After the declaration by WHO on 11
June 2009 of an influenza pandemic, caused by an H1N1 variant, large scale
vaccination was undertaken. There is a special European procedure for the
development and licensing of influenza vaccines. A so-called mock up dossier is
prepared using one influenza strain; later this strain is replaced by more
relevant strain. Limited clinical trials are carried out to determine safety
and efficacy, but these trials are not large enough to detect very rare adverse
effects. The adverse effect narcolepsy in children due to the vaccine Pandemrix
came as a big surprise. Narcolepsy is a naturally occurring disease affecting
about 1 in 2000 persons. The symptoms are sudden periods of uncontrolled sleep
and cataplexy, a short period of muscle weakness.
The disease makes a normal life
difficult and can be dangerous in traffic situations. There is no real cure.
The cause is degeneration of a group of nerve cells in the hypothalamus that
secrete hypocretin, a hormone involved in the control of waking and sleeping.

Last week I attended an expert
meeting in Geneva organized by the IABS and
the WHO.

The purpose of the meeting was to look back and
evaluate, also in the knowledge that there will be future outbreaks of
infectious diseases that require urgent mass vaccination with vaccines that not
have been tested in large cohorts.

The narcolepsy case is a true
detective story with initial doubts that vaccination had anything to do with
the disease, very difficult epidemiology due to the low incidence and genetic
predisposition for subject carrying the HLA-DQB1*0602 allele, the effect of media
attention on reported disease incidence and false research clues from a
retracted paper.

The first signals for a correlation
between vaccination with Pandremix and narcolepsy came from Finland in August
2010, but it took a long time before this correlation was validated. In Finland
1:16,000 vaccinated 4 to 19 years old developed narcolepsy. Vaccination in
Finland was stopped in September 2010. In populations with less genetic predisposition
the incidence was lower. In retrospect about 1300 cases of vaccine-associated
narcolepsy were identified among 30.5 million vaccinated persons. How
narcolepsy is caused is not yet know. The finding of protein homology between
viral proteins en hypocretin and the hypocretin receptor has led to a
hypothesis for autoimmunity, but this has not been proven. Work is going on to find
the exact cause.

Lessons learned were:
Adverse effects should be actively
monitored and quickly available for validation. This requires better Europe
wide monitoring.
Signals should be validated faster;
it took years before the causality was established.
When mass vaccination is carried out
against (potentially) serious diseases with new vaccines rare and unknown
safety problems may pop up.
If this happens real time
benefit-risk analysis should be in place to decide to continue with vaccination
or to stop.
Longer and broadly protecting
influenza vaccines are urgently needed. This would reduce the need for frequent
immunization and the connected adverse effects.