Zika-proofing the womb

The placenta could decode the effects of Zika virus on pregnant women and foetuses


Bethesda doesn't lose its charm even in bleak winter. Leafless trees glisten in the sun, like abstract pieces of art in a sculpture garden. The National Institute of Health (NIH) campus in the small town, in Maryland, US, appears rustic. Yet, it is a bustling research facility. “It stopped snowing just a little while ago,” says Dr Catherine Spong, deputy director of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development.

What keeps Spong on her toes these days is a comprehensive study on the impact of Zika infection on pregnancy. “The early studies included only children who had complications, like microcephaly [abnormal smallness of the head], at birth. But, we are realising that some children may look normal at birth, yet have problems later on, including acquired microcephaly,” says Spong. She says it is important to understand the timing of infection during pregnancy. “Both the foetus and the placenta develop across gestation. An infection in the first trimester is likely to have a different impact than the infection in the second or third trimester, or an infection as a newborn.”

I've always been fascinated about what it is about the placenta that prevents transmission from mother to child and whether that will contribute towards vaccine development. - Dr Rana Chakraborty, paediatric specialist

Babies born to mothers with Zika can have microcephaly, brain damage, hearing loss, vision impairment, orthopaedic problems and development delay.

In 2016, the NIH, in partnership with Brazil's Fundacao Oswalso Cruz-Fiocruz, a national scientific research organisation linked to the Brazilian health ministry, started a multi-country study on Zika. Called 'Zika in Infants and Pregnancy', the study seeks to enrol 10,000 pregnant women in six countries. It started in Puerto Rico, and has expanded to locations in Brazil, Colombia, Guatemala and Nicaragua. NIH will have its first analysis done after the first 2,000 participants are tested. “Hopefully by summer,” says Spong.

The outbreak of Zika in India hasn't been as bad as anticipated. Even in the countries that were badly hit, like Brazil, there is a drop in the number of cases reported. The World Health Organisation no longer classifies Zika as a world emergency. Does that mean the crisis is over? Experts at the US Centers for Disease Control and Prevention (CDC) say there is still cause for concern as the virus is likely to strike again. “Zika virus will continue to circulate indefinitely in most regions where it has been introduced,” says a spokesperson. “In island communities (like Yap in the Pacific Ocean), small population size and widespread immunity following a Zika virus outbreak may allow for interruption of transmission. In other areas where mosquito activity is low or absent during winter months, virus transmission can stop. However, in these settings, transmission may resume if the virus is reintroduced during mosquito season. However, mosquito-borne disease outbreaks are difficult to predict. There will be future outbreaks, including large ones, as well as years with reduced transmission, but it is impossible to know when or where these transmission patterns will occur.”

Dr Rana Chakraborty Dr Rana Chakraborty

Also, says Spong, “There are people infected with Zika who don't have any symptoms. From the early studies, it is estimated that symptoms occur only 20 per cent of the time.”

So far, only four cases of Zika have been reported in India. These were detected in Gujarat and Tamil Nadu. But, health experts say that the virus could be present in other parts of the country. If you visited an affected country in the recent past, there are chances that you have been exposed to the virus. According to CDC data, of the 5,658 symptomatic cases of Zika reported in the US from 2015 to 2018, 5,376 were diagnosed in people who had visited affected areas in the past. Worse still, if you get pregnant, unaware of the infection, the baby could be at risk.

Zika infects the placenta. So, could it be possible to protect the baby in the womb if the mother is infected? Dr Rana Chakraborty, a paediatric specialist at the Emory University School of Medicine, in Atlanta, has been trying to answer this question. And, interestingly, his previous studies on HIV gave him an edge while dealing with Zika. “Pregnant women with HIV who don't take antiretroviral therapy will have a high viral load,” he says. “However, their chances of transmitting the disease to their babies in utero is just 7 per cent. That means there is something amazing about the placenta that prevents transmission of diseases. I've always been fascinated about what it is about the placenta that prevents transmission from mother to child and whether we can understand anything from the placenta, which will contribute towards vaccine development.”

An infection in the first trimester is likely to have a different impact than the infection in the second or third trimester, or an infection as a newborn. - Dr Catherine Spong, deputy director of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development

He started working on this in 2009 and has published many papers. “People were not interested in the placenta at that time,” he recalls. As reports of the Zika virus infection started coming out from Brazil, Chakraborty collaborated with flavivirus specialists to gain more insight on what hinders or facilitates the mother-to-child transmission. They found that the Zika virus is smarter than other flaviviruses when it comes to breaking the placental barrier and infecting the baby. “We documented how the Zika virus infects immune cells in the placenta,” he says. “These cells replicate the Zika virus within the placenta and perhaps propagate it into the cord blood, infecting and causing in utero damage to the unborn child, resulting in complications related to congenital Zika infection. Now, we are looking at which receptors in these cells are important for allowing Zika infection and if we knock down those receptors, will it have any effect in terms of Zika proliferation in these cells or replication.”

The experiments were done on placentae donated by healthy volunteers who had caesarian deliveries. However, working on the placenta is quiet challenging, says Chakraborty. One of the main issues he encountered was that the cells became contaminated and infected very quickly. “So, you only have a certain period of time. You cannot leave your placenta overnight. You have to work on it as soon as you get it. That is problematic,” he says.

Despite the many problems Zika presents, scientists are certainly making headway. At the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the NIH, a team of scientists is upbeat. Their investigational DNA vaccine—cleared to be used on humans—entered phase 2 clinical testing last year. “Phase 1 data indicates that the vaccine is safe and able to induce a neutralising antibody response against Zika virus in healthy adults,” says a NIAID spokesperson. The phase 2 trial, which enrols participants at sites in the US, and Central and South America, is evaluating the vaccine's efficacy and safety, besides determining the optimal dose.

Dr Catherine Spong Dr Catherine Spong

How does the vaccine work? “The Zika candidate vaccine contains a small circular piece of DNA called a plasmid, into which scientists have inserted genes that encode two proteins found on the surface of the Zika virus. Once injected into muscle, the proteins assemble into particles that mimic the Zika virus and trigger the body’s immune system to respond,” says the spokesperson.

NIAID is also supporting other candidate vaccines, including a Zika purified inactivated virus vaccine—in which the virus cannot replicate—developed by scientists at the Walter Reed Army Institute of Research. Then there is a live-attenuated investigational vaccine (in which the virus has been weakened so that it cannot cause disease), and investigational mRNA vaccines (a gene-based platform similar to DNA vaccines).

Countries like Brazil are still reeling under the effects of Zika, as children with microcephaly are being abandoned by their parents. Even for the most dedicated parents, raising babies with microcephaly has been a daunting task.

The world is indeed looking forward to the much-needed vaccine.