Immunity after yellow fever vaccination in travelers using immunosuppressive medication-YETI study

The 17D-Yellow Fever vaccine is a live attenuated vaccine. The vaccine has been
proven safe and effective; however, in the immunosuppressed, there is a
theoretical risk of severe adverse events (SAEs), such as neuroinvasion and
encephalitis (1,2). The exact pathogenicity of these SAEs has not been
elucidated up to date. Possibly, they are the result of an impaired immunologic
host response, resulting in an increased replication of the virus.

Two recent studies on immunocompromised patients who received yellow fever
vaccinations showed that a total of 89 patients using immunosuppressive drugs
did not experience adverse events at a higher rate compared to healthy
vaccinees (3, 4).
However, SAEs happen at very low rates; 0.4/100.000 vaccinees develop yellow
fever vaccine associated viscerotropic disease (YEL-AVD), which resembles the
clinical course of yellow fever infection, and 0.8/100.000 develop yellow fever
vaccine associated neurotropic disease (YEL-AND) (5). Therefore, the numbers of
vaccinees in these studies are too small to draw any conclusions from.

Antibody responses were not measured in these studies. Previous studies on HIV
positive patients show lower rates of those with protective neutralising
antibodies (NA), and lower geometric mean titers (GMTs) of antibodies compared
to healthy controls (6).

We know that in the response to yellow fever 17D infection, a cascade of
immunologic responses ensues. This is initiated by the formation of TNF alpha
and type I interferons after binding to toll like receptors (TLRs) 2,7,8 and 9
(7, 8, 9, 10). Through stimulation of TLRs, both cellular (through Th1 cells)
and humoral (through Th2 cells) responses are triggered. Immune suppressive
medication interferes with this immune response in various ways.
In healthy vaccinees, we know that antibodies are present for several decades
(Plotkin). However, this response is possibly of a shorter duration in patients
using medication which suppresses the immune response. Depending on the type of
immune suppressive, immunologic memory might be supressed as well.

Local as well as systemic adverse events were lower in a population of elderly
vaccinees compared to young vaccinees (11), even though severe adverse events
are known to occur more often in the group of elderly subjects. Possibly, an
impaired initial response results in lower rates of local adverse events.

In this study we set out to retrospectively investigate the immunologic
response and the rate of adverse events in those using immunosuppressive
medication who have inadvertently received a yellow fever vaccination.

To compare:
- the rate of local and systemic adverse events
- height and duration of antibody presence using the plaque reduction
neutralization test;
- The number of yellow fever specific CD8+ T cells in peripheral blood
mononuclear cells (PBMCs);
in various groups of immune suppressive medication to healthy vaccinees,
vaccinated with the 17D-YF vaccine, so that:
- an assessment of the duration and height of immunologic response can, and
thus the effect of the immune compromising condition on the vaccination, be
made,
- advice can be formulated for future accidental vaccinations, and
- insight in the immunologic responses of various groups of immunosuppressive
medication can be gained.

Hypotheses

- The height and duration of the immune response, the longevity of immunologic
memory and the rate of adverse events differ more from that of the healthy
control group as the dose of immunosuppressive medication rises.

- Patients using low-doses of immunosuppressive medication (prednisolone (<20
mg/day), but also methotrexate, (<0.4 mg/Kg/week), azathioprine (<3.0
mg/Kg/day), or 6-mercaptopurine (<1.5 mg/Kg/day)), have an equal height and
duration of antibodies and an equal immunologic memory response, and a
comparable rate of adverse events. These groups can be regarded as healthy
vaccinees.

Observational case-control study.

Burden and risks:
Volunteers have a risk of bruising/a sore arm following venapunction, and they
shall be asked to visit the hospital which will cost time.
Benefit and group relatedness:
Volunteers shall be aware of their immune status (whether or not they are
protected against yellow fever).
In the long term, larger groups of patients using immunosuppressives shall be
better informed of their duration of protection after a yellow fever
vaccination.