CHICAGO/BANGKOK – Zika's rampage last year in Brazil caused an explosion of infections and inflicted a crippling neurological defect on thousands of babies — an effect never seen in a mosquito-borne virus.
It also presented a mystery: why had a virus that had been little more than a footnote in the annals of infectious diseases taken such a devastating turn in the Americas? How had Africa and Asia, where Zika had quietly circulated for decades, escaped with no reports of major outbreaks or serious complications?
Scientists initially theorized that Zika's long tenure in Africa and Asia may have conferred widespread immunity. Or, perhaps older strains were less virulent than the one linked in Brazil to more than 2,100 cases of microcephaly, a birth defect characterized by arrested brain development.
Now, amid outbreaks in Singapore, Thailand, Vietnam and other parts of Southeast Asia, a much graver explanation is taking shape: perhaps the menace has been there all along but neurological complications simply escaped official notice.
The question is driving several research teams, according to leading infectious disease experts and public health officials.
The answer is immediately important for Asia, the region most affected by Zika after the Americas. Thailand has been hardest hit with more than 680 reported Zika infections this year, followed by Singapore with more than 450 and Vietnam with as many as 60.
Much of the population lives in the so-called "dengue belt," where mosquito-borne diseases are prevalent. And vulnerable countries — including Vietnam, the Philippines, Pakistan and Bangladesh — are ill-prepared to handle an outbreak with any serious consequences, experts said.
Lacking evidence of varying degrees of virulence, public health officials have warned Asia leaders to prepare for the worst. The scientific community is following similar assumptions.
"Zika is Zika until proven otherwise. We assume that all Zikas are equally dangerous," said Dr. Derek Gatherer, a biomedical expert at Lancaster University in Britain.
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WHICH ZIKA?
The World Health Organization recognizes two major lineages of Zika. The first originated in Africa, where it was discovered in 1947 and has not been identified outside that continent. The Asian lineage includes strains that have been reported in Asia, the Western Pacific, Cabo Verde and, notably, the Americas, including Brazil.
The Asian lineage was first isolated in the 1960s in mosquitoes in Malaysia. But some studies suggest the virus has been infecting people there since the 1950s. In the late 1970s, seven cases of human infection in Indonesia were reported.
The first record of a widespread outbreak was in 2007 on Micronesia's Island of Yap.
Experts began to suspect a link to birth defects during a 2013 outbreak in French Polynesia when doctors reported eight cases of microcephaly and 11 other cases of fetal malformation.
In 2015, it hit Brazil, causing spikes in an array of neurological birth defects now called congenital Zika virus syndrome, as well as Guillain-Barre syndrome, a neurological disorder that can lead to temporary paralysis.
Viruses mutate rapidly, which can lead to strains that are more contagious and more virulent. Many researchers theorized early on that the devastation in Brazil was caused by an Asian strain that had mutated dramatically.
That theory relies, among other things, on the absence of Zika-related microcephaly in Asia. So when Zika broke out in parts of Asia earlier this year, researchers were on the lookout.
If researchers were to connect a case of microcephaly to an older Asian strain — and not one that boomeranged back from Brazil — it would debunk the early theory. It would mean Zika "did not mutate into a microcephaly-causing variant as it crossed the Pacific," Gatherer said.
At least three microcephaly cases have been identified in Asia, but the verdict is still out.
For two microcephaly cases in Thailand, public health officials could not determine whether the mothers had an older Asian strain of Zika or a newer one that returned from the Americas, said Dr Boris Pavlin, WHO's acting Zika incident manager at a recent briefing.
In Vietnam, where there have been no reports of imported Zika infection, officials are investigating a third case of microcephaly. If it is linked to Zika, Pavlin said it would suggest the older strains there could cause microcephaly and, perhaps, Guillain-Barre.
In Malaysia, where at least six cases of Zika infection have been reported, authorities have identified both an older Southeast Asian strain and one similar to the strain in the Americas, suggesting the possibility that strains from both regions could be circulating in some countries.
The hunt is on in Africa as well. In Guinea-Bissau, five microcephaly cases are under investigation to determine whether the African lineage of Zika can cause microcephaly.
It is a top research priority at WHO, said Dr Peter Salama, executive director of the agency's health emergencies program, in a press briefing Tuesday.
"That is a critical question because it has real public health implication for African or Asian countries that already have Zika virus transmission," Salama said. "We are all following this extremely closely."
HERD IMMUNITY
Scientists also are trying to learn whether people in places where Zika is endemic are protected by "herd immunity." The phenomenon limits the spread of virus when enough of a population is inoculated against infection through vaccination, prior exposure or both.
Experts believe Zika moved explosively in the Americas because there was no prior exposure. It's not clear how widely Zika has circulated in Africa and Asia, whether there could be pockets of natural immunity — and, importantly, whether immunity to one strain would confer immunity to another.
One recent review of studies suggests 15 to 40 percent of the population in some African and Asian countries may have been previously infected with Zika, said Alessandro Vespignani, a professor of health sciences at Northeastern University in Boston.
That's far below the 80 percent population immunity one mosquito borne virus expert estimated in the journal Science would be necessary to block Zika.
Researchers also believe it's possible that microcephaly went undetected in parts of Asia and Africa where birth defects weren't well tracked.
That too, is under investigation, said Dr David Heymann, Chair of the WHO Emergency Committee, at a press briefing last week.
"Now," he said, "countries are beginning to look back into their records to see on their registries what the levels of microcephaly have been."