|Year : 2020 | Volume
| Issue : 1 | Page : 1-9
Development of COVID-19 vaccines: A race against time!
Mohit Bhatia, Ranjana Rohilla
Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
|Date of Submission||28-May-2019|
|Date of Decision||20-May-2020|
|Date of Acceptance||27-May-2020|
|Date of Web Publication||4-Sep-2020|
Dr. Mohit Bhatia
All India Institute of Medical Sciences, Rishikesh, Uttarakhand
Source of Support: None, Conflict of Interest: None
The current COVID-19 pandemic has created a havoc with rapidly increasing morbidity and mortality rates globally. To tide over the current circumstances, it is imperative that novel vaccines are developed at the earliest. Development of a novel vaccine against SARS-Co-V-2 seems to be a daunting task at the moment. We will have to wait at least for a year before any such vaccine enters the global market. Issues pertaining to vaccine efficacy and safety remain unanswered at the moment. We are hopeful that the ongoing research on this mysterious virus will unearth valuable information in the days to come, which will help us develop most suitable treatment options and vaccine platforms respectively.
Keywords: COVID-19, SARS-CoV-2, Vaccines
|How to cite this article:|
Bhatia M, Rohilla R. Development of COVID-19 vaccines: A race against time!. J Patient Saf Infect Control 2020;8:1-9
| Introduction|| |
The current COVID-19 pandemic has created havoc with rapidly increasing morbidity and mortality rates globally. The dearth of knowledge and conflicting views regarding transmission dynamics, pathogenesis, protective immune response and treatment options pertaining to this dreaded infectious disease has led to further worsening of the situation. To tide over the current circumstances, it is imperative that novel vaccines are developed at the earliest. This review article delves into various aspects of ongoing research for developing safe and efficacious vaccines against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).
| Phases of Development of a Novel Vaccine-An Overview|| |
A novel vaccine candidate can be defined based on the following criteria:
- First of its kind based on the mechanism of protection
- First vaccine for a disease
New vaccine candidates are subjected to an elaborate development process after discovery. Regulatory agencies worldwide, namely European Medicines Agency (EMA), the World Health Organisation (WHO) and the United States Food and Drug Administration have divided this development process into:
- Pre-clinical stage:In vitro andin vivo testing in animals
- Clinical stage: Clinical trials in human subjects, which progress sequentially as Phases I, II, and III, respectively.
Phase IV studies are conducted after the successful completion of Phase III trials and following licensure of the product. [Table 1] summarises the features of Phases I to IV of vaccine development.,,,,,,,,,,,
| Overview of Antigenic Structure of Severe Acute Respiratory Syndrome-Coronavirus-2|| |
SARS-CoV-2 is a positive-strand RNA virus which belongs to order Nidovirales, family Coronaviridae, sub-family Orthocoronavirinae and genus Betacoronavirus. It is usually round or elliptical with a diameter of approximately 60–140 nm. The genome of this virus is approximately 29,700 nucleotides long and shares 79.5% sequence homology with SARS-CoV. It has a long ORF1ab polyprotein at the 5′ end, which encodes 15 or 16 nonstructural proteins. The 3′ end of the genome encodes four major structural proteins: spike (S) protein, nucleocapsid (N) protein, membrane (M) protein and envelope (E) protein., Structural organisation of SARS-CoV-2 is depicted in [Figure 1]. Features of structural antigens of this virus are summarised in [Table 2]. Research findings of some authors pointing towards immunogenic potential of major SARS-CoV-2 proteins (S, N and M) are summarised in [Table 3].
|Figure 1: Structural organization of severe acute respiratory syndrome-coronavirus-2|
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|Table 2: Summary of features of structural antigens of severe acute respiratory syndrome-coronavirus-2|
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|Table 3: Summary of research findings of some authors pointing towards immunogenic potential of major severe acute respiratory syndrome-coronavirus-2 proteins (S, N and M)|
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| The Covid-19 Vaccine Development Landscape-Progress So Far|| |
The publication of the genetic sequence of SARS-CoV-2 on 11th January, 2020 triggered intense global Research and Development activity to develop a vaccine against COVID-19. The unprecedented humanitarian and economic consequences of the COVID-19 pandemic have hastened the evaluation of next-generation vaccine technology platforms to accelerate the development of a novel vaccine against this dreaded disease. The first COVID-19 vaccine candidate entered Phase-1 clinical trials on 16th March, 2020.
