Masterarbeit

Regulatory-conform development of mucosal vaccines with a focus on quality, nonclinical and clinical aspects

Dr. Marian Wiegand (2022)

Summary
Language: English
From a public health perspective, vaccines have an unparalleled track record in preventing disease and death. Most vaccines today are administered parenterally by injection and consist of inactivated or subunit compounds. A different class of vaccines represent mucosal vaccines, which are via the oral or intranasal route. In order to properly stimulate immunity mucosal vaccines often consist of live-attenuated strains of viruses, bacteria or parasites. This combination of mucosal administration and live-attenuated phenotype implicates many particularities with regard to regulatory requirements for the development of safe and effective vaccines of high quality.
In the present thesis the existing relevant regulatory guidance in the EU and the US that applies to mucosal vaccine development is described. Complementary and specific guidance is provided by the WHO. Dissecting the product development pathways, pre- and post-licensure, for two more recently approved oral and intranasal mucosal vaccines, clearly identifies key development aspects and challenges with regards to manufacturing and controls, nonclinical and clinical aspects. Consequences from these developments but also other historical examples have shaped the current regulatory demands. Key aspects to consider related to quality are

• the use of comprehensively qualified starting materials and of all other materials that come into contact with the product,
• genetic stability of the attenuation phenotype of a LAV,
• product stability during long-term storage, preferably at 2-8 °C with some stability at higher temperatures.

Key aspects for clinical safety and efficacy are

• shedding and transmission need to be analysed;
• efficacy has to be measured based on disease incidence - as and ICP often not exists; here, statistically relevant sizes of subgroups need to be considered;
• safety has to be demonstrated for all subgroups to be included.

Taking all this into account, including existing general guidance, results in the suggestion of a regulatory-conform developmental pathway related to quality, nonclinical and clinical development of mucosal vaccines.
Pages: 60