Race for Reining Corona:
Oxford Vaccine May Win It

Bibekananda Ray

Even after four months of raging since its journey on 20th December 2019, there is no respite from NCOVID’19 which is now running amok in at least 185 countries in five continents. Its epicentre was Wuhan city of Central China and its first victim a woman sea-food vendor in the city’s wet market of live animals in December 2019. Soon more market employees were infected and from tiny coverage in inside pages, the viral disease soon made banner headlines in the media in every country, it spread to- Italy, Spain, Germany, France, the U K and other European and African as well as Asian countries and crossing the Atlantic to the continent of America. It has united 7.8 billion people all over the world in fear and resolve to fight and defeat it. In India, it has edged out the news and views on Delhi riots, the CAA, the NPR and the NRC. Like the WHO, New Delhi did not initially foresee its lethality when the first three cases, all of students returned from Wuhan University, were reported from Kerala. As it is a new virus, the UN body admits gaps in its knowledge, e.g., its path to human body, its origin and transmission, whether it is natural or man-made, whether it thrives in heat or cold and whether it will die naturally, lose its fang or go dormant. It does not foresee an early end to it until and unless a vaccine and drug are found and successfully tested and applied on human beings. A WHO spokesman says, like other viral diseases, it will not wholly disappear from the earth but will continue to erupt and break human resistance, like malaria, polio, HIV and Ebola.

Race For Vaccine
A race for developing a vaccine is now on in many of the affected countries including India. In this, the Jenner Institute under Oxford University, UK seems to be at the head, as has announced human trial of the one it has developed and named ChAdOx1, beginning with on two lady scientists- Prof. Sarah Gilbert and Elisa Granato- who are ‘optimistic’ of its success. The institute recruited over 800 volunteers for human trial; if it works, it could be available to doctors by middle of next year. Developed from a weak strain of adeno virus that causes common cold in chimpanzees, it has been muted for human application. A larger trial on about 5000 volunteers is to be launched in coming months; half of them will be given the vaccine for the SARS-COV2 virus, four strains of which are now circulating. The other half of volunteers will be administered a vaccine against meningitis for comparison.  The Institute had previously developed a vaccine against MERS, using the same technique. Around the world, some 80 groups are engaged in researches to develop vaccine and drug to stymie Corona pandemic. The first human trial for a vaccine was launched by scientists in Seattle, USA, unsuccessfully.

Around 29 major institutes and pharmaceutical companies that are now engaged in researches for vaccine are (names of vaccines, wherever available) : National Institute of Health, USA, Jenner Institute, University of Oxford(ChAdOx1),  Inovio Pharmaceuticals, USA (INO-4700 ), Entos Pharmaceuticals (Fusogenix), Gilead Sciences (Remdesivir),   National Medical Products Administration of China (Favilavir), Roivant Sciences ( Gimsilumab), Altimmune with the University of Alabama (Ad COVID), Tiziana Life Sciences (TZLS-501 ),  Oya Gen (OYA1), Beyond Spring (BPI-002), Altimmune, USA, Inovio Pharmaceuticals with Advaccine Biotechnology Company, Beijing (INO-4800 ), Algernon Pharmaceuticals (NP-120 Ifenprodil), Advaccine, Beijing, APEIRON Biologics, China ( APN01),  Moderna & Vaccine Research Centre, MIGAL Research Institute, Israel, Tonix Pharmaceuticals with Southern Research, Clover Biopharmaceuticals with GSK, Innovation Pharmaceuticals  (Brilacidin), Vaxart, CytoDyn (Leronlimab PRO 140), Linea Rx and Takis Biotech , Novavax, Generex, I-Mab Biopharma (TJM2) and Integral Molecular and AJ Vaccines.

