Editorial
EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
Expert Rev. Vaccines 14(3), 337–340 (2015)
Michel H Klein VaxiBio Inc, 54 Strathgowan Avenue, Toronto, Ontario, M4N 1B9 Canada [email protected]
Enterovirus A infections are the primary cause of hand, foot and mouth disease in infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 have emerged as neurotropic viruses responsible for severe neurological complications and a serious public health threat across the Asia-Pacific region. Formalin-inactivated EV71 vaccines have elicited protection against EV71 but not against coxsackievirus A16 infections. The development of a bivalent formalin-inactivated EV71/FI coxsackievirus A16 vaccine should be the next step towards that of multivalent hand, foot and mouth disease vaccines which should ultimately include other prevalent pathogenic coxsackieviruses and echovirus 30. This editorial summarizes the major challenges faced by the development of hand, foot and mouth disease vaccines.
Hand, foot and mouth disease (HFMD) is a global, self-limiting but highly contagious illness primarily caused by human Enterovirus A infections of infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the prevalent pathogens of HFMD and herpangina (HA) epidemics [1–3]. HFMD is characterized by a febrile papulovesicular rash on the palms, soles and buttocks with multiple painful oral ulcers. Clinical manifestations of HFMD and HA caused by human Enterovirus A are indistinguishable. However, EV71 is a neurotropic virus responsible for aseptic meningitis, acute flaccid paralysis, brain-stem encephalitis and fulminant neurogenic pulmonary edema associated with high mortality [1]. Sequelae include long-term impairment of neurological development and cognitive functions. EV71 has emerged as a major threat to public health across the AsiaPacific region. To control its socioeconomic impact and the widespread panic reactions of the population during outbreaks, some Asian countries have made of the development of a preventive EV71 vaccine a national priority [4–7].
EV71 has been classified into five genotypes A, B, C, D and F, further subdivided into B0–B5 and C1–C5 subgenotypes [1,2,8]. In the past 15 years, large EV71-related HFMD epidemics with severe neurological involvement and fatal outcomes spread throughout the AsiaPacific region [1,2,9,10]. Subgenotypes B4/ B5, C2/B4 and C2/B5 were responsible for severe epidemics associated with high mortality in Malaysia (1997), Taiwan (1998) and Singapore (2008), respectively. More than 7 million cases of HFMD with 2457 fatal outcomes linked to EV71 C4 infections have been reported in mainland China between 2008 and 2012. However, no correlation could be established between EV71 virulence and genotypes. Although cyclical epidemics may be caused by a single strain, divergent EV71 genotypes/subgenotypes often cocirculate during epidemics and between outbreaks which facilitates inter-typic and intra-typic genetic recombinations as well as the emergence of new variants with potentially increased virulence and fitness. Switches of EV71 genotypes/ subgenotypes observed during consecutive
KEYWORDS: coxsackieviruses A16, A6, A10 . cross-neutralizing antibody . Enterovirus 71 . hand foot and mouth diseases
informahealthcare.com
10.1586/14760584.2015.993385
.
human enteroviruses A
.
