The development of a new vaccine is a long and complex process. Each vaccine formulation must successfully pass the successive stages of research in the laboratory, preclinical studies on animals and clinical trials on humans.
COVID-19 vaccine
Research on a vaccine against COVID-19 began as soon as the genetic sequence of the SARS-CoV-2 coronavirus was published (11.01.2020). The humanitarian and economic impact of the COVID-19 pandemic was a great motivation for the researchers to work, so that the first vaccine prototypes, were ready to start human clinical trials as early as mid-March 2020.
There are 3 types of vaccine formulations in advanced clinical trials that, if positively evaluated by the registration office, could be used in the vaccination program against COVID-19: mRNA, vector and subunit vaccines.
To date, two mRNA vaccines (from BioNTech/Pfizer and Moderna) and one vector vaccine (from AstraZeneca) have been approved for marketing in European Union countries. These vaccines protect against COVID-19 symptoms caused by SARS-CoV-2 coronavirus. Vaccination involves the administration of 2 doses intramuscularly.
Protection appears 7 to 14 days after the second dose of the vaccine. Large clinical trials have confirmed the high efficacy of the vaccines in protecting against COVID-19 outbreaks. The trials also included people with concomitant diseases.
On March 11, 2021. The European Medicines Agency (EMA) issued a positive opinion on the vaccine from Janssen Pharmaceutica, part of Johnson & Johnson. The product has been approved for use in European Union countries.
Efficacy and side effects
Following the administration of the vaccines (both mRNA and vector), adverse reactions may occur in the form of pain at the injection site, fatigue, headache, muscle pain and chills, joint pain, fever and swelling at the injection site.
Below are excerpts from studies on vaccine efficacy and safety.
COMIRNATY vaccine (from BioNTech and Pfizer) – safety and efficacy studies.
The safety of COMIRNATY was evaluated in subjects 16 years of age and older in 2 clinical trials involving approximately 21,744 participants who received at least one dose of COMIRNATY.
In Study 2, a total of 21,720 participants aged 16 years or older received at least 1 dose of COMIRNATY and a total of 21,728 participants aged 16 years or older received placebo (including 138 and 145 adolescents aged 16 and 17 years in the vaccine and placebo groups, respectively). A total of 20,519 participants aged 16 or older received 2 doses of COMIRNATY.
At the time of the analysis of Study 2, a total of 19,067 (9,531 COMIRNATY and 9,536 placebo) participants aged 16 years or older underwent a safety evaluation for at least 2 months after the second dose of COMIRNATY. This included a total of 10,727 (5,350 COMIRNATY and 5,377 placebo) participants aged 16 to 55 years and a total of 8,340 (4,181 COMIRNATY and 4,159 placebo) participants aged 56 years and older.
The most common adverse reactions in participants aged 16 years or older were:
- injection site pain (>80%),
- fatigue (>60%),
- headache (>50%),
- muscle pain and chills (>30%),
- joint pain (>20%),
- fever and swelling at the injection site (>10%).
These actions were usually mild to moderate in severity and resolved within a few days of vaccine administration. A slightly lower incidence of reactogenicity events was associated with more advanced age.
Moderna’s vaccine – safety studies
The safety of COVID-19 Vaccine Moderna was evaluated in an ongoing, randomized, placebo-controlled, observer-blinded Phase 3 study conducted in the United States, which included 30,351 participants aged 18 years or older who received at least one dose of COVID-19 Vaccine Moderna (n=15,185) or placebo (n=15,166) (NCT04470427). The mean age of the population at the time of vaccination was 52 years (range 18 to 95); 22,831 (75.2%) participants were aged 18 to 64, and 7520 (24.8%) participants were aged 65 or older.
The most commonly reported adverse reactions were:
- pain at the injection site (92%),
- fatigue (70%),
- headache (64.7%),
- muscle pain (61.5%),
- joint pain (46.4%),
- chills (45.4%),
- nausea/vomiting (23%),
- swelling/tenderness in the armpit (19.8%),
- fever (15.5%),
- swelling at the injection site (14.7%),
- redness (10%).
Most of these local and systemic adverse reactions were mild to moderate in severity and resolved within a few days after vaccination. A slightly lower incidence of reactogenicity events was associated with older age of participants.
Overall, some adverse reactions were more common in younger age groups: the incidence of armpit swelling/tenderness, fatigue, headache, myalgia, arthralgia, chills, nausea/vomiting and fever was higher in adults aged 18 to 65 years than in those aged 65 years and older. Local and systemic side effects were reported more frequently with Dose 2 than with Dose 1.
Astra-Zeneca’s vaccine (new name Vaxzevria) – summary of safety profile.
