Since Zika emerged in the global spotlight during the 2015 epidemic, the National Primate Research Centers (NPRCs) across the United States have joined forces to conduct groundbreaking research on the virus. These research centers, funded by the Office of Research Infrastructure Programs at the National Institutes of Health, have made significant progress researching the complexities of Zika virus infections, particularly in pregnant primates and their offspring. These extensive research initiatives aim to understand Zika virus infections during pregnancy and their long-term consequences on infants, and advance work towards developing promising preventive measures to help mitigate the devastating risks of the disease.
Zika is a mosquito-borne virus contracted through the bite of an infected Aedes aegypti mosquito. The virus can cause severe brain defects such as microcephaly and other congenital malformations in infants. While there has not been a vaccine or medicine to prevent the contraction of Zika, the largely NIH-funded collaborations between the NPRCs have led to promising results that help us better understand this virus, may prevent the virus from passing from mother to fetus, and are advancing research on vaccines and treatments.
Scientists at the California National Primate Research Center have delved into the effects of Zika virus infection during pregnancy, primarily through fetal growth and infant-mother interactions. A study by Eliza Bliss-Moreau, Florent Pittet and colleagues focusing on the impact of Zika infection during the second trimester of pregnancy revealed that the pregnant animals were not visibly ill from the virus. Still, ultrasounds indicated that infection slowed fetal growth — the Zika infants were smaller than normal both pre-natal and post-natal. This study on group living and reared rhesus macaques revealed that the Zika virus altered interactions between infants and mothers. Infants spent much more time attached to their mothers through the first month than those without the virus. The researchers also found that Zika’s effects on interactions between mother and infant were more severe in male than in female infants.
Emory National Primate Research Center scientists have focused on the long-term behavioral consequences of Zika virus infections. Ann Chahroudi and her team achieved a significant breakthrough demonstrating that Zika virus infections soon after birth can lead to enduring brain and behavioral problems in infants. MRI scans revealed structural and functional brain changes and observed behavioral alterations, confirming the causal link between neurological structure and changes in behavior. Researchers observed behavioral changes such as reduced social interactions and impaired memory and motor abilities in the primates while studying rhesus monkeys equivalent to four to five years of human age. These findings highlight the need for understanding the long-term impact of postnatal Zika infection and may serve as a platform for testing treatments to alleviate neurological consequences.
Victoria Roberts and Dan Streblow at the Oregon National Primate Research Center focus their research on understanding how the Zika virus impacts placental and fetal development. Roberts and Streblow found that when a pregnant animal is infected in the first trimester, the virus causes significant damage to the placental tissue, changing its structure and properties. “Our research reveals that this disruption leads to compromised blood flow in the placenta, impacting its function and the ability to support the developing fetus adequately,” Streblow notes.
These scientists also discovered the ability of the virus to persist for long periods through the detection of viral RNA before and after pregnancy. They found viral RNA in animals that were not pregnant for up to 35 days after infection. In pregnant animals, the presence of viral RNA was detectable for a more extended period: 80 to 90 days post-infection, observed in various tissues of the mother, as well as in both the placenta and the fetus.
Jean Patterson and Corinna Ross at the Southwest National Primate Research Center at Texas Biomedical Research Institute aim to understand Zika virus’s impact on fetal development and interactions with other infections using common marmosets. Marmosets are sensitive to Zika infection, closely mirroring what happens in humans. They are also small, breed year-round and typically have twins and triplets, offering many advantages as a pregnancy model. In one study in collaboration with Trudeau Institute, the researchers found that marmosets previously exposed to dengue pass 100,000 times more Zika virus onto their fetuses than marmosets that had never been exposed to dengue. This finding underscores the importance of surveillance to detect outbreaks as well as track epidemics, especially as climate change and human travel increase risk of exposure to tropical diseases. The SNPRC team has also collaborated with Walter Reed Army Institute of Research to test WRAIR’s Zika vaccine. The candidate vaccine was effective at blocking the transmission of Zika virus from pregnant marmosets to their fetuses.
Nito Panganiban and Nick Maness led teams at the Tulane National Primate Research Center that advanced our understanding of Zika virus in a rhesus macaque model. Their research on the virus’s impact during pregnancy uncovered key insights into Zika’s neurological effects, immune reactions, and host interactions. They found that Zika causes significant nervous system inflammation, seen in both pregnant and non-pregnant adults, similar to inflammatory nerve diseases. This work indicates the rhesus macaque model could be extremely useful for studying Guillain-Barré Syndrome and developing Zika-related neurological treatments.
Scientists at the Washington National Primate Research Center working on Zika virus include Kristina Adams Waldorf, Michael Gale Jr., Lakshmi Rajagopal, Megan O’Connor, Jennifer Tisoncik-Go and Deborah Fuller. Waldorf, Gale and Rajagopal have focused on maternal Zika infections during pregnancy, emphasizing the limitations of current diagnostic criteria based on head size. They found that during the early stages of pregnancy, 26 percent of primates infected with Zika experienced a miscarriage or stillbirth even though the animals showed few signs of infection. Their study on fetal macaques revealed that despite standard head sizes, the brains of infected fetuses grew more slowly, indicating subtle brain damage.
Tisoncik-Go is working with Gale, O’Connor and Fuller to evaluate potential ZIKV vaccines candidates, such as a recombinant vesicular stomatitis virus (rVSV) vector-based vaccine. O’Connor and her colleagues have also identified the primary cells that Zika virus infects and published this important finding in Nature Communications. O’Connor is also investigating coinfections involving both SIV (the macaque version of HIV) and Zika virus.
At the Wisconsin National Primate Research Center, David O’Connor, Tom Friedrich and Ted Golos played a pivotal role in developing the first models of rhesus macaque infection with Zika during pregnancy. Today, Emma Mohr, who was mentored by and collaborates with these scientists, focuses on the long-term neural development of infant macaques exposed to the Zika virus prenatally. Mohr and developmental scientist Karla Ausderau look at rhesus macaques’ neurodevelopment, motor and sensory skills, hearing and visual function, interaction with their mothers, and interactions with peers through three years of age, which in human years is about nine years. Mohr also examines brain and retina development through structural MRIs, and the eye through electrophysiology. Their published papers offer further valuable insights into early development in the first month of life and the adaptation of assays from human models for macaques. Public health strategies advocated by Mohr include mosquito-borne disease prevention, addressing global health disparities, and advocating for the inclusion of Dengue virus immunity status in future clinical trials for a vaccine.
The National Primate Research Centers’ research on Zika virus emphasizes the importance of long-term follow-up for all Zika-exposed children, irrespective of head size at birth. The researchers stress the urgency for a Zika vaccine to prevent infections and subsequent neurological consequences in infants.
“Our findings, especially in developing a pregnancy model and testing vaccine efficacy, stress the importance of ongoing surveillance and the need for preparedness in the face of emerging tropical diseases,” says the SNPRC’s Patterson. “The scientific community’s collaborative efforts remain crucial as we navigate the complex landscape of infectious diseases in our ever-changing world.”
Virtually all of the NPRC studies involve interactions among the centers. Their collaborative endeavor to fight Zika virus serves as a paradigm for addressing emerging infectious diseases on a global scale. This synergy exemplifies the power of collective knowledge, paving the way for vaccines and other innovative solutions and, ultimately, protecting public health globally.