vaccines
2014 Informa UK Ltd
ISSN 1476-0584
337
Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
Editorial
Klein
outbreaks are unpredictable [1,2,9]. The development of an urgently needed EV71 vaccine was recently diligently undertaken by several Asian institutes and companies. Recombinant VP1 subunits, virus-like particles, vector-based vaccines, synthetic immunogens and DNA plasmid constructs have induced variable degrees of protective immune responses against EV71 lethal challenge [9,11,12]. However, formalin-inactivated virus vaccines formulated in alum were found to be the most efficacious immunogens in pre-clinical studies and were further developed for regulatory, economic and market acceptability reasons. Taiwan was the first country to evaluate a B4-based vaccine in human Phase I clinical trial [4], and a B2 immunogen was later tested by Inviragen [9]. Both induced strong neutralizing antibody titers against the vaccine strains. Furthermore, the B4-based vaccine elicited significant cross-neutralizing antibody responses against B1, B5 and C4a isolates but poorly neutralized an atypical C2 strain [13]. Three vaccines based on different C4 subgenotypes developed in mainland China were evaluated in large efficacy trials involving more than 30,000 healthy infants and young children who received two doses of vaccine 28 days apart [5–7]. The vaccines were found to be safe and well tolerated. They all elicited strong neutralizing antibody responses. They were shown to be ‡90% efficacious against EV71-related HFMD and prevent EV71-associated hospitalization and HA. They also elicited cross-neutralizing antibodies against EV71 B4, B5, C2 and C5 isolates associated with recent epidemics. The Phase III trials have unambiguously shown that humoral immunity is protective, that pre-existing immunity does not interfere with efficacy and that a neutralizing antibody a titer of 1/16 is a correlate of protection. However, immunity declined after 6 months and a booster immunization may be recommended 1 year after priming in particular if efficacious vaccination prevents natural immune stimulation as a result of EV71 exposure [14]. It is still imperative to conduct large multinational efficacy trials in countries where divergent epidemic isolates and potential recombinants circulate to fully assess the breadth, strength and duration of cross-protection induced by the current monovalent C4-, B4- and B2-based vaccines, as well as the risk of possible antibody-dependent enhancement of EV71 infection [15]. Such information is critical to determine whether multivalency is necessary for a universal EV71 vaccine. The role of cellular immunity in disease pathogenesis and control should also be determined in prospective longitudinal studies. In spite of their efficacy, EV71 vaccines failed to prevent CVA16 infections. Thus, they may not significantly reduce the number of clinical cases during an HFMD outbreak, which raises issues regarding their public acceptability. Indeed, CVA16 is the other prevalent etiologic agent of serious HFMD epidemics such as those which occurred in Taiwan, Singapore and Vietnam and reached epidemic proportions in mainland China in 2011–2012 [3]. Usually mild, CVA16 infections may also lead to severe neurological complications and fatal outcomes in a small percentage of infected infants. Co-circulation of EV71 and CVA16 may lead to exposure to the risk of severe disease as a result of co338
infection and/or genetic recombination [3]. Thus, the development of a bivalent EV71/CVA16 vaccine is the next most urgent step toward HFMD prevention. Experimental monovalent CVA16 vaccines are protective [3] and bivalent formalininactivated EV71/FI-CVA16 vaccines eliciting balanced neutralizing and protective responses against both viruses in animal models are promising [16]. CVA16 and several other coxsackieviruses A (CVA2, CVA4, CVA5, CVA6, CVA8, CVA9, CVA10) may co-circulate during HFMD epidemics [17,18] and the control of circulating EV71 by future vaccination programs may increase their prevalence. These viruses contribute to HA and classic or atypical HFMD outbreaks and they can cause severe disease with neurological complications [17–21]. Based on global molecular epidemiology surveillance, EV71, CVA16, CVA6 and CVA10 are the most prevalent pathogens of HFMD in children [1,3,17–21]. CVA6 and CVA10 are common causes of HA but are now recognized as emerging agents of serious sporadic HFMD dual outbreaks. These viruses accounted for 39% of all HFMD cases in the large epidemic in Singapore in 2008. CVA6 was the prevalent pathogen in Guangzhou (2010–2012) and Taiwan (2010) epidemics. It was responsible for severe atypical skin lesions and tissue destruction in children and adults, neurological involvement and onychomadesis. CVA10 has also been associated with severe HFMD [19,21]. The critical finding that antisera raised against a bivalent formalin-inactivated EV71/FICVA16 vaccine did not neutralize CVA6 and CVA10, justifies the need for integrating CVA6 and CVA10 into a tetravalent HFMD vaccine in the future [8]. Such a combination vaccine should significantly reduce the number of HFMD cases and prevent the severe complications observed during HFMD epidemics. Ultimately, HFMD vaccines should include coxsackieviruses B3 and B5 as well as echovirus 30 that cause myocarditis and aseptic