|Year : 2021 | Volume
| Issue : 1 | Page : 1-3
The COVID-19 Vaccines: A magic bullet?
British Columbia Centre for Disease Control Public Health Laboratory; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
|Date of Submission||06-Dec-2020|
|Date of Acceptance||12-Dec-2020|
|Date of Web Publication||06-Jan-2021|
British Columbia Centre for Disease Control Public Health Laboratory, 655 West 12th Avenue, Vancouver, British Columbia, V5Z 4R4
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Morshed M. The COVID-19 Vaccines: A magic bullet?. J Nat Sci Med 2021;4:1-3
The United Kingdom Medicines and Healthcare Products Regulatory Agency granted temporary authorization for emergency use of Pfizer and BioNTech's messenger RNA (mRNA) vaccine (BNT162b2) against COVID-19 (https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-achieve-first-authorization-world). This is astoundingly good news in a year that sorely lacked it. It has been a painful 11 months since the SARS-CoV-2 virus causing COVID-19 was first observed in Wuhan, China, in the late December 2019, and the viral pandemic still dominates over combined global efforts to contain it, affecting nearly every aspect of our daily lives. Aside from prepandemic lives coming to standstills, the medical impact is barely comprehensible. According to Johns Hopkins University, as of December 3, 2020, over 1.5 million lives have been lost in the past 11 months; there have been 65.0 million positive cases and people have faced life-threatening experiences (https://coronavirus.jhu.edu/map.html). Many countries that had managed to control the spread of the virus to a tolerable degree are now experiencing a strong second wave concomitant, with easing restrictions by allowing businesses and educational institutions to open, striving for a “normal” life. Few of us have doubts that we will continue to lose many more of our loved ones; unfortunately, none of us know when this nightmare will end. Given that it has been almost a full year without definitive treatment plans, the announcement of a COVID-19 “dream vaccine” represents a precious ray of hope in a hopeless year for a return to normal life.
Vaccines have historically been produced either by adapting the virus to weaken or inactivate it or by using isolated components of virus. Both methods render the virus safe to induce an immune response without causing disease or spread. Current scientific advances allow vaccine makers to exploit the virus' genomic blue print and human biology; viral DNA or RNA can be transported via plasmid, lipid, or adenovirus envelope to deliver the vaccine. Conventionally, vaccine development takes on an average of 10–11 years, from the scientific bench to being administered to the public. This process comprises multiple steps:
- Exploratory stage: Basic research and a strategy on how to construct the vaccine may take 2–4 years
- Preclinical stage: Determining whether the vaccine candidate can mount sufficient immunity in mammalian cells grown in laboratory or in laboratory animals
- Investigational new drug (IND) application: Submission of applications by companies or designated institutes to the US Food and Drug Administration (FDA) for an IND and the start of a Phase 1 vaccine trial
- Phase 1 vaccine trials: Assessment, in a small cohort of 45–100 of adults (in the age group of 25–60 years) of the safety and immunogenicity of the candidate vaccine, which may include dose finding
- Phase 2 vaccine trials: Evaluation, in a larger group of participants (usually several hundred in an expanded age range up to 70 years) and in a randomized fashion, of the safety, immunogenicity, dosage and schedule of immunizations, and the method of delivery. Randomization means that half of the participants are given the real vaccine and the remaining half receives a placebo. Successful Phase 2 candidate vaccines move on to Phase 3 trials
- Phase 3 trials: Further testing of vaccine efficacy in thousands to tens of thousands of participants. It is possible at this stage for producers to apply for approval and license for marketing
- Phase 4 trials: Not practiced by all companies, this is a further collection of data on safety and efficacy after the product has gone to market, ensuring the vaccine goals are still met.
In the case of SARS-CoV-2 and the pressing need for a vaccine, these have been abridged using an enormous combined work force in an expeditious manner. Thanks to over 200 years of accumulated vaccine knowledge and technological advances, scientists have squeezed that time from years to months by combining many of those steps mentioned above as well as performing safety checks on a “as time passes” basis. One thing is certain: scientists, entrepreneurs, and companies have proven once again that “necessity is the mother of all inventions” in coming up with an effective vaccine less than 10 months into their vaccine development journey. To date, over 200 companies are racing to develop an effective vaccine against SARS-CoV-2; 48 candidate vaccines are currently in clinical evaluation, 11 of which either completed or about to complete Phase 3 evaluations. A handful of these Phase 3 candidates are expecting emergency use authorization (EUA) from the FDA and EU within a week or 2. A further 164 vaccine candidates are in preclinical evaluations. Moreover, in the same timeframe, scientists have also characterized a novel illness, sequenced a new viral genome and shared that genome sequence globally, developed diagnostics, produced treatment protocols, and established hundreds of clinical trials to determine the efficacy of drugs other than vaccines. This is an enormous success and scientists and companies deserve kudos not just for the amount of scientific output but also for the collaboration that engendered it.
