COVID-19 vaccine: Fingers crossed

Umar Bin Abdul Aziz

Globally, as of 22 November 2020, there are 57,882,183 confirmed cases of COVID-19, including 1,377,395 deaths, reported to WHO.
Vaccine research is at the forefront of everyone’s minds as we collectively await a breakthrough in the fight against coronavirus disease 2019 (COVID-19). On average, a vaccine takes between (12-36) months to (10-20) years for its manufacturing before it is ready for distribution. Today, researchers are working at unprecedented speed to cut this timeline down to within 12 and 18 months. Is this fast-track approach safe? Can we count on the efficacy of a vaccine that is developed this quickly?
We don’t know the answers to these questions yet. Even WHO says ‘There are many strict protections in place to help ensure that COVID-19 vaccines will be safe? Like all vaccines, COVID-19 vaccines should go through a rigorous, multi-stage testing process, including large (phase III) trials that involve tens of thousands of people.’
Successful manufacturing of high-quality vaccines requires international standardisation of starting materials, production and quality control testing, and the setting of high expectations for regulatory oversight of the entire manufacturing process from start to finish, all while recognising that this field is in constant change.
Many potential vaccines for COVID-19 are being studied, and several large clinical trials may report results later this year. If a vaccine is proven safe and effective, it must be approved by national regulators, manufactured to exacting standards, and distributed.
Keeping all these points in mind let’s take a step back and review the vaccine development process from beginning to end.

