Update on Zika Virus

TODAY, ZIKA STANDS alongside Ebola and drug-resistant bacteria as one of the most frightening diseases threatening our faith in modern technology’s triumph over nature. Like earlier diseases such as polio and smallpox that once terrified entire populations, Zika stokes our most primal fears becauseit threatens the most vulnerable: the developing child during pregnancy. An expectant mother who is infected with Zika can pass the virus along to her child, causing the development of serious, debilitating and even life-threatening birth defects.¹

On Feb. 1, 2016, WHO had declared Zika outbreaks in Brazil and French Polynesia a public health emergency of international concern.² Thereafter, popular media coverage of Zika exploded when an epidemic occurred during the Rio Olympic Games in summer 2016. On the eve of the games, some health officials warned athletes and spectators to avoid the area due to risk of infection, while others reassured the public the risk was negligible. (Afterward, the World Health Organization [WHO] reported there were no infections of Zika during the Olympic Games.³)

What Is Zika?

There are two main strains of the Zika virus: Asian and African.⁴ Zika virus is a member of the same family of flaviviruses that cause dengue, West Nile and yellow fevers, and Japanese encephalitis. It is named for a region in Uganda, where it was first isolated in monkeys in 1947 by researchers studying yellow fever.⁵ The first human infection was noted five years later, and the first case outside of Africa was reported in Indonesia 11 years after that.⁶

Zika virus was originally and is still primarily transmitted by mosquitoes of two Aedes species: albopictus and aegypti.¹ Since its discovery, Zika has spread beyond its original tropical habitats in equatorial Africa and Asia and is now in the United States, southern Asia and the South Pacific.⁷ Today, more than 75 nations have reported a Zika outbreak.³ However, it remained relatively unknown outside specialist circles until a series of outbreaks in 2007.⁶

The Centers for Disease Control and Prevention (CDC) reports that in 2015 and 2016, slightly fewer than 5,000 Americans were reported to have contracted Zika, and only 219 of those contracted it in this country; the rest were infected while traveling abroad.⁸ However, health officials in Brazil estimate 1.5 million of Brazil’s 206 million population have had Zika. And even in the U.S. Caribbean territories, the number of those who have been infected is about 36,000.⁹

Transmission of Zika

Both strains of Zika are fairly fragile and cannot exist outside of a host. For instance, the virus cannot be spread via airborne transmission or casual contact, or through food. Instead, Zika spreads when mosquitoes bite someone infected with the virus, and then pass the virus to others they bite afterward. In addition, it can spread through unprotected sexual activity with an infected person — even in the absence of any symptoms, as was illustrated by a Maryland woman who contracted the disease from her partner in 2016 when he returned from a trip to the Dominican Republic.¹⁰

There has been at least one reported case of laboratory acquired infection, which occurred when a researcher accidentally pricked herself with a needle and became infected.¹¹ On another front, public health agencies are exploring whether Zika may spread through blood transfusions or organ transplants; however, as of this writing, no confirmed cases have been reported in the U.S. In March 2016, the U.S. Food and Drug Administration (FDA) approved an experimental test to screen blood donations for Zika virus.¹²

Expectant mothers can transmit the virus to their developing children through the placenta. But, there is no evidence of transmitting the virus to the child via breast milk, and Zikapositive mothers are encouraged to breastfeed their infants since the benefits outweigh any known risk at this time.¹³

It is also now thought that the Asian strain of Zika is responsible for all cases of congenital Zika syndrome. In fact, genome analysis shows the Zika virus most prevalent in the Americas is more closely related to the Asian strain.¹⁴

Both mosquito species that carry Zika are now found on all continents except Antarctica, and can be found across the southern United States, and even in the upper Midwest, as well as in American territories in the Caribbean.¹⁵ Aedes aegypti prefers to feed on humans rather than other animals, but it is confined to tropical, subtropical and some temperate climates. Aedes albopictus will bite humans, but it prefers other animals, and it can withstand a broader range of temperatures, so it is more widespread.¹³

The risk of contracting Zika is highest when mosquitoes are most active in areas with a current outbreak. Indeed, public health experts attributed the lack of Zika infections during the Rio Olympics to the games being held during the winter season in the Southern Hemisphere, when mosquito activity is lowest.

