Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice

Caine, Elizabeth A.; Fuchs, Jeremy F.; Das, Subash C.; Partidos, Charalambos D.; Osorio, Jorge E.

doi:10.3390/v7112916

Cited by 40 publications

(24 citation statements)

References 51 publications

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“…75, 85, 86 Recently, a trivalent-inactivated EV-A71/CV-A16/CV-A6 vaccine showed good protection from lethal challenge against each homologous virus in mice, which was similar to that of the corresponding monovalent vaccine groups. 87 Moreover, a combination of formalin-inactivated EV-A71, CV-A6, CV-A10 and CV-A16 multivalent vaccine candidates could elicit serotype-specific neutralizing antibody responses in mice and rabbits, and no cross-neutralization efficacy was found among these viruses. 88 However, many related studies are limited, particularly the national surveillance systems for non-EV-A71 and non-CV-A16 EVs in endemic areas.…”

Section: Discussionmentioning

confidence: 99%

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases

Mao

Wang

Bian

et al. 2016

Emerging Microbes & Infections

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Enteroviruses (EVs) are the most common viral agents in humans. Although most infections are mild or asymptomatic, there is a wide spectrum of clinical manifestations that may be caused by EV infections with varying degrees of severity. Among these viruses, EV-A71 and coxsackievirus (CV) CV-A16 from group A EVs attract the most attention because they are responsible for hand, foot and mouth disease (HFMD). Other EV-A viruses such as CV-A6 and CV-A10 were also reported to cause HFMD outbreaks in several countries or regions. Group B EVs such as CV-B3, CV-B5 and echovirus 30 were reported to be the main pathogens responsible for myocarditis and encephalitis epidemics and were also detected in HFMD patients. Vaccines are the best tools to control infectious diseases. In December 2015, China's Food and Drug Administration approved two inactivated EV-A71 vaccines for preventing severe HFMD.The CV-A16 vaccine and the EV-A71-CV-A16 bivalent vaccine showed substantial efficacy against HFMD in pre-clinical animal models. Previously, research on EV-B group vaccines was mainly focused on CV-B3 vaccine development. Because the HFMD pathogen spectrum has changed, and the threat from EV-B virus-associated severe diseases has gradually increased, it is necessary to develop multivalent HFMD vaccines. This study summarizes the clinical symptoms of diseases caused by EVs, such as HFMD, myocarditis and encephalitis, and the related EV vaccine development progress. In conclusion, developing multivalent EV vaccines should be strongly recommended to prevent HFMD, myocarditis, encephalitis and other severe diseases.

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Section: Discussionmentioning

confidence: 99%

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases

Mao

Wang

Bian

et al. 2016

Emerging Microbes & Infections

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“…What separated our animal model from others is the virus's ability to infect adult (Ն6-week-old) AG129 mice. This provided the opportunity to perform active-vaccination studies not possible in young animals (15,16). Although the mouse-adapted (mEV71) model was proposed to be useful for vaccine studies, further characterization was clearly required to identify the genetic correlates that caused adaptation, as well as to understand the virus's neurotropic behavior.…”

