SWITCH ON
Analysing the immunogenicity of additional booster vaccinations in healthcare workers.
A multicenter, randomised, controlled trial

Rationale:
Eighty percent of the Dutch population has completed a primary COVID-19
vaccination regimen, and 60% of the population received a booster vaccination.
Waning immunity, combined with the emergence of antigenically distinct
SARS-CoV-2 variants, has led to the consideration of additional booster
vaccinations in the Dutch population by autumn 2022. However, despite efforts
of the Dutch policymakers, the public's willingness to repeatedly receive
COVID-19 booster vaccinations is declining. This is mainly due to a reduced
burden of disease by COVID-19, fewer hospitalizations, and fewer deaths.
However, population immunity might be one of the major factors responsible for
this reduced burden of disease, possibly emphasizing the need for booster
vaccinations. In this proposal we will address an important question asked by
policymakers: *Are booster vaccinations in autumn recommended for the healthy
population?*

In the SWITCH ON study we propose to address this question by performing a
multicenter, randomized, controlled trial investigating the immunogenicity of
an additional COVID-19 booster vaccination in HCW. Here, we will answer two
sub-questions.
1. Is there an increase in antibody levels between day of boost and 28 days
after boosting HCW that were initially primed with either the Janssen or an
mRNA-based vaccine? This information obtained in a representative sample will
be directly shared with the policymakers to inform decision-making for
additional booster vaccinations.
2. Does booster vaccination lead to a rapid secondary recall response,
indicative of immunological memory? The presence of a rapid secondary response
could inform policymakers that the Dutch population is still readily *boost-
able*, and that booster vaccinations are not yet warranted.

Since the combined answer to the two sub-questions could indicate that booster
vaccinations in autumn are not yet warranted, policymakers will ask the
question when booster vaccinations are warranted. To this end, we propose to
perform the booster vaccinations in two separate phases: 1) as soon as possible
(Direct Boost - DB), and 2) 3-4 months from now (PostPoned Boost - PPB).

Our study cohort will consist of both Janssen-primed and mRNA-primed (Moderna
or Pfizer) HCW. The participants of the original SWITCH study (1-3), a unique
and well-defined cohort, will be invited for this follow-up study.
Additionally, we will invite participants of the Erasmus MC HCW study (4, 5)
that received an mRNA-based priming vaccination. These individuals were primed
with Moderna or Pfizer, samples were obtained before prime, 28 days after first
vaccination, and 28 days and 6 months after the second vaccination. Additional
samples were obtained before booster vaccination with an mRNA-based vaccine,
and 28 days and 6 months after boost. This makes the Erasmus MC HCW cohort
equally well-defined as the SWITCH cohort. By combining Janssen and mRNA-based
primed HCW in this study, we make the proposed study representative for the
Dutch population.

To provide supportive data for policymakers, we will administer a (to be
determined) booster vaccination to the above-described cohort before additional
booster vaccination is implemented in society (DB).
The PPB group will be used to investigate the effect of postponing a boost with
3 / 4 months on immune response and can be used to advice the policymakers if
the national vaccination campaign is postponed for healthy individuals. To get
comparable groups between DB and PPB all participants are randomized at the
start of the study and blood will be drawn for all participants at the first
study visit.

At this time, the primary endpoint used in most vaccination trials is 28 days
post-boost. However, we propose to additionally measure immune responses 7 days
post-boost in this study for 2 important reasons:
1. It is known that immunological memory remains intact longer than antibodies
can be measured in the periphery, and that this immunological memory is
responsible for rapid recall responses upon re-exposure. Measuring immune
responses as early as 7 days post-boost is a good alternative measure for
functional immunological memory. The presence of boost-able memory may be a
supportive argument for the reasoning that booster vaccination is not (yet)
necessary.
2. To reduce the time to provide data to policymakers. We propose to measure
both binding antibody levels and T-cell responses at day 7 and 28, and to
analyse whether the levels on day 28 can be predicted on day 7. If so, the
information from the proposed trial could fast-track the interpretation of
future studies by 3 weeks.

