Recent development of enterovirus A vaccine candidates for the prevention of hand, foot, and mouth disease

Abstract

Hand, foot, and mouth disease (HFMD) is a childhood illness commonly caused by enterovirus A. Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the most commonly identified viruses associated with HFMD. Recently, outbreaks caused by different enterovirus A including CV-A6 and CV-A10 are increasing. Being available now to protect against EV-A71 infection, inactivated EV-A71 vaccines cannot prevent coxsackievirus infections, thus limiting their general application in controlling HFMD. Multivalent HFMD vaccines are suggested to have broad cross-neutralizing responses against these emerging enteroviruses. Areas covered: We discuss the recent development of enterovirus A vaccines including the inactivated whole-virion vaccine and virus-like particle vaccine candidates and review the information of neutralization epitopes of these viruses. Expert commentary: Evaluation of the efficacy and safety of the coxsackievirus vaccine and the multivalent HFMD vaccine candidates in clinical trials is urgently required. Epitopic analysis showed that common immunodominant sites exist across these enteroviruses. However, variations of amino acid residues in these regions limit the induction of cross-neutralization antibodies, and therefore, a multivalent HFMD vaccine is required for broad protection against HFMD. With the inclusion of major circulating viruses in the development of multivalent HFMD vaccines, an increase in the success in HFMD control is anticipated.

Neutralizing Antibodies against Enteroviruses in Patients with Hand, Foot and Mouth Disease

“…Collectively, these data expand our knowledge about immunogenicity elicited as a consequence of EV-A71 vaccination and natural infection. Coxsackievirus vaccine development has not gone beyond animal experiments; thus, no similar data exist for CVA6, CVA10, or CVA16 (15,17).…”

“…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).…”

Immune responses against enterovirus A71 infection: Implications for vaccine success

“…Several EV‐A71 vaccine candidates have been investigated in animal models, such as recombinant viral proteins, virus‐like particles and DNA vaccines, peptide vaccines, live attenuated vaccines, and formalin‐inactivated whole virus vaccines . Several review papers have delved into the advantages and disadvantages of these vaccine candidates . Knowledge of immune responses and epitopes has been applied in vaccine development.…”

“…A few major epitopes have been identified in immunized rabbits [66][67][68] and mice 67,69 (Table 1). In VP1, the mapped regions are the N-terminal (amino acids 1-100), 66,73 amino acids 208-220 of the GH loop (also known as SP70/VP1-43), 67,69 and amino acids [163][164][165][166][167][168][169][170][171][172][173][174][175][176][177] of the EF loop (also known as SP55). 69 Moreover, passive transfer of mouse anti-SP70 antiserum protected 80% of suckling Balb/c mice against lethal EV-A71 infectivity.…”

“…[165][166][167] Several review papers have delved into the advantages and disadvantages of these vaccine candidates. 147,[168][169][170] Knowledge of immune responses and epitopes has been applied in vaccine development. One example is the study using the three described neutralizing epitopes (SP55, SP70, and VP2-28) showing protective immunity in mice.…”