Switching of COVID-19 vaccines: A solution for the problems? A multicentre, randomised, single blind, controlled trial among HealthCare Workers (HCW) vaccinated with Janssen: the SWITCH trial.

The first vaccines against COVID-19 were available in the Netherlands from
January 2021. The ability to combine vaccinations could make vaccination
campaigns more flexible in the future. It could speed up the process and reduce
the impact of supply disruptions. It can also elicit a broader immune response
(in terms of neutralizing antibodies and T-cell responses). These results
support the need to conduct clinical trials in humans to investigate the safety
and immunogenicity of heterologous vaccination regimens. Several studies have
already been set up to look at the safety and immunogenicity of a heterologous
vaccination regimen. These studies are ongoing in the UK and Spain where they
are combining Pfizer and AstraZeneca and vice versa (Com-COV & CombiVacS). For
these reasons, we decided to focus our study on adeno priming with Janssen,
which is not studied in other ongoing studies. As the vaccination rate in The
Netherlands is increasing rapidly, we decided to include HCW vaccinated once
with Janssen.

December 2021
All healthcare workers now have the option of a boost with Pfizer 30 micrograms.
This boost has already been investigated in the SWITCH and the Health Council
has made this decision based on this, among other things.
The main aim of this study is to determine whether there is a difference in the
production of antibodies of a dose of Pfizer 30 micrograms adminstered 6 months
after priming versus 3 months after priming. We also study the formation of
immune cells after vaccination and the occurrence of side effects.

February 2022
In mid-December, the government decided to advise everyone who had their last
COVID-19 vaccination 3 months or more ago to get a boost. This applies to all
our groups; Janssen/Janssen, Janssen/Moderna and Janssen/Pfizer (boosted at the
end of July/August). And later possibly also for Janssen/- who had their boost
last December (2021).

We also want to take extra blood from a small sample (monthly) to map the
kinetics (waning) of the decrease in the immune response. This concerns 15
people from each group (J/J, J/P, J/M).

Finally, we want to compare the 21 non-responders (defined as insufficient IgG
antibodies (+/- 4 months) after their prime with Janssen) with the 21 highest
responders from the J/- group. To this end, the immune response of these
subjects to previous vaccinations (national vaccination program, hepatitis B,
influenza) will be examined.

Primary objectives
Measuring the SARS-CoV-2-specific immune response against SARS-CoV-2 after
inoculation with a single-dose Janssen compared to a homologous vaccination
regimen with Janssen /Janssen and the comparison of a homologous vaccination
regimen (Janssen/Janssen) with a heterologous vaccination regimen
(Janssen/Pfizer + Janssen/Moderna).

Main endpoint
The immune response to SARS CoV-2 28 days after the second vaccination is the
primary endpoint.

Secondary objectives
1. To assess adverse events after SARS-CoV-2 vaccination.
2. To evaluate development of antibody and cellular response after homologues
versus heterologuest vaccination
3. To assess durability of the antibody response
4. To analyze the SARS-CoV-2-specific T and B cell response after vaccination

December 2021

Primary Goals
Measuring the SARS-CoV-2 specific immune response to SARS-CoV-2 after
inoculation with Pfizer 30 micrograms 6 months versus 3 months.

Secondary Objectives
1. To assess adverse reactions after SARS-CoV-2 vaccination.
2. Evaluation of the development of antibody and cellular response after the
heterologous versus homologous vaccination
3. To Assess the Durability of the Antibody Response
4. Analysis of SARS-CoV-2 Specific T and B Cell Responses After Vaccination

February 2022
Extra boost
Measuring the SARS-CoV-2 specific immune response against SARS-CoV-2 after
inoculation with Pfizer 30 micrograms (as second boost) and comparing this
immune response between the different groups (J/J, J/P and J/M).

Waning
Pharmacokinetic comparison of the decline of the immune response between the
different groups (J/J, J/P and J/M).

Non-responders
Finding an indicator to predict/identify non-responders.