Inovio Pharmaceuticals with Gene One Life Science is developing an intramuscular vaccine, using the Cellectra® delivery device. It has received a $5m grant from the Bill and Mellinda Gates Foundation to accelerate the development of the delivery device. It is well-tolerated and demonstrated high immune responses against the MERS-CoV in 94% of patients in the early-stage clinical trial in July 2019. It also generated broad-based T cell responses in 88% of the subjects. The company is collaborating with Beijing Advaccine Biotechnology Company to advance the development of the former’s vaccine, INO-4800. A clinical trial is planned to be conducted in parallel in China, by Beijing Advaccine. Generex is developing a vaccine following a contract from a Chinese consortium and will utilise its Ii-Key immune system activation technology to produce a peptide for human clinical trials.  Entos Pharmaceuticals is to use its Fusogenix drug-delivery platform that injects genetic payload directly into the cells, containing multiple protein epitopes, derived from SARS-COV-2 proteins to stimulate immune response in the body. Roivant Sciences is developing Gimsilumab, a monoclonal antibody that targets granulocyte-macrophage colony stimulating factor (GM-CSF. Altimmune with the University of Alabama is developing a single dose intranasal vaccine.  Tiziana Life Sciences is developing a monoclonal antibody that reduces lung damage. Oya Gen’s OYA1 has been tested successfully in laboratory. Beyond Spring is developing a small molecule agent that will activate CD4+ helper T cells and CD8+ cytotoxic T cells and enhance immunity. Design and synthesis of Altimmune’s intranasal vaccine have been completed; now animal testing will follow. Moderna with Vaccine Research Centre is developing a vaccine to target Spike (S) protein of coronavirus. Phase one human clinical trial began on 16th March at the Kaiser Permanente Washington Health Research Institute in Seattle, Washington. MIGAL Research Institute of Israel has developed an Infectious Bronchitis Virus (IBV) vaccine which is being modified to treat COVID-19. Tonix Pharmaceuticals with Southern Research has innovated a modified horsepox virus, using company’s proprietary horsepox vaccine platform. Innovation Pharmaceuticals’ vaccine showed antibacterial, anti-inflammatory and immune-modulatory properties in clinical trials. Clover Bio-pharmaceuticals is collaborating with GSK to develop a recombinant sub-unit vaccine using its patented Trimer-Tag© technology. The company identified antigen-specific antibody in the serum of fully recovered patients who were previously infected by the virus. Vaxart is developing an oral recombinant vaccine in tablet formulation, using its proprietary oral vaccine platform, VAAST. Linea Rx and Takis Biotech are trying to develop a linear DNA vaccine. Novavax that received $4m from the CEPI has produced several nanoparticle vaccine candidates for testing in animal models and aims to carry out human trials this year. It is designed to primarily bind to the major surface S-protein and developed using its recombinant nanoparticle vaccine technology. Generex will receive an upfront payment of $1m to commence the groundwork for the vaccine development and $5m licensing fee for its Ii-Key technology. I-Mab Biopharma is developing a neutralising antibody to treat cytokine storm in patients suffering from coronavirus infection. Integral Molecular is using its two technology platforms- Shotgun Mutagenesis Epitope Mapping and the Membrane Proteome Array to understand human immune response to the coronavirus and isolate the cellular receptors that enable the virus to spread quickly. AJ Vaccines launched the development of a vaccine against COVID-19. The company will use the latest technology to develop antigens that can mimic the native structures of the virus. The vaccine will be capable of inducing a strong immune response in the body thereby protecting against the infection. Australian researchers are injecting two potential vaccines on ferrets; human trials are in the offing.

Therapy May Be Further Away
More than a vaccine, i.e., a preventive, more urgently required are medicines for relief and cure. A silver lining in this unremitting gloom is the increasing number of the infected getting cured, one in four or five. The media should highlight these figures more to boost the morale of the infected and of the medical community, while the human trial of the Oxford vaccine continues. Hydroxychloroquine, a patent of Bengal Chemicals, Kolkata, which India is supplying to the USA and other countries probably gives some symptomatic relief but the US FDA is doubtful of its curative potential. In the USA, the death rate seems to be falling, perhaps owing to administration of tested drugs for the SARS epidemic in 2002. In Singapore, Hongkong, Macao and Taiwan, medicines for SARS and MERS initially gave some relief but did not go very far.

Therapies are being developed or tested, including a few traditional Chinese by around 24 institutes around the world; these are: Gilead Sciences (Remdesivir, GS-5734), Roche (Actemra), Biocryst Pharma (Galidesivir), Regeneron (REGN3048 and REGN3051), Synairgen Research (SNG001), Lattice Biologics (Amnio Boost), Enanta Pharmaceuticals, Predictive Oncology, Emergent Bio Solutions (COVID-HIG & COVID-EIG), CEL-SCI, Takeda Pharmaceutical Company, Heat Biologics, Pfizer,  Mateon Therapeutics, Hong Kong University of Science and Technology, Columbia University, The National Medical Products Administration, China (Favilavirt), Vir Biotechnology, Abbvie, Serum Institute of India (SII), Southwest Research Institute, Zydus Cadila, NanoViricides and Bioxytran (BX-25).

