Zika 5 years later: Still much to learn as ‘likely’ future outbreak looms
On Feb. 1, 2016, almost 70 years after Zika was first discovered by chance in a forest in Uganda, WHO declared a global public health emergency over an increase in microcephaly and neurological complications linked to the virus.
Five years later, despite advances in understanding the transmission, pathogenesis and clinical progression of the mosquito-borne disease, a lot is still unknown about Zika’s emergence as the cause of an unexpected epidemic centered in Brazil, according to experts.
Previously, Zika mostly circulated in monkeys in Africa and Asia and “rarely infected humans,” said Omar S. Akbari, PhD, a biologist, mosquito expert and associate professor at the University of California, San Diego.
“The few cases that were detected in humans were mild,” Akbari told Infectious Disease News. “When Zika virus came to Brazil in 2015, the Brazilian population had never been previously exposed to the infection. Moreover, new evidence suggests that mosquito populations outside of Africa can be more permissive to the virus. Therefore, when it arrived, the human population had no underlying immunity to the infection, and the mosquitoes had enhanced vector susceptibility — making it easier for the disease to spread through the population.”
Infectious Disease News spoke with experts about the sudden emergence of Zika virus — once considered medically benign — as a cause of fetal and infant birth defects in children and central nervous system disease in adults, and when the world can expect it to cause another outbreak.
Brazil experienced the harshest toll during the 2015-2016 epidemic, with approximately 321,000 suspected or confirmed cases, followed by Colombia and Venezuela, according to the Pan American Health Organization.
Kristina M. Adams Waldorf, MD, a professor of obstetrics and gynecology and adjunct professor of global health at the University of Washington, said Zika was likely imported to Brazil during a 2014 World Cup soccer competition or a world championship canoe race that was held in Rio de Janeiro the same year.
“It took some time for the virus to become established and another period of time for children to be born from infected pregnancies,” she said in an interview.
Congenital Zika syndrome
Zika virus can cause congenital Zika syndrome, which the CDC describes as “a unique pattern of birth defects and disabilities found among fetuses and babies infected with Zika virus during pregnancy,” including severe microcephaly, decreased brain tissue, eye damage, joints with limited range of motion and too much muscle tone, which restricts body movement after birth.
Deafness also is a common occurrence, said Cristina Cassetti, PhD, the deputy director of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases.
Although the virus’ effect on fetal development is well documented, “the precise mechanism by which Zika affects the development of the fetal and infant brain is still unknown,” Cassetti told Infectious Disease News.
A large 2019 study by Brady and colleagues reported that women infected with Zika virus during early pregnancy were 17 times more likely to have a child with microcephaly. The study was conducted in northeast Brazil, the region hit hardest by the epidemic, where cases of microcephaly reached “an abnormally high” rate of 56.7 per 10,000 births near the end of 2015, the researchers said.
At the time, Adams Waldorf told Infectious Disease News that the study “is likely to provide the most accurate estimate that we will ever obtain for the RR of microcephaly due to Zika virus infection in the first and second trimesters.”
A second study published the same year by Nielsen-Saines and colleagues found that one-third of children aged 3 years or younger who were exposed to Zika virus during their mother’s pregnancy experienced below-average neurodevelopment and/or eye abnormality or hearing assessments. In Rio de Janeiro, approximately one-quarter of infants exposed to Zika went on to develop eye abnormalities, according to a 2018 study by Tsui and colleagues.
The CDC estimates that Zika-related birth defects occur in 10% of babies born to women with confirmed Zika during pregnancy.
Akbari explained that Zika can pass from mother to fetus through the placenta.
“The virus disrupts the growth and development of the fetal neural cells, which causes brain abnormalities such as microcephaly,” he said. “This is particularly problematic in the early stages of fetal brain development. Adults do not have rapidly growing neural cells, so while they can get neurological disease associated with Zika infection”— including Guillain-Barré syndrome — “it is rare.”
This is correct, Cassetti said, “but there are many details about the mechanism by which the virus affects brain development that are still unclear. For example, why does the infection of the fetal brain result sometimes in microcephaly and sometimes in other types of neurological manifestations?”
Sarah B. Mulkey, MD, PhD, a fetal and neonatal neurologist at Children’s National Hospital, said gestational age and other factors can increase the risk for severe neurological effects, with the most damage occurring in infants infected early on in pregnancy.
“Zika is neurotropic for immature neurons in a baby’s developing brain,” Mulkey said. “Therefore, it preferentially infects immature neurons as opposed to mature neurons and causes those neurons to die, leading to the severe types of brain injuries and microcephaly seen from in utero Zika infection in the developing brain.”
Even Zika-exposed infants who do not develop congenital Zika syndrome are at risk for abnormal development, according to a study by Mulkey and colleagues that was published in 2020.
Adams Waldorf said scientists currently lack the medical tools necessary to determine the “direct impact” of Zika on stem cells in the brain.
