As coronavirus continues to spread, researchers worldwide are searching for means to curb the disease. A vaccine would be the ideal weapon against the virus, but developing a vaccine is easier said than done. In reality, fewer than 10 percent of drug candidates that enter into clinical trials are ever approved by the US Food and Drug Administration (FDA). The majority of the candidates fail in one way or another—they are not effective, they don't perform better than existing drugs, or they have numerous side effects.
Human Vaccines: A Lengthy and Iterative Process
The development of a new vaccine is the result of a long process involving several stages, often lasting 10-15 years. In the US, the current system for developing, testing, and regulating vaccines involves the following key steps:
- Exploratory Stage
- Pre-clinical stage
- Clinical development
- Regulatory review and approval
- Quality control
The Transition from the Laboratory to Clinical Trials
Vaccine development begins with the exploratory and pre-clinical stages, which consist of laboratory and animal studies. The exploratory stage involves basic laboratory research and often lasts two to four years. In pre-clinical studies, which usually last one to years, tissue-culture or cell-culture systems and animal testing are used to assess the vaccine candidate's safety and immunogenicity.
The transition of a novel vaccine candidate from the exploratory and pre-clinical stage to clinical trials depends on the attainment of crucial animal toxicity data, which is essential to determine the safe starting dose and dose range for clinical trials with human subjects and to identify potential adverse effects relevant to humans. The vaccine's possible impact on public health and cost-effectiveness are also considered before it advances to the development stage.
Clinical Trials with Human Subjects
Before initiating clinical trials with human subjects, the sponsor submits an Investigational New Drug (IND) application to the FDA. The IND describes the vaccine, its method of manufacture, quality control tests for release, and information about the vaccine's safety and immunogenicity. The sponsor also describes the proposed clinical study. Once the IND application is approved, the vaccine is subject to pre-marketing (pre-licensure) vaccine clinical trials, which are typically done in three phases.
In phase I, safety, and immunogenicity studies are performed in a small number of closely monitored subjects. A promising phase I trial will progress to phase II, in which tests are conducted in several hundred volunteers. The goal of phase II testing is to study the vaccine candidate's safety, immunogenicity, proposed doses, schedule of immunizations, and delivery method. Phase III involves comparative studies in which the experimental vaccine is tested against a placebo. Phase III studies typically enrol thousands of subjects and provide critical documentation of effectiveness and important additional safety data required for vaccine licensing.
The successful completion of all three phases of clinical development is followed by the submission of a Biologics License Application (BLA) to the FDA. The FDA assesses the efficacy and safety data provided to evaluate the risk/benefit of the vaccines. Based on their evaluation, the FDA either recommends or disapproves the vaccine. Due to the complexities associated with manufacturing biological products such as vaccines, a pre-approval inspection of the manufacturing facility is also carried out before a BLA is approved.
Is It Possible to Condense the Vaccine Development Timeline?
The pandemic has highlighted the dire need for a vaccine or treatment against coronavirus. The long process of vaccine development has compelled researchers and regulatory authorities to explore ways to condense the usual development timeline with the hopes of presenting the world with a viable vaccine in short order.
Development of vaccines using a ‘plug and play' viral platform
Traditional vaccines involve injecting whole attenuated viruses, or their whole proteins, into human bodies. The traditional approach is time consuming, as the whole virus or its proteins must be grown and inactivated. Using a ‘plug and play' viral platform allows faster development of vaccines as it bypasses the laborious tasks of inactivating viruses or isolating proteins.
A vaccine platform is a system that uses certain basic components, required to develop a vaccine, as a backbone or framework. Vaccine platforms can be adapted to immunize against different pathogens by inserting new genetic or protein sequences. In a 'plug and play' viral platform, critical components of a new virus required to make the vaccine are determined by rapid computer analysis and plugged into the platform to generate a vaccine. Virus components may be snippets of viral mRNA or DNA, which are modified to ensure that they activate immune cells that are critical in producing immunological memory.
Combining clinical development phases is considered a viable strategy to shorten the vaccine development process. Combining phase I and II may allow research questions to be answered more quickly or with fewer patients. Integrating phase I and II can also enable simultaneous evaluation of safety and immunogenicity endpoints of vaccine strategies and allow for the rapid cessation of strategies with insufficient safety or immunogenicity levels.
Repurposing research from work on SARS and MERS outbreaks
The coronavirus responsible for COVID-19 belongs to the same family as the coronaviruses that caused two previous outbreaks, severe acute respiratory syndrome (SARS), and the Middle East respiratory syndrome (MERS). Hence, groundwork from previous research from the SARS and MERS outbreaks could theoretically help researchers move through planning steps swiftly.
Emergency use authorization before getting formal approval
FDA's Emergency Use Authorization facilitates the availability of medical countermeasures during public health emergencies. Through the EUA, the FDA may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when there are no adequate, approved, and available alternatives. The EUA declaration is terminated when the emergency is over and all EUAs issued based on that declaration no longer remain in effect.
The FDA has already issued EUA to companies producing diagnostic tests, antibody tests, and treatments for COVID-19; the same law will apply for vaccines, however, experts believe that there's already a higher bar for vaccine approval than for drugs, and hence the bar for an EUA for a vaccine will undoubtedly be higher than an EUA for a drug.
Operation Warp Speed
The US government's Operation Warp Speed (OWS) will allow vaccines to be delivered to patients more rapidly while adhering to safety and efficacy standards. The OWS aims to deliver 300 million doses of a safe, effective vaccine for COVID-19 by January 2021.
To accelerate development, OWS will select the most promising vaccine candidates and provide coordinated government support in expediting development, manufacturing, and distribution of vaccines. The program has selected five vaccine projects—Moderna, Oxford University and AstraZeneca, Johnson & Johnson, Merck, and Pfizer—as the most likely candidates to produce a vaccine for COVID-19.
COVID-19 Candidate Vaccines Landscape by WHO
As per a draft landscape of COVID-19 candidate vaccines released by the World Health Organization (WHO) on June 22, 2020, there are 13 candidate vaccines in clinical evaluation and 129 candidate vaccines in pre-clinical evaluation. The following table summarized the candidate vaccines in clinical evaluation:
|Vaccine Platform||Type of Candidate Vaccine||Developer||Current Clinical Trial Phase|
|Non-Replicating Viral Vector||ChAdOx1-S||University of Oxford/AstraZeneca||Phase III|
|Non-Replicating Viral Vector||Adenovirus Type 5 Vector||CanSino Biologics [RM1]Inc./Beijing Institute of Biotechnology||Phase II|
|RNA||LNP-encapsulated mRNA||Moderna/NIAID||Phase II|
|Inactivated||Inactivated||Wuhan Institute of Biological Products/Sinopharm||Phase I/II|
|Inactivated||Inactivated||Beijing Institute of Biological Products/Sinopharm||Phase I/II|
|Inactivated||Inactivated + alum||Sinovac||Phase I/II|
|Protein Subunit||Full length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix-M||Novavax||Phase I/II|
|RNA||3 LNP-mRNAs||BioNTech/Fosun Pharma/Pfizer||Phase I/II|
|Inactivated||Inactivated||Institute of Medical Biology, Chinese Academy of Medical Sciences||Phase I/II|
|DNA||DNA plasmid vaccine with electroporation||Inovio Pharmaceuticals||Phase I|
|Non-Replicating Viral Vector||Adeno-based||Gamaleya Research Institute||Phase I|
|RNA||saRNA||Imperial College London||Phase 1|
mRNA: Messenger ribonucleic acid; LNP: lipid nanoparticle-mediated saRNA; (small activating RNAs)