For decades there has been a counterintuitive and hotly debated theory about dengue infections: that antibodies generated by a previous bout of dengue could actually put a person at risk of more severe disease if they contracted the virus a second time.

And now American and Nicaraguan scientists have published evidence that may silence the skeptics. Antibody-dependent enhancement, or ADE as it’s known in scientific circles, can happen, they reported, when subsequent infection occurs at a time when antibodies generated by the prior infection have fallen to a specific low range.

Nikos Vasilakis, an associate professor of pathology at the University of Texas Medical Branch, used to be among the disbelievers — primarily because, though ADE was seen in lab experiments (in vitro), proof in people (in vivo) had been absent.

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“I’m one of those people who for years I was questioning that,” he admitted.

“This paper, what it does, it shows for the first time the narrow range of antibody concentrations … that actually produces enhancement of disease in vivo,” said Vasilakis, who was not involved in the study. “I have bias against ADE in general, but this is a very good study.”

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The work was published in the journal Science.

A theory borne out

One might expect that the scientist who came up with the theory in the first place would also cheer the publication.

Dr. Scott Halstead has insisted for decades that dengue antibodies were responsible when people who’ve had the virus develop severe — and sometimes fatal — infections the second time around. But, he said, he does not see this paper as the first in vivo proof of ADE.

Halstead, a former U.S. Army scientist who is now semi-retired, told STAT that evidence was arrived at a couple of decades ago through studies conducted in Thailand. He acknowledged, however, that this is the largest study to show the effect.

And the fact that the paper was published by Science — one of the highest-impact journals in the world — suggests its editors, too, felt this research adds something significant to the scientific literature.

In the study, researchers followed a cohort of nearly 6,700 children between the ages of 2 to 14. They monitored them for 12 years — and continue to follow them — drawing blood for testing every year. And any time one of the children developed an illness with fever, which is a hallmark symptom of dengue infection, they were assessed medically.

Senior author Eva Harris, a professor of infectious diseases and immunology at the University of California, Berkeley, said the team analyzed the more than 41,000 blood samples they had accumulated over the years, looking for a pattern that could explain why some children develop severe disease — dengue hemorrhagic fever or dengue shock syndrome — on their second dengue infection.

They used three different statistical approaches to explore the question, and “all roads led to Rome,” Harris said.

“Amazingly not only do we find that there is a specific titer of antibody that is predictive of severe disease, but all the three methods came to the exact same range of titers,” she said.

Counterintuitive findings

Dengue is transmitted via the bite of mosquitoes that carry the viruses. It is an unpleasant disease that can cause high fever, severe headache, and joint and muscle pain. But in some people, it can also cause small blood vessels to leak, which can lead to failure of the circulatory system, shock, and death.

Severe disease can happen with any dengue infection but is more common on the second.

Harris and her colleagues found that when antibody levels fell to a certain point in children who had been previously infected, they were at greater risk of having severe dengue disease if they were again infected. In fact, for children whose antibodies fell to within this low range — a sort of anti-sweet spot — the risk was nearly eight times higher than for other children.

In contrast, higher antibody levels were protective against severe illness.

The belief is that low levels of antibodies cannot neutralize or kill the invading viruses. But they do bind to them and effectively usher them into susceptible cells, where the viruses then replicate.

Harris acknowledged that the idea that some antibodies could be more dangerous than no antibodies is counterintuitive. “Exactly. But that’s always been the trick around dengue. And that’s why everybody’s obsessed with this. Because antibodies are supposed to be protective,” she said.

She stressed, however, that the finding doesn’t explain all cases of severe dengue disease. In fact, some people develop the severe form the first time they are infected. “This is definitely not like there’s only one explanation,” Harris insisted. “It’s just saying that this particular explanation seems to be valid in humans.”

Vasilakis noted that Cuban scientists have also shown that people who are obese are more prone to severe dengue infection. “This tells me that, yes, ADE may play a role. But it’s not the only reason that we do have severe dengue disease.”

Harris and Halstead said that the findings also underscore the need to use dengue vaccines carefully. A study published last year suggested that the vaccine should be targeted to children who have already had at least one bout of dengue, and should not be given to children who have never contracted the virus.

The World Health Organization’s vaccine experts have recommended that countries that use the vaccine — Dengvaxia, made by Sanofi Pasteur — should use it only in places where there is a lot of dengue activity.