|Year : 2021 | Volume
| Issue : 5 | Page : 19-28
Biomedical advances in the treatment of COVID-19: An Indo-Canadian perspective
Rohin K Iyer1, Venkat Venkataramanan2, Grant N Pierce3, Nikita Thakkar4, Valle Natarajan5, Arun Chockalingam6
1 Cytiva Life Sciences, Marlborough, MA, USA
2 McRae Imaging, Mississauga; Lumentra Inc., Waterloo, Ontario, Canada
3 Canadian Centre for Agri-Food Research in Health and Medicine, Albrechtsen Research Centre; St. Boniface Hospital, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
4 Department of LaboratoryMedicine and Pathobiology, University of Toronto, ON, Canada
5 Orchid Pharmaceuticals, Chennai, Tamil Nadu, India
6 Department of Medicine, University of Toronto, ON, Canada
|Date of Submission||24-Aug-2021|
|Date of Decision||27-Sep-2021|
|Date of Acceptance||01-Oct-2021|
|Date of Web Publication||19-Nov-2021|
Department of LaboratoryMedicine and Pathobiology, University of Toronto, ON
Dr. Rohin K Iyer
Cytiva Life Sciences, Marlborough, MA
Source of Support: None, Conflict of Interest: None
This white paper summarizes the key outcomes, topics, and recommendations from the Canada-India Healthcare Summit 2021 Conference, Biotechnology Session, held on May 20–21, 2021. In particular, the authors have focused their attention on topics ranging from research and development into the etiology and treatment of COVID-19 to novel approaches, such as ultraviolet-C disinfection and cell and gene therapy. The paper also deals with important topics around the effects of food distribution and nutrition on COVID-19 and vice versa, as well as key considerations around research and development, innovation, policy, grants, and incentives, and finally, summarizes the ways in which Canada and India, being close allies, have already begun to partner to fight the pandemic (as well as future strategies to continue this excellent progress). We also include key points raised during the summit and summarize them as part of this white paper.
Keywords: Biotechnology, cell therapy, coronavirus, COVID-19, gene therapy, nutrition, pandemic, ultraviolet-C sterilization, vaccines
|How to cite this article:|
Iyer RK, Venkataramanan V, Pierce GN, Thakkar N, Natarajan V, Chockalingam A. Biomedical advances in the treatment of COVID-19: An Indo-Canadian perspective. Int J Non-Commun Dis 2021;6, Suppl S1:19-28
|How to cite this URL:|
Iyer RK, Venkataramanan V, Pierce GN, Thakkar N, Natarajan V, Chockalingam A. Biomedical advances in the treatment of COVID-19: An Indo-Canadian perspective. Int J Non-Commun Dis [serial online] 2021 [cited 2022 Nov 26];6, Suppl S1:19-28. Available from: https://www.ijncd.org/text.asp?2021/6/5/19/330647
| Introduction|| |
The COVID-19 pandemic took a devastating toll on the lives and livelihoods of both Indians and Canadians between 2020 and 2021. The combined effect of the biology underpinning the disease (SARS-CoV-2 and its variants) with the lack of adherence to government regulations around social distancing, and the slow rollout of vaccines, meant that citizens and governments of both countries were vulnerable to the spread of the disease and its effects on human health, the economy, and so much more. Fortunately, there are novel bio (medical) technologies being developed to address the issues at hand by research institutions as well as industry groups in Canada and India. This white paper summarizes many of these advances with strategies to mitigate future pandemics. The key themes of this white paper are, therefore, centered around COVID-19 strategies and are summarized as follows:
- Drugs and vaccines for COVID-19
- The association of nutrition with COVID-19
- Novel cell and gene therapy approaches for COVID-19
- Ultraviolet (UV)-C disinfection approaches for COVID-19.
The Canada-India Healthcare Summit (CIHS) Biotechnology Working Group has chosen these topics based on its expertise in these areas, as well as the current relevance of strides being made in these areas of research. The white paper is by no means an exhaustive compilation of strategies and knowledge on the topic, and readers are referred to the extensive list of citations/references for further reading on these and other related topics.
Additional material is available in a supplement at the end of the document, which centers around other areas that may be of interest to some readers, such as policy, immunity, research and development grants, tax breaks, industry collaboration, and tips on mask usage and social distancing. Finally, in the supplement, we have also briefly summarized the talks presented by invited speakers at the CIHS, presented on May 21, 2021, which will provide key perspectives on the different technologies being investigated in both Canada and India, along with examples of their use in clinical and industrial practice.
| Drugs and Vaccines for COVID-19|| |
Drugs for COVID-19 management – Novel designs and repurposing existing drugs
While the primary methods to contain the COVID-19 involve extensive vaccine inoculation, countries face several challenges in getting it accomplished. This primarily includes production and distribution of vaccines. Further, different vaccines have registered different efficacies when tested against different strains of the virus. Thus, we need other methods to manage COVID pandemic from saturating the healthcare system across the world. This makes room for COVID-19 treatment management through drugs and antibody therapies. The primary aim here is to be able to contain the severity and fatality due to COVID-19. As of May 2, 2021, there are 1856 clinical trials for COVID-19 intervention either for existing drugs or novel drugs in the pipeline. There are primarily two methods of COVID-19 interventions: antivirals and immune modulators. There are a few others that use a combination of both these methods. These drugs have been developed to target different phases of the coronavirus life cycle from entry to replication. Of these, the first to get authorization in the EU and the UK is remdesivir. Remdesivir is an antiviral drug that blocks the RNA-dependent RNA-polymerase, leading to premature termination of transcription and eventually RNA synthesis inhibition., Despite its efficacy against Ebola and HIV, the World Health Organization (WHO) found no impact on overall mortality, duration of patients at hospitals, as well as the need for ventilators for patients suffering from COVID-19. A study for combination therapy of remdesivir and barcitinib (JAK inhibitor) showed clinically significant results in reducing recovery time and accelerating improvements among COVID patients under high-flow oxygen or ventilator. A similar story was observed for the generic drug chloroquine. Chloroquine or hydroxychloroquine is a lysosomotropic compound that penetrates the lysosomes and impacts the cellular pH, which subsequently triggers cell apoptosis. However, the treatment with hydroxychloroquine for COVID patients was not proven to be beneficial compared to the controls.,,
Currently, there are several drugs and monoclonal antibody combinations that are recommended by the National Institute of Health (NIH) in the US for managing COVID patients. Monoclonal antibodies for COVID are laboratory-made proteins that are targeted against spike protein and prevent binding of the virus to human cells. The FDA in the US has emergency use authorization for bamlanivimab and etesevimab or casirivimab and imdevimab (monoclonal antibodies) for patients showing mild symptoms but who have a higher risk of disease progression. The combination of casirivimab and imdevimab is also approved for emergency use authorization in India. For patients in the hospital with the need for supplemental oxygen, a combination of remdesivir and dexamethasone (corticosteroid) lowers the inflammatory response.
There is an ongoing quest for novel drugs as well as repurposing existing drugs. The NIH will be starting a randomized clinical trial to test seven drugs that are already approved by the FDA for COVID treatment under the Accelerating COVID-19 Therapeutic Interventions and Vaccines program. Pfizer also has initiated a Phase 1 study of an oral antiviral 3CL protease inhibitor, which has the potential to block the virus from replicating. Repurposing generic drugs would be beneficial if effective against COVID due to their lower cost and hence affordability across low- and medium-income countries. There is some evidence that the generic drug disulfiram, commonly used for alcoholism, could be potentially used for treating COVID patients.,
Approved vaccines: Adoption, availability, efficacy, and safety
The emergence of COVID-19 in early 2020 brought a unique opportunity for rapid discovery and innovation globally. Companies and governments worked together to create a vaccine to conquer this pandemic. Of the different vaccine delivery platforms, three categories of COVID-19 vaccines exist: DNA and RNA delivery; recombinant vaccines based on viral, protein subunit, and peptide; inactivated and live-attenuated viruses.
