COVID-19: Visible Arrows, but Still in the Quiver

The pandemic outbreak has caught almost the entire global population on the hop. The rare retreat from the regular has sent the world in a tizzy. However, while this indefinite hiatus has put a halt on the “natural” course of actions, the research community is far from slowing down. In fact, a wide range of players have actively participated in the race to develop treatments related to COVID-19. Pharma and healthcare companies are in the mix, with other prominent universities and institutes.

The present generation is baffled for there is more ‘mystery’ around a novel virus than the UFOs. Notwithstanding this staggering encounter, the scientists and researchers have been using every muscle to demystify this virus. There has been a serious uptick in the research efforts to understand and control the SARS-CoV-2 virus. The genomic sequence of SARS-CoV-2, published by Chinese scientists on a public data repository in its very initial days, was a head start in this direction.¹ Moreover, the virus was promptly identified as betacoronavirus with a genomic sequence [3]closely related to that of the severe acute respiratory syndrome (SARS) coronavirus from 2003. However, the current literature and previous experiments have not been sufficient in preparing an elixir to stop the spread of this disease. Furthermore, the virus has manifested itself through a whole range of symptoms from respiratory to cardiac to renal to GID or has even gone undetected. With such a large portfolio of symptoms, the medication for this disease is still in an evolving state.²

As WHO describes it - ‘the virus is so new and different that it needs its own vaccine’.³ Until we reach that goal, existing drugs and therapies are being deployed at the experimental stage to curb the virus in the very first wave of pandemic.

1. Prophylaxis or preventive treatments are being devised as a response to the present state of emergency. These strategies are based on repurposing existing techniques and drugs. In the current scenario, it has been observed that the experimental antiviral therapy, together with the availability of intensive care unit beds in hospitals and rigorous government control measures, play an important role in dealing with this virus.⁴
   1. Antiviral therapy is essential to stop the virus from replicating itself in the host. Antiviral drugs such as remdesivir, which has been identified as the primary candidate and is undergoing clinical trials for its anti-SARS-CoV-2 effects. This drug has been previously administered to Ebola virus patients.⁵ Remdesivir has worked against corona viruses in animal models, as well as against the related MERS-CoV, including in NHPs. It’s likely effect on SARS-CoV-2 will likely terminate RNA synthesis, or lead to incorporation mutagenesis (genetic mutation), or both.⁶

      Other anti-virals like favipiravir and co-administered darunavir and umifenovir (in patient therapies) were also recently recorded as having anti-SARS-CoV-2 effects.⁷ French doctors had observed anti-malarial drug chloroquine and hydroxy-chloroquine to have antiviral effects in the case of COVID-19, which was further touted by the US President Donald Trump. However, due to weak evidence of benefits and potential side-effects of this drug, WHO has suspended the use of this drug to treat coronavirus infected patients.

      Pharmaceutical firms around the world are coming together to upscale the production of these antiviral drugs. Indian firms, including Cipla, have begun making favipiravir, an antiviral drug developed by the drugs arm of Japan’s Fujifilm. Other firms including Dr Reddy’s Laboratories, Jubilant Life Sciences and Strides Pharmaceuticals are tying up with American firms for the production of remdesivir.⁸

   2. Protease Inhibitors: These are a class of antiviral drugs which prevent viral replication by selectively binding to enzymes used by coronavirus to replicate itself in the host. A combination of the two licensed HIV inhibitors, lopinavir and ritonavir, is also being tested in clinical trials. Lopinavir is a bona fide protease inhibitor, whereas ritonavir was initially designed as protease inhibitor but was found to boost the half-life of lopinavir.⁹
   3. Convalescent Plasma: As a part of another investigational treatment, convalescent plasma is being collected from the patients who have recovered from COVID-19. Serological tests are being carried out to check for the presence of antibodies in the blood of these patients, who can be potential donors of convalescent plasma. Through the transfusion of plasma, passive immunity can be induced in the patient. ¹⁰

      These antibodies are important to fight back the virus before it starts replicating itself in the body. Antibodies are five different types of (glyco) proteins which serve to either neutralise the toxin in the pathogen or opsonise the pathogen.¹¹ Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19. ¹²

   The long haul of all the efforts is to achieve desirable vaccination coverage in order for herd immunity to be in effect. The criticality of vaccines for public health and world economy is uncontested in the present day. Vaccines have been instrumental in preventing the resurgence of infectious and virulent diseases. The more people are immune to a disease, the less likely it is to proliferate. Scientists, firms, regulators and individuals are coming together in an unprecedented global effort to develop vaccines for the current pandemic that has grappled all the countries alike. There is a hope that the realisation of a vaccine will be faster owing to the advances that humanity had made before a novel virus brought it to a halt.

