and cell-mediated immune responses in the ten intervention groups each year.

• Study Type: Interventional
• Enrollment (Actual): 1861
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Hong Kong, China
    • The University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 82 years (Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adult aged 65-82 years attending ECC and EDC who has not received 2017/18 seasonal influenza vaccine and is willing to receive annual influenza vaccination

Exclusion Criteria:

• Individuals who show signs of dementia (do not pass the Mini-cog test under Appendix 1a: Recruitment Screening Log) or significant cognitive impairment and are not competent to give their consent.

• Individuals who report medical conditions not suitable to receive inactivated influenza vaccines, such as:

  • Severe allergic reaction (e.g., anaphylaxis) after previous dose of any influenza vaccine; or to a vaccine component, including egg protein;
  • Moderate or severe acute illness with or without fever after any previous influenza vaccination; or
  • A history of Guillain-Barré syndrome (GBS) within 6 weeks of previous influenza vaccination.

• Individuals, who report medical conditions not suitable to receive intramuscular injection, such as:

  • bleeding disorders
  • habitually taking anticoagulants (with the exception of antiplatelets such as aspirin).
• Individuals who have any medical conditions not suitable to receive inactivated influenza vaccines as determined by a clinician.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard vaccine; Once-annual administration of standard vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: Standard inactivated influenza vaccine (NH formulation); 0.5mL FluQuadri®, Sanofi Pasteur, containing 60μg antigen - 15μg for each influenza strain included - with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating standard vaccine & adjuvanted vaccine; Alternating once-annual administration of standard inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of MF59 adjuvanted inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: Standard inactivated influenza vaccine (NH formulation); 0.5mL FluQuadri®, Sanofi Pasteur, containing 60μg antigen - 15μg for each influenza strain included - with strains recommended by the WHO for the northern hemisphere formulation.; Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); 0.5mL FLUAD(TM), Seqirus containing 45μg antigen; 15μg for each influenza strain included and MF59C.1 adjuvant (MF59®) with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating adjuvanted vaccine & standard vaccine; Alternating once-annual administration of MF59 adjuvanted inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of standard inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: Standard inactivated influenza vaccine (NH formulation); 0.5mL FluQuadri®, Sanofi Pasteur, containing 60μg antigen - 15μg for each influenza strain included - with strains recommended by the WHO for the northern hemisphere formulation.; Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); 0.5mL FLUAD(TM), Seqirus containing 45μg antigen; 15μg for each influenza strain included and MF59C.1 adjuvant (MF59®) with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating standard vaccine and high-dose vaccine; Alternating once-annual administration of standard inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of high-dose inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: Standard inactivated influenza vaccine (NH formulation); 0.5mL FluQuadri®, Sanofi Pasteur, containing 60μg antigen - 15μg for each influenza strain included - with strains recommended by the WHO for the northern hemisphere formulation.; Biological: High-dose inactivated influenza vaccine (NH formulation); 0.5mL Fluzone® High-Dose, Sanofi Pasteur containing 180μg antigen; 60μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating high-dose vaccine and standard vaccine; Alternating once-annual administration of high-dose inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of standard inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: Standard inactivated influenza vaccine (NH formulation); 0.5mL FluQuadri®, Sanofi Pasteur, containing 60μg antigen - 15μg for each influenza strain included - with strains recommended by the WHO for the northern hemisphere formulation.; Biological: High-dose inactivated influenza vaccine (NH formulation); 0.5mL Fluzone® High-Dose, Sanofi Pasteur containing 180μg antigen; 60μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating adjuvanted vaccine and high-dose vaccine; Alternating once-annual administration of MF59 adjuvanted inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of high-dose inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); 0.5mL FLUAD(TM), Seqirus containing 45μg antigen; 15μg for each influenza strain included and MF59C.1 adjuvant (MF59®) with strains recommended by the WHO for the northern hemisphere formulation.; Biological: High-dose inactivated influenza vaccine (NH formulation); 0.5mL Fluzone® High-Dose, Sanofi Pasteur containing 180μg antigen; 60μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating high-dose vaccine and adjuvanted vaccine; Alternating