Neutralizing Antibodies Against Enteroviruses in Patients With Hand, Foot and Mouth Disease

Lam Anh Nguyet; Tran Tan Thanh; Le Nguyen Thanh Nhan; Nguyen Thi Thu Hong; Le Nguyen Truc Nhu; Hoang Minh Tu Van; Nguyen Thi Han Ny; Nguyen To Anh; Do Duong Kim Han; Ha Manh Tuan; Vu Quang Huy; Ho Lu Viet; Hoang Quoc Cuong; Nguyen Thi Thanh Thao; Do Chau Viet; Truong Huu Khanh; Louise Thwaites; Hannah Clapham; Nguyen Thanh Hung; Nguyen Van Vinh Chau; Guy Thwaites; Do Quang Ha; H. Rogier van Doorn; Le Van Tan


Emerging Infectious Diseases. 2020;26(2):298-306. 

In This Article

Abstract and Introduction


Hand, foot and mouth disease (HFMD) is an emerging infection with pandemic potential. Knowledge of neutralizing antibody responses among its pathogens is essential to inform vaccine development and epidemiologic research. We used 120 paired-plasma samples collected at enrollment and >7 days after the onset of illness from HFMD patients infected with enterovirus A71 (EV-A71), coxsackievirus A (CVA) 6, CVA10, and CVA16 to study cross neutralization. For homotypic viruses, seropositivity increased from <60% at enrollment to 97%–100% at follow-up, corresponding to seroconversion rates of 57%–93%. Seroconversion for heterotypic viruses was recorded in only 3%–23% of patients. All plasma samples from patients infected with EV-A71 subgenogroup B5 could neutralize the emerging EV-A71 subgenogroup C4. Collectively, our results support previous reports about the potential benefit of EV-A71 vaccine but highlight the necessity of multivalent vaccines to control HFMD.


Since 1997, hand, foot and mouth disease (HFMD) has emerged as a serious childhood infection in the Asia–Pacific region[1,2] with the potential of spreading to other parts of the world. Indeed, HFMD epidemics, especially those caused by enterovirus A71 (EV-A71), have increasingly been reported worldwide, including in the United States and Europe.[3–5] Although HFMD is a mild infection in most cases, severe clinical complications (e.g., central nervous system involvement as brainstem encephalitis) may happen and can be fatal.[1,6] However, no antiviral drugs are available to the affected patients, including those with severe clinical phenotypes.

HFMD is caused by various serotypes of enterovirus A of the family Picornaviridae. Of these, EV-A71, coxsackievirus A (CVA) 6, CVA10, and CVA16 are the most common pathogens isolated from patients with clinically suspected HFMD, with CVA6 being increasingly reported.[7–9] In Vietnam, our recent report showed that of 1,547 patients with HFMD enrolled in a clinical study, EV-A71 was detected in 24.4%, followed by CVA6 (21.8%), CVA16 (10.8%), and CVA10 (7.9%). Other enteroviruses detected sporadically included CVA4 (1.7%), CVA12 (1.4%), and CVA2 (0.6%).[10] Infection with EV-A71 has received more attention because it frequently causes severe HFMD, especially in recent outbreaks recorded in the Asia–Pacific region since 1997.[6,11] Consequently, inactivated monovalent vaccines for EV-A71 have been successfully developed and licensed in China.[12–14] The use of those vaccines, however, has been voluntary and restricted within mainland China.

Because the viruses causing HFMD are diverse, ongoing efforts exist to develop multivalent vaccines, especially those including antigens of the aforementioned common serotypes.[15] Results from these preclinical studies using animal models showed a lack of cross-reactivity among EV-A71, CVA6, CVA10, and CVA16.[16,17] There is, however, scarce information about to what extent human infection with 1 HFMD-causing enterovirus serotype can elicit (cross-)neutralizing antibodies against homotypic and heterotypic enterovirus serotypes. Such data are of paramount importance to support the development of intervention strategies (including vaccines) and the design of epidemiologic research on surveillance and transmission dynamics of HFMD and will contribute to the expanded knowledge about host–pathogen and pathogen–pathogen interaction of this emerging clinical problem. We aim to fill the existing gaps in knowledge about seropositivity and (cross-)neutralization elicited as a consequence of human infection by EV-A71, CVA6, CVA10, and CVA16, the 4 most common serotypes responsible for the ongoing epidemic of HFMD worldwide, especially in Asia.