RESUMO
On 21 December 2020, the European Commission granted conditional marketing authorisation for the BNT162b2 COVID-19 vaccine 'Comirnaty', produced by Pfizer/BioNTech. This happened only twelve months after scientists first identified SARS-CoV-2. This stands in stark contrast with the usual ten years needed for vaccine development and approval. Many have suggested that the changes in required animal tests have sped up the development of Comirnaty and other vaccine candidates. However, few have provided an overview of the changes made and interviewed stakeholders on the potential of the pandemic's pressure to achieve a lasting impact. Our research question is: how have stakeholders, including regulatory agencies and pharmaceutical companies, dealt with requirements concerning in vivo animal models in the expedited approval of vaccine candidates such as 'Comirnaty'? We interviewed key stakeholders at the Dutch national and European levels (n = 11 individuals representing five stakeholder groups in eight interviews and two written statements) and analysed relevant publications, policy documents and other grey literature (n = 171 documents). Interviewees observed significant changes in regulatory procedures and requirements for the 'Comirnaty' vaccine compared to vaccine approval in non-pandemic circumstances. Specifically, the European Medicines Agency (EMA) actively promoted changes by using an accelerated assessment and rolling review procedure for fast conditional marketing authorisation, requiring a reduced number of animal studies and accepting more alternatives, allowing pre-clinical in vivo animal experiments to run in parallel with clinical trials and allowing re-use of historical data from earlier vaccine research. Pharmaceutical companies, in turn, actively anticipated these changes and contributed data from non-animal alternative sources for the development phase. After approval, they could also use in vitro methods only for all batch releases due to the thorough characterisation of the mRNA vaccine. Pharmaceutical companies were optimistic about future change because of societal concerns surrounding the use of animals, adding that, in their view, non-animal alternatives generally obtain faster, better, and cheaper results. Regulators we interviewed were more hesitant to permanently implement these changes as they feared backlash regarding safety issues and uncertainty surrounding adverse effects. Our analysis shows how the EMA shortened its approval timeline in times of crisis by reducing the number of requested animal studies and promoting alternative methods. It also highlights the readiness of pharmaceutical companies to contribute to these changes. More research is warranted to investigate these promising possibilities toward further replacement in science and regulations, contributing to faster vaccine development.
RESUMO
Neoadjuvant therapy is the cornerstone of modern rectal cancer treatment. Insights into the biology of tumor responses are essential for the successful implementation of organ-preserving strategies, as different treatments may lead to specific tumor responses. In this study, we aim to explore treatment-specific responses of the tumor microenvironment. Patients with locally advanced adenocarcinoma of the rectum who had received neo-adjuvant chemotherapy (CT), neo-adjuvant radiochemotherapy (RCT), neo-adjuvant radiotherapy with a long-interval (LRT) or short-interval (SRT) or no neoadjuvant therapy (NT) as control were included. Multiplex-immunofluorescence was performed to determine the presence of cytotoxic T-cells (T-cyt; CD3+CD8+), regulatory T-cells (T-reg; CD3+FOXP3+), T-helper cells (T-helper; CD3+CD8-FOXP3-), B cells (CD20+), dendritic cells (CD11c+) and tumor cells (panCK+). A total of 80 rectal cancer patients were included. Treatment groups were matched for gender, tumor location, response to therapy, and TNM stage. The pattern of response (shrinkage vs. fragmentation) was, however, different between treatment groups. Our analyses reveal that RCT-treated patients exhibited lower stromal T-helper, T-reg, and T-cyt cells compared to other treatment regimens. In conclusion, we demonstrated treatment-specific differences in the immune microenvironment landscape of rectal cancer patients. Understanding the underlying mechanisms of this landscape after a specific therapy will benefit future treatment decisions.