June 16, 2005
Fragment of Yellow Fever Virus May Hold Key to Safer Vaccine
Jan ter Meulen in the field in West Africa
In one of the first molecular studies of the human antibody response
to yellow fever, Howard Hughes Medical Institute (HHMI) researchers and
their colleagues have found the crucial bit of virus that people's
immune systems need to spot and quash this often-fatal re-emerging
disease.
The findings may help scientists improve the existing vaccine, which
has rare but severe side effects, said Jan ter Meulen, an HHMI
international research scholar and associate professor of virology at
Leiden University Medical Center in The Netherlands.
“Yellow fever research was neglected because the vaccine was so effective.”
Jan ter Meulen
The group has identified a specific region on one of the viral
proteins that elicits an immune response. Antibodies produced by the
immune system interact with this part of the protein, known as a
neutralizing epitope, to fight off infection.
To protect people from the disease, yellow fever vaccines must
contain this essential fragment of instruction to the immune system,
said ter Meulen, senior author of a study published in the July 5,
2005, issue of the journal Virology and published early
online.
These days, the horror of Ebola or Marburg hemorrhagic fever grabs
more attention, but yellow fever is the original viral hemorrhagic
fever. It strikes more than 200,000 people a year, mostly in Africa,
killing about 30,000 of them, the World Health Organization estimates.
No drug treatment is effective against the virus.
Since yellow fever is spread by mosquitoes, much of America has been
safe from the disease thanks to control efforts aimed at the insects
and a highly effective vaccine that has been available for 60 years.
Vaccination is the key strategy for people living in and traveling to
tropical Africa, South America, and several Caribbean Islands, where
yellow fever is endemic.
In the last 20 years, however, yellow fever has been on the rise,
mostly due to the lapse of immunization programs in high risk areas.
More recently, serious and potentially fatal side effects from the
vaccine have been reported, mainly in elderly persons in northern
Europe.
"Yellow fever research was neglected because the vaccine was so
effective," ter Meulen said. "Medical science works in cycles. As soon
as the problem is solved, the caravan moves on. Once the disease comes
back, people realize they are lacking certain information.”
To learn more about the immune response and to identify the
necessary components of an improved vaccine, ter Meulen turned to
survivors of acute yellow fever in the Republic of Guinea in West
Africa. Along the war-torn border with Sierra Leone, disruptions in
vaccination and medical services led to a large epidemic in 2000. In
collaboration with local health authorities, ter Meulen set up a viral
hemorrhagic fever laboratory in Conakry to collect and evaluate blood
samples from patients.
In people, the mosquito-borne virus incubates for three to six days.
Initial flu-like symptoms are followed by a brief remission of up to a
day. Then, about 15 percent of people suffer more dangerous
complications— jaundice, liver, kidney, and heart damage, and
bleeding from the mouth, nose, eyes or stomach. At that stage, ter
Meulen and colleagues reported last year in the Journal of
Infectious Diseases, a person's own immune system, disrupted by its
reaction to yellow fever virus infection, may lead to death rather than
recovery.
The most recent study was led by Stephane Daffis, a graduate student
at Philipps-Universitat in Marburg, Germany. Using blood samples from
two yellow fever patients who had recovered, and sophisticated
molecular techniques, the researchers generated a library of the
millions of specialized antibodies that made up their immune
repertoires.
Then they screened the libraries with a vaccine strain of yellow
fever. Four of the antibodies neutralized yellow fever. Genetic
analysis showed they all homed in on one particular part of the protein
coating the virus. The epitope is called E-71, signifying its address
on the envelope protein. Several other amino acids in another section
of the folded protein contributed to the neutralization.
Yellow fever virus—and its flavivirus cousins, including
dengue and West Nile—look like balls covered by approximately 100
cross-hatched pairs of envelope proteins lying on the surface. The
prongs of Y-shaped antibodies against yellow fever likely span the
pairs by grabbing the essential epitope on one and the supporting amino
acids on the other, ter Meulen speculates. The findings may apply to
the whole flavivirus family.
The results confirm and extend similar studies in mice, but the
human antibody-virus binding configuration looks more complex, ter
Meulen said.
In theory, the crucial antibodies, which have been cloned, could be
used for prophylactic protection after suspected exposure, or for
therapy, but ter Meulen does not think that pharmaceutical companies
are likely to take this approach. More realistically, he said, the
findings could help manufacturers design a more consistent vaccine
based on recombinant genetic technology, without the potential side
effects from variations of the weakened virus strain now grown in
fertilized chicken eggs.
Photo: Elisabeth Fichet-Calvet, Museum of National History, Paris
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Cindy Fox Aisen
