EVALUATION OF THE USE OF VACCINES AGAINST EPIDEMIC FLU AND THE PRESENCE OF CROSSREACTIVE T CELL RESPONSES AGAINST POTENTIALLY PANDEMIC INFLUENZA VIRUSES IN CHILDREN

SUMMARY
Rationale: Currently an ongoing outbreak of human infection with Novel
Swine-Origin Influenza A (H1N1) Virus has resulted in an influenza pandemic.
Until June 11th almost 30,000 people were infected with the virus of whom 144
died [5]. Excess morbidity and mortality is feared, especially in high risk
groups.

Cytoxic T lymphocytes (CTLs) play an important role in the control of virus
infections, including those caused by influenza viruses. In mice, mortality
caused by influenza viruses infection was reduced and more efficient viral
clearance was shown upon adoptive transfer of virus specific T cells [6]. In
humans, the level of influenza virus-specific CTL activity correlated with the
rate of viral clearance upon experimental infection [7]. In case of an
influenza pandemic caused by influenza viruses of a novel subtype, antibodies
provoked by vaccination with the common used vaccines will not be able to
protect against infection. However, CTLs provoked by natural infection, might
be able to protect against severe disease symptoms, because they are able to
recognize more conserved epitopes of the influenza A virus (cross protection)
[8]. Of special interest is the notion that especially younger individuals are
infected with influenza and for H5N1 viruses it is known that younger
individuals have a higher risk of fatal outcome of infection than older
individuals [4, 9]. Almost all people will be infected by influenza viruses
before the age of 3 years. In a number of countries, including the USA, Finland
and Austria, annual vaccination of all healthy children 6 to 59 months of age
is recommended since 2007 [10]. These children may not become infected with the
epidemic influenza A strains and do not develop a virus specific CTL response
and therefore might be at higher risk of severe disease and mortality in case
of an infection with a highly divergent influenza stain. Children with cystic
fibrosis are at high risk for serious infection and vaccinated annually. This
group allows us to check whether differences in immunity can be found between
influenza vaccinated children and children that are not. Clearly vaccination is
advantageous to children with well described risk factors for serious influenza
infection. It should be noted that this study is not designed to discourage
vaccination in these groups. However, may be the use of live attenuated
vaccines should be preferred rather than the use of inactivated subunit
vaccines. . The reason for this is that live attenuated vaccines do cause a
mild infection and thus expose most viral proteins to the host*s immune system
inducing cell-mediated immunity.

The aim of this study is to evaluate the presence and activity of cross
protective CTLs and antibodies in these children and compare these data with
data from children of the same age that are not vaccinated annually. The
outcome of this study can possibly be used for the development of optimal
vaccination strategies for influenza in both healthy children and children at
risk for serious complications..

The hypothesis of this study is that children that are vaccinated since birth
will have significant less or no cross protective CTLs compared to children
that have not been vaccinated since birth.
Objective: Determination of the effect of annual vaccination on the development
of cross-reactive T cell immunity during childhood.

Study design: Comparison of CTL immunity in two different groups of children.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness:
The burden associated with participation in this study is that one extra blood
sample of 5 ml will be collected. Since only one blood sample will be taken
from the study subjects, the burden is considered limited and the risks
associated with this procedure negligible. In addition 5 ml of blood will be
used obtained from children enrolled in the MIMIC study.

This study can only be performed in children. Currently, no cohort composed of
adult patients can be identified that has been vaccinated throughout life from
birth on. In addition occasionally the viral vaccination strain does not
correspond with its seasonal counterpart, thus providing only limited
protection and subsequently allows for infection. In conclusion, in time all
adults will eventually develop T cell immunity against influenza viruses due to
natural infection. Therefore, only in children there is an opportunity to
investigate the effect of vaccination on the development of virus-specific T
cell immunity.