While DNA-based vaccines deliver genes or fragments coding for immunogenic antigens to the host cell's nucleus for transcription to take place, mRNA vaccines enter the host cell ready for translation, skipping the transcription process. This decreases the technical challenge of delivering the vaccine as well as any fear of integration with the genome,, making it a highly attractive approach for vaccine development. There are two key types of mRNA-based vaccines that have emerged. The Pfizer-BioNTech COVID-19 (BNT162b2) vaccine encodes the mRNA of spike glycoprotein of SARS-CoV-2 in a lipid nanoparticle., In a trial of over 43,000 participants randomized to either Pfizer vaccine or placebo, there were only eight cases of COVID-19 with onset of at least 7 days after the second dose in those vaccinated, thereby estimating Pfizer efficacy to be 95%. Similar to the Pfizer vaccine, the Moderna vaccine (mRNA-1273) encodes the stabilized spike glycoprotein in a lipid–nanoparticle-encapsulating nucleoside-modified mRNA. To test the efficacy of the vaccine, 30,000 volunteers were randomized to either placebo or vaccine. Intriguingly, of the participants vaccinated, 11 contracted symptomatic COVID-19 while 185 in the placebo group did. As a result, efficacy was concluded to be 94.5%, with similar efficacy across 2-week intervals between doses with elderly patients. Both the Pfizer and Moderna vaccines have been widely used in the Canadian vaccination strategy.
In comparison to synthetic mRNA-based vaccines, genetically engineered nonreplicating viral vector-based vaccines take advantage of viral systems such as adenovirus to deliver SARS-CoV2 DNA into host cells. These engineered vectors trigger immune response but cannot create disease. Oxford/AstraZeneca and Johnson and Johnson (J and J) have developed vaccines using this system. University of Oxford and AstraZeneca collaborated in the development of a nonreplicating simian (chimp) adenovirus vector with codon optimized for COVID-19 spike protein (AZD1222). Double-blinded randomized controlled trials were conducted in the UK, Brazil, and South Africa to evaluate the response against COVID-19. Among 24,000 participants, the vaccine efficacy was overall 70.4%. The trial also evaluated vaccine efficacy due to vaccine dose response. A low dose followed by a standard dose gave a higher efficacy of 90% in comparison of two standard doses. Similarly, J and J (JNJ-78436735) also used a similar system of nonreplicating viral vector but from a human species. In a study enrolling 43,000 participants across eight countries, the vaccine was 66% effective at preventing symptomatic COVID-19 disease. The vaccines from Pfizer, Moderna, and AstraZeneca have been approved for inoculation in Canada, while only the AstraZeneca vaccine, branded as Covishield, is approved in India.
Approved in India, Bharat Biotech inactivated the whole virion of SARS-CoV-2 virus (BBV152). Thus, the inactivated virus will not replicate but will induce an immune response. Reportedly, among 26,000 participants in Phase 3 clinical trial, the overall efficacy is 81% based on smaller interim result. On the other hand, Novovax has developed a protein subunit vaccine which utilizes a spike protein enclosed in a lipid nanoparticle (NVX-CoV2373), and it is patented saponin-based Matrix-M technology to promote immune response and stimulate high levels of neutralizing antibodies. A study of 15,000 participants conducted in the UK demonstrated 96% against the original viral strain. While Bharat Biotech is approved in India, Novovax is a promising vaccine candidate currently undergoing Phase 3 clinical trials for approval.
With over a year tackling this pandemic, countries continue to experience detrimental second and third waves. This is largely attributed to the quick emergence of variants of COVID-19 and the comparatively decreased speed of vaccine production and distribution. In total, four variants have been reported globally (shown here according to the WHO nomenclature), including alpha (B.1.1.7), beta (B.1.351), gamma (B.1.128, P2), and the delta variants (B.1.617.1, B.1.617.2). All companies pertaining to Canada and India have reported some efficacy against the Alpha variant except for Johnson and Johnson.,,, In response to the Beta variant, AstraZeneca has failed to show vaccine efficacy and results are unknown from Bharat Biotech. Although there is little knowledge about the vaccines against the Gamma and Delta variants, scientists believe the vaccines should be effective. In particular, COVID-19 vaccine companies such as AstraZeneca, Bharat Biotech and Pfizer remain confident that their vaccine will work against the Delta variant. As the virus evolves and more mutants arise, companies are working to create booster shots that will enhance immunity against the mutant strains.
Of all the vaccines discussed here, AstraZeneca and Bharat Biotech are relatively cheaper to manufacture at $4 while mRNA-based Pfizer and Moderna are $40 and $36, respectively. Most vaccines require two doses except for the vaccine from J and J which only requires a single dose. The first dose creates an immune response, while the second dose enhances the long-term immunity and protection. Depending on the vaccine, the administration of the second dose is advised between 2 and 4 weeks after the first dose. As the first dose initiates the immune response, administering a first dose has been the priority for many countries including Canada. A study investigated the effect of increasing the frequency between the two doses to 9 weeks instead of the 4th-week and 3rd-week strategy initially proposed by Moderna and Pfizer, respectively. Delaying the second dose significantly enhanced the long-term immunity and protectiveness from the vaccine, with reduced hospitalizations and deaths. Similarly, a study extending the second dose administration from 22 to 90 days reported increased immune response from 55.1% to 88.1%. Overall protection measured by antibody levels did not change during this extended period. These data suggest that antibody responses increase with a larger interval between the two doses, supporting the rationale of administering as many first doses as possible.
The common side effects for most of these vaccines include short-term, mild-to-moderate pain at injection site, fatigue, and headache each with a low likelihood of adverse events. However, there have been reports of blood clots associated with viral vector-based AstraZeneca and J and J vaccines. This adverse effect, referred to as Vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), led to the pause on the rollout of the vaccine. Administration of these vaccines is thought to activate platelets during antibody production that stimulates clot formation and consequently thrombocytopenia and low platelet counts. On investigation, among those vaccinated with AstraZeneca in the UK, approximately 1 in 250,000 individuals experienced VIPIT, and approximately 0.0004% of 20 million people vaccinated. Comparably, of the 6.8 million doses administered of J and J, six cases of VIPIT have been reported in the US. To understand the risk of developing blood clots due to COVID-19, a study concluded that COVID-19 led to a stroke in approximately 1.6% and 30% with thrombocytopenia. Thereby, the potential benefit was concluded to be greater in receiving an early dose of these viral vector vaccines than suffering complications from severe COVID-19.
The Association of Nutrition with COVID-19
The past often predicts the future. The 1918 influenza pandemic killed 40–50 million of the world's population at the time. Most of the deaths were not the direct result of the influenza infection but instead occurred due to secondary opportunistic bacterial pneumonia infections. This has been shown to have produced, in those lucky enough to have survived the pandemic, nutritional deficits which ultimately resulted in growth deficiencies. It is likely to expect, therefore, that the current COVID-19 pandemic will induce similar nutritional and long-term growth deficiencies.
The nutritional behaviors exhibited and reported during the COVID-19 pandemic would support the short-term predictions at the very least. Food insecurity during COVID-19 in the third-world countries, and even in the disadvantaged communities of the United States, is at historic proportions. Food insecurity is defined by the (USDA) United States Department of Agriculture as reduced quality, variety, or desirability of the diet, multiple indications of disrupted eating patterns, and reduced food intake. The causes of these problems in food security have been suggested to be multifactorial in origin. Decreases in food quantity and quality, as well as a lack of access to food (due to delays in food distribution, and/or a loss in the financial capacity to purchase food due to job losses), have been identified as the primary risk factors. The result can be malnutrition. The prevalence of malnutrition in older patients with COVID-19 infection has been particularly elevated. This malnutrition was associated with a greater incidence of hospitalization in intensive care units (ICUs) and higher hospital deaths.
Changes in nutritional behavior observed in North American and European adults and youth during the COVID-19 pandemic have been very different than those in the elderly. Decreased consumption of warm meals, fruits, and vegetables and, conversely, increased consumption of salty snacks, carbonated sweetened beverages, sweets, and bread by adults have been observed.,,,, These trends were also observed in children and adolescents. Weight gain has been a common result with significant increases in serum glucose, total cholesterol, and Low-density lipoprotein (LDL) cholesterol levels. Social isolation and lockdowns have clearly been identified as two of the factors that have induced these changes.