The length of incubation of Zika is unknown, but it is thought to range from two to 12 days. Similarly, it is not known how long the Zika virus remains in the body, although it is recognized that the immune system eventually purges it. Researchers believe Zika may remain in the semen for up to six months.¹⁶

Symptoms and Progression of Zika The majority of patients infected with Zika will exhibit no symptoms. Researchers surveyed infected patients in Yap State — a four-island group in Micronesia where a 2007 outbreak infected an estimated 73 percent of the 7,400 residents — and found 77 percent with Zika antibodies never experienced any symptoms at all.⁹

Of those who develop symptoms, the most common are a non-itchy rash that may appear anywhere on the body, conjunctivitis, headaches, general muscle and joint pain, and fever. Symptoms will exhibit anywhere from two days to a week.¹⁸ Most healthy adults will fully recover from a Zika infection quickly with no further complications.

A small but unknown percentage of those infected develop autoimmune disorders that attack the body’s nervous system, including Guillain-Barré syndrome (GBS) and acute disseminated encephalomyelitis (ADEM). 19 GBS occurs when the body’s immune system attacks the myelin lining around nerve tissue, often leading to a weakening of the arms and legs and, in severe cases, affecting the ability to breathe.²⁰ While the specific cause of GBS is not widely understood, it is known to be associated with a previous infection, and GBS rates have increased in areas with high numbers of Zika infections, leading researchers to believe the virus can trigger GBS.²¹ When Zika migrates to the brain, it results in ADEM. Similar to GBS, the body’s attempt to fight the infection instead attacks the myelin sheath that surrounds all nerve tissue (including the brain), causing it to swell. The cause of ADEM is also not yet completely understood.²²

Pregnant women exhibit symptoms similar to other patients. While researchers believe there may be a link between miscarriage and a Zika infection, this has yet to be conclusively determined, and studies continue.²³

The damage that can be caused by the Asian strain of Zika to a developing child is devastating: One outcome linked to Zika is microcephaly, which results in the child’s brain failing to properly develop.⁷ Other brain deformities associated with congenital Zika infection (also known as congenital Zika syndrome) include ventriculomegaly, polymicrogyria, cortical deformity, cerebellar deformity and intracranial calcifications, among others.²⁴ Researchers now believe the virus directly attacks the nascent nervous system and brain in unborn children, preventing neural progenitor cells from properly reproducing — and even killing the cells. Magnifying the problem is a recent study conducted on mice that shows the Zika virus can disrupt the blood flow from the placenta to the baby, stunting growth of the child by denying it nutrients.²⁵

Researchers are also examining whether some babies infected in utero who do not develop microcephaly or other congenital Zika syndrome defects may have other, milder damage that is not immediately evident that will manifest over time.²⁵ However, there is no evidence yet that a child who contracts Zika after birth is at risk for microcephaly or other conditions associated with congenital Zika syndrome. It is thought, though, that the virus interacts differently with neural progenitor stem cells than with the nerve cells they differentiate into.²⁶

Diagnosing Zika

Diagnosis of Zika is made by examining patients’ symptoms and reviewing their travel history to determine possible exposure.²⁷ If either indicates possible infection and first symptoms appeared within two weeks of the examination, a physician may conduct an RNA nucleic acid test of patient bodily fluids to determine whether there is presence of Zika virus. If it has been longer than two weeks, a urine sample will be tested. If that molecular test is negative, however, or if the infection is thought to be further along, antibody testing may be warranted to ensure an accurate diagnosis. All testing options should be conducted on pregnant patients.²⁸

Because of the similarity of Zika virus to other flaviviruses — dengue fever, yellow fever and West Nile — false positives are not uncommon. A recent study indicated that dengue and Zika share 54 percent identical amino acid sequences, making an accurate lab diagnosis challenging.³ The most accurate method to differentiate between closely related viruses is a plaque-reduction neutralization test. However, currently, only a handful of laboratories around the world have the capability to perform this type of test, making it impractical for clinical use at this time.³

Treating Zika

There is currently no cure for Zika.³ Treatment is the same as for any other mild viral infection: Drink plenty of fluids, get plenty of rest and address fever and aches with over-the-counter medications.

