Background and rationale

Several studies suggest a waning of COVID-19 vaccines' effectiveness over time, raising
the question of whether booster doses should be offered to maintain protection against
severe COVID-19.

Studies of the effectiveness of taking one booster dose, which for most people
corresponds to a third vaccine dose, have shown promising results. Similarly, three
recent studies examining the effectiveness of a 2nd booster dose found that the 2nd
booster was associated with lower risk of severe COVID-19. All these studies are based on
data from Israeli registries, comparing outcomes among individuals who have taken the
booster, or not. Interpreting the findings from such non-experimental studies is
challenging since there are likely systematic differences between those who accept the
offer to take a booster dose, and those who do not. So called "healthy vaccinee bias"
implies that those who take the vaccine are healthier than those not taking the vaccine.
The opposite, however, may also be true: Those who perceive themselves to be more at risk
may be more prone to accept the offer of vaccination. A related type of bias is the
"premature efficacy bias" which is observed in many observational studies within one to
two weeks after vaccination, probably due to people refraining from taking the vaccine if
they suspect that they have already been infected. Comorbidities or socio-economic
factors that are not adequately controlled for can also lead to biased results. The
conventional approach to minimizing the risk of bias in effectiveness studies is to
conduct a randomized trial - if feasible.

The future of the COVID-19 pandemic is unknown. In Norway, a large winter wave driven by
the omicron variant of SARS-CoV-2 is receding after more than half the population has
been infected. The vaccination coverage in the Norwegian population is also very high.

In the autumn of 2022, a new wave of infections may start due to waning immunity, and/or
the emergence of a new variant.

Either way, vaccination will be the most important tool to reduce the risk of severe
disease in individuals. Based on previous experiences and the available data, it is
likely that health authorities in Norway (and probably other European countries) will
offer or even recommend a 2nd booster dose (the fourth dose) to those who are aged 65
years and above. For those who are younger and therefore at lower risk of severe
COVID-19, the value of a 2nd booster is less clear, making it difficult to decide for or
against offering a 2nd booster to this group.

The investigators therefore propose to conduct a register-based randomized trial (RRCT)
to provide evidence for the effects of offering a 2nd booster (a fourth dose) in the age
group 45-64 years.

Objectives Our primary objective is to determine the effect of offering vaccination with
a COVID-19 booster dose on severe COVID-19, measured by hospitalization and death caused
by COVID-19.

Our secondary objective is to determine the effects (intended and unintended) of offering
vaccination with a COVID-19 booster dose on the use of health care services, prescription
medication related to COVID-19, and on SARS-CoV-2 infection rate.

Trial design The trial is designed as a register-based randomized trial. The
investigators will draw a random sample from the whole population aged 45-64 years, which
will constitute the intervention group and will receive a personal offer to receive a 2nd
booster dose of a COVID-19 vaccine in their municipality. The rest of the population aged
45-64 will receive no such offer or information and will serve as control group. The
random sample will be defined by drawing a set of birth dates. This allows the
investigators to identify persons in the intervention group directly in the Norwegian
Preparedness Register for COVID-19 without identifying them individually, since personal
identification numbers are encrypted in this database. The random sample will receive the
offer of vaccination either (i) via Helsenorge (National online health services in
Norway) through a survey tool available to the Norwegian Institute of Public Health, or
(ii) directly from their municipality (to be determined).