once-annual administration of high-dose inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of MF59 adjuvanted inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); 0.5mL FLUAD(TM), Seqirus containing 45μg antigen; 15μg for each influenza strain included and MF59C.1 adjuvant (MF59®) with strains recommended by the WHO for the northern hemisphere formulation.; Biological: High-dose inactivated influenza vaccine (NH formulation); 0.5mL Fluzone® High-Dose, Sanofi Pasteur containing 180μg antigen; 60μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: High-dose vaccine; Once-annual administration of high-dose inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: High-dose inactivated influenza vaccine (NH formulation); 0.5mL Fluzone® High-Dose, Sanofi Pasteur containing 180μg antigen; 60μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Adjuvanted vaccine; Once-annual administration of MF59 adjuvanted inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); 0.5mL FLUAD(TM), Seqirus containing 45μg antigen; 15μg for each influenza strain included and MF59C.1 adjuvant (MF59®) with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Recombinant vaccine; Once-annual administration of recombinant hemagglutinin inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: Recombinant hemagglutinin inactivated influenza vaccine (NH formulation); 0.5mL Flublok®, Protein Sciences Corporation containing 180μg antigen, 45μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.
Experimental: Alternating recombinant vaccine and adjuvanted vaccine; Alternating once-annual administration of recombinant hemagglutinin inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter, and once-annual administration of MF59 adjuvanted inactivated influenza vaccine (northern hemisphere formulation) prior to the northern hemisphere winter throughout 4 years study period.	Biological: MF 59 adjuvanted inactivated influenza vaccine (NH formulation); 0.5mL FLUAD(TM), Seqirus containing 45μg antigen; 15μg for each influenza strain included and MF59C.1 adjuvant (MF59®) with strains recommended by the WHO for the northern hemisphere formulation.; Biological: Recombinant hemagglutinin inactivated influenza vaccine (NH formulation); 0.5mL Flublok®, Protein Sciences Corporation containing 180μg antigen, 45μg for each influenza strain included with strains recommended by the WHO for the northern hemisphere formulation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in antibody titres	The difference in antibody titres of participants measured by haemagglutination-inhibition (HAI) assay, evaluated by (1) the proportion of participants who achieve a target rise in antibody titre against each of the vaccine strains at 30 days, and (2) the geometric mean titre (GMT) ratios between the two groups against each of the vaccine strains at 30 days and 182 days. (The targeted rise in antibody titre is defined as the percentage of subjects with either a pre-vaccination HAI titre <10 and a post-vaccination HAI titre ≥40, or a pre-vaccination HAI titre ≥10 and a minimum four-fold rise in post-vaccination HAI antibody titre.)	30 and 182 days after each vaccination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seroprotection	The proportion of participants who achieve seroprotection defined as an HAI titre ≥40 after each vaccination before the winter seasons.	30 days after each vaccination
CMI responses	The vaccine-induced influenza-specific CD4+ and CD8+ T cell responses 7 days post- vaccination, proxy by anti-viral IFNγ production evaluated by Intracellular Cytokine Staining (ICS) assay. Responses for these and other relevant biomarkers are compared to baseline at the time of vaccination.	. 7 days after each vaccination
Adverse events	The rate of adverse events within 30 days after vaccination for each round of vaccination.	30 days after each vaccination
PCR confirmed infection	The rate of PCR-confirmed influenza infection in each round of the study.	182 days after each vaccination

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Centers for Disease Control and Prevention
• Investigators: Principal Investigator: Benjamin J Cowling, PhD, The University of Hong Kong

Publications and helpful links

General Publications

• Cowling BJ, Thompson MG, Ng TWY, Fang VJ, Perera RAPM, Leung NHL, Chen Y, So HC, Ip DKM, Iuliano AD. Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults. J Infect Dis. 2020 Sep 14;222(8):1383-1391. doi: 10.1093/infdis/jiaa255.
• Cowling BJ, Perera RAPM, Valkenburg SA, Leung NHL, Iuliano AD, Tam YH, Wong JHF, Fang VJ, Li APY, So HC, Ip DKM, Azziz-Baumgartner E, Fry AM, Levine MZ, Gangappa S, Sambhara S, Barr IG, Skowronski DM, Peiris JSM, Thompson MG. Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial. Clin Infect Dis. 2020 Oct 23;71(7):1704-1714. doi: 10.1093/cid/ciz1034.

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2017
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 10, 2017
• First Submitted That Met QC Criteria: October 30, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Physiological Effects of Drugs; Immunologic Factors; Coagulants; Agglutinins; Vaccines; Hemagglutinins
• Other Study ID Numbers: YHT005.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No