1. Exploratory Stage (2 – 4 years)
   The first step is the exploratory stage in which natural or synthetic antigens that may prevent or treat disease are identified in a laboratory setting. These antigens include live-attenuated viral components, inactivated viral components, recombinant (DNA), conjugate (combined weakened and strong antigens), subunit (no live component of viral particle), toxoid, and monoclonal antibodies. Gene-based vaccines use genetic engineering to carry nucleic acids (DNA or RNA) that hold instructions for making the viral protein which trigger an immune response.
2. Pre-Clinical Stage (1 – 2 years)
   Tissue-culture and animal testing are conducted next to evaluate the safety of the vaccine and its ability to elicit an immune response. During this stage, researchers:
   Assess the immune response that could occur in humans. Determine a starting dose for clinical trials. Improve the efficacy of candidate vaccines.
3. Investigational New Drug (IND) Application Stage
   Once the vaccine successfully completes the pre-clinical stage, an IND application is submitted by the research sponsor (typically a private company) to the Food and Drug Administration (FDA). The application will include:
   Description of the vaccine, Manufacturing and testing methods, Quality control tests for release, Summary of the laboratory reports, Description of the proposed study protocol, Information about the vaccine’s safety and Vaccine’s ability to elicit a protective immune response in animal testing.
   The FDA has 30 days to approve the application, then the vaccine moves on to human clinical trials. Prior to initiating these trials, the protocol must be reviewed by each research site’s institutional review board (IRB). The IRB is an independent committee that reviews and approves research involving human subjects, ensuring the protocol does not infringe on the rights and safety of the participants. Every clinical study protocol must include a detailed informed consent.
4. Clinical Development: Three Phases
   Phase-I Vaccine Trials (Several months)
   Phase-I human trials involve a small sample size, typically between 20 and 80 subjects. During this phase, researchers may know whether a vaccine or placebo has been given to a study subject. The primary goals are:
   Assess the safety of the vaccine
   Evaluate the extent of the immune response Phase-II Vaccine Trial (Several months to 2 years) Phase-II trials involve a larger sample size, usually several hundred study participants and often include the target demographic. These trials are randomized, controlled studies, typically dose-ranging, and include a placebo group. The primary goals are to further evaluate:
   Safety, immunogenicity and efficacy, proposed doses,schedule of immunisation, method of delivery.
   Phase-III Vaccine Trials (1 to 4 years)
   Phase-III trials are large studies involving thousands to tens of thousands of people. These are randomised, double-blinded studies that test the experimental vaccine against a placebo. Phase-III goals are:
   Assess vaccine safety in a large group of people, monitoring for rare side effects that may not appear in a smaller sample size
   Evaluate efficacy:
   Does the vaccine prevent disease?
   Does the vaccine prevent infection with the pathogen?
   Does the vaccine incite production of antibodies or other types of immune responses related to the pathogen?
5. Approval and Licensure
   Positive results from Phase-III, the vaccine researchers will submit a Biologics License Application (BLA) to the FDA’s Center for Biologics Evaluation and Research (CBER). This includes the efficacy and safety information needed to make a risk/benefit assessment. During this phase, the FDA will inspect the factory, where the vaccine will be manufactured and approve the vaccine label. Product labeling is extremely important as it provides clinicians with accurate information on the vaccine’s proper use as well as the benefits and risks that must be communicated to patients and family members.
   After licensure, the FDA will monitor vaccine production, periodically inspect facilities, and review the manufacturer’s tests for strength, safety and purity. Manufacturers may also be required to submit samples of each vaccine lot to the FDA for testing. FDA monitoring will continue as long as the manufacturer holds a license for the vaccine product.
6. Post-Licensure Monitoring of Vaccines
   Phase-IV trials
   Until a vaccine is administered to the general population, every potential adverse event can’t be anticipated. Phase-IV studies are optional trials conducted after the vaccine is on the market and include testing for safety, efficacy, and other possible uses.
   Operation Warp Speed
   Operation Warp Speed founded on 15 may 2020 is a public-private partnership, initiated by the U.S. Government to facilitate and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics and diagnostics. Their goal is to bring 300 million doses of a safe and effective vaccine to the general public by January 2021. In order to achieve this, OWS is providing Government support to the most promising vaccine candidates and steps in the traditional development timelines are occurring simultaneously.
   Fourteen (14) potential vaccines have been selected from over 100 contenders currently in development. Leading the pack (as of November 5, 2020), are Moderna’s mRNA-1273 vaccine undergoing phase III trials and Pfizer and BioNTech’s BNT162b2 vaccine in a combined phase II-phase III trial. Both vaccines utilise messenger RNA (mRNA) to carry genetic material that codes for viral proteins to the cell. Once inside the cell, mRNA instructs the cell to make copies of that protein, stimulating the immune system to respond. These vaccines can be produced rapidly and efficiently.
   Many candidate vaccines will not make it through the rigorous clinical development process. Even if one vaccine completes these stages in record speed, our fight against COVID-19 remains an uphill battle. The coronavirus vaccine has to have an efficacy of at least 70% to prevent an epidemic and at least 80% to extinguish an epidemic without any other measures (i.e. physical distancing).
   A vaccine will certainly get us one step closer to normalcy but only if it is proven safe and effective and achieves widespread acceptance. It is a waiting game and like all good things, we must be patient. PfizerandBioNtech announced their vaccine candidate against COVID-19 has achieved success in its first interim analysis from their Phase-III study. Their vaccine was found to be more than 90% effective in preventing COVID-19 in study participants without evidence of prior SARS-CoV-2 infection. The interim analysis included 94 confirmed cases of COVID-19 participants from over 43,000 study subjects enrolled. No serious safety concerns have been observed. Pfizer and BioNtech will submit an application for Emergency Use Authorisation (EUA) to the FDA after they reach a required safety milestone. They must observe for adverse events for at least two months and that two-month mark will occur at the end of November. The clinical trial will continue through final analysis when 164 confirmed cases are evaluated.
   Moderna, Inc., announced that their COVID-19 vaccine mRNA-1273 was found to have an efficacy of 94.5%. The interim analysis was conducted by an independent NIH-appointed Data Safety Monitoring Board (DSMB) for their Phase III study. The first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group that statistically points to an estimated vaccine efficacy of 94.5%.