[afro-nets] Fragment of Yellow Fever Virus May Hold Key to Safer Vaccine

[Leela McCullough <leela@healthnet.org>]

Fragment of Yellow Fever Virus May Hold Key to Safer Vaccine
------------------------------------------------------------
17 June 2005
Howard Hughes Medical Institute
http://www.hhmi.org

In one of the first molecular studies of the human antibody re-
sponse 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 avail-
able 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 in-
formation.

To learn more about the immune response and to identify the nec-
essary 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, dis-
ruptions in vaccination and medical services led to a large epi-
demic in 2000. In collaboration with local health authorities,
ter Meulen set up a viral hemorrhagic fever laboratory in Cona-
kry 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 remis-
sion 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-Universität 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, signify-
ing its address on the envelope protein. Several other amino ac-
ids 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 weak-
ened virus strain now grown in fertilized chicken eggs.

Contact: Jennifer Donovan
Howard Hughes Medical Institute
Tel.: +1-301-215-8859
mailto:donovanj@hhmi.org
http://www.hhmi.org



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