Co-Circulation and Genomic Recombination of Coxsackievirus A16 and Enterovirus 71 during a Large Outbreak of Hand, Foot, and Mouth Disease in Central China

Abstract

A total of 1844 patients with hand, foot, and mouth disease (HFMD), most of them were children of age 1–3-year-old, in Central China were hospitalized from 2011 to 2012. Among them, 422 were infected with coxsackievirus A16 (CVA16), 334 were infected with enterovirus 71 (EV71), 38 were co-infected with EV71 and CVA16, and 35 were infected with other enteroviruses. Molecular epidemiology analysis revealed that EV71 and CVA16 were detected year-round, but EV71 circulated mainly in July and CVA16 circulated predominantly in November, and incidence of HFMD was reduced in January and February and increased in March. Clinical data showed that hyperglycemia and neurologic complications were significantly higher in EV71-infected patients, while upper respiratory tract infection and C-reactive protein were significantly higher in CVA16-associated patients. 124 EV71 and 80 CVA16 strains were isolated, among them 56 and 68 EV71 strains were C4a and C4b, while 25 and 55 CVA16 strains were B1a and B1b, respectively. Similarity plots and bootscan analyses based on entire genomic sequences revealed that the three C4a sub-genotype EV71 strains were recombinant with C4b sub-genotype EV71 in 2B–2C region, and the three CVA16 strains were recombinant with EV71 in 2A–2B region. Thus, CVA16 and EV71 were the major causative agents in a large HFMD outbreak in Central China. HFMD incidence was high for children among household contact and was detected year-round, but outbreak was seasonal dependent. CVA16 B1b and EV71 C4b reemerged and caused a large epidemic in China after a quiet period of many years. Moreover, EV71 and CVA16 were co-circulated during the outbreak, which may have contributed to the genomic recombination between the pathogens. It should gain more attention as there may be an upward trend in co-circulation of the two pathogens globally and the new role recombination plays in the emergence of new enterovirus variants.

Is a multivalent hand, foot, and mouth disease vaccine feasible?

“…7,121,126 The co-circulation of several EV-A71 genotypes and CV-A16 during HFMD epidemics has been responsible for intra-typic genetic recombination between EV-A71 B and C genotypes in Taiwan and inter-typic recombination between EV-A71 and CV-A16 in China. 5,7,14,19,126,129 Another inter-serotypic recombination happened between EV-A71 genotype C2 and CV-A8 to create genotype B4, responsible for outbreaks in Japan and Taiwan in 1998. 7,126 The predominant C4a genotype may be a double recombinant virus among EV-A71 genotypes B, C and CV-A16.…”

The compatibility of inactivated-Enterovirus 71 vaccination with Coxsackievirus A16 and Poliovirus immunizations in humans and animals

“…CA16 often prevails independently or co-circulates with EV71 in different regions from time to time. 18,19 In addition, CA16 has the highest gene sequence homology (about 70%) with EV71. 20,21 Poliovirus is another important virus in EVs genus.…”

Evaluation of monovalent and bivalent vaccines against lethalEnterovirus71 andCoxsackievirusA16 infection in newborn mice

“…17 Importantly, the co-circulation of CVA16 and EV71 has resulted in co-infections, and recombination between the two viruses, which can cause more serious clinical symptoms compared with a single viral infection, making it more complex and difficult to control HFMD epidemics. [18][19][20] As no approved antiviral drugs or vaccines are available for HFMD, increasing the pace of vaccine development therefore has become a priority. Previous vaccine research for HFMD has focused only on EV71, and formalininactivated vaccine for this virus has been evaluated through a phase III clinical trial in Mainland China.…”