For patients who develop GBS, plasmapheresis and intravenous immune globulin (IVIG) are the two most common treatments. Plasmapheresis is a filtering process that removes antibodies from the bloodstream to reduce damage to the nervous system. IVIG is shown to help ease symptoms in most GBS patients, but it is not understood why it is effective.²⁹ However, a Dutch study of patients with GBS showed those receiving IVIG may be at higher risk of hypoalbuminemia, which has its own health risks, so patients on IVIG therapy should be monitored.³⁰

Those who develop ADEM are treated similarly to those with multiple sclerosis (MS), a similar autoimmune disorder. (ADEM is typically a one-time outbreak, rather than a chronic outbreak that marks MS.) Intravenous methyl prednisolone is typically the first-line treatment. If unsuccessful, plasma exchange may be an option, or IVIG may be tried if there is peripheral nervous system involvement. Specific treatments will vary by patient, depending on severity and secondary conditions.³¹

Children who develop microcephaly or other congenital Zika syndrome conditions before birth are likely to face significant health and developmental challenges throughout life, including vision and hearing problems. Depending on the severity, children may also suffer seizures. A full diagnostic workup and referral to early childhood development specialists can assist in developing a comprehensive care plan for children.³²

Children whose mothers test positive for Zika but who do not exhibit any symptoms of congenital Zika syndrome should be observed for a period of years because the full impact of Zika infection is still not fully understood.

Preventing Zika

There is no vaccination to prevent the Zika virus. Prevention efforts involve avoiding travel to areas with current Zika outbreaks, protecting oneself from mosquito bites, vector control to stop outbreaks by killing mosquitoes that transmit the virus, and using protection during sex or abstaining from sex during outbreaks.¹⁸

Pregnant women and women who are planning to become pregnant, or who are open to the possibility of pregnancy, should consult the CDC’s Zika Travel Information page at wwwnc.cdc.gov/travel/page/zika-travel-information to see where current Zika outbreaks have been reported. If possible, they should avoid travel to those areas.

If travel to an area with an active Zika outbreak is required, individuals are advised to protect against mosquito bites by covering as much of their body as possible with light-colored clothing, including full-length sleeves and pants, sleeping under mosquito netting, keeping doors and windows closed (or using screens), and using insect repellents containing DEET, IR3535 or picaridin (all of which are safe for use by pregnant women).¹⁸

Individuals should also dispose of standing water in containers because mosquitoes can breed even in a small bucket or pot. They’re also advised to contact local health authorities for assistance in treating large bodies of water such as ponds, lakes and abandoned pools.

Ongoing Research

Research is being conducted to further the fight against Zika on multiple fronts: improved diagnosis, treatment of active infections and inoculations.

Diagnosis. Better lab tests are needed to ensure physicians are able to accurately differentiate between Zika infection and infection by related flaviviruses. Consequently, the National Institute of Allergy and Infectious Diseases (NIAID) is funding research to fine-tune antibodies so a cross diagnosis between these closely related infections becomes less likely.³³

At the University of Bonn in Germany, a team that developed a standardized Middle East respiratory syndrome detection test is studying methods to improve diagnosis. An initial study showed that most polymerase chain reaction tests are not sensitive to low levels of the Zika virus in bodily fluids, and since tests made by various companies look at different parts of the RNA chain, they are not uniformly consistent in detecting different strains of Zika. The team has since developed a Zika “calibrator” so companies can ensure their testing systems are able to more accurately detect Zika RNA.³⁴

