Scientists discover why dengue fever gets worse the second time

WASHINGTON -- While some diseases leave the patient with immunity against future attacks, people with dengue fever get sicker the second time around. Scientists now believe they know why, and their finding may help lead to ways to fight the dangerous mosquito-borne illness.

The problem is "original antigenic sin" on the part of the immune system, according to a team led by Gavin Screaton of the MRC Human Immunology Unit at Weatherall Institute of Molecular Medicine at John Radcliffe Hospital in Oxford, England. Antigens battle diseases invading the body.

There are four subtypes of dengue, pronounced ding'-ee, and people infected with the disease mount an immune response to fight off the version that infects them.

If a patient later acquires a different subtype, however, the immune system mounts an attack directed at the original form of the disease, the researchers found in a study of volunteers in Thailand.

That means they produce immune cells that are less effective against the new form, which can then attack the victim more strongly, the team reports in a paper scheduled for the July issue of the journal Nature Medicine.

The paper by Screaton, Prida Malasit of Mahidol University in Bangkok, Thailand, and others, was being published today online.

Dengue fever causes severe headaches, fever and rashes. The more serious dengue hemorrhagic fever has a fatality rate of 5 percent, according to the Centers for Disease Control and Prevention. The virus is estimated to affect as many as 50 million people annually in tropical areas and kill 12,000 or so. No vaccine or specific treatment has been found.

Having the body respond to the wrong form of the dengue virus complicates the process of developing a vaccine. That is because a vaccine uses a dead or weakened virus to mimic an infection, so the body will recognize the invader and be ready to attack it.

For example, if the vaccine were to use Virus A, the immune system would learn to recognize that and attack it. Later, if a very similar, but not identical, form of the virus were to show up, the body would mobilize against the original one and produce immune cells that might not be fully effective against the new invader.

Screaton explained it this way: In second infections, the immune system does not choose new cells that exactly fit the antigen but instead "looks in its memory cells to see if anything already exists to do the job."

Because the memory cells already know something about the attacking virus, "in effect they are halfway round the track when the gun goes off," he said.

"The advantage is that a response can be quickly mobilized. The disadvantage is that as the response is shaped by previous antigen, it may not be the best fit to the current antigen," Screaton added.

This idea was originally developed in studies of influenza, which is caused by a virus that changes so often that new vaccines have to be developed annually.

The findings may help in the fight to prevent dengue, but much effort remains to fully understand it, Screaton said.

Vaccine initiatives are planned, he said, but "the risks are obvious: if you don't, in one stroke, protect against all dengue subtypes, you may make the situation worse."

It may be possible, he speculated, to design vaccines to generate an immune response to unique factors in each virus subtype.

Vaccines have successfully fought diseases over the past century, but some diseases -- HIV, malaria, tuberculosis, hepatitis-C, dengue fever -- have proved stubborn.

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On the Net: Background on dengue fever: http://www.cdc.gov/ncidod/dvbid/dengue/index.htm