This study will provide novel insight into the effects of repeat influenza vaccination with Flublok and FluMist on the strength and breadth of immune responses to influenza, the mechanisms underlying heterogeneity in vaccine response and vaccine failure, and biological factors that could explain variation in influenza vaccine effectiveness.

Annual vaccination remains a key public health approach to reducing the impact of influenza virus infections. However, numerous trials and observational studies, including our own, have demonstrated that repeated an-nual influenza vaccination can result in attenuated vaccine effectiveness in some years in a phenomenon called "repeat vaccination effects". Gaining insight into the varying efficacy of influenza vaccines across different individuals and populations is crucial for optimizing the use of current vaccines and designing universal ones. However, understanding the changes in vaccine effectiveness and immunogenicity among those receiving repeated vaccinations is challenging, especially in populations where universal vaccination is recommended. Repeated vaccinees differ significantly from both new vaccinees and non-vaccinees, potentially leading to residual con-founding in infection and vaccination histories, making it hard to isolate the effects of the vaccine itself.

The investigators will conduct a randomized trial to explore the effects of repeated vaccination and their immunological foundations in a population with low vaccine coverage and no influenza vaccination recommendation. The study will involve live attenuated influenza vaccines (FluMist, nasal spray) in addition to parenteral influenza vaccines (Flublok, injected) to stimulate different components of the immune system. The trial will involve 600 adults in Hong Kong, divided into four groups. The four groups will receive annual vaccination with Flublok, FluMist, alternating between these two vaccines, or alternating between Flublok and placebo. This structure enables comparisons of humoral, mucosal and cellular vaccine responses after different combinations of vaccines.

The resulting longitudinal data on immune status and influenza-specific responses will allow the investigators to develop predictive models for vaccine and infection responses, including those involving repeat vaccinations. The planned immunological profiling, alongside advanced statistical analysis, will enhance understanding of repeated vaccination's effects on seasonal influenza and inform strategies to anticipate vaccine non-responsiveness and improve vaccination approaches. Stored specimens will also allow future testing of new hypotheses.

Inclusion Criteria:

1. Aged 22-50 years at enrolment.
2. A. Participated in the DRIVE I or DRIVE II studies (for DRIVE IIIa). OR B. Did not participate in the DRIVE I or DRIVE II study (for DRIVE IIIb) and has not received influenza vaccination in the prior two years.
3. Capable of providing informed consent.
4. Resident in Hong Kong in the coming 2 years.

Exclusion Criteria:

1. Included in one of the priority groups to receive influenza vaccination in Hong Kong (priority groups include pregnant women, long-stay residents of institutions for persons with disability, persons with chronic medical problems (chronic cardiovascular, lung, metabolic or kidney diseases, obesity (body mass index 30 or above) and chronic neurological condition ), healthcare workers or persons working in poultry, pig farming or pig slaughtering industry).

2. With diagnosed medical conditions related to their immune system.

3. Currently taking medication for any condition that impairs immune system.

4. 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;
   • 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.

5. Individuals who report medical conditions not suitable to receive live attenuated vaccines, such as:

   • having asthma;
   • having close contact with severely immunosuppressed persons who require a protected environment; or
   • having immunosuppressive treatment (e.g. high-dose steroid, anti-cancer drugs and radiotherapy).

6. 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).

7. Individuals who have any medical conditions not suitable to receive inactivated or live attenuated influenza vaccines as determined by a clinician.

The investigators will share de-identified IPD via github after completion of the study

After completion of the study

Publicly available via github