Zika virus is at least vaguely familiar to the researchers and public health officials now taking up the battle against it in several different ways.
For one, Zika virus' closest relatives – dengue, West Nile, yellow fever and others – are a well-studied group.
National Institutes of Allergy and Infectious Diseases (NIAID) Director Anthony Fauci told the audience at a recent talk at the NIH, "we have a lot of experience with closely related flaviviruses. . . . It's unlike the situation we were faced with three and a half decades ago when HIV came upon us," catapulting its family, the retroviruses, from scientific curiosity to global infectious threat No. 1.
But if flaviviruses are Zika's closest biological relatives, the greatest public health lessons may come from rubella, a virus that is now eliminated in the U.S.
Elimination is not likely to be in the cards for Zika, which, unlike rubella, has an animal reservoir that is unlikely to be eliminated in the mosquito.
But the two infections are similar in that exposure is by far the most dangerous during the prenatal period.
The typical Zika virus infection is almost laughably mild. "It comes and goes, people get better, there's almost no mortality," Fauci said.
Eighty percent of infected individuals have no clinical symptoms.
But when the virus infects a pregnant woman, though the infection is no worse for the woman herself, it can damage the embryonic and fetal brain with heartbreaking precision, causing severe abnormalities.
The most salient of those abnormalities is microcephaly, defined as a head circumference that is two standard deviations below mean. That small skull is due to the small brain it contains.
Microcephaly reduces both life expectancy and quality of life – babies have abnormal neurocognitive development that can leave them with problems in everything from speaking to walking.
And, Fauci added, overtly microcephalic babies are very likely just the tip of the iceberg.
"If you have a certain percentage of microcephaly, it's almost certain you are going to have a larger percentage of more subtle abnormalities" that don't become apparent until later in development.
That thought is particularly sobering given that the risk of overt microcephaly is already extremely high. Estimates range from 1 percent to more than 50 percent depending on the study, but Fauci told BioWorld Asia the most likely number appears to be around 30 percent.
In the March 30, 2016, online issue of Cell Stem Cell, researchers described one possible reason Zika virus is so toxic to normal brain development. Its entry receptor appears to be the AXL kinase, which is highly expressed on radial glia.
Radial glia are a founder cell population that generates all cortical neurons, and their selective vulnerability to Zika could explain the high risk of microcephaly, as well as other symptoms in affected babies that have been observed, such as involvement of the eyes.
Scientists also have been racing to figure out how the virus crosses the placenta in the first place, since one of its roles is to protect babies from viral infections.
This week, researchers at the University of Pittsburgh gained new insights into how Zika virus does not cross the placenta by infecting placental cells themselves.
"Unlike cell lines of the human placenta, primary placental cell lines resist infection with Zika virus," co-corresponding author Carolyn Coyne, an associate professor of microbiology and molecular genetics, told BioWorld Asia.
In a study published in the April 5, 2016, online issue of Cell Host & Microbe, Coyne, co-corresponding author Yoel Sadovsky and their colleagues showed that placental cells release interferon lambda, rendering them resistant to Zika.
If it is not through direct infection, the question remains how Zika does get across the placenta. Coyne said that possible pathways include inside the immune cells, which is how HIV enters the brain, or is bound and transported by cross-reactive antibodies.
Whatever the mechanism is, "I suspect that the virus is crossing the placenta in ways that do not involve active replication," she said.
21st century rubella
Rubella, too, usually takes a fairly mild clinical course, and half of infected individuals have no symptoms. But if a woman is infected during the first trimester of pregnancy, there is at least a 20 percent chance of damage to the fetus. This congenital rubella syndrome can take the form of deafness, cataracts, heart defects, mental retardation or liver and spleen damage.
Rubella was entirely conquered by vaccine, which first became available in the U.S. in 1969. Today, the disease has been eliminated in the U.S., with fewer than a dozen cases reported annually over the past 10 years.
There are no antivirals against rubella, and although there are situations where a Zika drug would be useful, it is likely that here, too, a vaccine will be the key to bringing the epidemic and its consequences under control.
Though the NIAID is screening its libraries to find small molecules that are effective against the virus, even if researchers identify drug leads, it is an open question whether there would be industry interest in developing such leads, since it is the rare Zika case that is even noticeable to the patient.
Fauci was optimistic that such a vaccine could be developed rapidly.
"You never want to be overconfident," he said, and timelines become less certain further into the future. But a DNA-based vaccine is highly likely to be in phase I trials by September, and Fauci said he thinks approval is possible by 2018.
Once a vaccine is in phase II trials, "how soon you know if it works depends on two things," he said, "One, how good the vaccine is, and two, how many infections you have in the community."
If a highly effective vaccine is tried in a community where Zika is rampant, the necessary data for applying for FDA approval could be collected by early 2018.
According to Cortellis Clinical Trials intelligence, there are five Zika virus vaccines in development by Inovio Pharmaceuticals Inc./Geneone Life Science Inc., Newlink Genetics Corp., Sanofi AG, Immunovaccine Inc. and Replikins Ltd., respectively. And just this week Canadian immunotherapy firm Immunovaccine Inc. disclosed a deal with Leidos, a national security in infrastructure solutions company, to develop a vaccine against Zika virus infection.
So far, none have reached clinical testing.
Flavivirus vaccine development has overall been a fairly successful endeavor.
Developing a highly effective dengue fever vaccine has been challenging, although there is a vaccine that has been licensed and another one is now in phase III trials. But other flaviviruses do not have the multiple serotypes that have made developing a dengue vaccine such a challenge. There is an effective yellow fever vaccine, on the market, and a West Nile virus vaccine has stalled not because it has been scientifically challenging to develop, but because there are currently no takers on the industrial side – an apathy that seems unlikely with Zika virus. (See BioWorld Today, March 17, 2016.)