Zika virus: Down, but not out
Zika virus has largely disappeared from the Americas. No additional countries have reported active local transmission of Zika since late 2016, according to the Pan American Health Organization. Provisional data from the CDC show that in 2017, 424 cases of symptomatic Zika virus disease cases were reported in the United States, and 644 cases — excluding congenital disease — were reported in its territories. This year, health officials have recorded only one case of Zika virus disease so far in the U.S., reported in a traveler returning from an affected area.
Although the immediate threat of an outbreak has passed in the U.S., Zika has had significant and devastating aftereffects. Children born with microcephaly and other birth defects associated with Zika continue to struggle with these disabilities.
“In children born with birth defects related to Zika, these defects are going to be chronic, long-term problems,” Stephen S. Morse, PhD, professor of epidemiology at the Columbia University Medical Center, told Infectious Disease News. “That’s going to obviously represent a large challenge in developing countries, like South America, but even in the U.S., where we’re not at all attuned to dealing with long-term disability. I think it’s something we’re still learning to grapple with.”
Many infectious disease experts also believe that without a Zika vaccine, the disease is destined to have some degree of resurgence, if not nearly to the extent of the previous outbreak.
According to Peter J. Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston and endowed chair in tropical pediatrics at Texas Children’s Hospital, Zika will likely not make a significant return in the U.S. in the immediate future.
“I’m not seeing anything obvious that would suggest a big Zika outbreak in the U.S. this summer, but with one caveat — we’re on a steep learning curve,” Hotez said. “We’ve been surprised twice now. We’ve been surprised by how quickly Zika spread across the Western Hemisphere in 2015 and 2016, and we were equally surprised by how quickly it disappeared in 2017. Why it disappeared across the Western Hemisphere is still a mystery.”
Researchers continue to puzzle over what caused Zika to become so widespread in the first place. In paper published in 2017 in The Journal of Infectious Diseases, David M. Morens, MD, and Anthony S. Fauci, MD, — both from the National Institute of Allergy and Infectious Diseases (NIAID) — discussed the possibility that the virus, which has reportedly existed for years in Asian countries, may have undergone one or more viral mutations that enabled it to spread more easily.
Hotez said that to understand the possible re-emergence of Zika in the U.S., it is instructive to parse its routes of transmission in 2015 and 2016.
“What happened in the U.S. was the virus was introduced multiple times,” he said. “We know from genotyping of the virus that in Miami, it was introduced from the Caribbean and South America, whereas in South Texas, where there was also transmission, it was probably introduced from Mexico.”
Since that time, Hotez said, transmission of Zika in the Caribbean has declined sharply.
“That suggests that we might not see Zika coming back to Florida anytime soon,” he said. Conversely, some transmission is still occurring in Mexico, and a locally transmitted case was recently reported in South Texas, Hotez added.
“I think if we’re going to see Zika pop up again, it’s likely going to be in Texas, by introduction from Mexico,” he said.
Because local transmission requires an introduction of the virus and the presence of Aedes aegypti mosquitoes, Hotez said that recent freezing temperatures, particularly around Houston, could inhibit transmission in Texas. Although climatological factors may explain to some degree the precipitous decline in Zika transmission in the Americas, he does not believe this explains it entirely.
“If you look at the epidemiology curves coming out of the Pan American Health Organization, this steep rise and steep decline is among the more striking things I’ve seen in infectious disease epidemiology,” he said.
Many infectious disease experts believe that “herd immunity” — the effect that occurs when a large proportion of a population becomes immune to a disease — has reduced the incidence of Zika in the U.S.
“It was so prolific of a virus in the last season in the Americas that in this season, it’s exponentially much tamer,” Amesh Adalja, MD, senior scholar at the John Hopkins Center for Health Security and assistant professor at the Johns Hopkins Bloomberg School of Public Health, told Infectious Disease News. “There’s been so much infection in the population that there are fewer and fewer people who aren’t immune to the virus.”
According to Morse, this immunity cannot last indefinitely, and eventually the individuals in the population who are immune will be replaced by those who are not.
“Very often, what you see in that situation is the disease kind of smolders at a very low level while there are very few susceptibles,” he said, “and then in some cases, it may reappear when you have enough new susceptibles, such as new births or people moving to the area who have not had exposure.”
According to the CDC, some degree of Zika risk remains in Asia, Africa, the Caribbean, Central America, the Pacific Islands, South America and Mexico. Pregnant women are advised by the CDC not to travel to areas with risk for Zika — that is, areas with documented or likely Zika virus transmission.
Asia and Africa currently face the most significant risk, Hotez said.