If poor nutrition leaves an individual susceptible to COVID-19 infection, it is reasonable to propose that better, healthy nutritional habits may modulate or prevent COVID-19 symptoms and infection. A variety of nutraceuticals and Vitamin D, in particular, have been hypothesized to strengthen the immune system enough to protect against COVID-19 infection and symptoms.,,,,,,,,,,,, However, actual data showing a negative correlation of Vitamin D status and COVID-19 symptoms would cast serious doubt on the strength that this intervention may actually have on viral transmission.
Changes in nutrition have now been recognized as having an important impact on the gut microbiome and human health. Unexpected but as yet preliminary results have shown that the intestinal and oral microbiome composition predicted, with up to 92% accuracy, severe COVID-19 symptoms that led to death. This prediction of COVID-19 severity was superior to comorbidities currently in common use to triage patients in the clinic. The stool content of Enterococcus faecalis was the best predictor of COVID-19 disease severity. This association of the gut microbiome with human health, in general, and COVID-19 specifically has led some to propose modulation of the gut microbiome through nutritional intervention may prevent or alter the clinical course of COVID-19 infection.
The COVID-19 pandemic has had an impact on the food processing industry as well. Although the coronavirus can live 24–72 h on plastic, steel, and cardboard matrices under laboratory conditions, there is no evidence that such a transmission in the food industry exists to date. Similarly, because the virus needs living biological material to survive, the US Centers for Disease Control and Prevention (CDC) has concluded that it is highly unlikely that coronavirus transmission can occur through food itself. However, this does not lessen the importance of following recommendations to follow proper food hygiene and use personal protection equipment (PPE) to lessen any possibility of transmission. Data acquired from 3000 survey respondents showed that 6% did not use face masks in public places, 10%–12% exhibited improper hand washing, and 28% used incorrect products for cleaning and sanitizing food environments. Better adherence to food hygiene and personal protective measures was recommended.
| Novel Cell and Gene Therapy Approaches for COVID-19|| |
Cell and gene therapies (C and GTs) have recently come into focus for their potential to treat the underlying biology surrounding COVID-19. In this respect, they harness the very biology that underpins COVID-19 to treat and even eradicate its deleterious effects. The innate biology surrounding COVID-19 involves viral infection with the SARS-CoV-2 virus, usually via inhalation, which then infects and damages cells of the host bronchial epithelium and lung endothelium. This leads to a hyperinflammatory response causing acute respiratory distress syndrome (ARDS). As such, the current focus from a C and GT perspective is on the use of anti-inflammatory cells and/or antiviral cells to suppress this inflammation and even to detect and kill virus-infected cells.
Scientists have long used Mesenchymal Stem Cells and / or Mesenchymal Stromal Cells (MSCs) to treat ARDS due to their immunomodulatory properties – however, pre-COVID-19 clinical trials have restricted their use in the past. To this end, MSC-based technology pioneered by cell therapy industry players such as Athersys and Mesoblast (technology later acquired by Novartis) and several other MSC companies is now gaining significant momentum, even obtaining FastTrack designation and accelerated regulatory approvals for their products via the FDA emergency use program. This is partly because MSCs have already been demonstrated to be safe and effective to use for ARDS, which has enabled them to gain quicker acceptance by regulatory bodies. In the case of the Athersys, Inc. product, MultiStem, it is currently in Phase 3 trial investigation (MACOVIA trial), which represents the furthest advancement of a C and GT-based treatment for COVID-19. In fact, the majority of trials in the C and GT space for COVID-19 according to the website, www.clinicaltrials.gov, are currently MSC-based therapies. These trials will answer important questions surrounding the safety, efficacy, and wider-spread acceptance of this approach, though questions will remain around the financial viability of using cell-based therapies given recent progress with cheaper vaccines and drugs, as discussed above.
Other groups are investigating the utility of natural killer (NK) cells, which have the innate capacity to attack cancer cells as well as invading foreign species such as bacteria and viruses. As such, their use in COVID-19 represents an obvious, yet novel paradigm. Along with modified T-cells and coronavirus-specific T-cells, these cells represent an alternate approach that uses immunotherapy-based therapies rather than stem cell-based therapies to attack virus-infected cells. Immune cells such as T-cells or NK cells can be isolated from blood, expanded in a bioreactor, and then infused back into the patient as an adoptive immunotherapy approach. Given the rarity of some of these populations in blood, it can be challenging to isolate and expand sufficient numbers of cells, as well as carry out an apheresis blood collection on COVID-19 patients, who are typically very ill and might be undergoing immunosuppressive corticosteroid therapy (e.g., dexamethasone).
Other areas also under investigation are found in the use of acellular approaches such as gene therapies (e.g., delivery of cell cycle inhibitors via viral vectors to suppress T-cell activation) and other modalities involving exosomes that can deliver specific payloads. While the results are still in the early days and the outcomes are still pending from Phase 1 and 2 trials, it will be interesting to watch how these trials progress in the months ahead.
A key consideration in the delivery of these therapies is the industrial scale and logistics required to support their manufacture. Like many vaccines and biologics, C and GTs require careful manipulation in a closed and aseptic manner and might need to be manufactured at large scales in bioreactors of tens to hundreds of liters to support patient demand and allogeneic use. However, unlike biologics, C and GTs are essentially living biological factories. Like the cells in our bodies, they are susceptible to poor recovery, viability, and ultimately function if they are not handled properly during isolation, manufacturing, fill and finish, and cryopreservation.
Fortunately, systems are already in place to ensure closed, automated, and single-use processing thanks to innovations by several key industry players such as Cytiva, ThermoFisher, Sartorius, and Miltenyi Biotec, who have innovated key equipment, consumables, and reagents to meet the demands of this field. In particular, Cytiva has offered vein-to-vein solutions for cell isolation, viral transduction, activation, expansion, harvest, cryopreservation, and thaw, including both equipment and consumables, that are defining the standards for the field. A good example of this is the VIA Capsule™ system, a liquid nitrogen-free cryogenic shipper that can maintain a product below −120°C for up to 5 days with digital integration to ensure traceability and electronic batch record implementation. Recently, Cytiva acquired Vanrx systems for aseptic filling of vials, and its parent company, Danaher, acquired Precision NanoSystems (specializing in lipid nanoparticle production), both Canadian companies, and Aldevron (specializing in mRNA, plasmid DNA, and protein production). These platforms complement Cytiva's work in the areas of C and GT and will fuel the many innovations needed in the areas of automation, fill and finish, and novel drug manufacturing to drive next-generation therapies to the finish line.
As the pandemic draws to a close with the advent and rollout of several vaccines, the intersection of virology, immunology, and C and GT along with public demand for curative and durable therapies will undoubtedly lead to research and industry groups to harness the full potential of these therapies in the years to come.
| Ultraviolet-C Disinfection Approaches for COVID-19|| |
UV wavelength covers from 100 to 380 nm of the electromagnetic spectrum. Within that, a shorter ranger, UV-C (200–280 nm, also known as germicidal UV, with peak germicidal activity at ~260 nm) is well known to have strong germicidal effects and is used in disinfection systems for several decades.
UV-C technology has been proven to be successful in killing 99.9% of harmful bacteria such as Escherichia More Details coli, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Salmonella More Details typhimurium, as well as in the inactivation of viruses such as Influenza A, H1N1, H5N1, H7N9, and a host of other infection agents. Various strains of coronavirus, such as MERS-CoV and SARS-CoV, are also inactivated effectively by UV-C.,
Since the emergence of COVID pandemic, there has been an immediate interest in experimenting the efficacy of using UV-C for preventing the spread of the COVID. The SARS-CoV-2 remains viable in aerosols for various durations on different surfaces. For example, on porous textiles, the virus is found to be potent for 4–7 days, on stainless steel and plastic for 72 h, on glass for 48 h, while on copper for 4 h.