2. Vaccines: To set the tone right, there are no existing vaccines or production processes or large scale manufacturing capacity for coronavirus vaccines as yet. Even if we cut through the vaccine trial design for parts where sufficient data on similar vaccines is available or by accelerating regulatory approvals it will still take another few months, if not years to come to realisation. To ensure that the developed vaccines conform to the safety and efficacy standards, it must be done in a manner compliant with Good Laboratory Practice. Thereafter, current Good Manufacturing Practice (cGMP) needs to be followed to ensure constant quality and safety of vaccines.¹³ Finally, scalability, among other factors, needs to be taken into account until the vaccine is approved. In critical times, compassionate use is an option to make the limited number of doses available to health care workers and the most vulnerable segments of the population.

Edward Jenner, in the late eighteenth century, created the first successful vaccine against smallpox after showing that infectious material when inoculated into the arm of a young boy could prevent the young boy from acquiring the life-threatening virus. A century later, the father of immunology, Louis Pasteur produced an attenuated form of the virus, which he then used for immunization. These traditional ways have successfully contributed to the realisation of vaccines to eliminate infectious diseases in a population. However, since the 1980s, new technologies have made more complex vaccines possible. Technologies such as recombinant DNA, glycoconjugation of polysaccharides, reverse vaccinology and next-generation sequencing along with synthetic biology have been paving the way for the future of vaccine development. ¹⁴

Conventional approaches to develop vaccines have mostly been based on the cultivation of the microorganisms in vitro and only abundant components can be isolated by using biochemical and microbiological methods.¹⁵ However, with the advent of whole-genome sequencing, gene-engineering and advances in bioinformatics, one of the ways to develop a vaccine is by using a part of the virus or bacteria, like in the case of hepatitis B vaccine. The vaccine is composed of a protein that resides on the surface of the virus. This strategy can be used when an immune response to one part of the virus (or bacteria) is responsible for protection against disease.¹⁶

In the case of SARS-CoV-2 virus, scientists have sought this very technique. The previous studies for SARS-CoV-1 and the related MERS-CoV vaccines have identified the Spike glycoprotein or the S protein on the surface of the virus as an ideal target for a vaccine. The structure of the S protein, found in SARS-CoV-2, was solved in record time at high resolution. This has further contributed to our understanding of this vaccine target.¹⁷ By introducing the S protein via a vaccine, it is possible to activate the immune system against S protein in case of an actual viral attack. In the pipeline are the following candidates for a COVID-19 vaccine.

Live attenuated vaccine: Vaccine containing live but weakened virus- that has been cultivated under conditions that disable its virulent properties or which use closely related but less dangerous organisms to produce a broad immune response. E.g. -measles.

Inactivated virus vaccines: Vaccine containing inactivated or ‘killed’ virus, by means of heat or other chemicals. However, in this process, it is important that the antigen (S protein in this case) integrity is maintained even after the virus is out through the reaction. E.g.- Hepatitis A.

Recombinant viral-vector-based vaccines: Vaccine which uses weakened or harmless bacteria and viruses to stimulate the immune system. BCG or adenovirus is being investigated for this vaccine. ¹⁸

Recombinant-protein-based vaccines: Vaccine which uses recombinant proteins to introduce the antigen to the human immune system. E.g.- Hepatitis B.

DNA vaccines: Vaccine created by using a DNA molecule (Plasmid) to make a genetic blueprint of the virus. This DNA plasmid when injected into human cells, uses the instructions to make virus antigens that the immune system reacts to. There is no existing human vaccine using this platform. A company named Inovio and Applied DNA Sciences has launched clinical trials for this vaccine against MERS.¹

mRNA vaccines: Vaccine which uses a Messenger RNA (encapsulated in lipid nano-particles). When injected in a person, mRNA will use the cell's mechanisms to produce more S proteins and simulate a response. This has been the most promising and novel lead on COVID-19 vaccine so far. It is being co-developed by Moderna Therapeutics and the Vaccine Research Center at the National Institutes of Health, is currently the furthest in this quest.²⁰

The next generation technologies and platforms which are being employed for the development of these vaccines also suffer from a serious limitation. These technologies have not yet been used extensively to comply with safety nor can they be relied on for mass production. This is likely to increase the risks associated with delivering a licensed vaccine, and will require careful evaluation of effectiveness and safety at each step.

Clinical trials-What takes so long?

Before bringing a vaccine into clinical trials, the vaccine is tested in appropriate animal models to see whether it is protective. COVID-19-specific animal models are being developed, including ACE2-transgenic mice, hamsters, ferrets and non-human primates.

Pre-clinical stage: in vitro- human cells are cultured to check the toxicity of the drug on human cells.

Phase 0: in-vivo- less than 15 people are given tiny dosages. This safety check is done on healthy people (healthy implies sound immune systems and no co-morbidities).

