Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Status, challenges and regulatory framework for the development and registration of virus vectored vaccines in Europe

Dr. Francois-Xavier Orveillon (Abschlußjahr: 2016)

Summary
Language: English
Vaccines have considerably contributed to human and animal health. However, regardless of the remarkable success achieved in the past years, traditional approach of inactivated or live-attenuated vaccine immunization did not succeed in the reduction and control of certain infectious disease outbreaks such as HIV, dengue virus, Ebola virus and malaria. Also, improvement for vaccines such as tuberculosis and influenza virus is needed. For these infectious diseases and others, new approaches are currently being investigated. For instance, vector delivery technologies offer promising new strategies for vaccinations. These vectors are either non-pathogenic or attenuated, and they are engineered to carry and express genes encoding antigens of different pathogens. Vectored vaccines are promising as they can effectively induce both humoral and cellular immune response, while ensuring a strong safety profile. These advantages have driven an explosion of vectored viral vaccine development. The potential benefits for global health that are offered by this field are probably underestimated.
This master thesis will discuss selected viral vector systems and provides an overview of their specific characteristics, strengths, and limitations. Many viral vectored vaccines are currently in research phase, undergoing preclinical to clinical evaluation or even already granted a marketing authorisation. In this paper the development status of different viral vector systems and the targeted infectious diseases will be reviewed. Recombinant Adeno- and Poxvirus seem to be the most advanced platforms, although other vectors such as Flavivirus (e.g. yellow fever virus), Alphavirus (e.g. Venezuelan equine encephalitis virus) or Rhabdovirus (such as Vesicular stomatitis virus) may offer a good alternatives.
While only one viral vectored vaccine against infectious disease in humans has been licensed up to now (ChimeriVax-JE-a Japanese encephalitis vaccine based upon a yellow fever virus vector; licensed in Australia), several viral vectored vaccines have already been licensed in the veterinary field. Nonetheless, in the human field, some of the vaccine candidates under clinical evaluation against infectious diseases (such as HIV, malaria, dengue or tuberculosis for which effective vaccines are still lacking), could potentially reach the registration phase in the near future.
Selection of the best-suited vector is pivotal and requires focused in-depth knowledge of the vector and its performances as well as of the targeted pathogen against which protection is being sought. There is no single viral vector appropriate for all needs; rather, each of the vectors has its own advantages, limitations and range of applications.
The additional requirements to ensure the quality, safety and efficacy of viral vectored vaccines (GMO-containing medicinal product) as well as the regulatory pathways to proceed to clinical trials and obtain the marketing authorization (MA) in Europe will be detailed. To obtain MA, or a permit for a clinical trial, the environmental risk assessment (ERA) is a key document for critical safety evaluation which has to be performed, to identify the potential risks for public health and the environment that may arise due to the use and release of the GMO.
Finally, the major hurdles from an industry, authority and public point of view will be reviewed. Availability of correlates of protection, suitability of the animal model, antigenic variation of the targeted pathogen account for the main challenges faced by the developers. However pre-existing immunity to the vector before vaccination or development of vector-specific immunity upon repeated vaccination remain the major obstacle. In order to overcome anti-vector immunity and aid effective boosting of immune memory, careful consideration must be given to determine prime-boost schemes, epitope-capsid incorporation (monovalent versus polyvalent), transgene selection (homologous versus heterologous), vector dosing, and serotype selection. With regard to the regulators, expectations in terms of safety data package and data interpretation according to the vector categories probably need to be more detailed. Also the policy-makers and pharmaceutical industry should be prepared to communicate the risks and benefits of the genetically modified medicine/vaccines to general public in order to foster public acceptance of this new approach of vaccination.
The hope remains, that thanks to these technologies, more diseases will be combatted in the 21st century by novel preventative vaccines.
Pages:84