Influenza vaccine strains: Licensing perspectives

Abstract

Equine influenza is an acute contagious respiratory disease of horses worldwide caused by infection with equine influenza A virus. Current epidemiological surveillance suggests that equine influenza A virus strains of the H3N8 subtype (i.e. influenza A/equine 2 virus) are the major causative virus strains. It is known that antigenic drift occurs in the gene coding for the haemagglutinin protein of equine influenza A virus strains. This drift eventually leads to the circulation in the equine population of influenza virus strains that are antigenically heterologous to those used to produce the antigenic fraction of authorised equine influenza vaccines, thus compromising vaccine efficacy. An Expert Surveillance Panel, including representatives from the World Health Organization and the World Organisation for Animal Health (OIE) reference laboratories, annually review the epidemiological and virological information on equine influenza. Based on this review, the OIE Expert Surveillance Panel on Equine Influenza Vaccine Composition publishes, on an annual basis, recommendations on suitable viral strains to use in the manufacture of the antigenic fraction of equine influenza vaccines in order that they are protective against circulating equine influenza virus strains. On the basis of this annual review, it is expected that modifications to the equine influenza virus strains used to manufacture the antigenic fraction of authorised vaccines will be necessary on a regular basis. However, to date, no equine influenza vaccines authorised for use in the UK have been updated fully in line with the latest OIE recommendations and experience indicates that several years of development are required to establish new viral master seeds and generate the data needed to support a change to the respective Marketing Authorisations (MAs) to incorporate a new strain. In this article I will discuss the regulatory framework that applies to veterinary vaccines and the constraints that mean that addition or substitution of a vaccine strain is not a trivial task. In the EU it is illegal to market a veterinary medicinal product (VMP) unless an MA has been granted by the relevant competent authority. Veterinary medicinal products can either be authorised by a European centralised procedure managed by the European Medicines Agency, in accordance with Commission Regulation (EC) 726/2004 1, or nationally by individual member states, in accordance with Directive 2001/82/EC 2. In the case of centralised procedures, if approved the MA is issued by the European Commission and is valid throughout the EU. The Veterinary Medicines Directorate is responsible for authorisation of VMPs in the UK. There are also procedures for EU member states to mutually recognise products that are nationally authorised in other EU member states and also for coordinated assessment of new national applications. Irrespective of the authorisation route, the time allowed for regulatory authorities to assess applications for new products is specified in EU legislation as 210 days, although the total time from application to authorisation can be longer depending on the time taken for the applicant to respond to any requests for additional information. When a product is authorised, details of the approved indications, known adverse reactions and conditions of use are published in the Summary of Product Characteristics (SPC), which is used by the manufacturing authorisation holder as the basis for the information included on the labels and the product leaflet. The vaccination scheme described in the SPC is the one that has been supported by the data included in the application dossier and must be regarded as unique to the specific vaccine. Some equestrian organisations such as the British Horse Association and Fédération Equestre Internationale prescribe specific vaccination schedules for horses entering their competitions. If these schedules are not in line with the SPCs of the vaccines used, then they would have to be considered as off-label use, and therefore the responsibility of the prescribing veterinarian, because they are not supported by the data submitted by the MA holder. Irrespective of the route of authorisation, the basic data requirements for authorisation of vaccines against equine influenza are indicated in European Pharmacopoeia (Ph. Eur.) 3 monograph 0249 (Equine influenza vaccine [inactivated]). In addition to use of good quality ingredients this requires demonstration of safety for horses under the intended conditions of use and demonstration of protection against challenge for at least one of the strains included in the vaccine. To minimise the use of experimental animals, if one of the strains has been shown to protect against challenge then serological responses can be used to confirm the efficacy of other strains included in the vaccine. It is important to note that the only efficacy requirements of Ph. Eur. monograph 0249 are that ‘the claims for the product reflect the type of immunogenicity demonstrated (protection against challenge or antibody production)’ and that ‘the vaccine complies with the test if the vaccinated horses show no more than slight signs; the controls show characteristic signs. The average number of days on which virus is excreted and the respective virus titres are significantly lower in vaccinated horses than in control horses’. There is no absolute requirement for a specific percentage level of protection or a prevention of virus excretion. From a regulatory perspective, a decision to authorise a veterinary