When Thomas Monath, an expert on vaccines combating mosquito-borne diseases, thinks about developing an inoculation against Zika virus, he has a major concern: Guillain–Barré syndrome. The rare autoimmune disease can lead to paralysis, and recently it appears to be occurring more frequently than usual within at least eight countries and territories reporting Zika outbreaks. Mounting evidence suggests exposure to the mosquito-borne Zika is the culprit. Now that boost in Zika-linked Guillain (GBS) is stoking concerns that a vaccine designed to protect patients against Zika could inadvertently provoke more cases of the autoimmune condition.
“It’s a serious issue,” says Nicholas Jackson, vice president and head of global research at Sanofi Pasteur. “Understanding the cause of GBS is going to be very important for vaccine development.” The logic behind these concerns is relatively straightforward: If exposure to that virus can fuel GBS—by some estimates in as many as one in 5,000 cases—might the presence of a weakened or dead form of virus within the vaccine provoke GBS cases, too? Like a flu or polio vaccine, a shot designed to protect against Zika would need to contain some form of the virus in order to stimulate antibody protection against it. Worries about such virus exposure, however, have been echoed by more than a half dozen top vaccine experts and epidemiologists in interviews with Scientific American.
“There will be a risk. The question is if it is with a live, attenuated vaccine or a killed virus vaccine or both?” says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. Yet, “the risk of not having a vaccine overwhelms the risk of GBS,” he says.
At issue is what level of risk is acceptable. The best available statistics suggest that GBS generally occurs in one out of 100,000 people. It is most typically caused by a viral or bacterial infection—most often with the bacteria Campylobacter jejuni. More rarely, it occurs in the weeks or days following certain vaccinations. For example, GBS was linked to a 1976 flu vaccine designed to fight against swine flu virus. Yet analysis of past French Polynesian Zika patients, published in The Lancet, suggests that exposure to Zika exacerbates the baseline GBS threat some 20-fold. Fauci and others, however, say they are not yet convinced that The Lancet figure (one in 5,000 Zika patients) is the final word. An estimated four out of five patients with Zika virus are asymptomatic. So if scientists track such asymptomatic individuals for GBS, perhaps that statistic could change—likely dropping the chances of how often Zika-linked GBS occurs, they contend. More studies need to be conducted.
But scientists are also racing against the threat of an evolving pandemic. The first stage of clinical trials for at least one potential vaccine candidate is slated to begin in September, according to Fauci. There are no plans to push that timeline back, he says. “I have this ominous feeling we have yet to see the worst of [Zika],” he said at a summit focused on the disease in Bethesda, Md., earlier this week.
The picture of Zika-linked hazards has come into harsher focus over the past couple months. Strong evidence already linked the virus to microcephaly, a birth defect where babies are born with abnormally small heads. They also knew that sometimes there is debilitating brain damage. But recently new congenital problems have also been added to that list. Hearing loss, vision defects, impaired growth and abnormalities in infants’ leg and arm joints have also now been linked to Zika. Although some malformations are visible on ultrasounds many issues may not be apparent until birth. Moreover, recent evidence suggests that such problems can occur regardless of what trimester a mother is in when she encounters Zika.
At the heart of the consternation about vaccines is why GBS appears to be tied to Zika in the first place. There are two competing theories: One is that GBS is caused by a haywire self-attacking immune response from the body when it encounters Zika. The other is that the virus itself directly attacks neural cells and destabilizes the myelin sheath around them or damages axons to cause GBS. From a vaccine-development perspective, it would be particularly troubling if the former ends up being the case because it is hard to control immune response—especially when scientists are not sure what facet of the virus may set off that cascade of action.
Unfortunately, preliminary data suggests that this feared immune response is exactly what is happening, according to Jim Sejvar, a neuroepidemiologist with the U.S. Centers for Disease Control and Prevention who focuses on GBS. To date, doctors primarily diagnose GBS by observing its symptoms. They also typically scrutinize patients’ cerebrospinal fluid for two main signs: buildup of protein and the absence of inflammatory white blood cells, he says. If the virus was just attacking nerve cells there would still be that protein buildup but there would also be a buildup in white blood cells, he says. Yet so far, in published work on Zika patients in French Polynesia as well as unpublished work from Sejvar on recent Brazilian patients it appears there is no white blood cell buildup. “Is it absolute evidence? No, but it is strongly suggestive of an immune-mediated syndrome rather than a neuro-invasive process,” he says.
Scientists are also looking to past GBS studies to devise plans about how to sidestep this potential threat. One idea: if GBS is caused by an immune response from the body, perhaps using a killed virus vaccine could allay this issue. But even then there are no guarantees. “The question is, does part of the virus look like human proteins or peptides that generate the autoimmune reaction?” Sanofi Pasteur’s Jackson says. If that is the case, then perhaps the presence of those substances would still cause GBS, he says. “It’s too early to say,” agrees Monath, chief scientific and chief operating officer for the Infectious Disease division of NewLink Genetics, a biopharmaceutical firm.
There are some specific GBS insights scientists can use for future vaccine trials. Most importantly, analysis of GBS suggests the incidence of Zika increases by about 20 percent with every 10-year increase in age, says Sejvar, who published that finding in the journal Neuroepidemiology. So testing any vaccine on younger patients—say people in their 20s instead of their 40s—would be one safety precaution. Moreover, getting a better picture of what the virus looks like and understanding its properties through animal testing and studying patients’ blood might help vaccine developers pinpoint specific issues, says Pei-Yong Shi, a virologist at The University of Texas Medical Branch at Galveston. Yet all of that would need to be done very quickly to inform the initial steps of vaccine development and clinical trials starting this fall.
For Pedro Vasconcelos, director of the National Reference Laboratory for Arboviruses in Brazil at the Evandro Chagas Institute, there is no time to lose. Even concerns about GBS, a condition treatable with pricey therapies including plasma exchange or injections of immunoglobulins, cannot push back vaccine trials. “We need to do better work still, but we need to move forward,” he says. “Every day with Zika is a new surprise.”