In February 2016, WHO extended its Ebola-oriented Emergency Use Assessment and Listing protocols to Zika research. This protocol eliminates much of the bureaucracy normally required to bring new diagnostic testing technology to market. It is intended to encourage researchers and manufacturers to expedite new technology.³

And, researchers at Florida Atlantic University recently received a nearly $200,000 state grant to devise a proof-of-principle for a portable field testing device similar to one the same team devised to test for HIV. This would be available for use at airports and other nonhospital settings to help control outbreaks by identifying infected patients quickly and inexpensively.³⁵

Treatment. NIAID is conducting reviews of approved antiviral drugs to see if any are effective in treating Zika virus. One of the most recent and most promising was a Zika-specific test conducted with the antiviral compound BCX4430, a drug built around a small molecule that interferes with the ability of a virus to replicate its RNA.³⁶ It has been shown effective at blocking Ebola reproduction in laboratory settings, leading FDA to fast track the drug for human testing.³⁷

Another study is examining the differences between the ways in which Asian and African strains, as well as the closely related dengue virus, affect developing neural stem cells. The study offers some promising leads into the possibility that an inhibitor targeting protein P53 may be developed to stop the virus from harming human neural progenitor cells in unborn children.¹⁴

Because Zika has only fairly recently become a serious health threat, research on using antivirals against other flaviviruses are further along, particularly for dengue fever. This research is being reviewed to see if it might hold promise for Zika. Two other proteins associated with flaviviruses (NS3 and NS5) are the target of a potential inhibitor to tackle dengue fever. Similar approaches have yielded effective treatment for HIV and hepatitis C. If successful, this could lead to a possible approach for Zika as well.³⁸

To date, there are no approved antiviral drugs for any of the flavivirus infections,⁶ and many of the original studies are more than a decade old.³⁹ Still, several have shown promise in early testing, and further studies on those drugs are underway.⁴⁰

Vaccination. Multiple vaccines are currently being researched, and three have shown success in providing mice and monkeys full immunity against Zika:

• A purified inactivated virus developed by Army researchers at Walter Reed Hospital;
• An adenovirus vector-based vaccine with a fragment of Zika DNA coding developed at Beth Israel Deaconess Medical Center in Boston (BIDMC; affiliated with Harvard Medical School); and
• A plasmid DNA vaccine, also developed at BIDMC. Researchers have tested all three of these vaccines on either mice or monkeys, and have found that all three stimulated an effective immunity in test subjects. The next step is testing on humans.⁴¹

A fourth vaccine is a live-attenuated vaccine being developed from a cloned version of the virus. The cloning technology will allow for a rapid ramp-up to deployment if the vaccine proves successful.⁴²

Lastly, the inactivated vaccine project at Walter Reed is based on a successful vaccine program targeting Japanese encephalitis, a related flavivirus. The Zika study, called ZPIV, is already being administered to human volunteers.⁴³

Looking Ahead

Because mosquitoes that transmit Zika are found globally, and Zika is now known to also be transmitted sexually, it is likely that Zika will spread more widely from the tropics where it was first found. It may well be that travel advisories become useless in coming years if Zika becomes globally widespread.

WHO, the U.S. and other governments are putting significant resources into developing a vaccine and antiviral treatment. Last year, WHO received $25 million from various donors to fight Zika,⁴⁴ the U.S. Congress allocated $350 million toward Zika,⁴⁵ and the state of Florida recently allocated $25 million.⁴⁶ It is impossible to say whether or when such vaccines or treatments will prove successful and be approved for human use, but given recent advances in producing effective vaccines for related flaviviruses, it is reasonable that these preventatives will be ready sooner than later.

Still, until the day comes that we can vaccinate against Zika, common-sense precautions should be taken to control the spread of the disease, and ongoing support will be needed for families raising children with special needs due to the effects of infection in utero.