Genomic epidemiology of coxsackievirus A16 in mainland of China, 2000–18

Hand, foot, and mouth disease (HFMD), which is a frequently reported and concerning disease worldwide, is a severe burden on societies globally, especially in the countries of East and Southeast Asia. Coxsackievirus A16 (CV-A16) is one of the most important causes of HFMD and a severe threat to human health, especially in children under 5 years of age. To investigate the epidemiological characteristics, spread dynamics, recombinant forms (RFs), and other features of CV-A16, we leveraged the continuous surveillance data of CV-A16-related HFMD cases collected over an 18-year period. With the advent of the EV-A71 vaccine since 2016, which targeted the EV-A71-related HFMD cases, EV-A71-related HFMD cases decreased dramatically, whereas the CV-A16-related HFMD cases showed an upward trend from 2017 to October 2019. The CV-A16 strains observed in this study were genetically related and widely distributed in the mainland of China. Our results show that three clusters (B1a–B1c) existed in the mainland of China and that the cluster of B1b dominates the diffusion of CV-A16 in China. We found that eastern China played a decisive role in seeding the diffusion of CV-A16 in China, with a more complex and variant transmission trend. Although EV-A71 vaccine was launched in China in 2016, it did not affect the genetic diversity of CV-A16, and its genetic diversity did not decline, which confirmed the epidemiological surveillance trend of CV-A16. Two discontinuous clusters (2000–13 and 2014–18) were observed in the full-length genome and arranged along the time gradient, which revealed the reason why the relative genetic diversity of CV-A16 increased and experienced more complex fluctuation model after 2014. In addition, the switch from RFs B (RF-B) and RF-C co-circulation to RF-D contributes to the prevalence of B1b cluster in China after 2008. The correlation between genotype and RFs partially explained the current prevalence of B1b. This study provides unprecedented full-length genomic sequences of CV-A16 in China, with a wider geographic distribution and a long-term time scale. The study presents valuable information about CV-A16, aimed at developing effective control strategies, as well as a call for a more robust surveillance system, especially in the Asia-Pacific region.