adminFebruary 2021. Nearly 300 vaccine candidates have been under development since 2020 for the prevention of COVID-19 around the world. As of today, 20 vaccines are in phase III clinical trials, 6 are used for limited or emergency use, and 4 have been approved for full use. Here is a simple guide to understand the steps that lead to vaccine approval for use and its development strategies.
From lab bench to clinical testing: determination of vaccine safety and efficacy
In order to be recommended for use in the world population (including children) to prevent disease development and be officially commercialized, a vaccine has to meet safety (does it create adverse effects – generally a sign that the immune system has been activated – and what are they?) and efficacy (how does it protect from a pathogen?) standards. After the vaccine has shown to elicit an immune reaction in pre-clinical experiments (using cultured cells and animals), scientists test the safety and efficacy of the developed vaccine candidate through three different clinical phases in volunteers (I, II and III) (see also1).
Phase I
The vaccine is given to a small group of healthy volunteers, whereby the safety, tolerability and dosage are tested. Moreover, immune response is followed.
Phase II
The vaccine candidate is given to hundreds of volunteers with same characteristics such as gender and age. The safety and generated immune reaction are monitored. In this phase, different formulations, adequate amount of the medicine and its potential short-term side effects in the different volunteer groups are also studied.
Phase III
Eventually, the vaccine is tested in a group of thousands of people (typically more than 10’000) and its effects are compared with a placebo (a comparator product that is not the vaccine candidate) given to a second group of volunteers. In this phase, the clinical efficacy in disease prevention is thoroughly investigated and safety characteristics are followed in a heterogeneous population in a longer timeframe. It is important to know that the volunteers participating in the study and the scientists testing the vaccine do not know who receives what and are working in a blind-mode to avoid any misinterpretation of the data.
When the clinical trials come to an end, the obtained results are then submitted to regulatory and public health policy approvals. Importantly, after it has received recommendation for use and approved for commercialization, the medicine still goes through regular and continuous tests of safety and quality. Post-marketing surveillance (also called phase IV) is an important part of the clinical development process as it is performed by monitoring the safety of a pharmaceutical drug, including vaccine candidates or a medical device after it has been released on the market. Only due to a constant systematic market surveillance can manufacturers guarantee that the developed product provides the promised benefits to patients as well as the lack of any unrestrained risks.
Vaccine technologies applied for the development of COVID-19 vaccines
Over the past months, studies showing safety and efficacy of the most promising vaccine candidates have been published. In general, researchers all over the world target the surface Spike protein for the development of potential vaccines but several teams also use inactivated forms of the coronavirus to activate the immune systemHere are some of the key parameters of these candidates and the associated technological strategies to elicit an immune response against the coronavirus (see also Figure 1).
Figure 1. Key parameters of the COVID-19 vaccines already in use. Credits: Sanda Ljubicic
mRNA-based vaccines or genetic vaccines
The mRNA-based vaccines require the use of a messenger RNA that carries the genetical code for a specific protein and is transported generally in an envelope made of lipid-nanoparticle to allow the entry in the cells. For instance, in the case of COVID-19 vaccine, the cells are producing themselves the coronavirus viral proteins (typically the viral Spike protein) which will activate the immune system and prepare it to prevent a future potential coronavirus infection. This technology2, previously used for the development of vaccines for cancer immunotherapies and for the prevention of other infectious diseases such as the Zika virus, has been applied by the biotech company Moderna and the pharmaceutical leader Pfizer with the collaboration of its partner BioNTech to generate their COVID-19 vaccine candidates.
Moderna (Cambridge, United States)
Name Code: mRNA-1273 (or officially COVID-19 Moderna)
Target: Part of SARS-CoV-2 Spike sequence
Description: mRNA-1273 is an RNA encoding part of the spike protein and contained in a lipid-formulated envelop.
Mode of treatment: Given in 2 doses – 4 weeks apart
Phase III trials3 were performed on 30 000 US participants, including 7000 aged over 65 and 5000 under 65 with high-risk chronic diseases. There were 95 Covid-19 cases, of which 90 observed in the placebo group and 5 were reported in the vaccine group. There were 11 severe cases of Covid-19 reported, all of which occurred in the placebo group.
Overall Efficacy after second dose: 94.1%
Storage: 6 months -20°C. Once thawed, it can stay 30 days at +4°C
Pfizer and BioNtech (Germany and United States)
Name Code: BNT162b2 (or officially Cominarty)
Target: SARS-CoV-2 Spike protein
Description: BNT162b2 is a lipid nanoparticle-formulated RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.
Mode of treatment: Given in 2 doses – 3 weeks apart
Phase III clinical trials4 began in July and has so far enrolled nearly 44 000 participants, just under 39 000 of whom have received a second dose of the mRNA vaccine candidate. 94 cases of Covid-19 have been confirmed.