Gilead Sciences’ trials are being performed on 761 patients in a randomised, placebo-controlled, double-blind study in hospitals in Wuhan; results are expected in next few weeks. The New England Journal of Medicine (NEJM) reports that Remdesivir, administered to a coronavirus patient in the US, seemed to improve his clinical condition. The University of Nebraska Medical Center is also making clinical trials to test the safety and efficacy of the drug. The WHO has certified that Gilead’s Remdesivir works in treating the infection. China approved the use of Roche’s Actemra for the treatment of severe complications related to coronavirus. It can prevent cytokine storms or over-reaction of the immune system, considered the main reason behind organ failure and death in some patients. It is also being evaluated in a clinical trial in China. Galidesivir (BCX4430) has shown broad-spectrum activity against a wide range of pathogens including coronavirus; it is a nucleoside RNA polymerase inhibitor that disrupts the process of viral replication. It is currently in advanced development stage under the Animal Rule to combat multiple potential viral threats. Regeneron’s monoclonal antibodies- REGN3048 and REGN3051- are being studied against coronavirus infection in a first-in-human clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Regeneron has partnered with Sanofi to evaluate Kevzara, a fully-human monoclonal antibody, in a phase two and three clinical trials in patients. Kevzara is known to block the interleukin-6 (IL-6) pathway, which causes an overactive inflammatory response in the lungs of COVID-19 patients.  Both the antibodies bind to S-protein of MERS coronavirus. Synairgen Research is trying to develop an inhaled drug, to be tested by the University of Southampton to treat asthma, chronic obstructive pulmonary disease and lower respiratory tract illnesses, caused by corona. SNG001 is a formulation of naturally occurring Interferon-β, which is delivered directly to the lungs to reduce the severity of the infection caused by coronavirus. Enanta Pharmaceuticals is developing antiviral drug candidates to treat COVID-19 patients, by testing compounds from its existing antiviral compound library.  for potential efficacy in treating COVID-19. It has also launched a drug discovery programme to develop direct-acting drug candidates to treat COVID-19. Predictive Oncology has launched an AI Platform for the discovery and development of vaccines against coronavirus. The company has signed an agreement with Inventa Biotech to acquire Soluble Therapeutics, which provides it with access to the HSCTM Technology. It will use the HSCTM Technology along with its predictive modelling platform to deploy an AI discovery platform that can screen the ideal combination of additives and excipients for protein formulations. Emergent BioSolutions is developing two plasma-derived product candidates or hyper-immunes using its hyperimmune platforms for the treatment of coronavirus. The hyperimmune platforms have been used previously for the development of several approved products including vaccines for smallpox, botulism, and anthrax. The hyper-immunes are polyclonal antibodies derived from plasma, which are capable of generating an immune response and protecting against infection. Product candidate derived from human plasma is named COVID-HIG, while COVID-EIG is derived from equine plasma. Both will be explored for the treatment of patients with a severe case of infection. Developing immunotherapy against COVID-19 using its proprietary LEAPS peptide technology, which utilises conserved areas of the coronavirus proteins to generate T-cell responses and reduce viral load. The technology can also be used to develop immunotherapeutic peptides with both antiviral and anti-inflammatory properties. The peptides developed using this technology can help in reducing tissue damage from inflammation caused due to lung infection, which is a major cause of mortality in elderly patients. CytoDyn’s  Leronlimab (PRO 140). a CCR5 antagonist, as a potential coronavirus drug which is already being investigated in phase two clinical trials as a treatment for HIV and has been awarded fast-track approval status by the US FDA.  

On an average, one in four or five of the infected seems to be recovering, all over the world but the fact is, the NCOVID’109 has returned in many of them in China and South Korea. Despite maintenance of hygiene, keeping safe distance from the infected, prevention of mass gathering, compulsory use of masks and PPE, the death toll in every country is rising. Prolonged lockdown is being rigorously enforced in affected countries but its social costs, trauma and the plunge of the economy in chaos outweigh its plus points.

However, if the NCOVID’19 is a man-made virus, it may not be amenable to vaccine or drug. President Donald Trump has renewed charge of leakage of this virus, purported to be a biological weapon, from Wuhan Institute of Virology. Recently, a French and a Japanese virologist, both Nobel laureates, asserted that it is not a natural but was accidentally leaked from Wuhan Institute.  Chinese scientists and government have denied any deliberate or accidental leakage of the virus, but. Beijing has admitted, apropos President Trump’s charge, under-reporting of its mortality from NCOVID’19 and added 1290 cases to make the total up to 24th April 4532.

Relatively low incidences of infection and death by NCOVID’19 in India can be due to paucity and late acquisition of testing facilities. Even if a vaccine and drug are invented and pass human trials, there may not any respite from Corona before a year to 18 months. Virologists say, even afterward, the NCOVID may resurface, just as viruses of malaria, polio and chickenpox do even now; only its lethality might be reined.

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Frontier
Apr 28, 2020