meningitis. The efficacy of inactivated poliovirus and EV71 vaccines augurs well for the development of such vaccines. Monovalent EV71 vaccines represent a first step toward more complex HFMD vaccines, but all vaccines are faced with similar challenges. There is an urgent need to establish national and global surveillance systems as well as rapid diagnostic tests to monitor and coordinate the molecular epidemiology of EV71 and human Enterovirus A during HFMD/HA outbreaks. The harmonization and standardization of immunogens, immunoassays and animal models are of paramount importance. Epidemiological surveys, ethical considerations and economic analyses are required to further support the rationale for a multivalent HFMD vaccine. The lack of appropriate animal models has so far been a hurdle in the evaluation of vaccine potency [22]. The use of chimpanzees is prohibited for both ethical and financial reasons but the engineering of transgenic mice expressing the EV71/CVA16 SCARB2 receptor represents a very promising approach in future pre-clinical studies [23]. Different models must be established for CVA6 and CVA10 since they infect target cells through SCARB2-independent pathways. Assuming that an optimal EV71 vaccine is Expert Rev. Vaccines 14(3), (2015)
Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
EV71 vaccines
selected in the near future, logistically complex and lengthy efficacy trials will be required to assess the breadth, magnitude and duration of cross-protection induced by tetravalent vaccines against the 3, 4 and 5 genotypes of CVA16, CVA6 and CVA10, respectively [17]. Trials will have to be first conducted with individual coxsackievirus A vaccines, then with a bivalent EV71/CVA16 vaccine before undertaking the clinical development of a tetravalent HFMD vaccine. The development of multivalent vaccines will require a careful selection of strain genotypes/subgenotypes, the proper choice of cell substrates and efficient manufacturing processes to optimize virus yields to produce affordable vaccines [8,11]. Adjuvants stronger than alum might be necessary and the risk of interference between vaccine components might have to be overcome to ensure consistent vaccine immunogenicity and stability. Monovalent EV71 vaccines could be soon marketed in mainland China if they were stable and could be produced in sufficient amounts. It has been forecasted that a 70% efficacious EV71 vaccine at US $25 would be economically viable in most Asian countries [24], but improvements of the current manufacturing processes could markedly reduce production
1.
Solomon T, Lewthwarte P, Perera D, et al. Virology, epidemiology, pathogenesis and control of enterovirus 71. Lancet Infect Dis 2010;10(11):778-90
2.
Yip CCY, Lau SKP, Woo PCY, Yuen KY. Human enterovirus 71 epidemics: what’s next? Emerg Health Threats J 2013;6:19780
3.
Mao Q, Wang Y, Yao X, et al. Coxsackievirus A16: epidemiology, diagnosis and vaccine. Hum Vaccin Immunother 2014;10(2):360-7
4.
5.
6.
Cheng A, Fung CP, Liu CC, et al. A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine. Vaccine 2013;31: 2471-6 Zhu PC, Meng FY, Li JX, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvanted enterovirus 71 vaccine in children in Mainland China: a multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet 2013;381(9882): 2024-32 Zhu F, Xu W, Xia J, et al. Efficacy safety and immunogenicity of an enterovirus 71 vaccine in Mainland China. N Engl J Med 2014;370(9):818-28
7.
Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014;370(9):829-37
8.
Liu CC, Chow YH, Chong P, Klein M. Prospect and challenges for the development
informahealthcare.com
costs [11]. Cost-effective manufacturing should ultimately help produce multivalent vaccines at prices compatible with their future incorporation into Expanded Program on Immunization vaccines. The development of EV71 vaccines has so far been carried out by Asian institutions and companies. However, strong scientific rationale, large markets and substantial margins might now entice the global vaccine industry to collaborate on the development of HMFD vaccines to fulfill a yet unmet medical need. Financial & competing interests disclosure
M Klein is currently Chairman of VaxiBio Inc. He is a former Professor of Immunology at the University of Toronto and the former Corporate Vice-President Science and Technology at Aventis Pasteur (now Sanofi Pasteur). He is paid as consultant to various Scientific Boards. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
of multivalent vaccines against hand, foot and mouth diseases. Vaccine 2014. [Epub ahead of print]
References
9.
Kung YA, Hung CT, Liu YC, Shih SR. Update on the development of enterovirus 71 vaccines. Expert Opin Biol Ther 2014; 14(10):1455-64
10.
Xing W, Liao Q, Viboud C, et al. Hand, foot, and mouth disease in Mainland China, 2008-12: an epidemiological study. Lancet Infect Dis 2014;14(4):308-18
11.
Chong P, Hsieh SY, Liu CC, et al. Production of EV71 vaccine candidates. Hum Vaccin Immunother 2012;8(12): 1775-83
12.
Chou AH, Liu CC, Chang JY, et al. Immunological evaluation and comparison of different EV71 vaccine candidates. Clin Dev Immunol 2012;831282
13.
Chou AH, Liu CC, Chang JY, et al. Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody responses against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLoS One 2013;8(11):e79783
14.
15.
