The COVID-19 pandemic has put drug developers in tough conditions. Instead of the usual five to seven years that are needed for the creation of a medicine, it was necessary to prepare the vaccine for manufacturing in several months. Vladimir Gushchin, the Head of the Reference Center for Coronavirus Infection and the Laboratory of Mechanisms of Population Variability of Pathogenic Microorganisms of the FSBI Gamaleya National Research Center of Epidemiology and Microbiology of the Ministry of Health of Russia, told GxP News what had helped the institute cope with this task.
Preclinical studies
An effective response to the COVID-19 pandemic in the absence of etiotropic therapy is primarily based on the accelerated development and introduction of prevention products. In the context of the pandemic, only effective prevention can protect the health of citizens and pull the economy out of recession. Moreover, vaccination has historically been the most cost-effective way to combat infectious diseases. We worked out a scheme that allowed us to reduce the time from the development of a candidate vaccine against COVID-19 to its introduction to six months, which was followed by testing on tens of thousands of volunteers with convincing data on its efficacy in less than 12 months from the start of the cycle. This approach is universal and can be used in other pandemics caused by zoonotic viruses.
The stage of creating a prototype and its experimental testing was reduced from a year to a month and a half. And from the beginning of February to the middle of March 2020, it was shown that the created prototype vaccine has immunogenicity and leads to the production of the necessary antibodies to the S-protein. The production of experimental industrial series of the prototype vaccine was launched in parallel without confirmation of immunogenicity in animals. By the middle of March, 2020, batches were received that made it possible to start preclinical studies. At this stage, the key limitation was the lack of infectious models for researchers to test the efficacy of the product, so joint efforts were made with the Ministry of Health, and this made it possible to obtain a strain in the last decade of March and start modeling infection on immunosuppressed Syrian hamster model.
The further scope of preclinical studies was carried out in less than three months, and in early June a dossier was formed to obtain permission for conducting phase I–II clinical trials. As a result of the examination of the dossier by the Ministry of Health, trials with 76 volunteers started, and the tests ended in two months. When making the decision, we took into account the experience of creating adenoviral-based vaccines that were being developed at the time by the Gamaleya Center and other research centers of the world. Despite the transition to the clinical phase of research, animal experiments continued in order to further recheck the results obtained, increase the volume of data and expand the number of infectious models to obtain more convincing results.
An intensive plan implies parallel performance of tasks in all directions of development. The classic plan for creating medicinal products is much more linear and step-wise, it protects developers from excessive spending, allows them to work in many directions simultaneously, requires less manual control, makes it possible to apply competitive principles in the determination of partner organizations, and involves a relatively small number of sponsors. It is obvious that the standard plan is completely unsuitable for the introduction of a vaccine during a pandemic.
The plan for the development of Sputnik V vaccine assumed a radical acceleration of research and development, while keeping risks at a reasonable level. The best research groups of the Gamaleya Center joined the development process. All tasks were divided into blocks that included the development of the vaccine, the development of the product for preclinical and clinical studies, the isolation of the virus and the creation of an infectious model, conducting safety assessment experiments, working out immunogenicity assessment protocols, creating analytical systems such as RT PCR and ELISA, evaluating efficacy in animal models, preparing and launching a clinical research protocol, communication with external stakeholders. 70 researchers from the Gamaleya Center and dozens of specialists from other organizations took part in this work.
The main difference between the development of the Gam-COVID-Vac (Sputnik V) and a standard preclinical phase was the need to reduce the time of the research, which was due to the pandemic context. The availability of an adenovirus platform helped accelerate the development and trial of the vaccine, it made it possible to obtain a product that is highly efficient, safe, affordable and does not require extreme cold chain characteristics. For the most pronounced and long-lasting protective effect, we chose a two-component prime-boost scheme.
Clinical trials
Normally, phase I–II clinical trials for preventive products take a year, provided there are no problems with recruiting volunteers, and phase III takes from one to three years. In the case of Gam-COVID-Vac, phase I–II trials were carried out in two months. The third phase of the study was planned to be conducted within a year, but convincing quantitative data on efficacy and safety were obtained as part of the preliminary registration in the first three months of the study.
The acceleration was facilitated by the priority consideration of documents during the examination by the Ministry of Health, the possibility of concluding contracts with clinical centers, CRO and other organizations without bidding procedures, and the ease of recruiting volunteers in the context of the pandemic, since people were motivated by the opportunity to be the first to receive the vaccine that protects against infection.
The factors that are also worth mentioning include the participation of the Gamaleya Center clinical trial team, its interaction with developers and researchers, the readiness of the product at a time when preclinical trials had not yet been completed, as well as extensive experience in conducting close studies, including for adenovirus-based vaccines.
Phase III was complicated by the start of civil vaccination and the fact that the participants could easily unblind their status due to the availability of tests that showed whether a person received a vaccine or a placebo. However, the pandemic revealed a significantly higher number of cases in the placebo group compared to the group that received the vaccine.
The amount of data on the safety of the vaccine was not reduced. On the contrary, more information was collected during the study, including through the use of applications (Self-Observation Diary) introduced by the Ministry of Health and allowing the patient participating in the study to submit information about their condition.