Deuterated water labelling of specialized T cell subsets

Our immune system is invaluable. It not only gets rid of infectious pathogens
and dysfunctional cells upon encounter but also provides (life)long protection
via the formation of antigen experienced memory leukocytes. Vaccination and the
more recent application of memory leukocytes in cancer treatment are exemplary
for the potential of the function of these memory cells, but these application
also show that the system performs differently in specific applications. Time
for booster vaccination differs widely for different pathogens and efficacy of
T cell therapy differs between tumor type. While general process of adaptive
immunity are quite well defined, the presence and influence of heterogeneity in
the system has become more apparent but is less defined. We will investigate
how heterogeneity based on cell functionality and antigen interaction with T
cells affects the dynamic characteristics of these subsets. Quantification of
the lifespan, turnover and death rates of the different subtypes of memory
cells is off essential fundamental value and might steer targeting specific
subtypes for specific applications.
We plan to investigate memory subpopulation based on (1) antigen specificity,
(2) antigen/ TCR affinity (CD5hi/lo), (3) antigen overstimulation (β-
galactosidase+/-), and (4) absence of antigen stimulation, i.e. virtual memory
T cells.

The kinetics of the memory T cell population has been studied extensively.
However in humans, the predicted lifespan of yellow fever specific memory T
cells (485 days) showed disparity with that of total memory cells (150 days).
This difference in the expected lifespan was suggested to be due to the fact
that the memory T cell pool is composed of different specialized subpopulations
that have different kinetics.

Thus, in this study we will examine if different cell functionalities of
different T cell subsets correlate with different turnover rates.

Primary Objective:
1. Turnover rate of antigen-specific cells (group I)
2. Turnover rate of functional T-cell subsets (group II)

Secondary Objective(s):
• Determining absolute numbers of antigen (poliovirus, measles, Hepatitis A and
Hepatitis B) specific T cells during the study
• Monitoring cytokine profile and IgG antibody levels in blood in response to
the vaccine

The study has a longitudinal character and involves invasive procedures, i.e.
administration of the Hepatitis A and B vaccine **TWINRIX**, or polio vaccine
**Boostrix-IPV**, or the measles vaccine **M-M-RVaxPro** as well as the
temporary drinking of heavy water and the collection of multiple blood and
urine-or-saliva samples. The above mentioned vaccines are childhood vaccines in
the Netherlands except for TWINRIX which is given preventative to medical
students and travelers. All used vaccines are regarded as safe and efficacious.
Since not all analyzed cell subsets require a booster vaccination we divided
the participants of the study in two groups. Study group II will not receive a
booster vaccination and will have a lower study burden.

(I) Study group I will include participants who to take a booster vaccine of
either TWINRIX-Adult, M-M-RVaxPro or Boostrix-IVP as well as to follow the
drinking schedule and blood and urine-or-saliva donation.
(II) Study group II will include participants who will not take a booster and
only follow the drinking schedule and blood and urine-or-saliva donation.

Both groups are required to drink deuterated water and will donate multiple
blood and urine/saliva samples. Participants of study group I and II will be
self-reported healthy participants without a history of immune altering disease
or treatment. Participants of study group I will have a history of either of
the above mentioned vaccines.

Participants of group I of this study will get a booster dose of either
Boostrix-IPV, M-M-RVaxPro or TWINRIX vaccine and will have to drink 35 ml of
100% enriched deuterated water 3 times a week for 5 days followed by a daily
intake of 42 ml for a maximum of 9 weeks during the up-labelling phase. During
the study (up and down-labelling) the participants donate urine/saliva once a
week and blood (venipuncture) 2-6 times. Even though the physical burden and
risks of this study are minimal, the personal burden is higher: participants
will have to invest time and energy to visit the hospital, donate blood and
urine/saliva, and drink heavy water at home. There are no direct benefits for
the participants and the risks are minimal. Participants who participate in
group II will not receive any vaccines but will drink heavy water and donate
saliva/urine with the same schedule and donate blood maximum 8 times.