Publication in the Biotechnology magazine

“Early phase clinical trials of vaccines - challenges in the face of new threats”

Protective vaccination undeniably belong to one of the most ground-breaking discoveries of modern medicine. According to the World Health Organization (WHO), they save lives from two up to three million people a year. Immunization is acquired through contact with a disease causing agent, while vaccinations immunize against infectious diseases and prevent the spread of these diseases, without the need for contact with a dangerous pathogen. As a result vaccinations being widespread in the population, collective immunity is created, which further protects people, in whom vaccination is contraindicated.

Vaccinations have succeeded in diminishing the dangers of infectious diseases common in the past, but now the world must face new challenges. In the face of recent events, the global epidemiological threat caused by the spread of SARS-CoV-19 coronavirus has triggered changes in the functioning of entire societies. As much as social isolation is highly appropriate and justified and prevents further infections, it does not give a chance to naturally acquire resistance to a new virus due to lack of contact with the pathogen. At the same time, given the unpredictability and lack of sufficient data on the new virus and disease caused by it, "natural" acquisition of immunity does not seem a sensible solution.


A chance to control a difficult situation and return to normality is developing the vaccine against COVID-19, which would enable the immunization of society against this disease. Researchers around the world are developing various concepts for a potential vaccine and are conducting intensive preclinical studies, some of which have already entered the first phase of human studies. Various mechanisms of action are being used, including technologies of replication-defective adenovirus vector, plasmid DNA, RNA, yet others are based on attenuated or inactivated virus particles. Each of these concepts has its pros and cons, and the greater diversity in research, the greater the chances of getting an effective product.

A chance to control a difficult situation and return to normality is developing the vaccine against COVID-19, which would enable the immunization of society against this disease. Researchers around the world are developing various concepts for a potential vaccine and are conducting intensive preclinical studies, some of which have already entered the first phase of human studies. Various mechanisms of action are being used, including technologies of replication-defective adenovirus vector, plasmid DNA, RNA, yet others are based on attenuated or inactivated virus particles. Each of these concepts has its pros and cons, and the greater the diversity in research, the greater the chances of getting an effective product.

WHO RECOMMENDATIONS (TRS 1004, 2017, Annex 9 Guidelines on clinical evaluation of vaccines: regulatory expectations) - A FEW MAIN ASSUMPTIONS

The World Health Organization as the main goal of the clinical development program before authorisation determines the collection of relevant data proving the legitimacy of authorisation of the new product and its proper use. The essential elements of a clinical vaccine study are:

  • Description of the interaction between the vaccine and the host's immune response
  • defining a safe and effective dosing schedule
  • estimating the effectiveness of the vaccine by directly measuring the effectiveness and / or
  • providing evidence of the effectiveness of the response based on vaccine immunological properties
  • describing the safety profile
  • assessment of co-administration with other vaccines, if relevant.

GUIDELINES OF THE EUROPEAN MEDICINES AGENCY (EMEA / CHMP / VWP / 164653/2005)

EMA defines early phase studies as intended to ensure comprehensive delivery information on the safety and immunogenicity of antigens in potential a vaccine against a selected population to determine the pattern of immunization, and optimal dose for later testing. Pharmacodynamic studies mainly focus on vaccine studies determining immunogenicity. Pharmacokinetic studies are not required in this case, apart from situations when new auxiliary or supportive substances with unknown pharmacokinetic profile or new distribution systems are used. Immunogenicity means the ability to trigger a measurable immune response. The study protocol shall specify the biological fluids to be collected for the purpose of determining the immune response and well-defined time points for those samplings with appropriate rationale. Accurate methodology characteristics are required to identify the immune response to a given vaccine. This methodology should be consistent, validated and repeatable. Information must be provided on the quantitative and qualitative type of immune response (humoral, cellular) relative to the predictable properties that characterize a given antigen. The potential impact on the response should also be considered in the study documentation immune vaccines of various factors e.g. age, nutritional status, coexisting disease, immunosuppression and previous exposure to an infectious agent.

ACCELERATION OF PROCEDURES - Communication of 4 May 2020 EMA / 231636/2020

In the exceptional circumstances in which we have found ourselves recently, European Medicines Agency provides priority for research of new treatment and prevention therapies of COVID-19 and provides an accelerated procedure for giving opinions on clinical trial protocols that are critical to the current epidemiological situation. It enables acceleration of each stage in the approval process for the product to be authorized, while providing reliable evidence and scientific studies on effectiveness, safety and quality, justifying regulatory decisions.

REQUIREMENTS FOR CLINICAL SITES

Early phase vaccine studies differ in their specifics from traditional studies drugs. In the case of first administration in humans (First in Human studies - FIH) similarly as in drug research, hospitalization is usually required, but not such frequent blood sampling is required for pharmacokinetic studies (even every few minutes in research of new medicines). To keep in mind is that the first administration in humans always carry the risk of anaphylactic shock, so it is extremely important of the administration to take place in the intensive care unit, and the center to provide appropriate procedures and equipment used in life-saving situations. In addition, what should be taken into account is that as a result of administration of a new vaccine with an unknown safety profile and efficacy, a full-blown disease may develop. It is therefore justified that the center should cooperate with researchers specializing in infectious diseases and immunology. In the later phases, it is rarely required that the participant, except for several hours of observation after administration, has to stay at the center for a longer hospitalization. Further follow-up visits may take place on an outpatient basis. In the face of a pandemic, extremely important are internal procedures to ensure protection for both the study staff and study participants. Visits include a number of procedures such as physical examination, collection of blood samples, vital signs and any other tests provided in the study protocol. Properly validated and systematically controlled equipment is necessary for all procedures are the basis for correctly carried measurements. Blood and urine samples must be properly stored, processed and secured until picked up by the contracted transporting company to local or central laboratory. 

An undoubted advantage is the certification of the center in regard to compliance of internal procedures with GCLP rules, which is a guarantee of proper handling of samples in the study. Vaccines as an investigational product require special storage conditions in the appropriate temperature (often between 2 and 8 ° C) and under proper supervision. It is extremely important to guarantee continuous monitoring of storage temperature and strictly specific procedures must be followed in the event of any discrepancies. Procedures should ensure constant control over the product at every stage of the study. Depending on the technological process in the vaccine manufacturing process, it has various forms, including those that require preparation immediately before giving to the participant. In this case, the center must provide preparation conditions GMP compliant to guarantee the quality of the product.

SUMMARY

Today's clinical studies differ significantly from those in the past, both in level of advancement of technological and manufacture process of the vaccine, as well as in the scientific development of essential assumptions and procedures for such studies.


Despite significant progress in the world of science, the first applications invariably pose a risk to participants, especially in the case of a new virus. Research process for the new vaccine is long and complex. Clinical research centres around the world must be ready to take up the challenge and to conduct clinical phases at the highest level, ensuring the reliability and accuracy of conducted research and obtained data, which in turn are the basis for product authorization on the market. Above all, safety of study participants and protection against infection remains the highest priority.

Elwira Szewczyk
Pharmacist/Study Coordinator Assistant
BioResearch Group Sp. z o. o.

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