Epidemiological and Etiological Characteristics of Hand, Foot, and Mouth Disease Before and After Introducing Enterovirus 71 Vaccines in Sichuan, China: A 6-Year Retrospective Study
Hand, foot, and mouth disease (HFMD) remains a significant public health concern in China, particularly among children under five years of age. Characterized by its global distribution and association with enteroviruses (EVs), HFMD is predominantly caused by enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16), with EV-71 linked to severe neurological complications and fatalities. In 2015, China introduced three inactivated monovalent EV-71 vaccines, which demonstrated high efficacy against EV-71-associated HFMD but lacked cross-protection against non-EV-71 serotypes. This study conducted a six-year retrospective analysis (2014–2019) in Sichuan Province to evaluate the epidemiological and etiological shifts in HFMD before and after EV-71 vaccine implementation.
Epidemiological Trends and Impact of EV-71 Vaccination
From 2014 to 2019, Sichuan Province reported 565,408 probable HFMD cases, with an average annual incidence rate of 114.3 per 100,000 population. A biennial fluctuation pattern was observed, with peaks in even-numbered years (2014, 2016, 2018). The highest incidence occurred in 2018 (164.6 per 100,000), coinciding with increased circulation of non-EV-71 serotypes. Following EV-71 vaccine introduction in 2016, the proportion of EV-71-associated cases dropped significantly from an average of 27.5% (2014–2017) to 2.9% in 2018 and 4.6% in 2019. Conversely, non-EV-71 enteroviruses (referred to as “other EVs”) surged, accounting for 66.3% of confirmed cases post-vaccination (2017–2019) and peaking at 80.1% in 2018.
The introduction of EV-71 vaccines markedly reduced severe outcomes. Among 44,022 laboratory-confirmed cases, EV-71 caused 14.0% of infections but accounted for 58.3% of severe cases (585/1,003) and all 23 deaths recorded. Post-vaccination, the proportion of severe cases declined sharply, aligning with the reduced prevalence of EV-71.
Seasonal Patterns and Unusual Outbreaks
HFMD in Sichuan exhibited bimodal seasonal peaks: a primary peak between April and June and a secondary peak in November. However, 2018 deviated from this pattern, with a single epidemic peak between July and August. This anomaly coincided with an unusual surge in “other EVs,” particularly CV-A6 and CV-A10, and higher-than-average temperatures reported by the Sichuan Climate Center. The atypical seasonality suggested potential interactions between climatic factors and viral transmission dynamics, though direct causation was not confirmed.
Etiological Shifts and Genetic Diversity
Among 73,370 probable cases tested by real-time reverse transcription-polymerase chain reaction (RT-PCR), 44,022 (59.5%) were confirmed as EV-positive. Post-vaccination, the etiological landscape shifted:
- EV-71: Prevalence dropped from 27.5% (2014–2015) to 4.6% (2019).
- CV-A16: Remained stable at 26.5% of cases throughout the study.
- Other EVs: Increased from 59.5% to 80.1%, with 16 serotypes identified, including CV-A6, CV-A10, CV-A4, echovirus 11 (E-11), and echovirus 30 (E-30).
Genetic characterization of 1,153 viral sequences (907 VP1, 246 VP4 regions) revealed:
- EV-71: All strains belonged to subgenotype C4a, forming clusters with circulating Chinese strains.
- CV-A16: Two subtypes, B1a (20%) and B1b (80%), co-circulated.
- CV-A6: Dominated by subgenotype D3.
- CV-A10: Predominantly genotype C.
- CV-A4: Subgenotype D2 was most common.
Bayesian skyline plot (BSP) analysis demonstrated dynamic population changes post-vaccination:
- EV-71 (C4a): Rapid population growth in late 2017, potentially reflecting adaptive mutations under vaccine-induced selection pressure.
- CV-A16 (B1b): Expanded significantly after 2016.
- CV-A6 (D3): Steady increase from 2016 to 2019.
- CV-A10 (C): Two expansion phases in 2018 and 2019.
Implications of Serotype Replacement and Evolutionary Dynamics
The decline in EV-71 cases underscores the success of vaccination in reducing severe HFMD. However, the rise of non-EV-71 serotypes highlights challenges in broader HFMD control. CV-A16 maintained stable circulation, while CV-A6 and CV-A10 emerged as predominant pathogens, associated with severe manifestations in some cases. The genetic diversity of EVs, coupled with their rapid evolution, suggests ongoing viral adaptation and the potential for serotype replacement.
Phylogenetic analyses confirmed that Sichuan strains clustered closely with national and regional variants, indicating no unique local lineages. The persistence of multiple serotypes underscores the need for multivalent vaccines targeting CV-A16, CV-A6, and CV-A10, in addition to EV-71.
Methodological Overview
The study utilized data from China’s National Surveillance of Notifiable Infectious Disease Program. Probable cases were defined per national guidelines, with confirmation via RT-PCR. Viral RNA was extracted using QIAamp kits (Qiagen), and VP1/VP4 regions were amplified using published protocols. Sequencing and phylogenetic analysis employed BioEdit, BLAST, and BEAST software. Statistical analyses were performed using SPSS, with Pearson’s chi-square tests comparing pre- and post-vaccination periods.
Limitations
The study’s retrospective design and reliance on routine surveillance data introduced selection bias, as only 13.0% of probable cases underwent RT-PCR testing. Furthermore, sequencing was limited to 7.8% of confirmed cases, potentially underrepresenting rare serotypes. Regional climatic and socioeconomic factors influencing HFMD transmission were not fully explored.
Conclusion
This six-year study provides critical insights into HFMD’s evolving epidemiology in Sichuan Province. EV-71 vaccination successfully reduced severe cases and deaths but did not curtail overall HFMD incidence due to the rise of non-vaccine-targeted serotypes. Continuous molecular surveillance is essential to monitor viral evolution, serotype replacement, and the emergence of novel pathogens. These findings emphasize the urgent need for multivalent vaccines and comprehensive prevention strategies to address the complex etiology of HFMD.
doi.org/10.1097/CM9.0000000000001632
Was this helpful?
0 / 0