Severe Hand, Foot and Mouth Disease Outbreak in Vietnam Traced to a Single Introduction of Enterovirus A71 Subgenogroup B5

A severe outbreak of hand, foot and mouth disease that swept through Vietnam in 2023 has been traced back to a single introduction of enterovirus A71 subgenogroup B5, a viral lineage that first emerged in the region around November 2022. The finding, published in PLOS Neglected Tropical Diseases, comes from a detailed virological and epidemiological investigation led by researchers working in Ho Chi Minh City, one of the epicenters of the outbreak. By combining genomic sequencing of viral isolates with population-level serological surveys, the team has assembled one of the most complete pictures to date of how a dangerous enterovirus lineage can slip into a susceptible population and ignite widespread severe disease.

Hand, foot and mouth disease is a common childhood illness caused by several enteroviruses, most notably enterovirus A71 and coxsackievirus A16. While most infections resolve with mild fever, mouth ulcers and a characteristic rash on the hands, feet and buttocks, enterovirus A71 is notorious for its capacity to invade the central nervous system. Infected children can develop brainstem encephalitis, acute flaccid paralysis, pulmonary edema and cardiogenic shock, complications that can progress from first symptoms to death within hours. Vietnam has experienced repeated waves of severe hand, foot and mouth disease over the past two decades, and the 2023 outbreak raised urgent questions about which viral lineage was responsible and why the population appeared so vulnerable.

The investigation centered on enterovirus A71 subgenogroup B5, a variant that had been circulating elsewhere in the Asia-Pacific region before its appearance in Vietnam. Genomic analysis of viruses recovered from patients during the 2023 outbreak revealed a striking pattern: the Vietnamese B5 sequences were tightly clustered, indicating that the entire outbreak descended from a single introduction event rather than from multiple independent importations. This observation has important implications for outbreak preparedness, because it suggests that a single crossing of a border by one infected individual can be sufficient to seed a nationwide epidemic when the conditions are right.

One of the most intriguing questions the researchers addressed was whether subgenogroup B5 had evolved the ability to evade immunity generated by earlier enterovirus A71 strains. Vietnam had previously experienced outbreaks caused by other subgenogroups, including B5 viruses that circulated as far back as 2014. If the 2022 and 2023 viruses had drifted antigenically away from their predecessors, previously acquired immunity would offer little protection, explaining the severity of the new epidemic. To test this hypothesis, the team collected convalescent plasma from patients infected with subgenogroup B5 in both 2014 and 2023 and measured how effectively the antibodies in these samples could neutralize contemporary viruses in the laboratory.

The results were clear and, in a sense, reassuring. Plasma from patients infected in 2014 neutralized the 2023 viruses with titers comparable to those achieved by plasma from patients infected in 2023, and the same held true in the reverse direction. In other words, the antigenic properties of the virus had not appreciably changed over the nine-year interval, and there was no evidence of immune evasion. The severity of the 2023 outbreak therefore could not be attributed to a viral escape from pre-existing immunity. Instead, the explanation lay in the age structure of susceptibility within the population, particularly among the youngest children who had never encountered any enterovirus A71 strain.

Serological surveys conducted in Ho Chi Minh City revealed the scale of this vulnerability. At one month before the start of the outbreak, only 6.7 percent of children aged zero to under three years carried neutralizing antibodies against enterovirus A71. Even at six months before the outbreak began, the figure was similarly low. This meant that the vast majority of infants and toddlers in the city, the group at highest risk of severe disease, had no immunological defense against the incoming virus. When subgenogroup B5 arrived, it found an almost entirely susceptible cohort in the exact age bracket where infection is most likely to turn dangerous.

The study did not stop at documenting susceptibility before the outbreak. The researchers repeated their serological measurements as the epidemic unfolded, and the results traced the arc of the outbreak in real time. As the proportion of young children with neutralizing antibodies rose, the number of enterovirus A71 infected patients residing in Ho Chi Minh City fell. This inverse relationship, in which increasing population immunity coincided with declining transmission, suggests that the outbreak burned through the susceptible pool until so many children had been infected and immunized that the virus could no longer spread efficiently. It also demonstrates that serosurveillance, the systematic measurement of antibody levels in the population, can serve as a practical early warning tool.

The implications of this serosurveillance-based approach extend well beyond a single outbreak. Traditional disease surveillance relies on detecting clinical cases, which by definition identifies an outbreak only after substantial transmission has already occurred. Measuring the fraction of the population that lacks neutralizing antibodies, by contrast, can quantify the size of the susceptible reservoir before any cases appear. In the case of enterovirus A71, the Vietnamese data show that a seroprevalence of under seven percent in children under three years of age signaled an acute risk of severe epidemic emergence. Health authorities monitoring antibody levels in young children could, in principle, identify comparable windows of vulnerability in advance and intensify clinical preparedness, public communication and, where available, vaccination efforts accordingly.

Enterovirus A71 remains an active public health threat concentrated in the Asia-Pacific region, where periodic outbreaks of severe hand, foot and mouth disease continue to burden pediatric health systems. Vaccines against the virus have been developed and licensed in China, but coverage across the wider region remains incomplete, and no vaccine is universally deployed. The Vietnamese experience underscores how quickly a single imported lineage can exploit gaps in population immunity, and how the cyclical nature of enterovirus transmission creates recurring cohorts of susceptible infants between epidemic waves. The authors note that the virus has a high potential to become a global problem, and that it should therefore be closely monitored beyond its current geographic range.

Collectively, the study offers a model for investigating the emergence of any pathogen that causes severe disease in a defined age group. By integrating viral genomics, antigenic characterization and longitudinal serology, the researchers were able to rule out immune evasion, pinpoint the timing and origin of the introduction, quantify the susceptibility of the at-risk population and connect rising immunity to declining transmission. These insights into the epidemiological factors driving enterovirus A71 emergence are intended to inform outbreak preparedness and response, and to support the development of serosurveillance-based risk assessment frameworks that could be applied to enteroviruses and other emerging infectious threats alike.

Subject of Research: Virological and epidemiological investigation of a severe enterovirus A71 hand, foot and mouth disease outbreak in Vietnam in 2023

Article Title: Virological and epidemiological investigations of a severe hand foot and mouth disease outbreak, Vietnam, 2023

Article References: Nguyet, L. A., Anh, N. T., Quy, D. T., Hong, N. T. T., Minh, N. N. Q., Nguyen, P. N. T., Quang, P. V., Han, D. D. K., Ny, N. T. H., Nhu, L. N. T., Truc, T. H. C., Thuy, C. T., Hoang, N. N., Thien, T. B., Thanh, L. K., Hung, N. T., Khanh, T. H., Hiep, C. M., Ngoc, N. M., … Tan, L. V. (2026). Virological and epidemiological investigations of a severe hand foot and mouth disease outbreak, Vietnam, 2023. PLOS Neglected Tropical Diseases, 20(10), e0014789. https://doi.org/10.1371/journal.pntd.0014789

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014789

Keywords: enterovirus A71, hand foot and mouth disease, subgenogroup B5, Vietnam, serosurveillance, neutralizing antibodies, outbreak, pediatric infectious disease, genomic epidemiology, immune evasion, public health, Asia-Pacific