“Instead, we can check an MRI scan of the fetus’ or child’s brain to determine if the general anatomy looks normal,” she said. “Then we can follow babies over time to check their eyesight, hearing and head growth.”
Adams Waldorf warned that Zika can also potentially damage stem cells in the testes.
“I am concerned about the fertility of young boys and men who became infected with Zika virus during this epidemic and may be unaware that they have a low sperm count,” she said.
According to Susan Hills, MBBS, MTH, a medical epidemiologist in the CDC’s Division of Arboviral Diseases, at least nine Zika vaccine candidates are currently in development — although most are still in the early stages. There are no approved vaccines available to prevent Zika infection. When one is available, “vaccination of women of reproductive age would be the priority,” Hills said.
Cassetti explained that several vaccines and therapies were “rapidly initiated” during the 2016 outbreak, but because the epidemic “waned rapidly,” researchers were unable to evaluate the efficacy of candidates in field trials.
“The epidemic came and went too fast” to conduct phase 3 trials, she said.
In the event of another outbreak, Cassetti said scientists would be able to rapidly evaluate candidate vaccines and therapeutics via field trials. This is similar to what occurred during the recent large Ebola virus outbreak in the Democratic Republic of the Congo, in which researchers were able to conduct groundbreaking trials of Ebola vaccines and therapeutics, some of which are now licensed for use.
“We are definitively better prepared than the first time around,” Cassetti said. “Now we have many more tools for research, better diagnostics and several therapeutics and vaccines in development, including an mRNA vaccine candidate by Moderna” — the same technology used in Moderna’s recently approved COVID-19 vaccine.
Evidence of Zika vaccine safety and efficacy will preferably come from studies that measure clinical outcomes, Hills said.
“If not feasible, immunogenicity studies based on an accepted protective immunologic endpoint could be used,” she said. “A human challenge model also could possibly be used as a study approach [but] any study using this approach would need to be carefully considered and approved by appropriate authorities.”
Akbari said the COVID-19 pandemic has impacted efforts to prevent and respond to Zika, like it has with so many other diseases, including malaria, polio and tuberculosis.
“Mosquito surveillance and control activities have been reduced in some countries, including the United States, due to COVID-19 prevention efforts,” Akbari said. “Many of these countries are at risk of — or, as in the case of some South American countries, such as Brazil — are currently experiencing a mosquito-borne disease outbreak fueled by the same mosquitoes that transmit Zika.”
The reason, Akbari said, is that the pandemic “has required public health organizations to reallocate funding and resources from mosquito-borne disease efforts to COVID-19 prevention, which may have devastating impacts on human health, especially in areas with already limited public health resources.”
In other emerging research, a 2020 study by Aubry and colleagues revealed that Aedes aegypti mosquitoes residing outside of Africa can transmit Zika more easily than a related subspecies that lives in sub-Saharan Africa, perhaps explaining why the Americas — where A. aegypti mosquitoes have been the virus’ primary vector — had a large outbreak and Africa did not.
Other research has suggested that Zika may be cross-reactive with other viruses. A 2020 study by Katzelnick and colleagues found that prior Zika infection significantly increases the risk for severe dengue, just as a prior dengue infection can.
“This finding reflects the complexity of the immune response in these regions where people are exposed to several related viruses,” Adams Waldorf said. “In some cases, an individual’s antibody response to prior viruses might pose a risk for the way their body manages a new infection.”
Sahotra Sarkar, PhD, a professor of philosophy and integrative biology at the University of Texas at Austin, said a “troubling” development since the epidemic has been the establishment of Brazilian monkeys as reservoirs for the virus, which is presumably due to transmission from humans to monkeys, he said.
“There is a possibility of future endemics when the virus, perhaps after some evolution, jumps back into the human population,” Sarkar told Infectious Disease News. “There is an enormous amount of research that needs to be done.”
He said “Zika will definitely be back,” and noted that mosquito control and gene drives — a technology that allows scientists to make desirable edits in an organism’s genetic material — may be useful tools in mitigating a resurgence.
“Our best strategy would be dedicated mosquito control of both Aedes aegypti and Aedes albopictus, even though the latter is not a very good vector,” Sarkar said. “I advocate for the use of gene drives using CRISPR technology to make them all male to control the disease. Removing these mosquitoes will also bring several other diseases under control, including dengue — the spread of which is a very serious problem — chikungunya and yellow fever.”
Akbari and colleagues have already built gene drives for A. aegypti mosquitoes and engineered them to be resistant to Zika, which, once combined with mosquitoes, could safely control wild populations of mosquitoes to combat the virus, they asserted.
“The technology is already here, and it works,” Akbari said.
Although it is unclear when the technology could be used, Akbari and others outlined what he called “a safe path forward” for using gene drives, writing in a recent paper published in Science that they “aim to prepare for potential field trials that are scientifically, politically, and socially robust, publicly accountable, and widely transparent.”
