Editorial

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The current state of vaccines used in thefield for foot and mouth disease virusinChina
Expert Rev. Vaccines 10(1), 1315 (2011)

Zhiyong Li
Author for correspondence: State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Grazing Animal Diseases of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agriculture Sciences, 1Xujiaping, Lanzhou, 730046 China Tel.: +86 931 834 2685 Fax: +86 931 834 0977 li_zhiyong56@yahoo.com.cn

Foot and mouth disease is the most important disease of the Office International des Epizooties listA due to its effect on trade. The highly infectious nature of the disease, combined with its ability to cause persistent infections and to exist as multiple types and variants, makes foot and mouth disease difficult to control.
Foot and mouth disease (FMD) is the highly contagious disease of livestock that causes severe economic loss in susceptible cloven-hoofed animals such as cattle, swine, sheep and goats. FMD virus (FMDV) is a member of genus Aphthovirus of the family Picornaviridae. Seven immuno logically distinct serotypes (A, O, C, Asia1, SATI, SAT II and SAT III) have been identified [1] . Viral infection or immunization with one serotype does not confer protection against the other serotypes [2] . In recent years, three serotypes of FMDV have caused epidemics in China. In March 2005, FMDV serotype Asia1 was found in Hong Kong. Subsequently, this type of the virus was reported in mainland China in April 2005 [3] . In 2009, type A FMDV caused outbreaks of FMD in cattle in Wuhan, Hubei Province, Shanghai and Beijing. In early 2010, a typeO FMDV outbreak was recorded in Shenzhen, Guangzhou Province. So far, outbreaks of FMDO have been reported in several provinces and autonomous regions of China, which suggests that the virus might have crossed China. Foot and mouth disease is the most important disease of the Office International des Epizooties (OIE) listA due to its effect on trade. The highly infectious nature of the disease, combined with its ability to cause persistent infections and to exist as multiple types and variants, makes FMD difficult to control[4] . The Chinese government undertook vaccination of livestock by preventive vaccination programs, supplemented by the slaughter of infected animals and susceptible in-contact animals. The types of FMDV vaccines that have been developed in China include: inactivated vaccine; synthesized peptide vaccine; recombinant adenovirus, pseudorabies or fowlpox-vectored vaccine; empty capsid-like particles produced from recombinant baculoviruses; DNA vaccines; and oral vaccine produced from transgenic plants [512] . Among these, the inactivated vaccine and synthesized peptide vaccine are currently available for use in governmentapproved disease control programs in China, and the vaccine composed of inactivated antigen and empty capsid-like particles produced from recombinant silkworm baculovirus are used in eight provinces and autonomous regions of China. Other vaccines are still under evaluation in the laboratory or field to establish their safety and efficacy.
Inactivated vaccine

Jixing Liu
State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agriculture Sciences, 1Xujiaping, Lanzhou, 730046China

The inactivated vaccine is produced by infecting baby hamster kidney (BHK)-21 cells with virulent FMDV, followed by

Keywords : China empty capsid vaccine foot and mouth disease virus inactivated vaccine
safety synthesized peptide vaccine vaccination

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2011 Expert Reviews Ltd

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Li & Liu

inactivation with binary ethyleneimine (BEI) and purification by ultrafiltration [13] . The vaccines can be monovalent or multivalent, including viruses of different serotypes of FMDV. Only monovalent/multivalent vaccines for typeO, typeA and type Asia1 are now produced and used in China. All companies in China producing FMDV-inactivated vaccines do so under strict biosecure conditions.
Problems

Type O & Asia-1 bivalent vaccine (empty capsid vaccinecompound)

Although the inactivated vaccine has been shown to be effective, it may lead to new outbreaks of FMD, either because of the incomplete inactivation of FMDV in large-scale production or owing to the escape of the live virus from vaccine plants. It has been proven that the virus involved in FMD outbreaks was sometimes closely related to virus strains used in vaccine manufacturing plants. The FMD outbreak in the UK in 2007 was caused by an FMDV 01 BFS67-like virus that only existed in FMD reference laboratories and pharmaceutical manufacturing plants. In addition, the FMDV circulating in China in 2005 was genetically closely related to an Indian FMDV vaccine strain [14] . In addition to the aforementioned disadvantage, the vaccine may also contain varying degrees of contaminating viral nonstructural proteins (NSPs), depending on the manufacturer. Currently, the diagnostic tests to distinguish virus-infected carrier animals from vaccinated animals are based on the detection of antibodies to viral NSPs. As a result, it is difficult to distinguish between vaccinated and field-infected animals by currently approved diagnostic tests[15] .
Synthesized peptide vaccine

The type O and Asia1 bivalent vaccine (empty capsid vaccine compound) is composed of typeO inactivated antigens and type Asia1 empty capsid-like particles produced from recombinant silkworm baculoviruses. It was licensed for use in eight provinces and autonomous regions of China in 2008. The company producing the vaccines follows the guidelines of the Veterinary Bureau at the Ministry of Agriculture for Veterinary Medicines Products. Clinical, immunological and virological data documenting the efficacy of these vaccines are required by the Veterinary Bureau at the Ministry of Agriculture.

