Fitting vaccine research into one year – Were animals used?
27.10.21
In the space of a year, the research community has delivered four COVID-19 vaccines, approved by the EMA, the EU regulatory authority for medicines. It represents an unparalleled, collaborative achievement, achieved in record time without ever compromising on safety. The speed of development raised a number of queries on whether animal testing was part of the process of COVID-19 vaccines research and development, and what are the implications for the use of animals in research in the future. We therefore decided to have a closer look.
During the research and development of new vaccines, the evaluation of quantity and quality of immune responses and the ability to efficiently translate the results of basic research into the clinic are critical to ensure that vaccines meet their therapeutic potential, this involves the use of in silico, in vitro methods and animal models. In this battle against time, scientists used the best available technologies and models to research and develop safe and efficient vaccines to be brought to the market. Data from patients was also used to accelerate research and to deliver therapeutic solutions. Exchanging information between research groups was also key to access rapidly to reliable scientific information about the disease and the virus.
While usually regulators require that the industry shows a product is safe in animals before it goes to clinical trials, for COVID-19 vaccines, regulators accepted that preclinical studies could be conducted in some cases in parallel to the first clinical studies to save time considering the urgent need for COVID-19 vaccines.
Our members supported the outcomes of the International Coalition of Medicines Regulatory Authorities (ICMRA) Global regulatory workshop on COVID-19 vaccine development (18 March 2020):
- For all SARS-CoV-2 vaccine candidates it is necessary to obtain data in animals and to characterise the immune response induced by a SARS-CoV-2 vaccine candidate.
- It is not required to demonstrate the efficacy of the SARS-CoV-2 vaccine candidate in animal challenge models prior to proceeding to FIH clinical trials (doing animal testing in parallel with human testing).
The data from animals were an important component in giving the vaccine manufacturers and regulators the evidence of safety needed to rapidly progress into larger human clinical trials[1]. Furthermore, the developmental and reproductive toxicity studies in animals also provided important preclinical information on the safety of testing the vaccine in people of reproductive age[2]. There have been a large number of publications giving clear indication on the different animal models (and in vitro) used in the development of the different COVID-19 vaccines. Numerous publications outline the animal species used which range from mice, rats, pigs, ferrets, hamsters, rabbits and non- human primates. The industry has been transparent in providing information on their preclinical studies through press releases[3],[4], publications including peer-reviewed[5],[6] and the publication of the vaccine regulatory authorisation decisions and public assessment reports by the different regulatory authorities [7],[8],[9],[10],[11],[12],[13],[14],[15].
Fitting vaccine research into one year – How was this possible
Still there is a lot of curiosity of how this could all take place in the course of only one year and here are some explanations we have identified[16][17],[18],[19]:
- Global focus on vaccines – At the time of writing this blog, there were 4 approved in EU, 184 in preclinical development stage and 103 in clinical trials[20]. Never before have so many laboratories, institutions been working at the same time to identify a vaccine against the same virus.
- Global sharing of the genetic sequencing of the RNA of the virus right at the start of the spread of the virus ensured a quick start.
- Many of the technologies used have been under development for many years (mRNA). It was therefore about adapting these technologies towards COVID-19 vaccine development. Furthermore, there had been years of extensive research on other Coronaviruses (SARS, MERS) which gave scientists a head start.
- Regulators accepted that preclinical studies could be conducted in some cases in parallel to the first clinical studies to save time considering the urgent need for COVID-19 vaccines.
- Huge sums of funding were made available globally towards vaccine development[21].
- Collaboration – Sharing practices and technologies, partnering on development has speed up the science and vaccine development. A stand out example in the EU is the Innovative Medicines Initiative[22].
- CRO and laboratories, including animal species, were prioritised for COVID-19 vaccine development and testing.
- Clinical phase: Clinical trials started without delay, research data was collected electronically, studies attracted huge numbers of volunteers and trials yielded rapid results.
3Rs in vaccine development and production
Medicine and vaccine developers are required to demonstrate that potential new medicines and vaccines are effective and safe in humans, and that potential side effects are identified before they get a license to produce and go to market. This process involves testing strategies which include in vitro and in silico models in the earlier stages, with animals being used in the later phase of preclinical development. For vaccines, the use of animals in previous research has led to successful vaccines for polio, several types of meningitis, typhus, whooping cough, smallpox, tetanus, measles, cholera, etc. However, in these modern times, advances in science are leading to fewer tests and experiments on animals, and to new ways to reduce the impact on animals. Medicines and vaccines developers continue to be involved in a number of initiatives, which affirm the key principles of the 3Rs (Replacing animal experiments wherever possible with alternatives; Reducing the number of animals used; and Refining experiments to minimise the impact on animals) or change the current research paradigm.
On general activities to improve animal welfare and 3Rs for scientific purposes, EFPIA publishes regular reports[23] on the many 3R and animal welfare initiatives (Podcast on the pharmaceutical sector). Furthermore, science, technology and research practice evolve every day and bring new tools to address scientific questions differently.
For vaccines, there is extensive ongoing work to decrease and, in some cases, remove the use of animals in both the research and development phases and the production phase.