Overall Efficacy after second dose: 95%
Storage: 6 months -70°C. Once thawed, it can stay 30 days at +4°C
The side effects reported fort the mRNA-vaccines can be transient but sometimes elicit allergic reactions. Participants in clinical studies and already vaccinated people have reported the following vaccine-related discomforts: injection site pain, flu-like temporary effects (fever, muscle pain, chills, fatigue, nausea). Rarely, the mRNA-vaccines cause allergic reactions and anaphylaxis, which can be a life-threatening condition and can be removed by using adrenaline Epipen injections.
Adenovirus-based vaccines (or viral vectors vaccine)
The adenovirus-based vaccine contains a harmless mutated viral vector called adenovirus and engineered to transport and transfer the coronavirus genetic code into the cells of our body. This technology has been used by the companies AstraZeneca and Gamaleya to develop their candidates.
AstraZeneca-Oxford (United-Kingdom)
Name code: ChAdOx1 nCoV-19 vaccine (AZD1222)
Target: SARS-CoV-2 Spike protein
Description: The vaccine is made up of a DNA encoding the coronavirus Spike protein that is shuttled into cells in a harmless chimpanzee adenovector (ChAdOx).
Mode of treatment: 2 doses separated by either 4 or 12 weeks
Phase III clinical trials5 performed on 23 848 participants and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the primary efficacy analysis. 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.
Overall Efficacy after second dose: 70.4% as of the first results when second dose is given 4 week after the first and has just been reported to be 84.3% by giving the second dose 12 weeks after the first6.
Interesting facts: The vaccine has shown a strong immune response in older people. Even if the vaccine at a low dose has 61% of efficacy in fighting against asymptomatic infections, the question remains whether the standard dose of the vaccine used is capable of fighting asymptomatic infection.
Storage: 6 months -20°C. Once thawed, 30 days at +4°C
The list of side effects reported comprise injection site pain and flu-like temporary effects (fever, muscle pain, chills, fatigue and nausea).
Gamaleya (Moscow, Russia)
Name code: Gam-Covid-Vac (or officially Sputnik V)
Target: SARS-CoV-2 Spike protein
Description: The vaccine uses harmless adenoviral vectors to deliver the gene for the SARS-CoV-2 spike proteinThe vaccine is based on two human adenovirus vectors (Ad5 and Ad26).
Mode of treatment: Given in 2 doses – 3 weeks apart
Phase I and II trials were conducted on almost 80 adultsThe phase III includes 40’000 peopleAs of January 2021, 39 confirmed cases of COVID-19 infection in 18’794 volunteers receiving the Russian vaccine, seven days after they received the second dose7,8.
Overall efficacy after second dose as of January 2021: 91.4%
Storage: In dry form at 2-8 °C.
Here are the reported side effects: injection site redness, tenderness, flu-like temporary effects (fever, weakness and headache).
Inactivated or neutralised virus-based vaccines
This traditional methodology is based on the use of a chemically inactivated coronavirus to expose the body’s immune system to the viral particles, without inducing the development of a serious disease response.
Sinopharm (Bejing, China)
Name code: BBIBP-CorV
Description: the vaccine is an inactivated SARS-CoV-2 virus.
Mode of treatment: Given in 2 doses – 3 weeks apart
Phase I and Phase II included 192 adults and 448 adults respectivelyThe first clinical studies for the BBIBP-CorV vaccine showed that BBIBP-CorV is safe and well tolerated among vaccinated volunteers9Results from Phase III trials are still on going around the world (including Argentina, Peru, Morocco and United Emirates) and are performed among 60’000 individuals.
Overall efficacy after second dose as of January 2021: 79.34%
Storage: Stable at 2-8 °C
The side effects reported among participants include: injection site pain, swelling, rash, flu-like temporary effects (headache, fever, muscle/joint pain, cough)Rarely it causes symptoms such as chills, loss of taste, tremor, nose bleeding.
Sinovac Biotech (Hong Kong, China)
Name Code: CoronaVac
Description: The team used an inactivated SARS-CoV-2 virus to generate the vaccine.
Mode of treatment: Given in 2 doses – 2 weeks apart
Results of a complete Phase III Clinical Trial as of December 2020 are not yet available and are ongoing in Brazil, Turkey, Chile and IndonesiaPhase I and II trials were conducted on nearly 700 adults.
Efficacy of vaccine: variable among tested regions – Turkey reported an efficacy of 95%, while in Indonesia, the results showed 65.3 %In Brazil, the efficacy showed 50.3 % for those who showed very mild cases and 78% for mild to severe cases10.
Storage: Stable at 2-8 °C for up to three years
The side effects include injection site pain, flu-like temporary effects (fever, muscle pain, fatigue).
Some important facts
Can someone get the first dose of one vaccine type and the second with another type?
Both first and second vaccine doses should be performed with the same type. In addition, the period between first and second doses can be longer for one or two weeks than what has been proposed during clinical studies, as our immune system is strong enough to remember the antigen it was exposed to. For example, for the mRNA-vaccines, the second dose can be given up to six weeks after the first dose, if needed.
Should people who were infected with COVID-19 get vaccinated?