The past few weeks was an exciting time as BioNTech/Pfizer, Moderna/NIAID and University of Oxford/AstroZenca all published press releases on their progress on a vaccine against SARS-CoV-2. For the Phase 1 studies, BioNTech/Pfizer enrolled 45 healthy participants, 18–55 years of age, in a randomized design. The study population consisted of healthy male and female participants with a mean age of 35.4 years (range, 19–54 years); 51.1% were male and 48.9% were female. Participants were given two doses 21 days apart. After the second dose, pain was reported by 83.3% (10 out of 12) and 100.0% of individuals who received 10 and 30 μg BNT162b1, respectively, and by 16.7% of individuals who received the placebo. All local reactions were mild or moderate in severity, except for one report of severe pain after the first dose of 100 μg BNT162b1. Moderna/NIAID's Phase 1 trial also enrolled 45 healthy adults, aged 18–55 years; participants received two vaccinations with mRNA-1273, 28 days apart. mRNA-1272 was also reported to induce anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified.
More recently, both BioNTech/Pfizer and Moderna/NIAID announced that their mRNA vaccines reached 95% efficacy in clinical trials of tens of thousands of people. Moderna's vaccine, mRNA-1272, relies on a novel technology that uses mRNA to code for a protein called the spike that studs the surface of the pathogen. Moderna announced the final results of its 30,000-person Phase 3 trial in a press release on November 16: Only 11 participants who received two doses of the vaccine developed COVID-19 symptoms after being infected with SARS-CoV-2, versus 185 symptomatic cases in a placebo group, representing an efficacy of 94.1%. Moderna's candidate had 100% efficacy against severe disease. There were zero such COVID-19 cases among those vaccinated, but 30 in the placebo group. The geometric mean of spike-specific antibody titers showed a rapid increase in all the participants. Seroconversion was observed after 15 days, and the median magnitude of antibody responses was similar to the magnitude in convalescent sera. However, the pseudovirus neutralizing activity was not high before the administration of the second dose, which indicates the requirement for a two-dose vaccination schedule. Furthermore, the serum neutralizing activity, a generally accepted functional biomarker of the in vivo humoral response against respiratory viruses, was not determined at the time of writing.
Pfizer and BioNTech's candidate BNT162b1 is a similar mRNA approach targeting the SARS-CoV-2 spike protein. Pfizer/BioNTech also reported excellent results on November 18, with an efficacy of 95%, in the final analysis of their 45,000-person Phase 3 trial performed at 150 sites in several countries (https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine).
In that study, which ended after 170 cases of COVID-19 were identified, only 10 severe cases occurred, and just one was in the vaccinated group. BNT162b1 induced high, dose-dependent neutralizing antibody titers along with the spike-binding IgG concentrations after the second dose. This was accompanied by robust CD4+ and CD8+ T-cell responses. The administration of the vaccine was accompanied by adverse symptoms such as fatigue, fever, chills, and muscle pains. All this good news is however tempered by issues of vaccine storage: Long-term storage of BNT162b1 needs to be at −80°C, which may pose a substantial obstacle to distribution and access in many parts of the world. Kaur and Gupta also report on the Phase 3 activities of other companies, most of them having positive outcome in regard to immunogenicity and safety.
Given what we know about the complexity of disease, no vaccine is a magic bullet but can be a part of an arsenal to tackle a highly transmissible disease like COVID-19. Despite the recent and imminent applications to the FDA and European Agency for EUA, many unanswered questions remain that needed to be addressed sooner rather than later. Topics such as the longevity of protection, long-term side effects, how to differentiate immune responses in naturally infected versus vaccinated individuals, potential for long-term autoimmunity, user-friendly storage, and frequency of booster vaccination are all discussion topics in the vaccine community. Furthermore, financial and political questions of equitable and timely distribution exist: Which country will receive their ordered doses first? How will each country handle immunization hesitance when even simple safety mask use has become a social and political stand-off? How will countries prioritize vaccine distribution among their residents? Will the Global Alliance for Vaccines and Immunizations, the remit of which is to procure vaccines for underdeveloped and developing countries, be able to raise the funds to secure enough doses for these areas in a timely manner? mRNA vaccines will be more expensive than inactivated or live attenuated vaccines. What will the vaccines actually cost? Given the cost, would any of developing countries be able to choose their vaccine?
Right now, there are many more questions than answers surrounding the COVID-19 vaccines. Hence, would this vaccine be a magic bullet? The simple answer is NO. As much as the recent positive news gives us reason to hope for a more normal future, we still need to adhere to public health guidance such as universal mask wearing, hand washing, as well as physical distancing, where possible.
| References|| |
Schmidt C. Genetic engineering could make a COVID-19 vaccine in months rather than years. Scientific American 2020;322:40-3. [Doi: 10.1038/scientificamerican0620-40].
Struck MM. Vaccine R&D success rates and development times. Nat Biotechnol 1996;14:591-3.
Heaton PM. The COVID-19 Vaccine-Development multiverse. N Engl J Med 2020;383:1986-8.
WHO. World Health Organization's Draft Landscape of COVID-19 Candidate Vaccines; 12 November, 2020. Available from: file:///C:/Users/morshedm/Downloads/novel-coronavirus-landscape-covid-19-(7)%20(1).pdf. [Last accessed on 2020 Dec 02].
Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al.
Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020;586:589-93.
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al.
An mRNA vaccine against SARS-CoV-2-Preliminary report. N Engl J Med 2020;383:1920-31.
Kaur SP, Gupta V. COVID-19 vaccine: A comprehensive status report. Virus Res 2020;288:198114.