Collaborations are key in driving forward the shift towards replacement. Bringing together experts and scientists in the field from different key players drives this change. For this reason, industry engages across different partnerships on focused topics. The European Partnership for Alternatives to Animals (EPAA) is one of these such partnerships. This is a unique voluntary collaboration between the European Commission and Industry stakeholders (companies and associations) to facilitate development, validation, acceptance & implementation of alternative approaches across 7 industry sectors (Animal Health, Chemicals, Cosmetics, Crop Protection, Fragrances, Pharma). Projects of relevance include focus on Clostridium septicum vaccine validation of alternatives to in-process control tests (tox/residual toxoid toxicity – MLD, and toxoid antigenicity - TCP) which has been ongoing since 2013 (and builds on from a previous EPAA Vaccines Consistency Approach project (2010-2015). The ultimate goal is the regulatory acceptance of the validated in vitro assays through their inclusion in the Ph. Eur. Monographs to achieve replacement of the current animal tests. Another EPAA project ongoing is that of the Human Rabies Vaccines focusing on Potency test replacement of in vivo rabies potency test by in vitro methods.
Vac2Vac[24] is an Innovative Medicines Initiative (IMI) project where the public and private sector consortium members are working on vaccine batch to vaccine batch comparison by consistency testing and they aim to develop and validate quality testing approaches for both human and veterinary vaccines using non-animal methods.
During the recent World Congress on Alternatives and Animal Use[25] which took place virtually, attended by 1300 participants, there were a number of very interesting presentations given on numerous on-going activities focusing towards moving away from animal research and testing for vaccines. These presentations included the IMI Vac2Vac project mentioned previously, and also specific company strategies working towards a full in vitro approach for certain vaccines, including DTaP (Diphtheria, Tetanus, Pertussis) potency testing, whereby the aim is to have the animal approach removed from regulatory requirements worldwide. Furthermore, strategies are also being implemented for meningitis, pyrogenicity and human rabies vaccines where the focus is again towards a complete animal free process. Great progress has been made across the board, whereas intermediate steps reduction and refinement processes have already been taken up.
In a recent webinar, EFPIA has teamed up with the Animal Free Safety Assessment Collaboration[26] (AFSA), in collaboration with the International Alliance of Biological Standardization (IABS) to organize a virtual workshop on “Accelerating Global Deletion of the Abnormal Toxicity Test - Planning common next steps”. The event aims at establishing a concrete way forward to the global deletion of the Abnormal Toxicity Test from regulatory requirements for human vaccines and biologicals.
In addition to the gradual replacement of animal testing methods by alternative methods and in anticipation for all the alternative methods to be made available, which may still take up to 20 years, Vaccines Europe in particular continues to call on Europe in compliance with 3R and the Official Control Authority Batch Release (OCABRs) for vaccine batch release to reduce or even eliminate redundant animal tests carried out by European Official Medicines Control Laboratory (OMCLs), in accordance with what the European OCABRs already authorised and recommended.
In addition, in accordance with the WHO guidelines recommending the development of control and release strategies based on an approach based on risk management (for the benefit of patients) and in a manner comparable to what is already in place in the United States and Canada, we have recommended "reliance" to see the extension of mutual recognition agreements with these countries to control and release of batches (in particular for in vivo methods) in order to prevent these tests on animals already performed redundantly by the authority of the exporting country, to be repeated for the third time by European OMCLs for vaccines from the US and Canada.
The overall plan is therefore to accelerate the development of analytical methods to replace animal testing, and in the meantime to support drastic reduction and repetition of redundant tests by the authorities to the bare minimum required to protect public health.
References
[1] BNT162b vaccines protect rhesus macaques from SARS-CoV-2 | Nature (openathens.net)
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163337/
[3] https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-data-preclinical-studies-mrna
[4] https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-publication-new-england-journal-medicine-non/
[5] https://www.nature.com/articles/s41577-020-0377-3
[6] https://www.news-medical.net/news/20210422/Preclinical-study-from-NIHModerna-Correlates-of-SARS-CoV-2-immunity-in-non-human-primates.aspx
[7] https://www.ema.europa.eu/documents/assessment-report/vaxzevria-previously-covid-19-vaccine-astrazeneca-epar-public-assessment-report_en.pdf
[8] https://www.ema.europa.eu/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf
[9] https://www.fda.gov/media/144416/download#page=46
[10] https://fda.report/media/144673/Moderna+COVID-19+Vaccine+review+memo.pdf#page=52
[11] https://www.fda.gov/media/146338/download#page=56
[12] https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19
[13] https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca
[14] https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna
[15]https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1003840/CMA_UKPAR_COVID_19_Vaccine_AstraZeneca_PAR_16.07.2021.pdf (p13)
[16] https://download.valuingvaccines.org.uk/?video=MAR_Safety_video_1_COVID_Dev_15.mp4
[17] Ten reasons we got Covid-19 vaccines so quickly without 'cutting corners' | Adam Finn | The Guardian
[18] https://www.sciencenews.org/article/covid-coronavirus-vaccine-development-speed
[19] https://www.nature.com/articles/d41586-020-03626-1
[20] https://www.vaccineseurope.eu/vaccine-industry-response-to-covid-19
[21] https://ec.europa.eu/info/research-and-innovation/research-area/health-research-and-innovation/coronavirus-research-and-innovation_en
[22] https://www.imi.europa.eu/news-events/press-releases/imi-announces-covid-projects-boosts-funding-pot-eur-72-million
[23] https://www.efpia.eu/media/412869/efpia-report-2019-putting-animal-welfare-principles-and-3rs-into-action_updated.pdf
[24] http://www.vac2vac.eu/
[25] https://www.wc11maastricht.org/
[26] https://www.efpia.eu/news-events/events/efpia-event/accelerating-global-deletion-of-the-abnormal-toxicity-test-planning-common-next-steps/