People who were infected with COVID-19 have in their blood antibodies against the viral proteins up to 3-4 months after infection. Studies show that after 6 months, 15% of the people who contracted COVID-19 still have significant levels of antibodies against the virus. However, it not clear if a first infection does not protect for a life-long period. Therefore, up to 3-4 months after the infection with the virus (or COVID-19 diagnosis), it is recommended to verify the levels of antibodies in a standard blood test before getting vaccinated.
What happens if a person gets COVID-19 after the first shot of the vaccine?
A person can be infected after receiving the first dose of COVID-19 vaccine. If this is the case, the person should wait and verify the levels of antibodies against the virus up to 3-4 months after the infection and get the second vaccine shot when they decline.
How long does the vaccine efficacy last and are there any long-term side effects?
As of today, data supporting the duration of the vaccine efficacy still don’t exist, as the phase III clinical trials to test the COVID-19 vaccines started less than a year agoFor this same reason, the long-term effects are not known yet.
Who should not get vaccinated?
The people who are allergic to one or several components of the vaccine, should consult their medical doctor first. For example, in the case of mRNA vaccines, people allergic to polysorbate (an emulsifying agent used in diverse pharmaceutical drug preparations) should get vaccinated with another COVID-19 vaccine type, where this agent is absent. The people who have a very serious allergic reaction (which translates into a reaction 4 hours within administration) to the first dose of the vaccine should not get the second dose. This is the case for one person in 100’000. There are no data supporting the safety and efficacy of the vaccine on pregnant or breastfeeding women, however, they can consult with their gynaecologist, as more and more specialists advise to get the vaccine in this specific group. In addition, there are no COVID-19 vaccines yet for children under 16 and no data supporting their negative or positive effects in this part of the population.
Do the vaccines protect against the virus new strains?
Several days ago, scientists announced that the Pfizer/BioNtech as well as the Moderna vaccines can protect from the emerging new SARS-CoV-2 coronavirus strains (UK and South African strains), the efficacy being however reducedThis is also the case for the Russian vaccine Sputnik, according to Russian scientists and the Chinese vaccinesIn the case of the AstraZeneca candidate, it is likely that it does not prevent from developing the South African COVID-19 strain, but as scientists underly, will probably prevent from a serious illness leading to hospitalization and a fatal outcome. However, further studies need to be performed, and a vaccination booster against the strains could be applied soon.
It is important to understand that because the viruses new mutations emerge during contamination from one person to the other and constant replication inside the cells, vaccinating people will reduce and prevent this process and stop the spread of the virus and its new strains.
Why was the process of vaccine development so fast?
There are several reasons for this. Firstly, the coronavirus family of viruses are not unknown to virologists, experts in this field (for a review, please refer to11). Indeed, they already got experienced working with lethal viruses such as SARS-CoV and MERS-CoV coronaviruses in early 2000 and 2012 respectively and have been already working on the development of potential vaccines. In addition, several companies, such as Moderna, have worked on a large portfolio of projects consisting in the development of mRNA-based vaccines for cancer immunotherapies as well the prevention of other infectious diseases, even before the COVID-19 pandemic. This technology has already been developed more than 20 years ago and other technologies using viral vectors-based vaccines or vaccines using inactivated viruses are more traditional. Finally, in the objective to slow down and eventually stop the present pandemic, scientific laboratories working on COVID-19 received a huge global financial support coming essentially from governments, which allowed the process of vaccines development to be significantly accelerated.
Consultation with the primary care physician is key before getting the vaccine.
The present article was written after a nice discussion with Dr. Jelena Bozilovic-Djurovic, who is a medicinal chemist and expert in the development of tests allowing the identification of viruses.
References:
- https://www.who.int/news-room/feature-stories/detail/how-are-vaccines-developed
- Reichmuth et al. (2016). mRNA vaccine delivery using lipid nanoparticles. Ther Deliv 7(5): 319–334.
- Baden et al. (2021). Efficacy and safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 384 (5) : 403-416
- Polack et al. (2020). Safety and Efficacy of the BTN162b2 mRNA COVID-19 vaccine. N Engl J Med 383 (27): 2603-2615
- Voysey et al. (2020). Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet S0140-6736(20)32661-1
- https://www.ema.europa.eu/en/documents/product-information/covid-19-vaccine-astrazeneca-product-information-approved-chmp-29-january-2021-pending-endorsement_en.pdf
- Logunov et al. (2020). Safety and immunogenecity of an rAd26 and rAd5 vector-based tereologous primer-boost COVID-19 vaccine in two formulations: two open, non-randomised phase ½ studies from Russia. The Lancet 396 (10255) : 887-897
- https://sputnikvaccine.com
- Zhang et al. (2020). Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis S1473-3099(20)30843-4
- Palacios et al. (2020). Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccines Manufactured by Sinovac – PROFISCOV: A structured summary of a study protocol for a randomised controlled-trial. Trials 21: 853.
- Vincent C. et al. (2007). Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clinical Microbiology Reviews: 660–694