mentioning

confidence: 99%

A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

Caine

Moncla

Ronderos

et al. 2016

J Virol

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Hand, foot, and mouth disease (HFMD) has spread throughout the Asia-Pacific region, affecting millions of young children, who develop symptoms ranging from painful blisters around their mouths and hands to neurological complications. Many members of the genus Enterovirus (family Picornaviridae) cause HFMD. Enterovirus 71 (EV71) is one of the primary causative agents and has been linked to severe disease. Vaccine efficacy and pathogenesis studies for EV71 have been limited because there is a lack of suitable animal models. Previously, we generated a mouse-adapted EV71 (mEV71) capable of infecting 12-week-old interferon receptor-deficient AG129 mice and used the model to evaluate the efficacy of candidate HFMD vaccines. Here, we present data investigating the genetic correlates of EV71 adaptation and characterize the virus's tissue tropism in mice. Using reverse genetics, a VP1 mutation (K244E) was shown to be necessary for mEV71 virulence in adult mice. Another VP1 mutation (H37R) was required for mEV71 recovery on rhabdomyosarcoma (RD) cells. Viral loads determined by real-time reverse transcription (RT)-PCR confirmed the presence of mEV71 in the sera and multiple organs of mice. Histological analysis revealed signs of meningitis and encephalitis, characteristic of severe human disease. The further description of this model has provided insight into EV71 pathogenesis and demonstrates the importance of the VP1 region in facilitating mEV71 adaptation. IMPORTANCEEV71 is a reemerging pathogen, and little is known about the genetic determinants involved in its pathogenesis. The absence of animal models has contributed to this lack of knowledge. The data presented here improve upon the existing animal models by characterizing a mouse-adapted strain of EV71. We determined that a VP1 mutation (K244E) was needed for EV71 virulence in adult AG129 mice. While this mutation was found previously for EV71 adaptation in 5-day-old BALB/c mice, neurotropic disease did not develop. Using interferon-deficient mice, we raised the age of susceptibility beyond 6 weeks and provided clear evidence that our model mimics severe human infections. The model can be exploited to identify determinants of EV71 virulence and to reveal molecular mechanisms that control the virus-host interaction, especially those associated with neurotropic disease. Furthermore, these data provide useful information regarding the importance of VP1, specifically position 244, in host adaptation and tissue dissemination. O ver the past decade, enterovirus 71 (EV71) (family Picornaviridae) was identified as one of the main causative agents responsible for large outbreaks of hand, foot, and mouth disease (HFMD) across the Asia-Pacific region. Other members of the genus Enterovirus cause HFMD, including coxsackieviruses A16, A6, A5, A7, A9, A10, B2, and B5, but EV71 has been linked to severe complications, including brainstem encephalitis, aseptic meningitis, and pulmonary edema (1-3). Picornaviruses, including the enteroviruses, have positive-sense, single-s...

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“…Bivalent EV-A71/CV-A16 vaccines based on inactivated viruses or VLPs can elicit high titres of neutralizing antibodies in immunized mice and protect from EV-A71 and CV-A16 infections [146]. Yet broader protection is desired to mitigate other HFMD contributors, such as coxsackievirus A6 (CV-A6) [147], and one trivalent EV-A71/CV-A16/CV-A6 inactivated vaccine candidate protecting mice from lethal challenge with these viruses was reported [148].…”

Section: Neutralization Of Picornaviruses Neutralization Of Ev-a71 Anmentioning

confidence: 99%

“…Although studies of EV-A71 have already resulted in two CFDA-approved HFMD vaccines, multivalent HFMD vaccines to control different EV-A71 genotypes and also co-circulating CV-A16 are the next goal. The proof-of-concept studies for such vaccines are promising [148,178], but further work is needed to identify the optimal combination of antigens for balanced, broadly protective immunity. Targeting multiple viruses with a single vaccine also requires delivery systems for the effective presentation of multiple epitopes.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Human picornaviruses associated with neurological diseases and their neutralization by antibodies

Anastasina

Domanska

Palm

et al. 2017

Journal of General Virology

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Picornaviruses are the most commonly encountered infectious agents in mankind. They typically cause mild infections of the gastrointestinal or respiratory tract, but sometimes also invade the central nervous system. There, they can cause severe diseases with long-term sequelae and even be lethal. The most infamous picornavirus is poliovirus, for which significant epidemics of poliomyelitis were reported from the end of the nineteenth century. A successful vaccination campaign has brought poliovirus close to eradication, but neurological diseases caused by other picornaviruses have increasingly been reported since the late 1990s. In this review we focus on enterovirus 71, coxsackievirus A16, enterovirus 68 and human parechovirus 3, which have recently drawn attention because of their links to severe neurological diseases. We discuss the clinical relevance of these viruses and the primary role of humoral immunity in controlling them, and summarize current knowledge on the neutralization of such viruses by antibodies.

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Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice

Cited by 40 publications

References 51 publications

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases

A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

Human picornaviruses associated with neurological diseases and their neutralization by antibodies

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