The typical decontamination method used is manual wiping surfaces with chemicals, such as alcohol, sodium hypochlorite, quaternary ammonium salts, citric acid, and hypochlorous acid. Some of these are highly corrosive. While the chemical disinfection method has been adapted as an immediate solution to contain the virus spread, there has been concern about the long-term health effects on workers, specifically on those with asthma and allergies.
While chemical wiping is widely practiced to decontaminate surfaces, little has been done for airborne pathogens. This is due to the fact that we have very limited tools available at our hands. Fumigation and fogging with chemicals can minimize airborne risks. However, these methods are better suited for empty rooms, typically for the end of the day cleaning. Furthermore, critical places such as ICU cannot be disinfected by these methods as several electronic equipment and surfaces such as plastics and leather are damaged by the chemicals.
UV-C is a well-known germicidal agent that has been used for over 70 years in critical areas such as ICU and surgical facilities in conjunction with air circulators and HEPA filters in upper room air ducts. When COVID-19 was declared as a pandemic, there was an immediate shortage of PPE. Several hospitals were forced to reuse N95 masks after cleaning and UV-C emerged as an immediate solution for decontaminating masks before reuse. Based on earlier studies that clearly show the efficacy of UV-C for decontaminating N95 from influenza virus, the US-CDC provided guidelines on reusing masks in noncritical areas after UV-C decontamination., UV-C stops the spread of the microbes by penetrating their cell walls and disrupting their genetic materials, thereby inactivating them. It is found to be effective against a broad spectrum of pathogens, including bacteria, viruses, and fungi. The UV-C is generally eye safe for short exposures and found to have minimum long-term effects on skins, with easy protection methods such as using full-sleeve shirts. Besides, UV-C devices are engineered to minimize and in most of the cases totally avoid human exposure. They help avoid corrosive and environmentally harmful chemicals and manual labor in deploying them.
Strom et al. reported on rapid and complete inactivation of SARS-CoV-2 by UV-C radiation on both wet and dry samples. A dose of 0.849 mW/cm2 of 254 nm is found to be sufficient for decontamination within 6–8 s. Similar results were soon reported by others as well.,, Gerchman et al. reported on the UV-C wavelength dependence of disinfection efficacies for SARS-CoV-2.
Risks and Unknowns
While UV-C has been used as a germicidal agent for more than 70 years, there are some known risks and a few unknowns.,,
Of critical importance are:
- Direct, chronic exposure to UV-C is harmful to humans. UV is a well-known carcinogen (under extreme cases). It is advisable to avoid direct exposure. Hence, upper-room ventilation is the safest mode of application. In-room disinfection with UV-C should only be carried out in the absence of any human and with timer controls. Enclosed systems for small object (such as masks, tools, and handheld electronics) should use proper engineering controls to fully contain the radiation
- UV can also cause photochemical degradation on plastics. Elastic bands in N95 masks degrade rapidly with UV-C as well. Proper material choice is critical to ensure device reliability
- Radiation at the wavelength range of 175–210 nm can generate ozone. Excimer UV-C devices and some medium-pressure mercury lamps emit radiations that can generate ozone. For such devices, adequate ventilation is necessary during use
- In general, UV-C is a broad-spectrum germicidal agent. However, proper dose is critical to ensure disinfection against a variety of pathogens. It is important to perform a risk assessment to identify potential pathogens for the use case and ensure appropriate doses and wavelengths.,,
| Discussion and Conclusions|| |
As discussed above, we summarized key themes surrounding the coronavirus, its etiology, and the strategies being used to address the pandemic (such as through nutritional approaches, novel cell and gene therapies, and UV-C disinfection techniques). We have also addressed critical bottlenecks in policy, in granting structures, and in terms of compliance with policy, as well as inequities in the distribution of critical supplies that should serve as a call to action to both state and local governments in India and Canada. In addition, we have summarized expert talks from the CIHS 2021 meeting that have highlighted key advances in biotechnology [Appendix 1]. Taken together, it is clear that both India and Canada have made great strides in their response to the pandemic but have more work ahead to address the evolving needs of both nations.
Recommendations: Collaboration, promise, and lessons learned
This pandemic has truly proven that we are a global community without borders. As such, it is quite important that nations actively communicate, participate in knowledge exchange, and share resources. In this white paper, we particularly emphasize Canada's and India's approach to tackling the pandemic and the associated strengths and weaknesses of both nations.
As a large producer of affordable vaccines, India has exemplified generosity with donating vaccines to help countries in their fight with COVID-19. In fact, India has been a collaborator with Japan, Australia, and US through the Quadrilateral Security Dialog to distribute 1 billion vaccines to developing countries in Asia. Similarly, India stepped up to the occasion to aid the Canadian government during their second wave. To mitigate the rise in COVID-19 cases, Prime Minister Trudeau reached out to Prime Minister Modi to ask for vaccine supply. India graciously helped to strengthen the countries ties which will likely extend to global issues such as climate change and economic recovery.
As countries begin to recover their economies, it is essential that each government critically reflects on the strengths and weaknesses of their pandemic strategy. One aspect of the strategy was the use of technology as many countries used apps to assist with COVID-19–related information or assess exposure including the Canadian COVID alert app and the Indian ArogyaSetu app. However, as of February 2021, only 16.5% of Canada's population downloaded the COVID alert app, and approximately 2% of those who tested positive recorded it in the app. As it is likely that most countries experienced low engagement with the app, each nation should reflect on how to efficiently and productively use technology to inform and convey messages. Similarly, some testing recommendations that have been proposed are preparing a universal Canadian framework for testing, including increasing testing and laboratory capacity. Furthermore, there is an urgent need to invest in PPE production within Canada. Whether it be Canada's leading hospitals such as UHN or India's Apollo Hospital, both countries employed efficient strategies such as teleconsultations, health monitoring, and COVID-19 screeners. In addition, Apollo Hospital also participated in a multi-stakeholder partnership to extend hospital care into hotel rooms to keep up with the rapid spread of COVID-19. As COVID-19 will likely be an ongoing endemic, nations must invest, prepare, and collaborate to better equip themselves for future outbreaks.
Understanding current and future directions for novel research into vaccines and drugs, C and GTs, nutritional considerations for COVID-19, and UV-C disinfection techniques will also help to bolster the impact of Canadian and Indian research into methods for ending it expeditiously.
The authors gratefully acknowledge Dr. Santosh Hariharan of Pfizer Inc. for providing scientific clarification during the whole process and to all members of the CIHS 2021 Committees, particularly the Biotechnology Committee, for their unfailing guidance and support in the preparation of this manuscript and the associated forum materials.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Appendix|| |
| Appendix 1|| |
| Immunity|| |
Immunity in its most basic form can be defined as a combination of innate and adaptive immunity. The one that is most familiar to us is the concept of innate immunity, the kind we are born with and programmed into our genetic code, that allows us to fight off infections (bacterial, viral) even very soon after birth or even in the womb. Unfortunately, the nature of coronavirus, having purportedly originated from animals such as bats and pangolins and traversed into humans through zoonotic transmission, has made it nearly impossible for humans to stave off the disease through innate immunity alone, due to the foreign origins of the virus.,
Equally familiar, but equally ineffective from a COVID-19 immunity standpoint, is the adaptive immune response, which involves the generation of antibodies by B-cells in response to detected viral spike proteins. This concept is the primary mode of action of all current-approved vaccines (both mRNA and non-mRNA) and is currently proving to be an effective strategy for reducing severe hospitalization and symptoms.
