Summer’s coming! What’s new with Zika?

March 21, 2017
On November 18, 2016, the World Health Organization (WHO) declared that an “international emergency” no longer existed with regard to the Zika virus (ZIKV). At the same time, however, the global health agency and other healthcare entities urged researchers to continue to increase efforts to better understand Zika and its effects on pregnant women and their babies, to improve diagnostics, to develop vaccines and therapeutics, and to refine epidemiological surveillance techniques that would help in controlling Zika and other vector-borne diseases. The mosquito season was coming to an end in the Northern Hemisphere, but the battle against the Zika virus was just beginning.

Indeed, efforts in all of those areas and more have ramped up in the months since the WHO’s declaration. Here are some updates on recent studies and ongoing research.

Twenty-fold increase in birth defects due to ZIKV

The proportion of Zika-affected pregnancies with birth defects is approximately 20-fold higher compared with the proportion of pregnancies seen in 2013-2014, before Zika was introduced into the Americas, according to an article recently published in the Center for Disease Control and Prevention’s (CDC) Morbidity and Mortality Weekly Report. The types of birth defects—including brain abnormalities and/or microcephaly, neural tube defects and other early brain malformations, eye defects, and other central nervous system problems—were seen in about three of every 1,000 births in 2013-2014. In 2016, the proportion of infants with these same types of birth defects born to women with ZIKV infection during pregnancy was about six percent, or nearly 60 of every 1,000 completed pregnancies with Zika.

The researchers analyzed 2013-2014 data from three birth defects surveillance programs in the United States, in Massachusetts, North Carolina, and Georgia, to provide the baseline frequency for Zika-related birth defects. To assess the effect of ZIKV infection during pregnancy, the scientists compared that 2013-2014 baseline number with previously published numbers among pregnancies with ZIKV infection from the US Zika Pregnancy Registry (USZPR) from 2016.

They identified 747 infants and fetuses with one or more of these defects from the programs in MA, NC, and GA, from 2013-2014. Brain abnormalities and/or microcephaly were the most frequent conditions reported. Data from the USZPR identified 26 infants and fetuses with these same birth defects among the 442 completed pregnancies of women with possible Zika infection from January through September 2016. These findings demonstrate the importance of having monitoring systems that collect data on birth defects.

Additional mosquito species may transmit ZIKV

So far, the Zika virus is known to have been spread primarily by Aedes aegypti or Aedes albopictus. But Zika may be transmitted by more mosquito species, according to a new predictive model created by ecologists at the University of Georgia and the Cary Institute of Ecosystem Studies. Their findings, published last month in eLife, offer a list of potential candidate species.

Targeting Zika’s potential vectors—species that can transmit the virus from one host to another—is time-consuming and expensive, requiring collection of mosquitoes in affected areas, testing them to see which ones are carrying the virus, and conducting laboratory studies. The new model could streamline the initial step of pinpointing Zika vectors.

“What we’ve done is to draw up a list of potential vector candidates based on the associations with viruses that they’ve had in the past as well as other traits that are specific to that species,” says paper co-author Courtney C. Murdock. “That allows us to have a predictive framework to effectively get a list of candidate species without having to search blindly.”

Data used in the model consisted of information about the traits of flaviviruses—the family that includes Zika and dengue—and all the mosquito species that have been associated with them. For mosquito species, these included general traits such as subgenus and geographic distribution as well as traits relevant to the ability of each species to transmit disease, such as proximity to human populations, whether they typically bite humans, and how many different viruses they are known to transmit. For viruses, traits included how many different mosquito species they infect, whether they have ever infected humans, and the severity of the diseases they cause.

Analyzing known mosquito-virus pairs, the researchers found that certain traits were strong predictors of whether a linkage would form. The most important of these for mosquitoes were the subgenus, the continents it occurred on, and the number of viruses it was able to transmit. For viruses, the most important trait was the number of mosquito species able to act as a vector.

Researchers used the model to test the combination of ZIKV with all the mosquito species known to transmit at least one flavivirus. The model found 35 predicted Zika vectors, including 26 previously unsuspected possibilities. Seven of those occur in the continental U.S.

New device could rapidly detect ZIKV

About the size of a tablet, a portable device that could be used in a host of environments such as airports or remote locations (e.g., in South America) may hold the key to detecting the Zika virus accurately, rapidly, and inexpensively using a saliva sample. Researchers from Florida Atlantic University are working to develop a diagnostic tool to reduce the impact of the outbreak until a vaccine is identified.

“Most of the Zika cases in the United States and especially in Florida are travel-related,” says Waseem Asghar, PhD. “We are working to develop a tool that can be used without expensive laboratory equipment and skilled technicians in various settings like an airport or a community health center to provide reassurance to expectant families and those concerned because of recent travel. For about two dollars and within 15 minutes, we hope to accurately determine whether or not an individual has an active infection.”

Currently, patients are diagnosed by testing whether they have antibodies against the ZIKV in their bloodstream. However, the antibody test cannot discriminate accurately between the Zika virus and other flaviviruses such as dengue, West Nile virus, and chikungunya. The more accurate method for detecting the virus is by looking for pieces of the viral genome in a patient’s blood sample using a test known as polymerase chain reaction (PCR).

This new device is based on technology that Asghar and colleagues developed to detect human immunodeficiency virus (HIV). It uses inexpensive paper- or plastic-based materials, a cassette-sized container holding up to 12 samples at a time, and a receptacle about the size of a tablet. These materials are easy to make, easy to use, and can easily and safely be disposed of by burning, providing an appealing strategy for developing an affordable tool for diagnosing ZIKV in developing countries as well as low- and middle-income countries where there is limited laboratory infrastructure.