Editorial
Shenyu W, Jingxin L, Zhenglun L, et al. A booster dose of an inactivated enterovirus 71 vaccine in chinese young children: a randomized. double-blind, placebo-controlled clinical trial. J Infect Dis 2014;210(7):1073-82 Han JF, Cao RY, Deng YQ, et al. Antibody dependent enhancement infection of
Enterovirus 71 in vitro and in vivo. Virol J 2011;8:106-13 16.
Lin CW, Liu CC, Lu TC, et al. Immunogenicity studies of bivalent inactivated virions of EV71/ CVA16 formulated with submicron emulsion systems. Biomed Res Int 2014;670506
17.
Chen JF, Zhang RS, Ou XH, et al. The role of enterovirus 71 and coxsackievirus A strains in a large outbreak of hand, foot and mouth disease in 2012 in Changsha, Mainland China. Int J Infect Dis 2014;28C:17-25
18.
Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand, foot and mouth disease in Singapore in 2008: The role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis 2010;14(12):e1076-81
19.
Lu QB, Zhang XA, Wo Y, et al. Circulation of Coxsackievirus A10 and A6 in hand-foot-mouth disease in Mainland China, 2009-2011. PLoS One 2012;7(12): e52073
20.
Di B, Zhang Y, Xie H, et al. Circulation of Coxsackievirus A6 in hand-foot-mouth disease in Guanzhou, 2010-2012. Virol J 2014;11:157-63
21.
Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand foot and mouth disease/herpangina associated with coxsackie A6 and A10 infections in 2010, France: a large citywide, prospective observational
339
Editorial
Klein
study. Clin Microbiol Infect 2012;18(5): E110-18 Wang YF, Yu CK. Animal models of enterovirus 71 infection: applications and limitations. J Biomed Sci 2014;21:31-41
Lin YW, Yu SL, Shao H, et al. Human SCARB2 transgenic mice as an infectious animal model for enterovirus 71. PLoS One 2013;8(2):e57591
24.
Lee BY, Wateska A, Bailey RR, et al. Forecasting the economic value of an enterovirus 71 (EV71) vaccine. Vaccine 2010;28(49):7731-6
Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
22.
23.
340
Expert Rev. Vaccines 14(3), (2015)
EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
Expert Rev. Vaccines 14(3), 337–340 (2015)
Michel H Klein VaxiBio Inc, 54 Strathgowan Avenue, Toronto, Ontario, M4N 1B9 Canada [email protected]
Enterovirus A infections are the primary cause of hand, foot and mouth disease in infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 have emerged as neurotropic viruses responsible for severe neurological complications and a serious public health threat across the Asia-Pacific region. Formalin-inactivated EV71 vaccines have elicited protection against EV71 but not against coxsackievirus A16 infections. The development of a bivalent formalin-inactivated EV71/FI coxsackievirus A16 vaccine should be the next step towards that of multivalent hand, foot and mouth disease vaccines which should ultimately include other prevalent pathogenic coxsackieviruses and echovirus 30. This editorial summarizes the major challenges faced by the development of hand, foot and mouth disease vaccines.
Hand, foot and mouth disease (HFMD) is a global, self-limiting but highly contagious illness primarily caused by human Enterovirus A infections of infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the prevalent pathogens of HFMD and herpangina (HA) epidemics [1–3]. HFMD is characterized by a febrile papulovesicular rash on the palms, soles and buttocks with multiple painful oral ulcers. Clinical manifestations of HFMD and HA caused by human Enterovirus A are indistinguishable. However, EV71 is a neurotropic virus responsible for aseptic meningitis, acute flaccid paralysis, brain-stem encephalitis and fulminant neurogenic pulmonary edema associated with high mortality [1]. Sequelae include long-term impairment of neurological development and cognitive functions. EV71 has emerged as a major threat to public health across the AsiaPacific region. To control its socioeconomic impact and the widespread panic reactions of the population during outbreaks, some Asian countries have made of the development of a preventive EV71 vaccine a national priority [4–7].