Herd immunity is a concept in which a large number (e.g. up to 80%) of individuals in a population or community are immune to a virus or disease; this protects the remaining members who are not (20%). The concept is relevant in the sense that if we are able to get individuals who are (a) most vulnerable and (b) most likely to continue spreading the virus to be vaccinated, we may achieve this herd immunity artificially. Factors working against this include the spread of variants and the inability of vaccines to cope with them, as well as an irrational fear of vaccination, leading to vaccine hesitancy among some groups. Combining these concepts, we can see that while the COVID-19 pandemic has taught us much about our inability to stave off infection, it also presents an opportunity to “artificially” achieve herd immunity through a combination of widespread vaccination, social distancing, and adherence to public health guidelines.
| Policy|| |
Coronavirus pandemic has engulfed the whole world in such a short time. COVID-related policies on prevention, management, and control need to be coordinated by a central body such as the World Health Organization (WHO). However, the WHO has no power promulgate policies in any individual country, or for that matter, the whole world. In contrast, the WHO provides guidelines as to what to do in terms of COVID prevention – use of masks and personal protective devices; validation of therapies and vaccines; and equity in distribution of vaccines. These WHO guidelines are adopted by the national-level expert committees and policymakers. Thus, policies are developed and implemented at the local, regional, national, and global level. There is no uniform policy applicable to all countries of the world.
Country-specific policies depend on many factors, including the principle of governance, level of economy, and political will. As an example, well-developed nations have put policies and procedures in place for every aspect of “pandemic life,” including all aspects surrounding the manufacturing, distribution, and use of vaccines – development, testing, regulatory approval, and ethical, equitable distribution, for example.
In this case, policy on vaccine development to stop the spread of COVID-19 saw an accelerated approval process. Within a record time of 11 months, effective vaccines have been developed, tested, and inoculated in humans.
In an ideal world, global distribution process of vaccines must be equitable. However, the current realities show inequalities; while high-income countries have a much higher rate of inoculation, low- and middle-income countries have much lower vaccination rates. There are glaring disparities between the rich and poor countries – the rate varies between 75% in high-income countries and as low as 1.5% in low-income countries., Until 50% of the population in each and every country gets inoculated, herd immunity will not happen, and the world will not return to a pre-COVID “normal” life. Here, a global policy must be put in place, which will happen only when all countries agree to provide equitable distribution of affordable vaccines.
| Research and Development, Funding, Grants, and Tax Breaks|| |
Within weeks to months of the onset of the COVID-19 pandemic, global industry came to an abrupt halt, except in the case of industries that were directly supporting COVID-19 remediation such as essential services such as hospitals and antiviral drug/vaccine manufacturers. Soon thereafter, an uptick in the research and development (R and D) was also seen for those players who were able to quickly pivot and refocus their efforts on COVID-19 therapeutic development. This uptick, funded primarily by private industry players in the case of vaccine development (most notably with approvals granted to Pfizer-BioNTech, Moderna, Astra-Zeneca/Oxford, and J and J in the majority of countries), was a key force for change in the seemingly unending saga of the COVID-19 pandemic and continues to deliver life-saving vaccines, drugs, diagnostics, and other countermeasures.
Having said this, more can be done to bolster R and D and funding in dealing with the outbreak. While private sector players dominate the field for delivering vaccines, small-to-medium biotech companies, despite their innovative ideas and approaches, may not be able to compete with the industrial scale of operation and efficiencies achieved by their larger counterparts and likely have either closed shop or moved onto other initiatives. A concerted effort is needed to continue to innovate at the academic, small biotech, and large industry level to prevent future pandemics. For example, while new variants of the coronavirus have already emerged with higher infectivity compared to the original strain, questions immediately arose as to the efficacy of the vaccines already rolled out in preventing the spread. Further, R and D would help to avoid all doubt and to develop “universal vaccines” that can be easily tailored to fight off new infections caused by changes in viral coat protein structure, viral infectivity, etc. Similarly, currently approved vaccines require cold chain management, while others can be stored at room temperature. Ideally, innovations resulting from R and D would have obviated the need for expensive ultra-low temperature shippers, freezers, and storage devices, but this is yet to be demonstrated motivating further R and D spending into ways of achieving this.
A key mechanism for inviting further innovation and incentivizing companies with limited R and D spending is to offer tax incentives, grants, and bursaries to these innovative and agile companies for contributing novel solutions to the pandemic effort. This must be institutionalized at the municipal, provincial and federal levels of government in both India and Canada for it to have a meaningful impact on the status of R and D in both countries.
As discussed above, governments and organizations such as the WHO jumped in and delivered grant money to help bolster medical care, R and D, and vaccine development efforts, Canada was a key contributor to the WHO's COVID-19 response fund, which has undoubtedly helped many nations in the rapid development and dissemination of therapies and swift approvals thereof. Given the changing etiology of the virus and population dynamics, as well as the high likelihood of further waves as vaccines are slowly rolled out and people begin to resume a semblance of normal, further funding and money is needed to continue progress made in developing better testing methods, diagnostic procedures, equipment, and vaccine delivery modalities.
| Scaling Production and Accelerating Approvals|| |
The emergence of COVID-19 in early 2020 brought a unique opportunity for discovery and innovation globally. Companies raced to develop vaccines while countries raced to ensure sufficient access to these vaccines for their populations. This provided a unique collaborative effort as countries invested in obtaining vaccines before approval, thereby allowing for financial support in mass production of vaccines. In addition to the investment of funds, COVID-19 vaccine development was accelerated as all countries were following emergency use approval. As a result, this allowed for a 10–15-year complex procedure of developing a vaccine, to be accelerated for wide distribution in less than a year. Although approvals were accelerated, each vaccine underwent the same thorough investigation to accurately validate the efficacy and safety of these vaccines. The global scale of high-priority submissions ensured successful approval of the vaccines in both Canada and India. However, Canada has not been as successful as India in the distribution of vaccine.
India has been extremely successful in mass production and distribution of vaccines. The collaboration with the University of Oxford and AstraZeneca in the mid-2020 was indeed fruitful as India gained easier access and control to vaccines readily available. In addition, India heavily invested in the testing and production of Covaxin with Bharat Biotech. With local mass production being so successful, India was able to navigate and implement its distribution protocol as efficiently as possible with such a large population. These collaborations and investment into production within the country ensured sustainable and cost-effective vaccine production. In contrast, Canada has been slow on the implementation of vaccine programs. Although Canada did successfully procure 76 million doses before approval with Health Canada, without a manufacturing partnership, Canada has completely relied on external resources for vaccine supply. As a result, Canada is challenged with difficulty in mass vaccinating its population when the supply is largely unknown. However, Canadian companies developing COVID-19 vaccines such as Medicago, Novovax, and Precision Nanosystems are promising. The approval of these vaccines anticipated for late 2021 could aid with successful supply and implementation of mass vaccination.
| Social Distancing and Mask Recommendations|| |
Necessity of practicing social distancing
COVID-19 can live for hours or days on a surface, depending on factors such as sunlight, humidity, and the type of surface. It may be possible that a person can get COVID-19 by touching a surface or object that has the virus on it and then touching their own mouth, nose, or eyes. This route is thought to be the main way the virus spreads. Social distancing helps limit opportunities to come in contact with contaminated surfaces and infected people outside the home.
Although the risk of severe illness may be different for everyone, anyone can get and spread COVID-19. Everyone has a role to play in slowing the spread and protecting themselves, their family, and their community. In addition to practicing everyday steps to prevent COVID-19, keeping space between you and others is one of the best tools we have to avoid being exposed to this virus and slowing its spread in communities.
Maintaining a physical distance (commonly called social distancing) of about 6 feet is the finest way to limit virus transmission through respiratory droplets. The WHO and CDC-USA have suggested and proved that social distancing is an effective and vital tool that must be implemented all over the world to reduce the spread of COVID-19.
Age plays an essential role in SARS-CoV-2 acute infections and also with individuals who suffer from comorbid conditions. This results in a higher rate of mortality.
Social distancing associated with mental and social health
Limiting the number of gatherings, maintaining at least 6 feet of distance between people, closing non-essential enterprises, teleworking, distance learning, and shelter-in-place orders are all ways to achieve social separation.
Understanding the link between social distancing motivations, mental health, and social health is essential for adolescents, who may be at risk of harmful psychological impacts from COVID-19 social distancing. Adolescents may be at higher risk of manifesting numerous psychological problems, such as anxiety and depression if isolated from friends and loved ones. Furthermore, during adolescence, a number of hormonal and neurological changes are associated with increased emotional reactivity as well as the continued development of coping strategies and stress control. At the same time, adolescence is defined by a higher reliance on peers for social support and increased relevance of peer interactions. Peer connections contribute to adolescent social health by increasing their sense of belonging and decreasing their burdensomeness on others, both of which are important interpersonal needs.
