Immunity after yellow fever vaccination in HIV positive travelers - YELLAR 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 neuroinvasion and encephalitis. The exact pathogenicity of
these SAEs has not been elucidated up to date. Possibly, those are the result
of a hampered immunologic response in the host, resulting in an increased
replication of the virus.

A recent retrospective study with a Swiss cohort of 102 HIV infected patients
vaccinated with the yellow fever vaccine (YFV) reported that HIV positive
vaccinees have lower rates of seroconversion, and lower geometric mean titers
(GMTs) of neutralizing antibodies (NAs) compared to healthy controls. A study
from Mali reported no adverse events in their cohort of 115 HIV positive
patients vaccinated with YFV.

In the Swiss study as well as in other studies of yellow fever vaccination in
HIV positive vaccinees, neither adverse events (AEs) or severe adverse events
(SAEs) have been described to occur at a more frequent rate compared to healthy
vaccinees. These studies were however not powered to detect differences in
serious SAEs, because these 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).
In a population of elderly vaccinees, both local as well as systemic adverse
events occurred at a lower rate compared to young vaccinees, whereas severe
adverse events are known to occur more often in this population. Possibly, a
hampered initial response results in lower rates of adverse events.

In response to yellow fever 17D infection, a cascade of immunologic responses
follow. 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. Through stimulation of
TLRs, both cellular (through Th1 cells) and humoral (through Th2 cells)
responses are triggered. We would expect a hampered response of these Th1 and
Ths cells among HIV infected patients, as the number of CD4+ cells declines.
This relationship has been described in the Swiss cohort (3).
A recent study has however described antibody responses to be independent of
CD4 count but strongly determined by the presence of plasma HIV-RNA. (18). By
measuring viraemia and neutralising antibodies in relation to CD4 count and the
presence of plasma HIV-RNA, we aim to add to insights into the predictive
factors for an effective immune response. Additionally, we will measure several
parameters indicative for an activated innate immune response as well as T cell
responses. By comparing all these parameters in HIV positive patients and
healthy controls at set timepoints after vaccination, we aim to acquire a
comprehensive overview of the immune response to the YF 17D vaccine in HIV
positive patients.
We aim to assess whether the immune response is delayed or lower in HIV
positive patients compared to healthy controls. This gives an indication
whether the yellow fever vaccine is a risk for SAEs in HIV positive patients.
In our center, approximately 10 HIV positive patients with CD4 counts ranging
from 200-500 are vaccinated annually with the yellow fever vaccine.

Primary Objective:
To determine the height and duration of viremia, the seroconversion rate and
the level of neutralising antibodies in relation to
- the actual number of CD4 positive cells
- the nadir of CD4 positive cells
- the duration of CD4 count above 200
- and the viral load of HIV

Secondary Objective(s):
To evaluate the local and systemic side effects of yellow fever vaccination in
HIV positive patients.
To evaluate the innate response and T cell responses following yellow fever
vaccination in HIV positive patients.
To compare all responses between HIV positive patients and healthy controls.

Observational case-control study. The duration of the study will be
approximately 2 years. The setting is either the Academic Medical Center,
University hospital Leiden or the Havenziekenhuis in Rotterdam.

It is beneficial for subjects to be aware of their protection against yellow
fever virus, if needed additional preventive measures can be taken in the case
of travel to a yellow fever endemic area. In the future, better pre-travel
advice can be formulated in travelers with HIV needing a yellow fever
vaccination.