EV71 has been classified into five genotypes A, B, C, D and F, further subdivided into B0–B5 and C1–C5 subgenotypes [1,2,8]. In the past 15 years, large EV71-related HFMD epidemics with severe neurological involvement and fatal outcomes spread throughout the AsiaPacific region [1,2,9,10]. Subgenotypes B4/ B5, C2/B4 and C2/B5 were responsible for severe epidemics associated with high mortality in Malaysia (1997), Taiwan (1998) and Singapore (2008), respectively. More than 7 million cases of HFMD with 2457 fatal outcomes linked to EV71 C4 infections have been reported in mainland China between 2008 and 2012. However, no correlation could be established between EV71 virulence and genotypes. Although cyclical epidemics may be caused by a single strain, divergent EV71 genotypes/subgenotypes often cocirculate during epidemics and between outbreaks which facilitates inter-typic and intra-typic genetic recombinations as well as the emergence of new variants with potentially increased virulence and fitness. Switches of EV71 genotypes/ subgenotypes observed during consecutive
KEYWORDS: coxsackieviruses A16, A6, A10 . cross-neutralizing antibody . Enterovirus 71 . hand foot and mouth diseases
informahealthcare.com
10.1586/14760584.2015.993385
.
human enteroviruses A
.
vaccines
2014 Informa UK Ltd
ISSN 1476-0584
337
Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
Editorial
Klein
outbreaks are unpredictable [1,2,9]. The development of an urgently needed EV71 vaccine was recently diligently undertaken by several Asian institutes and companies. Recombinant VP1 subunits, virus-like particles, vector-based vaccines, synthetic immunogens and DNA plasmid constructs have induced variable degrees of protective immune responses against EV71 lethal challenge [9,11,12]. However, formalin-inactivated virus vaccines formulated in alum were found to be the most efficacious immunogens in pre-clinical studies and were further developed for regulatory, economic and market acceptability reasons. Taiwan was the first country to evaluate a B4-based vaccine in human Phase I clinical trial [4], and a B2 immunogen was later tested by Inviragen [9]. Both induced strong neutralizing antibody titers against the vaccine strains. Furthermore, the B4-based vaccine elicited significant cross-neutralizing antibody responses against B1, B5 and C4a isolates but poorly neutralized an atypical C2 strain [13]. Three vaccines based on different C4 subgenotypes developed in mainland China were evaluated in large efficacy trials involving more than 30,000 healthy infants and young children who received two doses of vaccine 28 days apart [5–7]. The vaccines were found to be safe and well tolerated. They all elicited strong neutralizing antibody responses. They were shown to be ‡90% efficacious against EV71-related HFMD and prevent EV71-associated hospitalization and HA. They also elicited cross-neutralizing antibodies against EV71 B4, B5, C2 and C5 isolates associated with recent epidemics. The Phase III trials have unambiguously shown that humoral immunity is protective, that pre-existing immunity does not interfere with efficacy and that a neutralizing antibody a titer of 1/16 is a correlate of protection. However, immunity declined after 6 months and a booster immunization may be recommended 1 year after priming in particular if efficacious vaccination prevents natural immune stimulation as a result of EV71 exposure [14]. It is still imperative to conduct large multinational efficacy trials in countries where divergent epidemic isolates and potential recombinants circulate to fully assess the breadth, strength and duration of cross-protection induced by the current monovalent C4-, B4- and B2-based vaccines, as well as the risk of possible antibody-dependent enhancement of EV71 infection [15]. Such information is critical to determine whether multivalency is necessary for a universal EV71 vaccine. The role of cellular immunity in disease pathogenesis and control should also be determined in prospective longitudinal studies. In spite of their efficacy, EV71 vaccines failed to prevent CVA16 infections. Thus, they may not significantly reduce the number of clinical cases during an HFMD outbreak, which raises issues regarding their public acceptability. Indeed, CVA16 is the other prevalent etiologic agent of serious HFMD epidemics such as those which occurred in Taiwan, Singapore and Vietnam and reached epidemic proportions in mainland China in 2011–2012 [3]. Usually mild, CVA16 infections may also lead to severe neurological complications and fatal outcomes in a small percentage of infected infants. Co-circulation of EV71 and CVA16 may lead to exposure to the risk of severe disease as a result of co338