Examining the links between social distancing motivations and mental and social health in youth could provide valuable insight into potential routes for minimizing the psychological repercussions of social distancing in this vulnerable group.
Social distancing recommendations
- Know before you go: Before you go out, familiarize yourself with, and follow the advice of your local public health authority
- Prepare for transportation: When running errands or going to and from work, consider social distancing choices such as walking, bicycling, wheelchair rolling, or taking public transportation, rideshares, or taxis. When taking public transportation, attempt to keep a distance of at least 6 feet from other passengers or transit operators, such as when waiting at a bus station or choosing seats on a bus or train. Avoid pooled rides where numerous passengers are picked up, and sit in the back seat of larger cars to keep at least 6 feet away from the driver when utilizing rideshares or taxis
- Limit contact when running errands: Only go to stores that sell home items in person when you absolutely have to and keep at least 6 feet away from strangers while shopping and waiting in lines. To limit face-to-face contact with others, use drive-thru, curbside pick-up, or delivery services whenever available. During exchanges, keep a safe distance between yourself and delivery service providers and wear a mask
- Choose safe social activities: Calling, using video chat, or staying connected through social media can help you keep socially engaged with friends and family who do not reside in your house. Stay at least 6 feet away from those who are not from your household while meeting others in person (e.g. at small outdoor events, yard or driveway events with a small number of friends or family members)
- Keep distance at events and gatherings: It is best to keep away from busy venues and parties where staying at least 6 feet away from those who are not from your household may be challenging. If you are in a crowded area, always keep at least 6 feet between you and other people and wear a mask. Masks are particularly useful when physical separation is problematic. Attendees should follow any physical indicators, such as tape markings on floors or signs on walls, directing them to stand at least 6 feet apart in lines or at other times. When passing by other individuals in both indoor and outdoor settings, give them 6 feet of space.
- Masks and face coverings can prevent the COVID-19 virus from spreading to others and may offer some protection to the wearer. Face coverings have been demonstrated in multiple studies to contain droplets ejected from the wearer, which are responsible for the majority of virus transmission
- By preventing anyone, including those who are inadvertently carrying the virus, from transmitting it to others, universal mask use can drastically limit virus transmission. According to disease modeling, wearing masks by a large section of the population, in combination with other measures, could result in considerable reductions in case numbers and mortality
- Coronavirus transmission was kept under control in the Hong Kong Special Administrative Region (HKSAR) for the first 100 days, from December 31, 2019, to April 8, 2020. The virus propagated at a much slower rate than in other countries. To understand the overall effect of our control methods implemented in HKSAR, the epidemiology of COVID-19 in HKSAR was compared to that of comparable countries in North America, Europe, and Asia using publicly accessible information from the WHO website. For comparison, countries with a well-established healthcare system, where face mask use was not extensively accepted in the community, and with more than 100 confirmed cases by day 72, when the WHO proclaimed a pandemic were chosen.
In China, cases have shown that contact with the body may not be the primary cause of illness. A few individuals who were admitted to a small hospital in China due to a bone fracture were shortly diagnosed with coronavirus illness and continuous fever. After the case was verified, almost 60 close-contact healthcare practitioners were immediately quarantined. The results of several testing revealed that none of them were affected. However, because the patient did not always wear a mask at home, the patient's wife was shortly proven positive. Hundreds of such cases have been reported in China, highlighting the importance of masks in preventing person-to-person transmission through “indirect” contact.
Another advantage with utilizing facial masks is that people may touch their faces more frequently when wearing one than when not wearing one. Face touching is a voluntary human activity that is difficult to control, according to several studies (an average test indicated at least 1–2 touches within 3 min if not purposefully controlled). Face masks reduce the chance of direct contact with the mouth and nose. Furthermore, there is no evidence that people who wear masks believe they are safer and consequently are more careless than others; on the contrary, persons who wear masks are more cautious.
After 2–8 h of usage, sterilization by autoclaving, and PortaCount fit testing, the reusability of nonrebreather masks (NRMs) was obtained from volunteer personnel. For the past few months, the production of N95 masks has been declining. This gave them an idea of how they could reuse the N95 mask after sterilization and PortaCount fit testing. NRMs were collected and autoclaved at 121°C for 30 min + 15 min of drying time after being worn by volunteer Animal Care Centre laboratory employees for 2–8 h (total cycle length 48 min). The mask goes through a prewarming stage at 45°C–55°C overnight before being sterilized. A trial of 14 NRMs was used for several hours by volunteer employees from our hospital's Animal Care Centre throughout their typical workday, then collected for autoclave sterilization, and fitted testing using a PortaCount. When the mask was sterilized for the first time, it passed the test and could be reused; however, when it was sterilized again, 2% of the masks failed the fit test.
While major industry players in developed countries have already initiated major trials and achieved marketing approval for vaccines, there remain significant challenges with production, distribution, and vaccination in countries hardest hit with COVID-19. This is particularly important in countries with higher populations and higher numbers of cases, such as India, which necessitates a collaborative approach to learn from past mistakes and progressively move past them with targeted action plans.
Examples of collaborations that may aid in this sense include private–private, private–public (e.g. nonprofit or government), and public–public partnerships. As an example of a private–public collaboration, the Government of Canada issued R and D grants via its “Innovative Solutions Canada” program to accelerate R and D supporting the treatment and mitigation of COVID-19. Similarly, Shastri Indo-Canadian Institute established similar innovation grants to aid in the treatment of COVID-19 with a mandated bi-national focus. Less popular are private–private partnerships and public–public partnerships; however, given the impact that COVID-19 has had on the private sector, this certainly begs the question as to why more private–private partnerships have not been seen. To this end, PWC hosted the “COVID-19 Private Sector Global Facility” to bring together members of the public and private sector in concert with The United Nations Development Programme, the United Nations Global Compact, and the International Chamber of Commerce being established
The longstanding positive relationship and cultural ties between India and Canada, as well as the significant medical expertise amassed by both countries, presents both an opportunity and significant challenges in terms of sharing of knowledge, resources, and disseminating this to address the still-growing issue of the pandemic. As we saw with the announcement that India would be supplying Canada with the lion's share of its Oxford/AstraZeneca vaccine branded as “CoviShield,” this was a win for international relations between the two countries. Indeed, Canada reciprocated this gesture with a $10M care package to the Indian Red Cross, which brought India essential medical supplies during its time of need. While these efforts to help each other were a positive sign of collaboration and camaraderie among nations, still more can be done to leverage the strengths of both nations collectively.
From a vaccination standpoint, given that India has one of the oldest, most extensive, and most effective vaccine distribution networks in the world, India has the potential to educate Canadian policymakers on best practices. As noted by many leading experts, India is leading the way in terms of its vaccination program via the Serum Institute, and many countries are now following its example and hoping to partner with India to bring down manufacturing costs to enable wide-scale distribution.
| Canada-India Healthcare Summit Day 2 (May 21, 2021) – Speaker Summaries|| |
As part of the Canada India Healthcare Summit (CIHS), expert speakers from the USA, Canada, and India were invited to present on novel areas of biotechnology advancement in the treatment of COVID-19. These seven talks were moderated by panel members from the CIHS Biotechnology Working Group and are summarized in this appendix.