Amendment
We would like to follow the participants for a longer period of time through
blood samples. Participants are free to obtain a new booster through the GGD.
We would like to take blood samples just before, 7 and 28 days AFTER the
vaccination.
We recently had 12-month blood tests for the direct boost group, so they do not
have to have blood taken in advance. This is the case for the postponed boost.
So for the DB it is 2 extra blood draws if they get a boost: day 7 and day 28.
For the PPB group, there are 3 extra blood draws if they get a boost: BEFORE
boost, day 7 and day 28.

Key objective
The key objective of the study to determine whether it is necessary to boost
the healthy population in autumn.

Primary endpoint:
The primary endpoint is to determine the fold change in antibody level at day
of boost and 28 days after an additional COVID-19 booster vaccination in the
direct boost group, comparing Janssen with mRNA-primed HCW.

To specifically answer the key objective, we have defined two questions with
the following outcome parameters:

1. Is there an increase in antibody levels between day of boost and 28 days
after boosting HCW that were initially primed with either the Janssen or an
mRNA-based vaccine?
Outcome: level and fold change of antibodies determined by a quantitative IgG
assay comparing the Janssen primed and mRNA-based primed HCW.

2. Does booster vaccination lead to a rapid secondary recall response,
indicative of immunological memory?
Outcome: Level and fold change of antibodies and T-cell responses determined by
a quantitative IgG assay and whole blood IFNγ release assay, respectively,
comparing day 7 and 28 post boost.

Depending on whether it is possible to conduct this study with a bivalent
vaccine, we will add an Omicron BA.1 IgG test to the arsenal of analyses.

A multicenter, randomized, controlled trial comparing immune responses 7 and 28
days after an additional COVID-19 booster vaccination between Janssen and mRNA
primed HCWs to describe the immune response in a cohort representative of the
Dutch population, in order to eventually provide data for Dutch policy makers.

Setting
Multicenter study conducted through four university hospitals (i.e, Amsterdam
UMC, Erasmus MC, Leiden UMC, and UMC Groningen).

Trial duration
Total duration of each participant will be 8 months from the administration of
the additional boost.

Study groups
This study will consists of 2 cohorts; SWITCH study (Janssen prime - from four
university hospitals; Amsterdam UMC, Erasmus MC, Leiden UMC, and UMC Groningen)
and HCW study (mRNA prime from Erasmus MC) (n=200 per cohort).

To describe the immune response in a cohort representative of the Dutch
population if boosted in autumn in order to provide data for Dutch
decisionmakers. Participants will be randomised into a Direct boost (DB) or a
Postponed Boost (PPB) after stratification for priming (mRNA versus Janssen).
Immune response will be measured at start of the study (first study visit, all
participants) and 0, 7, 28 and 84 days after boost.

Group Intervention* Number of participants Neutralisation (3 variants)
DB mRNA Boost 100 15
DB Janssen Boost 100 15
PPB mRNA Boost 100 15
PPB Janssen Boost - 100 15

*The intervention consist of a boost vaccination. At the time of this proposal,
the RIVM (i.e., National institute for the public health and environment) still
needs to decide which boost will be used in the campaign. This depends on
availability, EMA/FDA registration, and governmental decisions.

1. The group of people approached for this study are all healthcare providers.
This means that they belong to a group of employees who have a higher exposure
to COVID-19 during their work. By offering them to participate in this study,
these employees can be protected against COVID infections more quickly.

2. Each participant will be informed of their immune status. This allows
"non-responders" to be identified and a vaccine (read protection) can still be
offered to them.

3. The people in the deferred boost group are promised that, if a boost turned
out to be necessary for the immediate boost group, they will still be boosted
in the short term.

4. It is important to note that the vaccines for this study will NOT be
collected from a stock reserved for patients or other individuals.

5. A potential drawback to participating in this study is that participants are
boosted while it may be concluded afterwards, based on our data, that a boost
was not necessary.

6. Bruising may occur as a result of the blood samples.

Conclusion
Based on the above considerations and an assessment of both the risks and
benefits of this study, we conclude that there is a positive risk-benefit
analysis to proceed with this study.