infection and/or genetic recombination [3]. Thus, the development of a bivalent EV71/CVA16 vaccine is the next most urgent step toward HFMD prevention. Experimental monovalent CVA16 vaccines are protective [3] and bivalent formalininactivated EV71/FI-CVA16 vaccines eliciting balanced neutralizing and protective responses against both viruses in animal models are promising [16]. CVA16 and several other coxsackieviruses A (CVA2, CVA4, CVA5, CVA6, CVA8, CVA9, CVA10) may co-circulate during HFMD epidemics [17,18] and the control of circulating EV71 by future vaccination programs may increase their prevalence. These viruses contribute to HA and classic or atypical HFMD outbreaks and they can cause severe disease with neurological complications [17–21]. Based on global molecular epidemiology surveillance, EV71, CVA16, CVA6 and CVA10 are the most prevalent pathogens of HFMD in children [1,3,17–21]. CVA6 and CVA10 are common causes of HA but are now recognized as emerging agents of serious sporadic HFMD dual outbreaks. These viruses accounted for 39% of all HFMD cases in the large epidemic in Singapore in 2008. CVA6 was the prevalent pathogen in Guangzhou (2010–2012) and Taiwan (2010) epidemics. It was responsible for severe atypical skin lesions and tissue destruction in children and adults, neurological involvement and onychomadesis. CVA10 has also been associated with severe HFMD [19,21]. The critical finding that antisera raised against a bivalent formalin-inactivated EV71/FICVA16 vaccine did not neutralize CVA6 and CVA10, justifies the need for integrating CVA6 and CVA10 into a tetravalent HFMD vaccine in the future [8]. Such a combination vaccine should significantly reduce the number of HFMD cases and prevent the severe complications observed during HFMD epidemics. Ultimately, HFMD vaccines should include coxsackieviruses B3 and B5 as well as echovirus 30 that cause myocarditis and aseptic meningitis. The efficacy of inactivated poliovirus and EV71 vaccines augurs well for the development of such vaccines. Monovalent EV71 vaccines represent a first step toward more complex HFMD vaccines, but all vaccines are faced with similar challenges. There is an urgent need to establish national and global surveillance systems as well as rapid diagnostic tests to monitor and coordinate the molecular epidemiology of EV71 and human Enterovirus A during HFMD/HA outbreaks. The harmonization and standardization of immunogens, immunoassays and animal models are of paramount importance. Epidemiological surveys, ethical considerations and economic analyses are required to further support the rationale for a multivalent HFMD vaccine. The lack of appropriate animal models has so far been a hurdle in the evaluation of vaccine potency [22]. The use of chimpanzees is prohibited for both ethical and financial reasons but the engineering of transgenic mice expressing the EV71/CVA16 SCARB2 receptor represents a very promising approach in future pre-clinical studies [23]. Different models must be established for CVA6 and CVA10 since they infect target cells through SCARB2-independent pathways. Assuming that an optimal EV71 vaccine is Expert Rev. Vaccines 14(3), (2015)
Expert Review of Vaccines Downloaded from informahealthcare.com by Nanyang Technological University on 04/27/15 For personal use only.
EV71 vaccines
selected in the near future, logistically complex and lengthy efficacy trials will be required to assess the breadth, magnitude and duration of cross-protection induced by tetravalent vaccines against the 3, 4 and 5 genotypes of CVA16, CVA6 and CVA10, respectively [17]. Trials will have to be first conducted with individual coxsackievirus A vaccines, then with a bivalent EV71/CVA16 vaccine before undertaking the clinical development of a tetravalent HFMD vaccine. The development of multivalent vaccines will require a careful selection of strain genotypes/subgenotypes, the proper choice of cell substrates and efficient manufacturing processes to optimize virus yields to produce affordable vaccines [8,11]. Adjuvants stronger than alum might be necessary and the risk of interference between vaccine components might have to be overcome to ensure consistent vaccine immunogenicity and stability. Monovalent EV71 vaccines could be soon marketed in mainland China if they were stable and could be produced in sufficient amounts. It has been forecasted that a 70% efficacious EV71 vaccine at US $25 would be economically viable in most Asian countries [24], but improvements of the current manufacturing processes could markedly reduce production
1.
Solomon T, Lewthwarte P, Perera D, et al. Virology, epidemiology, pathogenesis and control of enterovirus 71. Lancet Infect Dis 2010;10(11):778-90
2.
Yip CCY, Lau SKP, Woo PCY, Yuen KY. Human enterovirus 71 epidemics: what’s next? Emerg Health Threats J 2013;6:19780
3.
Mao Q, Wang Y, Yao X, et al. Coxsackievirus A16: epidemiology, diagnosis and vaccine. Hum Vaccin Immunother 2014;10(2):360-7
4.
5.
6.