Dr. Deborah Fuller, Professor, University of Washington, USA
Next-generation COVID-19 DNA and RNA vaccines to combat new variants and for worldwide distribution
Dr. Deborah Fuller provided insight into vaccine strategies to combat new variants. The various types of vaccines available include mRNA, viral vectors, inactivated, and protein subunit-based vaccines as described in Vaccine section of this paper. In general, the vaccine strategy leverages two immune defenses to combat COVID-19: (1) produce antibody responses to prevent the virus from infecting a cell and (2) T-cell responses which detect and kill infected cells. With the rise of variants, the latter immune strategy of T-cell responses is thought to be critical in maintaining vaccine efficacy. By recognizing conserved epitopes, T-cells are able to target variants largely abolishing the variants' ability to evade host immune responses. Nevertheless, the emergence of new variants is expected ongoing viral replications through new infections. As such, it is critical to develop second-generation vaccines. An ideal second-generation vaccine should induce immunity through one-dose, long-term antibody and T-cell responses and is equally effective across multiple demographics, ability to rapidly scale up and stable at room temperature. Currently, the Fuller Lab is hard at work to develop three second-generation vaccines that fit the ideal criteria listed.
The first type of vaccine is self-amplifying RNA vaccines (repRNA) which are cost-effective, immunogenic, and require 4° storage. As traditional RNA vaccines deliver a single strand, the repRNA vaccine is coded with replicase which instructs the RNA to amplify copies of itself provoking innate immune responses as well as enhancing viral protein transcription and translation. As many countries do not have access to deep-frozen storage of vaccine vials, the Fuller Lab in collaboration with HDT developed a novel nanoparticle formulation (LION) where the RNA is on the particle surface instead of inside the particle. This is highly advantageous with rapid scale-up, easily sourced materials, and longer room temperature shelf-life with 3 weeks. The Fuller Lab has conducted pilot studies using this technology and has observed positive results with no adverse events, sustained antibody response for 7+ months after a single dose, strong response in aged animals, and sustained protection for 7+ months in nonhuman primates. A second vaccine consists of stable room-temperature DNA and repRNA vaccines and is self-administered via a needle-free gene gun called “supersonic” co-founded by Orlance Inc. As COVID-19 is considered to be an ongoing endemic, another vaccine in development is a pan-coronavirus nucleic acid vaccine which would create a basal level of immunity to prevent severe coronavirus disease, essentially protecting individuals from future pandemics. With the likely event of COVID-19 being a re-occurring pandemic, there is a need for innovation and development of second-generation vaccines like those under development in the Fuller Lab that are immunogenic, effective, and easily distributed.
Dr. Andre Boulet, President/CEO, Devonian Health Group, Canada
Cytokine storm in COVID-19: The prospect for botanical drug's polymolecular approach
Through Dr. Andre Boulet's presentation, the session was enlightened on the impact of COVID-19 cytokine storm on patient health and prospective strategies to tackle this. Respiratory symptoms in severe COVID-19 patients can be accompanied by symptoms of hyperinflammation and cytokine storm, unfortunately leading to multiple organ failure. Binding interactions between the virus and ACE2 receptor can disrupt the reactive oxygen species pathway, consequently initiating communication between dendritic cells, triggered macrophages, neutrophils, and activated T-cell to produce an influx of cytokines. As such, targeting this cytokine storm presents a unique opportunity to decrease COVID-19 adverse events and fatality.
One therapeutic strategy is antivirals. In particular, remdesivir is the only FDA-approved drug which significantly decreases recovery time from 18 days on placebo to 12 days in severe disease cases. Currently, there are no FDA-approved antiviral therapeutic approaches to treat patients with all stages of disease. In addition, several therapeutic strategies are being investigated to target cytokine storms through interleukin receptor blockers, alpha-HMGB inhibitors, broad-spectrum chemokine inhibitors, COX inhibitors, corticosteroids, platelet activating factor inhibitors, and upregulation of fork head box protein 3. All of these regulate detection and recruitment of immune cells, especially upregulation of T-cells. An emerging candidate for cytokine storms are JAK inhibitors which present two clinical advantages of inhibiting cytokine signaling as well as simultaneously targeting an ACE2 regulator, AP2-associated protein kinase-1. While dexamethasone has shown positive results in moderately to severely ill hospitalized patients, dexamethasone demonstrates a negative impact in mild-to-moderate disease, highlighting the need for specific therapeutic approaches based on COVID-19 severity.
A main aspect of viral infections is an imbalance in redox homeostasis. Interestingly, glutathione (GSH) is a master antioxidant in all tissues with critical functions in both innate and adaptive. In fact, lower GSH levels are associated with increased susceptibility of infection and deficiency in GSH has been linked as the most likely cause of serious COVID-19 cases. COVID-19 mortality is known to be higher in males, elderly, and those with chronic diseases. Intriguingly, GSH levels are known to be lower in males and chronic disease patients. As such, the GSH pathway presents a target to regulated redox pathways and thereby immune responses to fight viral infections. Thykamine is a novel botanical drug extracted from baby spinach leaves composed of pigments, proteins, lipids, and phenolic compounds which contain anti-inflammatory, antioxidant, and immunomodulatory properties. Thykamine serves as an antioxidant, lipid inflammatory mediator, decreases inflammatory biomarkers, cytokines, Th1/Th2 ratio, neutrophil activity as well as prevents lymphocyte apoptosis, and has direct intracellular effects. Future research is investigating the impact Thykamine can have in intensive care unit (ICU)-admitted patients. Collectively, multiple targeting therapeutic approaches through combinations of antivirals, anti-inflammatory drugs, and botanical drugs are needed to target COVID-19 across all levels of diseases and prevent adverse events such as cytokine storms.
Dr. Anurag Agarwal, Director, CSIR-Institute of Genomics and Integrative Biology, India
Dr. Anurag Agarwal provided an important perspective on why genomics and informatics are absolutely critical in the fight of COVID-19. As an RNA virus, COVID-19 is bound to mutate and change. Although COVID-19 did not mutate much in the beginning, if a low mutating virus is able to infect enough people and thus replicate enough times, a virus is bound to mutate. As such, more transmissible variants arose, and with this, the previous strain of COVID-19 was eliminated with the shift of the original A lineage to the B lineage. The WHO emphasized the need for sequencing to identify the strains of the virus, investigate spread, study virus evolution, and understand changes in its behavior including infectivity, severity, and immune escape. The first variant of concern was B.1.1.7 sequenced first in the United Kingdom. With the arrival of this variant, the reproduction number which describes the number of people an infected individual will infect exploded. During this period, India streamlined their efforts to set up their consortium activity through Indian SARS-CoV-2 Consortium on Genomics. Currently, there are five variants of concern: (1) B.1.1.7. sequenced in UK, B.1351 sequenced in Africa, B.1.617 sequenced in India, and B.168 sequenced in Brazil. It is important to note that the country that sequenced the variant may not be the country of origin.
As India continued to battle COVID-19, sequencing allowed scientists to identify the differences in variants between Northern India and Western India. While Northern India was dominated with B.1.1.7, Western India was dominated by B.617. Interestingly, using sequencing, scientists were able to conclude that identical virus samples were found from different districts of Northern India, indicating a massive gathering had occurred which led to massive spread. However, the recent outbreaks are neither of the two found previously. In fact, an adapted variant similar to B.617 that lost some mutations arose called B.617.2. Initially found in Maharashtra, the B.617 variant contained two nucleotide changes in spike proteins L452R and E484Q. Although L452R was thought to increase transmissibility and E484Q to improve vaccine escape, scientists were wrong. While E484Q has been lost, a new sublineage of T478K exists that is the dominant lineage today and the L452R mutation increases transmissibility from 1.25 to 2. As we globally witness the rise of variants in various countries, including Canada and India, stretching the healthcare systems, it is critical to realize that there are no boundaries in this global world. Using these tools, countries can stay ahead of the virus and take appropriate actions to prevent COVID-19 and future pandemics.