The overall safety of AstraZeneca’s COVID-19 Vaccine is based on an interim analysis of pooled data obtained from four clinical trials conducted in the UK, Brazil and South Africa. At the time of analysis, 23,745 participants aged ≥18 years were randomized to receive AstraZeneca’s COVID-19 Vaccine or were included in the control group. Of these, 12,021 participants received at least one dose of AstraZeneca’s COVID-19 Vaccine and 8,266 participants received two doses. The median follow-up time was 62 days after the second dose.
The most commonly reported adverse reactions were
- tenderness at the injection site (63.7%),
- pain at the injection site (54.2%),
- headache (52.6%),
- fatigue (53.1%),
- muscle pain (44.0%),
- malaise (44.2%),
- Fever (including feeling feverish (33.6%) and fever >38oC (7.9%)),
- chills (31.9%),
- joint pain (26.4%),
- nausea (21.9%).
Most of these side effects were mild to moderate in severity and usually passed within a few days of receiving the vaccine. Compared to the first dose, adverse reactions reported after the second dose were milder and reported with lower frequency.
Reactogenicity was generally milder and was reported less frequently in the elderly (aged ≥65 years).
The safety profile at the start of the study was consistent among participants previously manifesting symptoms of SARS-CoV-2 infection as well as participants without such symptoms; the number of seropositive participants at the start of the study was 718 (3.0%).
Johnson & Johnson Company’s vaccine – summary of safety profile.
The safety of Janssen’s COVID-19 Vaccine was evaluated in an ongoing Phase 3 study (COV3001). A total of 21,895 adults aged 18 years and older received the COVID-19 Vaccine Janssen vaccine. The median age of study participants was 52 years (range 18-100 years). Safety analysis was performed after a median follow-up time of 2 months after vaccination. A longer, >2-month safety follow-up is available for the 11,948 adults who received Janssen’s COVID-19 Vaccine.
In the COV3001 study, the most common local adverse reaction reported was injection site pain (48.6%).
The most common systemic adverse reactions were:
- headache (38.9%)
- fatigue (38.2%)
- muscle pain (33.2%)
- nausea (14.2%).
Fever (defined as body temperature ≥38.0°C) was observed in 9% of participants.
Most adverse reactions occurred within 1-2 days after vaccination and were mild to moderate in severity and of short duration (1-2 days).
Reactogenicity was generally milder and less frequently reported in elderly subjects (763 subjects aged ≥65 years).
The safety profile was consistent at the start of the study among participants manifesting prior symptoms of SARS-CoV-2 infection as well as participants without such symptoms; a total of 2,151 adults seropositive at the start of the study received Vaccine Janssen’s COVID-19 vaccine (9.8%).
How do mRNA vaccines work?
COVID-19 mRNA vaccines consist of an informative mRNA ribonucleic acid encoding the S (spike) protein of the SARS-CoV-2 virus encapsulated in a lipid nanoparticle capsule. The capsule has a protective function as well as a transport function to help it penetrate the cell by overcoming the cell membrane barrier. Based on the mRNA, the S (spike) protein SARS-CoV-2 is synthesized in the host cell, which, being a potent antigen, stimulates an immune response in the form of neutralizing antibodies (humoral response) and stimulation of T (cytotoxic) lymphocytes (cellular response).
Although mRNA vaccines have never before been used on a large scale in humans, the mRNA platform has already been used for many years in the development of vaccines, such as those against CMV, Zika, influenza, rabies, and malaria. The mRNA technology has also been successfully used in the development of cancer vaccines and therapeutic efforts.
mRNA is a synthetic vaccine. Its production does not require working with the virus. Only its genetic information is needed. And this is what marks a real revolution in the vaccine manufacturing process. We bypass working with the infectious agent (SARS-CoV-2 virus), we don’t need to inactivate it, attenuate it (weaken its virulence), which is the case in the production of classical vaccines. This greatly simplifies the entire vaccine production process. In classical vaccines, it was necessary to grow the virus in the laboratory, which required time and specialized control procedures.
The use of mRNA technology eliminates these challenges. The use of mRNA technology also allows for a significant reduction in the time required to produce a vaccine, which is of great importance in a situation such as a pandemic. For example, producing an influenza vaccine currently requires about six months; with an mRNA vaccine, a single batch of vaccine can be produced in as little as a week.
How do vector vaccines work?
Vector vaccines are based on special vectors – fragments of active viruses that have been modified to thereby induce an immune response against the SARS-CoV-2 virus. They do not contain coronavirus antigens. However, they are equipped with a weakened version of adenovirus (the cause of the common cold), which delivers the appropriate genetic code to human cells and stimulates them to produce SARS-CoV-2 proteins.
This resembles a natural infection, resulting in a strong immune response. Vector vaccines have been developed using a new technology that has so far been used in HIV and Ebola virus research, among others.
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