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Two Enterovirus 71 Vaccines Perform Well in Phase 3 Trials: Potential for Ameliorating Neurological Complications

Fitzgerald, Susan

doi: 10.1097/01.NT.0000446547.13195.6f
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Two vaccines developed and tested in China provide good protection against enterovirus 71 (EV71), which causes hand, foot, and mouth disease in children and sometimes results in potentially fatal neurologic complications.

Results from two phase 3 trials of the vaccines show that they were effective in preventing hand, foot, and mouth disease or herpangina in infants and young children, and one study reported that EV71-related hospitalizations were reduced. Both papers were published in the Feb. 27 issue of the New England Journal of Medicine (NEJM).

Outbreaks of EV71 have occurred in China and other countries in Southeast Asia since the late 1990s, and health officials have become increasingly concerned about the serious neurologic complications being caused by the virus.

“EV71, which is one of a number of enteroviruses, has recently emerged as a significant public health problem,” James Sejvar, MD, a neuroepidemiologist at the National Center for Emerging and Zoonotic Infectious Diseases at the Centers for Disease Control and Prevention, told Neurology Today.

EV71, which appears sporadically in the US, has traditionally been associated with relatively mild illness characterized by skin rash, mouth sores, and fever. But in Southeast Asia “in recent years — for reasons we haven't been fully able to explain — this particular strain of enterovirus has been associated with more neurologic manifestations including encephalitis and anterior myelitis, as well as higher rates of case fatality,” Dr. Sejvar said.

An editorial that accompanied the publication of the findings on the two vaccine trials, noted “over the past decade, it's been estimated, there have been more than 6 million cases of EV71 infection worldwide, and more than 2,000 of them have been fatal.”



If the promise of the vaccines “is realized, a priceless gift will have been given to the children of the Asia-Pacific region and to the rest of the world,” said the editorial by Peter C. McMinn, MD, PhD, of the University of Sydney in Australia.

The two vaccines tested involved an EV71 subgenotype, C4, which has been predominant in the Southeast Asian outbreaks.

The trials, which involved a total of more than 22,000 children, were not designed to measure whether the EV71 vaccines could ultimately reduce the incidence of neurologic complications, including aseptic meningitis and brain-stem encephalitis.

A previous trial carried out in China with another EV71 vaccine also produced encouraging results.

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In the first trial, more than 10,000 healthy infants and children between the ages of 6 and 35 months were randomly assigned to receive two intramuscular injections, 28 days apart, of either EV71 vaccine or a placebo. A Chinese company, Sinovac Biotech, which sponsored the trial, manufactures the inactivated vaccine, and various Chinese agencies collaborated in the design and implementation of the trial.

The study participants, who were enrolled at 35 sites in Jiangsu Province in China, were tracked for 12 months. The primary outcome measure was the occurrence of EV71-associated hand, foot, and mouth disease or herpangina.

According to published results, EV71-associated disease was identified in 0.3 percent of children (13 out of 5,041) who received the vaccine and 2.1 percent of those who were given the placebo (106 out of 5,028).

“The vaccine efficacy against EV71-associated hand, foot, and mouth disease or herpangina was 94.8 percent [CI, 87.2 to 97.9; p<0.001] in this cohort,” a team of researchers from the Jiangsu Provincial Center for Disease Control and Prevention and elsewhere reported. “Vaccine efficacies against EV71-associated hospitalizations (0 cases vs. 24 cases) and neurologic complications (0 cases vs. 8 cases) were both 100 percent.”

The researchers reported a favorable safety profile for the vaccine. Serious adverse events occurred in 2.2 percent of the vaccinated children and 2.6 percent of the placebo group. The most common systemic adverse reactions were fever, diarrhea, and loss of appetite. Soreness at injection site also occurred.



The researchers studied a subgroup of children to determine immunogenicity. “An anti-EV71 immune response was elicited by the two-dose vaccine series in 98.9 percent of participants at day 56,” they reported

The researchers reported that, as had been expected based on previous research, the vaccine offered no protection against hand, foot, and mouth disease or herpangina caused by coxsackievirus A16 or other enterovirus subtypes.

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The second trial reported in the NEJM involved another inactivated EV71 vaccine using the subgenotype C4 that was developed by the Institute of Medical Biology of the Chinese Academy of Medical Sciences. A total of 12,000 children between the ages of 6 and 71 months were randomly assigned to either two doses of the vaccine or a placebo, four weeks apart. The trial took place in China's Guangxi Zhuang Autonomous Region.

The children were monitored for up to 11 months and the primary endpoint was protection against hand, foot, and mouth disease caused by EV71. According to the published report, 155 cases of disease caused by EV71 were identified — four in the vaccine group and 151 in the placebo group. “Over the course of two epidemic seasons, the vaccine efficacy against EV71-associated hand, foot, and mouth disease was 97.4 percent [95% CI, 92.9-99.0],” the study found. They said the seroconversion rate for the vaccine was 100 percent four weeks after the second dose.

Adverse events, such as fever, were more common the week after vaccination among children who received the vaccine (41.6 percent) compared with the placebo group (35.2 percent). A total of 68 serious adverse events were reported in the vaccine group, compared to 124 among the controls. A total of 41 vaccinated children were hospitalized for hand, foot, and mouth disease, compared to 88 in the placebo group.

As was the case with the other EV71 vaccine, this one did not protect against coxsackievirus A16 or other enteroviruses.

The two studies do have limitations. For one, the EV71 antibody status of the children who participated was not tested prior to the start of the trials, so it's possible that some had protection regardless of whether they got the vaccine or not.

Still, “I find that the results of the studies of the vaccines' efficacy are very reassuring,” said Dr. Sejvar. “While neither of the articles specifically addresses whether the vaccines protect against neurologic disease, by virtue of prevention of EV71 illness in general, it is reasonable to suspect that they would.”

Qihan Li, MD, PhD, of the Institute of Medical Biology and a coauthor of the second study, told Neurology Today in an e-mail that since only two cases of serious neurologic complications occurred in the course of the study, it was not possible to make a statistically valid conclusion about the vaccine's ability to prevent severe disease.

The research team is continuing to track children to collect longer-term data. “The expanding populations (from various trial phases) and long-term [results] following observation will be needed to determine the protective effects of this vaccine,” Dr. Li said.

Kenneth Tyler, MD, FAAN, Reuler-Lewin Family professor and chairman of neurology at the University of Colorado Denver, said the results were promising and the studies were well designed. “It was impressive to see how quickly progress was made on the development of this type of vaccine,” he said.

Dr. Tyler, an associate editor of Neurology Today, said that while EV71 outbreaks have not been a concern in the US, any progress in curbing emerging diseases in other parts of the world is by extension good for the global community.

“Our planet has gotten a lot smaller,” said Dr. Tyler, noting that expanding travel patterns mean more opportunities for the spread of infectious diseases.

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•. Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014; 370:829–837.
    •. Zhu F, Xu W, Xia J, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med 2014; 370:818–828.
      •. McMinn PC. Enterovirus vaccines for an emerging cause of brain-stem encephalitis. N Engl J Med 2014: 792–794.
        •. CDC Reports on non-polio enteroviruses:
          © 2014 American Academy of Neurology