Dr. Arun Shrivats and Debshish Talukdar, Directors, Prescient Healthcare Group, USA
Biotechnology contributions to overcoming COVID-19
Dr. Arun Shrivats and Mr. Debshish Talukdar asked five key questions that they believe should be considered by both Canada and India to overcome COVID-19. These questions target various aspects, including overcoming COVID-19, building COVID-19 toolkit, crafting COVID-19 response, managing COVID-19 aftermath and Canada-India collaboration. The first question is “What is a bold, yet realistic ambition” to overcome COVID-19. This entails understanding the shape of recovery as previous pandemics have each caused multiple waves with increased mortality for 2–5 years. In other words, although the acute impact occurs in 12–18 months, there is a broader effect that takes place over several years. As such, the burden of COVID-19 and opportunity associated with it are not over and (2) we must never forget and learn from this. The second question asks “What opportunities exist beyond vaccines?” in a COVID-19 tool kit. In addition to preventing COVID-19 through vaccine rollout, there are protective therapy opportunities including novel immune modulators, predictive, prophylactic, and prognostic tools for adverse events. Furthermore, promotive opportunities can aid in decreasing severity through individual and societal well-being including weight loss and clean air as impaired lung function and obesity lead to adverse COVID-19 events. This provides opportunities to indirectly tackle COVID-19 by targeting factors such as comorbidities to decrease disease mortality and morbidity.
The third question inquires “How do we craft collaborations outside national boundaries?” in crafting the COVID-19 response. Challenges associated with waiving intellectual property protections, sharing technology and raw materials must be examined to promote collaboration in the hunt for a solution. The fourth question explores “What compromises our new national healthcare priorities?” in managing the COVID-19 aftermath. There are obvious impacts of COVID-19 on healthcare infrastructure which demands establishing biotechnology research centers, increasing manufacturing capacity, improving emergency preparedness, investing in clinical care and research talent as well as international and global collaboration. However, there are also priorities in healthy living infrastructure that needs to be addressed, including the obesity crisis, clean air for cities, open spaces, mental health support, work–life balance, financial health, and prosperity. Finally, Dr. Shrivats and Mr. Talukdar questioned, “What are our roles in shaping a safer, COVID secure future” with an emphasis on Canada and India collaboration. Two critical resources to secure a safer future include software and hardware, people and skills as software and tools and technologies as the hardware. In addition, countries must promote (1) academic collaborations to advance research into tools and technologies, (2) health systems and policy collaboration with think tanks to shape policy, and (3) industry-academia collaboration as demonstrated by Oxford University-AstraZeneca and Serum Institute of India. By addressing these questions and investing in the necessary infrastructure, people, and technology, both Canada and India can learn from COVID-19 and be prepared for the future.
Dr. Paul Hodgson, Associate Director, VIDO (Univ. Saskatchewan), Canada
A national resource in Canada's COVID-19 response
Dr. Paul Hodgson presented a national resource in Saskatoon, Canada, which has played an instrumental role in vaccine production and medicine. An integral part of University of Saskatchewan, VIDO is a world-class facility with over 45-year history in veterinary medicine applied to model human diseases and has commercialized eight vaccines included Vicogen™ for Escherichia coli. With a significant containment capacity and access to diverse employees with world-class expertise from 25 countries, VIDO has contributed substantial efforts toward COVID-19. With some of the largest containment level 3 facilities and animal holding rooms, VIDO has played a key role as a developer and enabler for mobilizing science and technology for COVID-19. This included being the first to isolate the virus in Sunnybrook and National Microbiology Lab, the first to establish animal challenge models required for clinical trial applicators and drugs as well as the first Canadian university to conduct Phase 1 trials. Open to collaboration and mobilizing information, VIDO is not only a member of three WHO expert groups that meet weekly but also has assisted over 100 groups with antivirals, vaccines, and therapeutic advice, 50% in Canada and 50% international including India. One such advice is to look at body weight postviral challenge to get an early insight into the efficacy of the vaccine. An effective vaccine should block weight-loss postchallenge.
As VIDO continues to contribute to innovating, collaborating, and developing technology to aid with fighting diseases such as COVID-19, they are continuously striving to learn and better prepare for the future. To prevent the large socioeconomic impact of a pandemic, nations must invest to mitigate future threats and act in a faster manner. In addition, creating a national/global center for pandemic research, including expanding animal capacity to include exotics, expanding facilities for containment level 3 and 4 manufacturing and integration. Investing into a manufacturing facility will streamline the process of innovation to products. At VIDO, experts are continuing to manipulate science, biotechnology, structural virology, bioinformatics, and artificial intelligence to predict viruses and produce broadly effective vaccines while expanding opportunities of collaboration, synergistic technologies, and trainee and scientist exchanges.
Subbu K. Vasudevan-Lead Medical Affairs and Nutraceuticals of Murugappa Groups
Spirulina - Daily support to our defense system
Spirulina is a blue-green alga belonging to cyanobacteria. This is one of the wonderful future food sources for the last 40 years which is utilized by many of the food industries. Dosage of spirulina is about 3–10 g in metabolic syndrome conditions and has been widely used around the world. Spirulina has food source contains 60% of protein (all the essential amino acid), vitamins, minerals and fatty acids (gamma-linolenic acid-key FA%), and pigments, which is the major part entire spirulina baggage (carotenoids, chlorophyll-A, C-phycocyanin).
A systematic review was done for the understanding of spirulina as a food source and how beneficial it is for human consumption.
In vitro and in vivo studies of the antiviral property of spirulina have been done to provide a brief explanation of this food source. The extracted spirulina has a certain amount of antiviral property which is seen on most of the respiratory tract viruses such as influenza and measles. These were tested in the lab with the help of hemagglutination inhibition assay wherein the minimal inhibitory concentration was close to 50 μl/mg. Animal trials were also done with this condition. Therefore, some kind of antiviral property was found in spirulina polysaccharide which is the extract from spirulina. Simultaneously, human studies were conducted with HIV-infected individuals in Cameroon, where 100+ patients were enrolled in the study. One group was given antiretroviral therapy along with spirulina 10 g/day. Another group was given antiretroviral therapy along with protein diet. This study was done for 12 months and the CD4 counts were noted down for both groups. It was found the CD4 count did not fall when the individuals consumed spirulina, and also, the viral load was decreased. Spirulina, in cellular level experiment, is found to improve the antioxidant property, improve the superoxides and improve the catalase enzyme.
Phycocyanin and COVID-19
Phycocyanin being a natural product has the propensity to bind to the active site of the NSP. Microbial modulating activities of spirulina could prevent dysbiosis. The antibacterial activity of spirulina could protect the host from infections. Alterations of gut microbial composition also result in changes in the metabolites generated in the gut from microbial activity, essential for gut homeostasis.
Dr. Manoj Nesari, Advisor (Ay) - Ministry of AYUSH
Evidence-based Ayurveda intervention for COVID-19
AYUSH 64 is a medicine for COVID-19 that has been introduced in the market. In 1984, this product was used for malarial fever and over the years was found to be very effective in treating viral fever, thus was considered for treating COVID-19. Large clinical trials as well as the other laboratory studies have been conducted by the Ministry of AYUSH in collaboration with the Department of Biotechnology as well as with the Council of Scientific and Industrial Research (CSIR). AYUSH 64 contains four medicinal plants, Picrorrhyza, Alphenia, Swertia chirata, and the Alstonia scholaris. It is a polyherbal formulation developed by the Central Council for Research in Ayurvedic Sciences, which undertook extensive pharmacological toxicological examination at the same time in clinical studies. Following this examination, the Ministry of Health and the Ministry of AYUSH, Government of India, jointly launched the national protocol for COVID-19 management, including AYUSH 64 as a COVID-19 medicine.
Some studies of AYUSH 64 in use for treating COVID-19 were:
- AYSUH and CSIR collaborative study was conducted at KGMU, Lucknow, DMIMS, Wardha, BMC COVID Care Centre, Mumbai. The experiment was conducted with a sample size of 140, treating people with AYUSH 64. The subjects showed an improvement
- Another experiment was done in Governmental Medical College, Nagpur. The recovery rate was 36% on the 7th day, 60% on the 15th day, 72% on the 22nd day, and 100% on the 30th day. It was also found that the reduction level of IL6, D-dimer, and TBF alpha was statistically significant
- Another study was done in A and U Tibbia College, New Delhi. This also showed a great recovery rate of 97.2% in 14 days through consumption of AYUSH 64
- Another study was conducted at Guru Govind Singh Government Hospital, Jamnagar, with a sample size of 80, and this also resulted in a good recovery rate
| References|| |
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