A multicentre, randomized, single-blind, controlled study. Only registered,
available vaccines will be administered (Pfizer, Moderna and Janssen). For
administration of the first vaccine, participants are randomized to a single
dose, homologous vaccination strategy (two of the same vaccines) or a
heterologous vaccination strategy (two different vaccines). Blood will be drawn
at 4 different times: day 0 (before 2nd vaccination), on day 28 (primary
endpoint), day 180 ((+/- 14 days) and day 365 (+/- 14 days). The primary
outcome parameter is similar to the other studies (humoral response at 28 days
after 2nd vaccination). Questionnaires will be used to check for adverse events
after each vaccination and to evaluate any breakthrough SARS-CoV-2 infections
and outcome despite vaccination.

December 2021
We would like to boost the Janssen solo group with Pfizer 30 micrograms.

The research is being conducted among the participants of the Janssen solo
group. That was about 108. In the meantime, 18 have lost weight because these
people were insufficiently protected against COVID based on their antibodies.
These people have already been vaccinated.

February 2022
Extra boost: A second boost with Pfizer 30 micrograms is offered to the groups
J/J, J/M and J/P.

Waning: all participants from groups J/J, J/M and J/P are asked if they would
like to participate in a study on the decline of the immune response over time.

Non-responders: the non-responders and high responders of the J/ group (at the
time of Study Visit 2 - +/- 4 months after prime with Janssen) are asked
whether they want to participate in a study to find out why someone makes a
reduced immune response to a single vaccination with Janssen.

All adults in the Netherlands are vaccinated on a voluntary basis, the
intervention is aimed at comparing homologous versus heterologous vaccination
strategy.
Key endpoints: The immune response to SARS CoV-2 after vaccination at various
time points, with antibody response 28 days after the second vaccination being
the primary endpoint.

December 2021
The participants will be boosted with Pfizer 30 microgram.

RISK - BENEFIT ANALYSIS

1. The group of persons that will be approached for this study are all Health
Care Workers. This means that they belong to a group of HCW with a higher
exposure to COVID-19 during their work. On the other hand, due to a shortage of
vaccines this group is not yet assigned to vaccination. By offering them to
participate to this trial, these HCW (and their family) can be accelerated
protected to COVID infections.
2. Full vaccination with two boosters can at this moment only be assured if
combinations of vaccines are applied. Vaccination with only one booster is not
recommended by virologists.
3. If combination of two different vaccines will not lead to sufficient
protection as seen in the titer of neutralizing antibodies, this will be
identified within 2 months after the first injection. This can be the case for
both an individual or a group. If this appears, adequate measures will be taken
to reassure the safety of the HCW.
4. As two different vaccines will be administered, it may be the case that
through vaccinations with slightly different vaccines the immune-response may
even be improved.
5. With the upcoming Variants of Concern (e.g. the british variant), it has
been suggested that the present vaccines could be changed a bit to improve the
vaccination against these variants. In that case it might even be a necessity
to combine vaccines to cover all different VoC.
6. It is difficult to predict whether the occurrence of adverse events will
increase or decrease. In the comirnaty-trial can be seen that the systemic
adverse events are increased after the 2nd dose. Most of these adverse
reactions can be seen as an immune response. As the 2nd dose in this study
differs from the 1st, the immune response may be less prominent in the first 2
days.
7. The occurrence of anaphylaxis might increase as the HCW are exposed to two
different regimens. The incidence of anaphylaxis appears to be so low that this
might not be of clinical significance. To mitigate the occurence of anaphylaxis
the HCW will be monitored after the 1st and the 2nd dose for at least 15
minutes.
8. It is important to state that the vaccines for this study will NOT be
retrieved from a stock reserved for patients or other persons.In the past days
we have shown that we get more vaccinations from 1 flacon than stated by the
manufacturer. The extra flacons that will be gained by this method will be used
for this study. This statement is strengthened by the cooperation of hospital
pharmacists from the region who support this trial.
9. As stated in the introduction of the study, due to shortages, logistic
problems and reservations of vaccines for the 2nd booster, the velocity of
vaccination is hampered all over the world. If this non-inferiority study
concludes that boosting the immune system against COVID-19 can be done with
different vaccines, this has a huge societal impact for the world.

December 2021
10. All HCW will be vaccinated anyway with Pfizer 30 microgram.

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