The Coalition for Epidemic Preparedness Innovations (CEPIs) is working with global health authorities and vaccine developers to support the development of COVID-19 vaccines. CEPI has developed a landscape database which not only includes vaccine development programmes reported through the WHO's continually updated list but also other projects identified from publicly available and proprietary sources.
The deployment of advanced techniques such as next-generation sequencing and reverse vaccinology may cut short the time required for development novel vaccines during epidemics or pandemics. The different types of potential SARS-CoV-2 vaccine platforms and their characteristic features are depicted in [Figure 2]. Adjuvants could enhance immunogenicity of some of these platforms, thereby enabling vaccination of more people at lower doses without compromising protection. [Table 4] provides a summary of potential adjuvants that could be used for the aforementioned purpose. At the time of writing this review, the global COVID-19 vaccine Research and Development (R and D) landscape includes 115 vaccine candidates (78: under active development and 37: uncertain development status). Seventy-three of the 78 confirmed active projects are currently in exploratory or preclinical stages. The most advanced vaccine candidates which have recently moved into clinical development are enumerated and summarised in [Table 5]. Recently, Oxford University's COVID-19 vaccine (ChAdOx1 nCoV-19), which is among the top candidates that are currently being tested on humans, failed to prevent rhesus monkeys from being infected with SARS-CoV-2 in trials. The results, however, suggested that the vaccine may help to reduce the severity of the disease.
|Figure 2: Different types of potential severe acute respiratory syndrome-coronavirus-2 vaccine platform|
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|Table 4: Summary of potential adjuvants for developing coronavirus disease-19 vaccines|
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|Table 5: Summary of severe acute respiratory syndrome-coronavirus-2 vaccine candidates undergoing clinical trials|
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While 72% of the confirmed active vaccine candidates are being developed by private sector, 28% of the remaining projects are being taken up by academic, public sector and other non-profit organisations. Some of the well-known multinational companies such as Janssen, Sanofi, Pfizer and GlaxoSmithKline are engaged in COVID-19 vaccine development. Lead developers of active COVID-19 vaccine candidates are distributed across 19 countries, which collectively account for over three-fourth of the world's population. Most COVID-19 vaccine development activity is underway in North America followed by Asia, Europe and Australia.
Keeping in mind the rapidity of COVID-19 vaccine development projects, the global scientific community believes that vaccines could be available under emergency use or similar protocols by early 2021. This would represent a paradigm shift from the traditional vaccine development pathway (which takes approximately 10 years) to novel development platforms, which will be an amalgamation of new technology, parallel and adaptive development phases, innovative regulatory processes and scaling manufacturing capacity.
| Potential Challenges in Covid-19 Vaccine Development|| |
Some of the challenges which all nations could phase in developing safe and effective vaccines against SARS-CoV-2 are as follows:,,
- Antigen design:The spike protein of SARS-Co-V-2 is a promising immunogen for protection. However, optimising antigen design is critical to ensure an optimal immune response. Researchers are speculating about the best approach with respect to targeting the full-length protein or only receptor-binding domain
- Safety: Concerns regarding patient safety with respect to deployment of COVID-19 vaccines have been raised by some scientists. For example, studies have shown that full-length S protein can cause:
- Severe liver damage
- Enhanced infection due to antibody-dependent enhancement (ADE), probably caused by S protein-specific antibodies.
As of now, there is no clarity regarding the domains and key amino acids in the S protein of SARS-CoV-2, which are involved in liver damage.
According to a report, the enhanced virulence mediated by mouse hepatitis virus strain JHM (murine coronavirus) is associated with a glycine at residue 310 of the S protein. This mutation may contribute to the spread of infection within the central nervous system (CNS). Concerns regarding immunogenicity and safety of mRNA vaccines are also questionable, as these have not been approved for use in human beings before.
