In a real-world setting, inactivated monovalent enterovirus A71 (EV-A71) vaccines were effective in preventing non-severe hand, foot, and mouth disease with EV-A71 virus infection in children aged 6 months to 71 months, according to study results published in The Lancet Child & Adolescent Health.

In China in 2016, three inactivated monovalent EV-A71 vaccines were licensed with a vaccination schedule of 2 doses administered 28 days apart. Although available in China, these vaccines are not covered by the national immunization program and must be paid out-of-pocket. While randomized controlled trials have shown a high efficacy in preventing EV-A71-associated hand, foot, and mouth disease, this study entailed post-licensure monitoring of vaccine effectiveness in children with hand, foot, and mouth disease admitted to the Henan Children’s Hospital in Zhengzhou, China within 7 days of illness onset; all 3 licensed EV-A71 vaccines were available.

In this test-negative case-control study, 1803 children from age 6 to 71 months with hand, foot, and mouth disease were enrolled between February 15, 2017 and February 15, 2018. The number of doses received and date of each vaccination were obtained from parents or legal guardians via a standard questionnaire. Children who received 2 doses of vaccine were considered fully vaccinated; children who received 1 dose were considered partially vaccinated, and children who received no EV-A71 vaccine were considered unvaccinated before hospitalization.

EV-A71 infections were confirmed through virologic testing of throat swabs and stool samples, with 234 children testing positive for this virus strain. The other viral etiologies included Coxsackievirus A6 (n=528), Coxsackievirus A16 (n=342). Of note, 29 children had negative tests for all enterovirus strains. Throat swabs and stool samples were missing from the 11 remaining children; thus, they were excluded from further analyses.

The primary outcome was pediatric hand, foot, and mouth disease associated with EV-A71 virus infection requiring hospitalization. Secondary outcome was hand, foot, and mouth disease associated with Coxsackievirus A16 or Coxsackievirus A6 requiring hospitalization.

Compared with test-negative patients, test-positive patients were usually older (P <.0001), more likely to reside in rural areas (P =.0053), and had parents with lower levels of education (P =.00048).  

Of the 1558 test-negative patients, 164 reported being fully vaccinated and 103 reported being partially vaccinated. The overall vaccine effectiveness was estimated to be 85.4% (95% CI, 53.2-95.4) for fully vaccinated children and 63.1% (95% CI, 13.1-84.3) for partially vaccinated children. There was no significant association between fully or partially vaccinated children with either Coxsackievirus A6 or Coxsackievirus A16-related hand, foot, and mouth disease.

Estimates of vaccine efficacy were directly proportionate to increasing age. The vaccine efficacy for full vaccination was estimated to be 91.1% in children aged 24 to 71 months but only 78.0% in children aged 6 to 23 months. Similarly, vaccine effectiveness for partial vaccination was 77.9% in children aged 24 to 71 months and 40.8% in children aged 6 to 23 months.

 “Given that the prevalence of EV-A71 antibodies increases with age, pre-existing EV-A71 antibodies might play a part in vaccine effectiveness increasing with age,” noted the researchers, although more research is needed in this area.

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In addition, there was an indication that the vaccine effectiveness against clinically milder cases might be higher than clinically severe cases in fully and partially vaccinated children. Due to the small sample size of this study, however, further research is needed to make any “definitive conclusions on vaccine effectiveness against different clinical severities,” stated the researchers.

Since the percentage of other enteroviruses has been increasing in cases of  hand, foot, and mouth disease both in China and worldwide, “vaccines that have combined effectiveness against EV-A71 and other enteroviruses, such as [Coxsackievirus]-A16, [Coxsackievirus]-A6, and [Coxsackievirus]-A10, should be developed for control of  hand, foot, and mouth disease epidemics,” concluded the researchers.

Reference

Li Y, Zhou Y, Cheng Y, et al. Effectiveness of EV-A71 vaccination in prevention of paediatric hand, foot, and mouth disease associated with EV-A71 virus infection requiring hospitalisation in Henan, China, 2017-18: a test-negative case-control study [published online July 30, 2019]. Lancet Child Adolesc Health. doi:10.1016/S2352-4642(19)30185-3