“The problem there is you have previously circulating strains in Africa and Asia that have been around for decades, so the picture is really complicated,” he said. “In Africa and Asia, we don’t always know what Zika strain it is. This current pandemic strain appears to have started out in Micronesia and Polynesia in the South Pacific, Fiji, then made its way into the Americas. Now it’s working its way across the Atlantic back into Asia, and it’s hard to tell what is an older Zika strain and what is this new strain.”
Hotez also discussed recent research showing that of the two main lineages of Zika — Asian and African — only the Asian strain is associated with microcephaly. The Asian strain was the one present in the 2015-2016 epidemic in the Americas. According to the study, the Asian lineage stops the propagation of brain stem cells and inhibits their ability to develop into brain nerve cells.
Findings published in Science in 2017 showed that a single mutation in the Asian strain, which arose before the 2013 Zika outbreak in French Polynesia and had been maintained throughout the epidemic in the Americas, increased the virus’ infectivity in both human and mouse neural progenitor cells, and it led to more significant microcephaly in mouse fetuses and higher mortality in neonatal mice. The mutation, researchers said, may help explain the incidence of microcephaly in recent outbreaks.
“There’s a lot of controversy over whether it’s only this new strain that is associated with microcephaly,” Hotez said.
The situation is further complicated by the strong presence of the chikungunya and dengue viruses in the same countries where Zika is prevalent, Hotez said.
“So, you can’t really identify noncongenital Zika on a symptomatic basis,” he said. “You have to go in and not only do the serology to see who has seroconverted to Zika; you also have to genotype the virus to see if it’s the old one or the new one.”
Since the epidemic spread through the Americas, several Zika vaccine candidates have been in development. However, these vaccine candidates are still in early clinical trials, or development has been halted altogether. In three phase 1 clinical trials, the early results of which were published in The Lancet in December 2017, researchers found that the Zika purified inactivated vaccine (ZPIV) yielded an immune response to Zika in 90% of study participants. The vaccine was also safe and well-tolerated. ZPIV was developed by Sanofi Pasteur in partnership with the Walter Reed Army Institute of Research (WRAIR), the NIAID and the Biomedical Advanced Research and Development Authority (BARDA). However, in August 2017, BARDA told Sanofi that it planned to pare down its Zika-related research and would restrict funding for the project. The funding would be enough to cover only a case definition and surveillance study. Sanofi said it would not seek licensure of the vaccine.
“I think it’s an important lesson that the majority of infectious diseases, although they might grab headlines and cause a lot of panic, often are not great market opportunities for pharmaceutical companies,” Adalja said. “The public realizes that these vaccines are not necessarily great business prospects for many companies, so it’s important that we encourage these companies to be involved in this.”
Another effort toward developing a Zika vaccine is being undertaken by government researchers at the NIAID. The vaccine, which uses a DNA-based platform, has shown positive results in phase 1 clinical trials. The NIAID investigators developed two different plasmids for testing: VRC5288 and VRC5283. These plasmids are almost duplicates, differing only in the specific regions of genes that might affect protein expression. The NIAID conducted a study of VRC5288 in 80 healthy individuals aged 18 to 35 years. They received either two or three doses of the vaccine at different time intervals. In a separate trial, the NIAID investigated the VRC5283 plasmid in 45 healthy individuals aged 18 to 50 years. Similarly, participants received either two or three doses of the vaccine at different time points.
In both trials, the researchers found that vaccines were safe and well-tolerated, except for mild to moderate reactions at the injection site. At 4 weeks after the final vaccine dose, the researchers reported that 60% to 89% of participants showed positive antibody responses to VRC5288, whereas 77% to 100% of participants generated a positive antibody response to VRC5283. Those who received the VRC5283 plasmid vaccine via a needle-free injector all had detectable positive antibody responses and demonstrated the highest levels of neutralizing antibodies. The NIAID researchers said VRC5283 was the most promising of the two vaccines and initiated an international efficacy trial to study it further.
Morse said that although the phase 1 results of many of these vaccine candidates are promising, the focus placed on developing new vaccines tends to be transient.
“I’m not sure when we will see a Zika vaccine,” he said. “I think to a large extent, once the crisis has passed, we tend to move on to other crises. We don’t have a very sustainable approach.”
Hotez expressed a similar concern that the lack of current transmission in the Western Hemisphere “will throw cold water on investor interest in the [Zika] vaccine.” Moreover, he said problems regarding Sanofi Pasteur’s dengue vaccine, Dengvaxia — including the fact that it has been causally associated with pediatric deaths and may cause more severe disease in nonimmune patients who become infected after vaccination — “may reduce overall enthusiasm for arbovirus vaccines, including Zika, in the near future.”