Pre-clinical experience with vaccine candidates for SARS and Middle East respiratory syndrome (MERS) has raised concerns about exacerbating lung disease, either directly or as a result of ADE. These findings are alarming and call for testing in suitable animal models followed by rigorous safety monitoring in clinical trials.
- Adjuvants: These are primarily required for generating a sufficient immune response and dose sparing. Compounds triggering Th1 and high neutralising-antibody responses are theoretically more likely to be protective and avoid the risk of immunopathology. However, more data need to be generated in this regard
- Correlates of protection: These may be inferred from experience with SARS and MERS vaccines but are not yet established. The potential duration of immunity is unknown. It is also uncertain whether single-dose vaccines will confer immunity or booster doses will be required
- Genetics of SARS-Co-V-2: According to a recent report, 149 sites of mutations were identified across the genome of 103 sequenced strains of SARS-CoV-2. The virus has evolved into two subtypes, termed L and S subtype which display considerable differences in geographical distribution, transmission ability and severity of the disease
- The approaches being applied for COVID-19 vaccine development, which include a new virus target, novel vaccine technology platforms and novel development paradigms, are likely to increase the risks associated with delivering a licensed vaccine
- Attrition rates of >90% have been reported for licensed vaccines, which underwent a traditional development pathway, as per the industry benchmarks
- A careful evaluation of effectiveness and safety will be required at each step
- To assess vaccine efficacy, COVID-19-specific animal models are being developed which include ACE2-transgenic mice, hamsters, ferrets and nonhuman primates
- Biosafety-level 3 containment measures are imperative for animal studies involving live-virus challenges. The demand for such facilities is likely to require enhanced international coordination for capacity building.
Intersectoral coordination and cooperation between vaccine developers, regulators, policymakers, funders, public health bodies and governments will be required to ensure that promising late-stage vaccine candidates can be manufactured in sufficient quantities and equitably distributed to all affected areas, especially low-resource countries.
| Bacille Calmette-GuÉrin Vaccination and Covid-19|| |
To the best of our knowledge, there is no evidence that the Bacille Calmette-Guérin vaccine (BCG) protects people against SARS-COV-2 infection. At present, the WHO does not recommend BCG vaccination for the prevention of COVID-19. The WHO has reiterated the fact that neonatal BCG vaccination is extremely important in countries or settings with a high incidence of tuberculosis and diversion of local supplies may result in neonates not being vaccinated, resulting in the increased incidence of morbidity and mortality related to tuberculosis.
Although animal and human studies have provided some experimental evidence about the nonspecific effects of the BCG vaccine on the immune system, these effects remain less well characterised with unknown clinical relevance. As of April 2020, the WHO updated its ongoing evidence review of the major scientific databases and clinical trial repositories, using English, French and Chinese search terms for COVID-19, coronavirus, SARS-CoV-2 and BCG. The review yielded three ecological studies posted online before peer review, in which the authors had compared the incidence of COVID-19 cases in countries where the BCG vaccine is used with respect to those where it is not used. It was uniformly observed that countries where the vaccine was routinely being used in neonates had less reported cases of COVID-19 to date. However, the global scientific community is sceptical about these findings, as such studies are prone to significant bias from many confounders which are as follows:
- Differences in national demographics and disease burden
- Testing rates for COVID-19 virus infections
- The stage of the pandemic in each country.
Currently, there are two registered protocols for clinical trials, both of which aim to study the impact of BCG vaccination given to health-care workers directly involved in the care of patients suffering from COVID-19.
| Conclusion|| |
Development of a novel vaccine against SARS-Co-V-2 seems to be a daunting task. We will have to wait at least for a year before any such vaccine enters the global market. Issues pertaining to vaccine efficacy and safety remain unanswered at the moment. We are hopeful that the ongoing research on this mysterious virus will unearth valuable information in the days to come, which will help us to develop the most suitable treatment options and vaccine platforms.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]