Safety facts about the GM horse flu virus vaccine now deployed in Australia

An earlier post on a GMO vaccine coming to the rescue of the Australian horse racing industry
explains how horses can be protected from equine influenza. This posing provides facts relating to the safety of that vaccine, quoting from a recent scientific review.

Development and registration of recombinant veterinary vaccines. The example of the canarypox vector platform.

Poulet H, Minke J, Pardo MC, Juillard V, Nordgren B, Audonnet JC.

Merial SAS, 254, rue Marcel Mérieux, 69007 Lyon, France. herve.poulet@merial.com

Vaccine. 2007 Jul 26;25(30):5606-12. Epub 2006 Dec 8.

The canarypox vaccine vector (ALVAC) technology has been used to develop and license several vaccines for companion animals and horses in the European Union and USA. ALVAC is a ubiquitous vector with high biosafety since it is non-replicative in mammalians, is genetically and physically stable, and able to induce both humoral and cell-mediated immune responses against the expressed transgene product. Specific rules apply for the development and registration of
recombinant vector vaccines. The biology of the vector as well as the recombinant virus must be thoroughly documented to allow the risk assessment of its use in the target species. In particular, its safety for the host and the environment must be extensively demonstrated before field trials can be authorized.

Some selected passages from the Poulet H, et al. paper relating to vaccine safety:

1. Introduction

Veterinary medicine has been at the forefront of cutting edge vaccine technology as illustrated by the number of non-conventional vaccines available in the animal health market... ...Interestingly, live recombinant vector vaccines for food animals, as well as for companion animals represent the majority of those new technology vaccines, and most of them are based on poxvirus vectors.

...The development of avipoxvirus vectors for mammals was extremely attractive from a biosafety standpoint. Efficacy results against Rabies suggested that the canarypox virus was a better candidate than the fowlpox virus for the development of a non-replicative vector for mammals [11]. Several canarypox virus recombinant vaccines have been developed and licensed for dogs, cats, ferrets and horses (Table 1), and many new candidates are currently being tested in both animals and humans.

Table 1. Canarypox virus vector vaccines licensed for veterinary use
Target- Inserts -Species - Country
Canine distemper HA and F Dog, ferret USA, Argentina, Brazil, Colombia, Canada, Uruguay

Rabies G Cat USA, Canada

Feline leukemia Env, Gag/pro Cat Europe, USA, Canada

Equine influenza HA Horse Europe

West-Nile prM-E Horse USA, Canada

HA, hemagglutinin; F, fusion protein; G, glycoprotein G; Env, envelope glycoprotein; Gag, group specific antigen; Pro, protease; prM-E, pre-membrane and envelope proteins.

2. Advantages of the canarypox virus vector

The ALVAC vector is a canarypox virus clone obtained after four rounds of plaque purification of a strain from a vaccine for canaries. Despite an abortive replication cycle in mammalian cells, ALVAC can express appropriately engineered foreign genes resulting in de novo synthesis of proteins which are then presented to the immune system in a manner similar to a natural infection and generate both antibodies (Ab) and cell-mediated immunity (CMI)...

2.2. Safety

As for conventional attenuated vaccines, safety must be evaluated in the target species under laboratory and field conditions. In Europe, laboratory studies include the safety of an overdose, which is equal to 10 times the maximum release dose of the vaccine, and the safety of the repeated administration of one dose. These studies are done in the most susceptible animals, such as animals at the minimum age recommended for vaccination.

The safety of ALVAC-based vaccines has been extensively evaluated in cats, dogs, ferrets or horses. At very high doses administered subcutaneously ..., the most common post-vaccinal reactions consist of transient hyperthermia with or without lethargy, mild and transient local pain and swelling at the injection site. This reactogenicity has been a consistent feature of the various ALVAC constructs tested so far. Histological examination showed that the inflammatory reaction induced by ALVAC-FeLV at the injection site was mild, localized and transient (Day et al., submitted).

At commercial dose, the reactogenicity of recombinant canarypox virus vaccines is low: in large scale field safety trials with combined canarypox-FeLV vaccines in cats, the rate of local reactions, such as pain, itching and transient swelling ranged from 1 to 3.6%. A similar safety profile has been reported in humans [41]...

More generally, safety has been confirmed in a wide range of species as well as by different routes of administration (Table 2).

Table 2. Safety of ALVAC-based vaccines has been demonstrated in various species and conditions of use

Species
Cat [29], dog [36], horse [34] and [35], ferret [54], sheep [50], pig [51], monkey [26] and [44], rabbits, guinea-pigs, mice [44]. Canary [44], chicken, duck, goose, crow [40], human [19], [20], [21], [22], [23], [24], [25] and [55]

Age Young animals, new-born mice [46]

Immune status
Nude mice, cyclophosphamide treated mice [55]. FIV or FeLV infected cats [29]. Immuno-compromised individuals: HIV infected humans [21], cancer patients [22], [23], [24] and [25]

Route of administration
Subcutaneous [29] and [44], intra-muscular [34] and [35], transdermal [32], [44] and [55], oral [44] and [55], ocular [44], intra-venous [56], intra-cerebral [44], intra-tumoral [57]


3. Development and registration of live recombinant vector vaccines for veterinary use

The development of a live recombinant vector vaccine is highly regulated. It follows the general rules of the development of conventional attenuated vaccines. In addition, a very detailed characterization of the vaccine strain must be provided, as well as an extensive evaluation of its biosafety, supported by specific studies.