Phase 1: Dose check- includes 20-80 individuals to check the highest tolerable dose that can safely be given. This phase also checks for routes of administration.

Phase 2: Working with a larger cohort of about 100 patients (not necessarily infected or recovered from COVID-19).

Phase 3: Drug comparison- more than 3000 patients are included in this phase. According to the FDA, only 33% drugs are able to make it from P2 to P3. The method followed for the comparison is a double blind study.

After this comes the approvals, however even after the drug is out for sale, it is continuously monitored under the Phase 4. ²¹ Also protective immunity is reached will be achieved only 1–2 weeks after the effective number of doses of the vaccine is given to the patient. The effective number of doses will likely be two or more than two, since the population is still naive to SARS-CoV-2.

Current status of Clinical Trials

Lead developers of active COVID-19 vaccine candidates are distributed across 19 countries.²² Given below are some of those developers who are ahead of the pack.

University of Oxford-Astra Zeneca (P1) - ‘ChAdOx1 nCoV-19’ is a recombinant viral vector vaccine which uses ChAdOx1- a weakened version of adenovirus (common cold virus) that causes infections in chimpanzees- with S proteins, to generate a response from the body’s immune system. The vaccine, so prepared, has been genetically changed so that it is impossible for it to grow in humans.²³

Britain’s Astra Zeneca is leading the group of global firms that have come together to develop this vaccine. The US government has announced an investment of up to $1.2 billion to expedite the delivery of the vaccine.²⁴ The group has further teamed up with Indian and European companies to diversify its manufacturing capabilities. The Serum Institute of India, which is the world's largest maker of vaccines by volume, has been closely working with the researchers at Oxford. The institute has already taken the responsibility to scale-up the production of the vaccine, once the trials are completed. It has procured mass-manufacturing facilities to create stockpiles of cheap vaccines available for low- and middle-income countries. It has announced the production of 40mn-50mn doses by September.²⁵

Moderna Therapeutics (P1): P2 for the novel m-RNA vaccine has been approved by the FDA. The U.S. government pledged up to $483 million to speed mass production if the trials go well.²⁶ The company recently claimed that eight subjects successfully generated an immune response in the Phase 1 trials of the vaccine. However this claim was not supported by any data, which is awaited in the scientific community.²⁷

PFizer and Biontech (P1) : are working on four vaccine candidates, each representing a different combination of messenger RNA method and target antigen. The trials are ongoing with an emphasis on scalability as well.²⁸

Sinovak (P2) : Beijing-based Company, having tried the chemically inactivated vaccines on rhesus macaques, has started human trials. The company is seeking WHO permission for P3 in severely affected areas.²⁹

Other prominent names in the development of COVID-19 vaccine include Johnson & Johnson, Sanofi and GlaxoSmithKline and Novavax. Governments have been keenly eyeing these developments while heavily investing to speed-up the development process.

Paradigm Shift

This novel coronavirus has allowed rather novel paradigms to accelerate recovery and development from a global crisis situation. The global R&D efforts against the pandemic have been unprecedented in terms of scale and speed. But even as we are acquainted with daily breakthroughs we must not break away from the larger reality. We cannot outpace the stipulated mandates which ensure safety and efficacy rendered by the vaccine. Therefore, we need to practice caution against a hurried approach for the development and employment of this vaccine.

The absence of a specific drug is a glaring opportunity to re-establish and revive alternative medicine systems. The Traditional Chinese Medicine (TCM) has been into R&D on handling new pandemics, while receiving a validation from the WHO. The WHO has welcomed scientifically proven traditional medicine for COVID-19 treatment while being thoroughly tested. The call for interdisciplinary approach to virus research creates substantial space for the Indian Systems of Medicine (ISM), especially Ayurveda owing to its holistic approach to disease management. ³⁰ At this point, ISMs can reclaim their rightful spot in the landscape of modern medicines with the right R&D support from the government.

Also, there is a greater need for international coordination and cooperation for the final distribution and administration of the licensed vaccines. The passion displayed by the scientific community must be translated into compassion by the political leaders. The benefit of this development must not be kept away from Low Income and Middle Income Countries. Sufficient and equitable resources must be made available to all affected as well as vulnerable populations. In the past many global organisations including Global Alliance for Vaccines and Immunization (GAVI), the Vaccine Fund and the Bill & Melinda Gates Foundation have come together for this cause and this spirit only needs to be boosted in the contemporary phase.

More importantly, post-COVID period requires a major shift in the investments that are made in vaccines against emerging viruses that can lead to loss of human lives and burden the global economy. We must seek a political will and vision to churn out vaccines for use in the global population quickly and effectively, potentially stopping an emerging virus in its tracks. The takeaways from this experience must be used to recoup the existing gaps in the health and supply structures.

References

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7. Supra 4
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9. ibid<.li>
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15. ibid
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20. ibid
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