“We recognize our responsibility to work openly; we acknowledge that many innovations beyond those in the laboratory are still needed; and we welcome others, including a broad array of stakeholders in partner countries, to join us in conversation about appropriate governance of this technology and to advance together equitably, safely, and responsibly,” they wrote.
‘We need to be ready’
According to WHO, as of July 2019, 87 countries and territories had evidence of current or previous mosquito-borne Zika transmission. In the U.S., where both Florida and Texas reported local transmission of Zika virus in 2016 and 2017, no locally acquired cases were reported in 2019.
Mulkey said the rapid decline of Zika cases was a result of multiple factors, including population-level development of protective antibodies, positive changes to mosquito-bite prevention practices and improvements to mosquito control efforts.
“The virus is still present but circulating at low levels,” Mulkey said. “It is not known when it will return, but based on other flaviviruses, a future outbreak is likely.”
Hills also warned that another outbreak is possible and noted three regions where ongoing low-level transmission is probable: parts of Africa, Asia and the Americas.
“People living in or traveling to countries where there is a risk of transmission should protect themselves from mosquito bites,” she said. “Measures to prevent exposure to mosquito-borne diseases are recommended in general.”
Cassetti said the timeline for another outbreak relies on a number of factors, including the density of Zika-naive patients and mosquito vectors in populated areas, as well as the virus’ introduction frequency in new areas.
“Will the population that have no Zika virus immunity, who were born after the epidemic, be sufficiently large in another 5 years to ‘break’ the herd immunity and allow another epidemic? It is hard to know, but we need to be ready,” Adams Waldorf warned.
The possibility of another major Zika outbreak in the Americas is also dependent on when the virus enters a sylvatic cycle — a time period when viral transmission among mosquitos and an animal reservoir is sustained, Adams Waldorf said.
Hills said that although researchers learned a great deal about the virus during the epidemic — like its potential transmission routes — the world should remain vigilant for a potential resurgence of Zika or the emergence of a new mosquito-borne disease.
To prepare for another outbreak, WHO has developed the Zika Strategic Response Framework — a plan to advance research for Zika prevention, develop and strengthen surveillance systems for the virus, improve lab capacity for testing, support global vector control efforts and strengthen care of children and families affected by Zika.
“Strong disease surveillance, appropriate assessments to understand risk for transmission, maintaining and enhancing laboratory testing capacity, and mosquito surveillance and control measures are all key to preventing, preparing for, detecting and rapidly responding to the next outbreak,” Hills said.
- Aubry F, et al. Science. 2020;doi:10.1126/science.abd3663.
- Brady OJ, et al. PLoS Med. 2019;doi:10.1371/journal.pmed.1002755.
- Buchman A, et al. P Natl Acad Sci USA. 2019;doi:10.1073/pnas.1810771116.
- CDC. 2019 case counts in the US. https://www.cdc.gov/zika/reporting/2019-case-counts.html. Accessed December 26, 2020.
- CDC. Zika and pregnancy. https://www.cdc.gov/pregnancy/zika/data/index.html. Accessed December 10, 2020.
- CDC. Zika Travel information. https://wwwnc.cdc.gov/travel/page/zika-information#:~:text=Zika%20continues%20to%20be%20a,aegypti%20and%20Ae. Accessed December 3, 2020.
- CDC. Zika virus. https://www.cdc.gov/zika/index.html. Accessed November 17, 2020.
- Connelly CR, et al. MMWR Morb Mortal Wkly Rep. 2020;doi: 10.15585/mmwr.mm6928a6.
- Godfred-Cato S, et al. Trop Med Infect Dis. 2020;doi:10.3390/tropicalmed5040168.
- Katzelnick LC, et al. Science. 2020;doi:10.1126/science.abb6143.
- Li M, et al. eLife. 2020. doi:10.7554/elife.51701.
- Long KC, et al. Science. 2020;doi:10.1126/science.abd1908.
- Mulkey SB, et al. JAMA Pediatr. 2020;doi:10.1001/jamapediatrics.
- Nielsen-Saines K, et al. Nat Med. 2019;doi:10.1038/s41591-019-0496-1.
- Tsui I, et al. Pediatrics. 2018;doi:10.1542/peds.2018-1104.
- WHO. Zika epidemiology update. https://www.who.int/emergencies/diseases/zika/epidemiology-update/en/. Accessed November 17, 2020.
- WHO. Zika virus. https://www.who.int/news-room/fact-sheets/detail/zika-virus. Accessed December 10, 2020.
- For more information:
- Kristina M. Adams Waldorf, MD, can be reached at email@example.com.
- Omar S. Akbari, PhD, can be reached at firstname.lastname@example.org.
- Cristina Cassetti, PhD, can be reached at email@example.com.
- Susan Hills, MBBS, MTH, can be reached at firstname.lastname@example.org.
- Sarah B. Mulkey, MD, PhD, can be reached at email@example.com.
- Sahotra Sarkar, PhD, can be reached at firstname.lastname@example.org.
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