The complete control and eradication of foot and mouth disease virus can only ultimately be achieved by a combination of vaccination, extensive surveillance and an effective monitoring program.
Compared with synthetic peptide vaccines, the empty capsid vaccine contains the entire repertoire of antigenic sites present on the 140S virion, thereby decreasing the possible selection of antigenic variants from the quasispecies. Empty viral capsids are as immunogenic as the 140S virions; however, they are noninfectious as they lack nucleic acid. The safety is thus improved and the empty capsid vaccine is considered safer than the inactivated vaccine[17] . The type O and Asia1 bivalent vaccine (empty capsid vaccine compound) consists not only of the pure empty capsid-like particle component but also includes the type O inactivated antigen. However, the production of type O inactivated antigens still requires the use of live virus in the manufacturing process. This means that the safety of the compound vaccine is lower than that of the pure empty capsid vaccine. It is the authors opinion that this compound vaccine needs to be replaced by pure empty capsid vaccine. However, the empty capsid-like particles of typeO are more difficult to obtain by genetic engineering techniques as the viral capsid of typeO is more acid-sensitive than other types of FMDV[18] .
Conclusion

The FMDV (type O) synthesized peptide vaccine for swine has been used in the field in China since 2007. Now the synthesized peptide vaccines market share is close to that of the inactivated vaccine. The synthetic peptide vaccine has been designed with the B-cell sites spans the entire GH loop domain and extensive flanking sequences, has a unique consensus sequence to confront the hypervariability of serotype O viruses and a promiscuous artificial Th site. It has shown good immunogenicity in swine but limited immunogenicity in cattle.
Problems

The synthesized peptide vaccine reduces the risk of outbreak from laboratories or vaccine-manufacturing plants because it does not use the virus in its manufacturing process. Although the synthesized peptide vaccine is safer than the inactivated vaccine, it has several potential disadvantages. First, some of the antigenic sites on FMDV are discontinuous and involve different regions of a capsid protein or more than one protein. Therefore, only a limited number of antigenic sites and T-cell epitopes of FMDV can be synthesized and consequently the vaccine is not able to induce significant protection. Second, the quasispecies nature of FMDV invites the selection of antigenic variants not targeted by the vaccine that could cause outbreaks in animals vaccinated with peptide vaccines [16] . Of note, the outbreak of typeO FMDV seen in China in 2010 coincided with the widespread use of the synthesized peptide vaccine in the field. This interesting finding requires further investigation.
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The vaccine is a fundamental component of strategies aimed at Chinas control and eradication of FMD. The inactivated vaccine remains the most widely used FMD vaccine in the world. However, some measures need to be strengthened to ensure the quality and safety of the vaccine. First, a greater emphasis should be placed on quality assurance/quality control in order to reduce the risk of spreading viruses from manufacturing plants. Second, the FMD inactivated vaccine should be purified by industrial ultrafiltration and chromatography in order to remove unwanted cellular protein contaminants and viral NSP. As a new-generation vaccine, the synthesized peptide vaccine is safer than the inactivated vaccine, but whether the synthesized peptide vaccine could overcome the quasispecies problem still needs to be evaluated. The typeO and Asia1 bivalent vaccine (empty capsid vaccine compound) should be evaluated in the field based on
Expert Rev. Vaccines 10(1), (2011)

Vaccines for foot & mouth disease virus in China

Editorial

clinical, immunological and virological data. After successful assembly of the empty capsids of typeO FMDV, the compound vaccine should be replaced by pure empty capsid vaccine. It is the authors opinion that the empty capsid vaccine should be used predominately in Chinas FMD control policy in the future and that the empty capsid vaccine would also be greatly beneficial to control outbreaks of FMD in disease-free countries. Although the control strategies that include culling FMD-infected animals and susceptible animals, but not vaccination, allow the countries to resume FMD-free status quickly, it is not economical and ethical to implement mass slaughter of healthy animals. After the outbreak in UK in 2001, some reports recommended the development of both improved vaccines and modern diagnostic methods to control FMD [19] . According to this recommendation, we believe the empty capsid vaccine would be greatly beneficial to control outbreaks of FMD in disease-free countries. As the empty capsid vaccine lacks infectious viral nucleic acid, the FMD disease-free countries do not need to worry about the escape of infectious virus. In addition, the animals vaccinated with the empty capsid vaccine can be distinguished from infected or convalescent carrier using currently approved diagnostic assays. In addition to the aforementioned vaccines, newgeneration efficacious vaccines, such as virus-vectored vaccine,
References
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should be developed. Moreover, research concerning appropriate adjutants for vaccines to induce either a Th1 or a Th2 response is also required. The vaccination strategy has been effective and has played an important role in the control of FMDV infection in China. Despite the successes obtained with the vaccination strategy, China still faces challenges in its efforts to eliminate FMDV circulation in livestock. The complete control and eradication of FMDV can only ultimately be achieved by a combination of vaccination, extensive surveillance and an effective monitoringprogram.
Acknowledgement

The authors would like to thank Lauren Constable at Expert Reviews Ltd for her helpful comments.
Financial & competing interests disclosure

This work was supported by grants from National 863 Project of China (No. 2006AA02Z440) and Chinese Funding for Social Public Interests (No. 2005DIB4J041). The authors have 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.
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