Cheng A, Fung CP, Liu CC, et al. A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine. Vaccine 2013;31: 2471-6 Zhu PC, Meng FY, Li JX, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvanted enterovirus 71 vaccine in children in Mainland China: a multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet 2013;381(9882): 2024-32 Zhu F, Xu W, Xia J, et al. Efficacy safety and immunogenicity of an enterovirus 71 vaccine in Mainland China. N Engl J Med 2014;370(9):818-28
7.
Li R, Liu L, Mo Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014;370(9):829-37
8.
Liu CC, Chow YH, Chong P, Klein M. Prospect and challenges for the development
informahealthcare.com
costs [11]. Cost-effective manufacturing should ultimately help produce multivalent vaccines at prices compatible with their future incorporation into Expanded Program on Immunization vaccines. The development of EV71 vaccines has so far been carried out by Asian institutions and companies. However, strong scientific rationale, large markets and substantial margins might now entice the global vaccine industry to collaborate on the development of HMFD vaccines to fulfill a yet unmet medical need. Financial & competing interests disclosure
M Klein is currently Chairman of VaxiBio Inc. He is a former Professor of Immunology at the University of Toronto and the former Corporate Vice-President Science and Technology at Aventis Pasteur (now Sanofi Pasteur). He is paid as consultant to various Scientific Boards. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
of multivalent vaccines against hand, foot and mouth diseases. Vaccine 2014. [Epub ahead of print]
References
9.
Kung YA, Hung CT, Liu YC, Shih SR. Update on the development of enterovirus 71 vaccines. Expert Opin Biol Ther 2014; 14(10):1455-64
10.
Xing W, Liao Q, Viboud C, et al. Hand, foot, and mouth disease in Mainland China, 2008-12: an epidemiological study. Lancet Infect Dis 2014;14(4):308-18
11.
Chong P, Hsieh SY, Liu CC, et al. Production of EV71 vaccine candidates. Hum Vaccin Immunother 2012;8(12): 1775-83
12.
Chou AH, Liu CC, Chang JY, et al. Immunological evaluation and comparison of different EV71 vaccine candidates. Clin Dev Immunol 2012;831282
13.
Chou AH, Liu CC, Chang JY, et al. Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody responses against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLoS One 2013;8(11):e79783
14.
15.
Editorial
Shenyu W, Jingxin L, Zhenglun L, et al. A booster dose of an inactivated enterovirus 71 vaccine in chinese young children: a randomized. double-blind, placebo-controlled clinical trial. J Infect Dis 2014;210(7):1073-82 Han JF, Cao RY, Deng YQ, et al. Antibody dependent enhancement infection of
Enterovirus 71 in vitro and in vivo. Virol J 2011;8:106-13 16.
Lin CW, Liu CC, Lu TC, et al. Immunogenicity studies of bivalent inactivated virions of EV71/ CVA16 formulated with submicron emulsion systems. Biomed Res Int 2014;670506
17.
Chen JF, Zhang RS, Ou XH, et al. The role of enterovirus 71 and coxsackievirus A strains in a large outbreak of hand, foot and mouth disease in 2012 in Changsha, Mainland China. Int J Infect Dis 2014;28C:17-25
18.
Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand, foot and mouth disease in Singapore in 2008: The role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis 2010;14(12):e1076-81
19.
Lu QB, Zhang XA, Wo Y, et al. Circulation of Coxsackievirus A10 and A6 in hand-foot-mouth disease in Mainland China, 2009-2011. PLoS One 2012;7(12): e52073
20.
Di B, Zhang Y, Xie H, et al. Circulation of Coxsackievirus A6 in hand-foot-mouth disease in Guanzhou, 2010-2012. Virol J 2014;11:157-63
21.
Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand foot and mouth disease/herpangina associated with coxsackie A6 and A10 infections in 2010, France: a large citywide, prospective observational
339
Editorial
Klein
study. Clin Microbiol Infect 2012;18(5): E110-18 Wang YF, Yu CK. Animal models of enterovirus 71 infection: applications and limitations. J Biomed Sci 2014;21:31-41
Lin YW, Yu SL, Shao H, et al. Human SCARB2 transgenic mice as an infectious animal model for enterovirus 71. PLoS One 2013;8(2):e57591
24.
Lee BY, Wateska A, Bailey RR, et al. Forecasting the economic value of an enterovirus 71 (EV71) vaccine. Vaccine 2010;28(49):7731-6
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