The researchers are working to adapt their device to diagnose the Zika virus, and they recently received a grant from the Florida Department of Health to establish proof-of-principle and then further test and commercialize this device.

Scientists uncover how ZIKV causes microcephaly

A multidisciplinary team from The University of Texas Medical Branch (UTMB) at Galveston has uncovered the mechanisms that ZIKV uses to alter brain development. These findings are detailed in Stem Cell Reports.

Since a normal brain develops from simple cells called stem cells that are able to develop into any one of various kinds of cells, the UTMB team deduced that microcephaly is most likely linked with abnormal function of these cells.

There are two main lineages of the virus, African and Asian. Recently, the UTMB team found that only the Asian lineage has been linked with microcephaly. So, what is it about this particular form of the virus that inflicts such damage?

The researchers established a method of investigating how Zika alters the production, survival, and maturation of brain stem cells using cells donated from three human fetal brains. They focused on the impact of the Asian lineage ZIKV that was involved in the first outbreak in North America in late 2015.

“We discovered that the Asian lineage Zika virus halted the proliferation of brain stem cells and hindered their ability to develop into brain nerve cells,” says Ping Wu, senior author on the study. “However, the effect that the Zika virus had on the ability of stem cells to develop into specialized cells differed between donors. This difference seems to be linked with a Zika-induced change in global gene expression pattern. It remains to be seen which genes are responsible. The unique system containing stem cells from three donors will allow us to dissect molecular mechanisms underlying Zika virus-induced brain malformation.”

Promising investigational ZIKV mRNA vaccine

A novel, gene-based investigational vaccine protected mice and monkeys against Zika virus infection after a single dose, according to a study appearing online in Nature. The research was conducted by investigators funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), NIAID scientists, and other partners. The candidate vaccine, called ZIKV prM-E mRNA-LNP, uses messenger RNA (mRNA), with which the body produces Zika virus proteins designed to elicit infection-neutralizing antibodies. Scientists at the University of Pennsylvania in Philadelphia and at the company BioNTech in Mainz, Germany, developed the vaccine.

Similar to DNA vaccines, mRNA vaccines do not contain live or inactivated virus and therefore cannot cause Zika infection. The mRNA vaccine platform can be quickly adapted to express most viral proteins and can be manufactured efficiently. NIAID and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services, are developing additional mRNA vaccines against Zika.

For this study, investigators vaccinated 19 mice with a single shot of ZIKV prM-E mRNA-LNP, and they gave a placebo vaccine to a control group consisting of 14 mice. They then exposed 18 mice (nine control and nine vaccinated) to Zika virus two weeks after vaccination and exposed the remaining mice (five control and 10 vaccinated) to Zika virus 20 weeks after vaccination. Nearly all control mice had Zika virus in the blood by day three, while all of the immunized mice showed no detectable virus. Investigators also gave various doses of the vaccine to five monkeys and gave a placebo vaccine to a control group of six monkeys. All monkeys were injected with Zika virus five weeks after vaccination. All monkeys in the control group had Zika virus in their blood, while four out of the five monkeys in the vaccinated group, including those that received the lowest dose, were protected from infection with no detectable virus.

The authors note that additional research is required to explore adding a boost to the vaccine regimen to see if that would increase its immunogenicity and to determine whether the investigational vaccine can prevent Zika infection and disease in humans.

NIH begins study of vaccine to protect against mosquito-borne diseases

The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) has also launched a Phase 1 clinical trial to test an investigational vaccine intended to provide broad protection against a range of mosquito-transmitted diseases, such as Zika, malaria, West Nile fever and dengue fever, and to hinder the ability of mosquitoes to transmit such infections. The study, which is being conducted at the NIH Clinical Center in Bethesda, MD, will examine the experimental vaccine’s safety and ability to generate an immune response.

The investigational vaccine, called AGS-v, was developed by the London-based pharmaceutical company SEEK, which has since formed a joint venture with hVIVO in London.

Unlike other vaccines targeting specific mosquito-borne diseases, the AGS-v candidate is designed to trigger an immune response to mosquito saliva rather than to a specific virus or parasite carried by mosquitoes. The test vaccine contains four synthetic proteins from mosquito salivary glands. The proteins are designed to induce antibodies in a vaccinated individual and to cause a modified allergic response that can prevent infection when a person is bitten by a disease-carrying mosquito.

The clinical trial is expected to enroll up to 60 healthy adults ages 18 to 50. Participants will be randomly assigned to receive one of three vaccine regimens. The first group will receive two injections of the AGS-v vaccine, 21 days apart. The second group will receive two injections of AGS-v combined with an adjuvant, 21 days apart. The adjuvant is an oil and water mixture commonly added to vaccines to enhance immune responses. The third group will receive two placebo injections of sterile water 21 days apart. Neither the study investigators nor the participants will know who is assigned to each group.

Participants will return to the clinic twice between vaccinations and twice after the second vaccination to undergo a physical exam and to provide blood samples. Study investigators will examine the blood samples to measure levels of antibodies triggered by vaccination.

Each participant also will return to the Clinical Center approximately 21 days after completing the vaccination schedule to undergo a controlled exposure to biting mosquitoes. The mosquitoes will not be carrying viruses or parasites, so the participants are not at risk of becoming infected with a mosquito-borne disease. Five to 10 female Aedes aegypti mosquitoes from the insectary in NIAID’s Laboratory of Malaria and Vector Research will be put in a feeding device that will be placed on each participant’s arm for 20 minutes. The mosquitoes will bite the participants’ arms through the netting on the feeding devices.

Afterward, investigators will take blood samples from each participant at various time points to see if participants experience a modified response to the mosquito bites as a result of AGS-v vaccination. The study is expected to be completed by summer 2018.