medicinal product is made on the basis of a positive benefit:risk assessment, which is based on the safety and efficacy information provided in the application dossier. A clinically relevant degree of efficacy and compliance with the Ph. Eur. monograph need to be demonstrated but it is important to recognise that authorised vaccines can only be expected to confer the level of efficacy indicated in the SPC, which is based on data submitted by the applicant. Shedding of influenza virus from vaccinated horses is often considered by clinicians as ‘vaccine breakdown’. However, none of the equine influenza vaccines currently authorised in the UK is claimed to prevent viral shedding, only to reduce viral shedding. In this sense, isolation of influenza virus from horses vaccinated according to the SPC does not necessarily imply a lack of efficacy in the terms of the authorisation. In the French outbreaks described in the report by Legrand and colleagues in the current issue, equine influenza was detected in both vaccinated and unvaccinated horses but the vaccinated horses had a lower prevalence of fever 4. Updating of influenza virus strains in authorised equine influenza vaccines requires a variation application. The procedures for variation applications through the centralised or mutual recognition routes are laid down in Commission Regulation (EC) 1234/2008 5. Although this regulation originally did not apply to products that are authorised only nationally, its scope is being extended to encompass nationally authorised products by Directive 2009/53/EC 6. Thus the procedures to vary veterinary vaccines authorised by any of the various routes are effectively harmonised within the EU. The regulation includes special provisions for variations concerning the replacement of a strain in a veterinary vaccine against equine influenza. The timeline for initial assessment of such an application is specified as 90 days and the overall time taken is typically 3–8 months depending on whether additional information is needed and how long it takes the applicant to provide that information. To facilitate the replacement or addition of strains to already authorised vaccines the Committee for Medicinal Products for Veterinary Use Immunologicals Working Party has recently developed a guideline on the data required to support such variations (Guideline on the Compliance of Authorised Equine Influenza Vaccines with OIE Requirements, EMA/CVMP/IWP/97961/2013 QDraft 7), which has been released for consultation. This guideline is intended to replace the previous Note for Guidance: (Harmonisation of Requirements for Equine Influenza Vaccines – Specific Requirements for Substitution or Addition of a Strain or Strains, EMEA/CVMP/112/98-FINAL 8), which did not allow for the type of changes that vaccine manufacturers need to make to their vaccines in order to comply with the latest OIE recommendations. It should be noted that regulatory authorities can only respond when companies apply to update the virus strains in their vaccines. Although they can recommend such changes, they have no power to compel vaccine manufacturers to update their vaccines when OIE recommendations change. How long it takes for such recommendations to be adopted therefore depends mainly on the time needed for vaccine manufacturers to generate the required supporting data. Although the OIE publishes recommendations for virus strains to be included in vaccines on an annual basis, regulatory authorities are unable to compel vaccine manufacturers to make changes to their products unless significant safety concerns have been identified. After authorisation, the performance of veterinary medicines in the field is monitored by pharmacovigilance. In the UK, reports of adverse reactions or suspected lack of efficacy are sent to the Veterinary Medicines Directorate and in the event of a significant number of reports of suspected lack of efficacy this would be discussed with the manufacturers. However, any decision to change the strains would be made by the company on commercial grounds. The strain recommendations made by the OIE are to provide for the closest match between vaccine strains and the strains circulating in the field. However, inclusion of different strains in the vaccine does not necessarily mean that the vaccine will not be efficacious because a degree of cross-protection can be expected. In this context it may be relevant that, in contrast to most human influenza vaccines, most equine influenza vaccine contain adjuvants to potentiate the immune response. It may therefore in practice only be necessary to actually change the vaccines when they are no longer efficacious. In consideration of the time needed to generate the data needed to support a change of strain, as an interim measure, in some cases vaccine manufacturers have chosen to demonstrate that their existing vaccine formulation provides protection against newer circulating strains. A variation application is still required to include such a claim in the SPC and on the labels for the product but since new quality and safety data are not required the overall time for this can be much reduced compared with strain substitution. The draft guideline EMA/CVMP/IWP/97961/2013 7 also gives guidance on the type of data that would be needed to support such a variation. It is suggested that, if a correlation between antibody titre and protection against the newly circulating strain has been demonstrated, then serological responses may be used to demonstrate efficacy, otherwise protection against challenge with the newly circulating strain will need to be demonstrated.