Developing a yellow fever vaccine

Since 1963, one of the most reliable vaccines for yellow fever has been produced by the Robert Koch Institute, Berlin. Over 2.5 million doses of the vaccine have been distributed. Based on attenuated viruses grown on chicken eggs, the vaccine is safe, highly immunogenic and well tolerated. Protection starts from ten days after a single dose and persists for at least ten years. Crucell is developing a yellow fever vaccine based on the know-how it has received from the Robert Koch Institute.

In a clinical phase III bridging study, the immunogenicity and safety of Crucell’s yellow fever vaccine Flavimun^® was compared to the original RKI Yellow Fever vaccine and to the commercially available yellow fever vaccine Stamaril® (sanofi aventis).
 
All three vaccines elicited an effective immune response with seroprotection achieved in 100% of individuals in each vaccine group at a neutralizing antibody titer of ≥ 1:10. In addition, at the ≥ 1:450 level, Crucell’s yellow fever vaccine was associated with a significantly higher seroprotection rate than Stamaril^® (P=0.0025).

The immune response to Flavimun^® and RKI-YF was very similar, with no significant difference in antibody titer between the two groups. However, Stamaril® vaccination resulted in a significantly lower antibody titer (P<0.0001 versus the YF-vaccine of Crucell). As a result, Crucell’s yellow fever vaccine was concluded to be at least as effective as the two other vaccine products.

 
All three vaccines were well tolerated. The incidence of solicited local reactions in the Stamaril^® group (36.8%) was comparable to that in the Crucell’s Flavimun® vaccine group (36.7%, P = 0.9794), but was significantly higher in the RKI-YF group (57.1%, P = 0.0032).
 
In summary, Crucell’s yellow fever vaccine has been proven to be highly immunogenic, safe and well tolerated. Additionally the manufacturing consistency of the vaccine has been demonstrated.
 
Flavimun^® was submitted for registration in Switzerland in March 2009. A dedicated team is currently reviewing outstanding questions from the Swiss authorities and will respond as soon as possible.

About yellow fever

Yellow fever is an acute viral disease and a major cause of hemorrhagic (bleedings) illness. The ‘yellow’ in the name refers to the jaundice (yellowish discoloration of the skin) that affects some patients. It is the only disease that still requires official proof of vaccination when entering or leaving infected areas.

Global yellow fever burden
After three to four days, most patients improve and symptoms disappear. However, in 15% of cases, the disease enters a ‘toxic’ phase - fever reappears, and the patient develops jaundice and sometimes bleeding. Around half of the patients who enter a toxic phase die within 10 to 14 days.

Geographical distribution
Yellow fever is endemic in 45 countries in Africa and Latin America, which have a combined population of more than 900 million. According to the World Health Organization (WHO), yellow fever causes an estimated 200,000 cases and 30,000 deaths worldwide each year. Mandatory mass preventive vaccinations between 1925 and 1953 in Francophone West Africa kept the number of cases very low. Since 1980, however, there has been an increase in the frequency of outbreaks and in the number of cases.

How yellow fever is transmitted
Mosquitoes are the primary carriers of the disease and transmit it from one host to another; generally between monkeys, from monkeys to humans, and from person to person.

Symptoms
Yellow fever is difficult to recognize, particularly during the early stages. It can easily be confused with malaria, typhoid and several other diseases. The first symptoms usually appear three to six days after infection. The first, or ‘acute’, phase is characterized by fever, muscle pain, headache, shivers, loss of appetite, nausea and vomiting.

Current treatment and prevention
There is no cure for yellow fever. Treatment is symptomatic, aimed at reducing the symptoms for the comfort of the patient. The disease can, however, be effectively prevented by vaccination with a yellow fever vaccine.

Further information