Part II.H of the European registration file and the Summary of Information Format (SIF) document must be submitted to US authorities in order to obtain authorization to conduct field trials. These documents contain a detailed description of the genetically modified organism and the risk assessment of its release into the environment. This description includes information on the vector itself, the inserted genes and the properties of the final organism.

Due to the natural host restriction of the canarypox virus and its attenuation as a vaccine strain, ALVAC is not pathogenic for canaries, other birds or mammals. Canarypox virus is genetically stable, replicates in the cell cytoplasm of the permissive host and its large genome allows the insertion of several genes. Among several potential insertion sites, two of them located in the inverted terminal repeats are commonly used...

The genotypic and phenotypic traits of the final organism, its genetic stability, its tissue and host tropism and its safety for the target species and the environment must be documented for each new construct. The genetic stability of each ALVAC vaccine is indirectly confirmed by serial passages at a low multiplicity of infection in chicken embryo fibroblasts and immunoplaque assay or hybridization with a DNA probe specific for the inserted gene. The purity of the plaque virus is ensured by the absence of hybridization with a DNA probe specific for the deleted gene. The number of passages encompasses the passages from Master Seed virus to production batch. It is generally accepted that at least 95% of the plaques must express the transgene at the production batch level.

The host tropism of each new recombinant canarypox virus is tested both in vitro and in vivo. Serial passages are performed on primary cells and cell lines of the target species. Attempts to passage and adapt recombinant canarypox viruses on feline, canine or equine primary cells or cell lines of the same species have failed whatever the tested construct...

The absence of change in the tropism of ALVAC after insertion of a foreign gene is confirmed in the safety studies carried out in canary birds and other species. The safety of each new recombinant canarypox virus is tested in canary birds in comparison with the parental strain by inoculation with a high dose via the transcutaneous route. Whatever the transgene, the recombinant canarypox virus does not induce clinical signs apart from mild local lesions at the inoculation site. The virus can be isolated from the skin at the site of inoculation and from various organs, but titres progressively decrease over time until virus cannot be detected.

All recombinant viruses tested so far have been at least as safe as the parental strain, and no change of tropism has been observed. Because domestic birds may be in close contact with vaccinated animals, safety of ALVAC based vaccines is also tested in chickens. Control of each new master seed virus includes a safety test in mice by the intra-cerebral route. The LD50 of ALVAC has been shown to be at least 10,000 times lower than the Copenhagen vaccinia virus strain administered by intra-cerebral route in newborn and 3-week-old mice [46]. In addition, the inoculation of 109 TCID50 virus in nude immunodeficient mice did not cause any lesions, or any signs. These data showed, indirectly, the absence of in vivo replication of ALVAC. The safety data in nude mice highlight that the lack of replication cannot be attributed to an active immune response of the host and therefore is an inherent property of the canarypox virus.

The risk of horizontal gene transfer or recombination must be evaluated for each new recombinant vaccine in the context of its use. Canarypox virus is used as a vector in species which are not a reservoir of avipoxvirus, reducing thereby the risk of in vivo recombination. Nonetheless, cats have occasionally been infected with cowpox virus [47] and although there has been no report of recombination between avipoxviruses and orthopoxviruses, this risk must be evaluated before the release of recombinant canarypox virus vaccines. The likelihood to have co-localization (infection of the same cells in the same host) of a recombinant canarypox virus and a cowpox virus in natural conditions is extremely low. In addition, the genetic distance between avipoxvirus and orthopoxvirus minimizes the risk of recombination. This was confirmed by BLAST analyses of the region of the insertion sites showing that the risk of horizontal transfer of the transgene is very low.

In the European Union, registration of vaccines using the recombinant DNA technology must be done through the centralized procedure managed by Committee for Veterinary Medicinal Products (CVMP) at the European Medicines Evaluation Agency (EMEA). In the USA, it is regulated by Animal and Plant Health Inspection Service and Center for Veterinary Biologics (APHIS/CVB) of United States Department of Agriculture (USDA) in compliance with the National Environmental Policy Act. In addition to the general guidelines governing the development and registration of veterinary vaccines, specific guidelines apply for live recombinant vector vaccines with a strong emphasis on the safety for the target species and the environment. Authorization to do field trials is granted at the national level and requires a complete risk analysis (equivalent to part II.H in the European Union; SIF in the USA). In addition to the risk assessment, the applicant must explain how the risk will be managed in the trial. In the USA, the public is notified about the request to do field trials with the recombinant vaccine through the Federal Register. The overall “Finding Of Non Significant Impact” process may take from 1 to 2 years, and may add considerable delays to the overall development.


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Related Links In Pubmed Database

Antibody and IFN-gamma responses induced by a recombinant canarypox vaccine and
challenge infection with equine influenza virus. [Vet Immunol Immunopathol. 2006]
PMID:16621023

The safety and use of canarypox vectored vaccines. [Dev Biol Stand. 1995]
PMID:7796950

Immunization of colorectal carcinoma patients with a recombinant canarypox virus
expressing the tumor antigen Ep-CAM/KSA (ALVAC-KSA) and granulocyte macrophage
colony- stimulating factor induced a tumor-specific cellular immune response.
[Clin Cancer Res. 2003] PMID:12855617

Recombinant nipah virus vaccines protect pigs against challenge. [J Virol. 2006]
PMID:16873250

Safety profile of recombinant canarypox HIV vaccines. [Vaccine. 2004]
PMID:14741163