Vaccine Regulatory and Production Issues

To successfully introduce a new MAP vaccine into the market will require provision of clear and repeatable results from experiments demonstrating significant protection plus a validated manufacturing process capable of regulating a consistently safe and effective product.

National regulation authorities (NRAs) are responsible for control of these processes. Consultation with authorities to obtain recommendations that will guide how best to obtain marketing authorization is now required from very early design stages. NRAs, initially instigated to standardize methods in the light of tragic vaccine contamination incidents such as smallpox in 1901 (Lilienfeld, 2008), BCG in 1931 (Calmette, 1931) and polio in 1955 (Nathanson and Langmuir, 1995), exist in all developed countries, and some who are licensing vaccine products as a pre-qualification for sale to United Nations agencies (Saidu et al., 2013). The degree and complexity of regulations will differ depending on the type of vaccine to be used. All LAV or live attenuated vector subunit vaccines will be classified as a genetically modified organism (GMO), while most of the European Union (EU) Member States do not regulate DNA vaccines as a GMO as this is not considered an organism. Likewise, human cells transfected with plasmids are not GMOs, provided the plasmid is not replicative and is unlikely to integrate into the cell genome. Legislation in these areas is not globally uniform and international cooperation is hindered by significant complexities in the way regulations are interpreted and administered between countries due to diverse divisions in the responsible departments. In the EU, all GMO vaccine authorizations are granted through the European Commission, with applications scientifically evaluated by the European Medicines Agency (EMA). In the US GMO legislation is currently less defined and animal vaccines reside under the FDA and Center for Veterinary Medicine mantle; similarly in China, with the China Institute for Veterinary Drug Control.

While some improvements are being targeted (Crager, 2014) and fast-track mechanisms for getting vaccines where they are most needed are active for human diseases, animal vaccines are less well supported.

The current indication that live attenuated vaccine strains or replication-deficient delivery vectors may provide modes for improved vaccine efficacy has presented a new wave of applications for trials of GMOs in animals and humans. Concerns for the safe release of GMOs has prompted the need for NRAs to provide precise definitions of what constitutes a GMO while still allowing dynamic review. However, there is no universally accepted definition of a GMO. The EU defines a GMO as 'an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination' (EU Directive, 2001).

Controlled storage of master seed stocks of a stringently defined vaccine strain is mandatory in all countries to ensure consistent quality. Standard testing for strain purity and contamination that conforms to a country's good manufacturing practice (GMP) regulations is also required (Schmeer etal., 2017). In the EU, for example, GMP is required for the ‘active' antigen alone and for the finished vaccine product containing the ‘active' antigen in combination with delivery organisms and/or adjuvant preparations (Heldens et al., 2008).

Regular testing of manufactured vaccine batches is needed throughout the designated shelf life to determine the degree of safety, potency and efficacy to the target species from single, repeated and up to ten-fold overdoses. This includes a recommendation for an in vivo test to predict clinical efficacy and remove the need to regularly test vaccine batches on animals (EMeA, 2016). As discussed in this chapter the relationship between vaccine efficacy and in vitro attenuation testing parameters is still highly uncertain; thus, demonstrations of immunological activity as a measure of potency may be more practical.

Exceptionally, for some recombinant proteins and polysaccharide vaccines, physico-chemical testing that correlates well with biological effectiveness is an acceptable and preferred replacement under regulatory pathways for licensing vaccines aimed for developing countries (Milstien and Belgharbi, 2004). This may also be applicable to certain MAP subunit vaccines.

Many countries require vaccines that comprise or derive from live GMOs to have additional assessments, particularly with reference to virulence and biosafety. In the EU, for example, important factors include: zero transfer of genetic material from the vaccine into the host chromosome (EMeA, 2004); a minimum requirement to show genetic stability and an absence of reversion to virulence in a GMO during at least five consecutive passages within a designated test animal species (EMeA, 2007); no significant increase in capacity for survival or shedding over the parent wild-type organisms in either the environment or susceptible hosts; use of a registered adjuvant (EMeA, 2018); and an optimum route of administration, particularly relevant to orally administered vaccines.

The requirement for complete regulatory compliance has been escalated by the expectation of zero risk demanded from the public, and this has led to introduction of larger clinical trials and widening of the safety margins for GMO release. Many older registered vaccines would not be acceptable in the current regulatory climate. GMOs that contain antibiotic markers are now unacceptable (Leunda and Pauwels, 2019). This affects vaccines using plasmids expressing immunologically active agents delivered via bacterial vectors and requires that the majority of novel DNA constructs referred to in the works discussed above would need some heavy restructuring, and restabilizing. Resistance to heavy metals may be acceptable, provided that this phenotype does not confer a fitness advantage on the GMO (Favre and Viret, 2006). Of additional interest, however, and a point that is still not clearly defined in the law of some countries, is the status of the recipient of a GMO or DNA vaccine and whether the actual act of vaccination demands that the recipient be reclassified as a GMO in itself.

If agreed, this would certainly impact on animal importation regulations. As an additional control on GMO release, some countries have also introduced the concept of a ‘new organism'. New Zealand regards all organisms that were not present in the country immediately before 1998 or subsequently eradicated as ‘new' and thus subject to special conditional release application (SCNZ, 2003).

While none of the new generation of MAP vaccines has yet shown sufficient promise to warrant commercial development, these regulatory hurdles suggest that a long and involved process awaits.

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Source: Behr Marcel A., Stevenson K., Kapur V. (eds.). Paratuberculosis: Organism, Disease, Control. 2nd edition. — CAB International,2020. — 439 p.. 2020

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