Cyclical Patterns of Hand, Foot and Mouth Disease Caused by Enterovirus A71 in Malaysia

Abstract

Enterovirus A71 (EV-A71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (HFMD) in children. In Malaysia, since the first EV-A71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2–3 years for reasons that remain unclear. We hypothesize that this cyclical pattern is due to changes in population immunity in children (measured as seroprevalence). Neutralizing antibody titers against EV-A71 were measured in 2,141 residual serum samples collected from children ≤12 years old between 1995 and 2012 to determine the seroprevalence of EV-A71. Reported national HFMD incidence was highest in children <2 years, and decreased with age; in support of this, EV-A71 seroprevalence was significantly associated with age, indicating greater susceptibility in younger children. EV-A71 epidemics are also characterized by peaks of increased genetic diversity, often with genotype changes. Cross-sectional time series analysis was used to model the association between EV-A71 epidemic periods and EV-A71 seroprevalence adjusting for age and climatic variables (temperature, rainfall, rain days and ultraviolet radiance). A 10% increase in absolute monthly EV-A71 seroprevalence was associated with a 45% higher odds of an epidemic (adjusted odds ratio, aOR1.45; 95% CI 1.24–1.69; P<0.001). Every 10% decrease in seroprevalence between preceding and current months was associated with a 16% higher odds of an epidemic (aOR = 1.16; CI 1.01–1.34 P<0.034). In summary, the 2–3 year cyclical pattern of EV-A71 epidemics in Malaysia is mainly due to the fall of population immunity accompanying the accumulation of susceptible children between epidemics. This study will impact the future planning, timing and target populations for vaccine programs.

Immune responses against enterovirus A71 infection: Implications for vaccine success

“…Similar seropositive rates were reported in Thailand, Taiwan, and Vietnam . In Malaysia, the EV‐A71 seropositive rate in children <12 years was higher during epidemic years compared with nonepidemic years, with increasing seropositive rate as age increased . Children in rural villages had higher seropositive rates than urban children, reaching >80% seropositive by 3 years and >95% by 12 years .…”

“…The well‐reported anti–EV‐A71 IgG epitopes SP70 and VP2‐28, identified by mice and rabbit sera respectively, were not recognized by human sera, suggesting that human sera target different linear or discontinuous conformational epitopes compared with animal sera . Nonetheless, all the identified immunogenic epitopes in humans or animals induced neutralizing activities, suggesting the importance of neutralization responses during EV‐A71 infection …”

Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

“…EV-A71 specific-IgM and -IgG antibodies in sera samples were detected using an EV-A71 IgM-capture enzyme-linked immunosorbent assay (ELISA; Beijing Wantai Biological Pharmacy Enterprise CO., Ltd., China) [28], and western blot and virion-based ELISA analyses, respectively. The neutralization activity of antibodies in sera specimens were tested in triplicate and analyzed by microneutralization assay as previously described [29,30]. A sample was considered positive if the neutralizing titer was ≥1:8.…”

Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

“…In recent years, several Hand-foot-and-mouth disease (HFMD) outbreaks have occurred in Asia-Pacific region and Europe [1][2][3][4]. Among them, enterovirus 71 (EV71) and coxsackie A16 (CA16) infection is main cause of HFMD outbreaks, and patients with EV71 infection are inclined to develop into severe symptoms [5,6].…”