Recently, the FDA granted fast-track status to Takeda’s Zika virus vaccine candidate. The company said the inactivated vaccine TAK-426 is currently being evaluated in a phase 1 trial in the continental U.S. and U.S. territories.
Although vaccination is one important approach to combating Zika, it is also essential to control the population of the disease’s main vector, the A. aegypti mosquito.
The U.K. company Oxitec has undertaken this effort by developing a self-limiting strain of A. Aegypti, named OX513A. The company releases males of this strain, which do not bite or spread disease, to mate with wild females. The mosquito offspring that result die before reaching adulthood. Repeated releases of the self-limiting males are designed to ultimately reduce the wild A. aegypti population below the level required to transmit Zika and other diseases.
“It’s called the ‘friendly Aedes aegypti’ — one that’s been genetically modified so that its offspring can’t mature, similar to a strategy that controlled blowfly at one point in the United States,” Morse said. “There have been other high-tech approaches, none of which have been heavily utilized.”
According to research recently conducted in Mexico and published in Scientific Reports, A. aegypti may not be the only vector of Zika. The investigators isolated Zika virus from the salivary glands of wild-caught female Culex coronator, C. tarsalis and A. vexans mosquitoes as well as from A. aegypti and other known vectors. Zika was also found in different body parts of wild-caught female C. quinquefasciatus and in whole males from both A. aegypti and C. quinquefasciatus species.
Adalja emphasized the importance of vector control in preventing the resurgences of mosquito-borne illnesses.
“I think the danger of mosquito-borne illnesses is, once these mosquitoes stop grabbing headlines, people stop worrying about the mosquitoes, but the mosquitoes are still there,” he said. “I think it’s important that people don’t drop their guard against mosquito-borne illnesses like Zika and dengue and chikungunya, because the control is just not robust enough.”
Congenital Zika syndrome
One of the most damaging and long-term effects of the Zika virus is its association with chronic birth defects. Congenital Zika syndrome is a term that encompasses a specific pattern of birth defects. According to the CDC, these defects include severe microcephaly with partial collapse of the skull; decreased brain tissue with a pattern of brain damage, including subcortical calcifications; damage to the back of the eye, including macular scarring and retinal mottling; congenital contractures such as clubfoot or arthrogryposis; and hypertonia that restricts body movement shortly after birth.
In a 2016 paper published in JAMA Pediatrics, Hotez noted that it could take many years for pediatricians to understand the full clinical and neurologic spectrum of disease caused by Zika virus infection.
In October 2017, the CDC updated its guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection. The recommendations can be found on the agency’s website. The CDC also updated its guidance for the treatment and follow-up of infants with congenital Zika virus infection, according to Peggy Honein, PhD, MPH, acting director of the Division of Congenital and Developmental Disorders at the CDC’s National Center on Birth Defects and Developmental Disabilities.
“The updated recommendations emphasize that it is important for pediatric health care providers to assess risk of congenital Zika virus infection, to communicate closely with obstetrical providers, and to remain alert for any problems that may develop in infants without birth defects born to mothers with possible Zika virus exposure during pregnancy,” she said.
A report published in late January showed that Zika virus caused more birth defects in the U.S. than expected. Health officials reported a 21% increase in the birth defects most strongly linked to Zika infection during pregnancy in areas with local Zika virus transmission — including south Texas, south Florida, and Puerto Rico — in the last half of 2016 compared with the first half of the year. They expect the number of cases to remain elevated when data from 2017 become available.
Honein also discussed the long-term care that is necessary to manage congenital Zika syndrome, which has lasting repercussions for affected infants.
“Because the types of services needed to care for infants with congenital Zika syndrome are complex, CDC recommends coordinated care by a multidisciplinary team and an established medical home,” she said, “As a critical component of patient care and early identification of any developmental delays, families should be empowered to be active participants in their child’s monitoring and care.”
Honein addressed the importance of early intervention services — starting from birth to 3 years of age — including therapies to help children sit, stand, walk or communicate in other ways, and to interact with others. These therapies can have a major impact on a baby’s ability to learn new skills, she said.
The CDC’s various diagnosis and treatment recommendations for congenital Zika syndrome — and their continual updates — are designed to address a public health issue that is expected to be ongoing, Honein said.
“CDC remains committed to protecting the health of Americans, and in particular, pregnant women, fetuses and infants most at risk of adverse health outcomes associated with Zika, and will continue working 24/7 to protect the nation from the threat of Zika,” she said. “We know that babies will continue to be born with congenital Zika syndrome in 2017 and beyond, underscoring the need to stay committed to following these infants and ensuring care.” – by Jennifer Byrne
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Disclosures: Adalja, Honein, Hotez and Morse report no relevant financial disclosures.