Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2021 | Month : September | Volume : 15 | Issue : 9 | Page : KE01 - KE08 Full Version

Vaccines, Repurposed Drugs and Alternative Biomedicines for the Management and Prevention of COVID-19


Published: September 1, 2021 | DOI: https://doi.org/10.7860/JCDR/2021/49523.15342
Jeyalakshmi Kandhavelu, Ramesh Veeriah, Kumar Subramanian, Priyatharsini Rajendran, Olli Yli-Harja, Meenakshisundaram Kandhavelu, Akshaya Murugesan

1. Senior Researcher, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa. 2. Senior Researcher, Department of Zoology, University of Madras, Chennai, Tamil Nadu, India. 3. Senior Researcher, Department of Translational Medicine, Lund University, Malmö, Sweden. 4. Professor, Department of Zoology, Lady Doak College, Madurai, Tamil Nadu, India. 5. Professor, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 6. Professor, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 7. Professor, Department of Zoology, Lady Doak College, Madurai, Tamil Nadu, India.

Correspondence Address :
Akshaya Murugesan,
Professor, Department of Zoology, Lady Doak College, Madurai, Tamil Nadu, India.
E-mail: akshaya@ldc.edu.in

Abstract

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) popularly called as COVID-19, is a pandemic having affected >200 countries. Globally, quarantine measures have been implemented to slow down the spread of the virus. Yet, the available vaccines and drugs for treating COVID-19 are still in design and developmental stage, requiring clinical validation. This review is focused on the progress in the development of medicines against SARS-CoV-2. As an alternative approach, both conventional and traditional biomedicines are also reported to be in practice, to treat the SARS-CoV-2 infected patients. Considering the therapeutic values of the folk medicines, this review focuses on the usage of high value added products from plants, against COVID-19 in managing the symptoms like fever, cough, cold, sore throat, respiratory disorders and kidney dysfunctions enlisting a few used since time immemorial. It is ardently hoped that scientific intervention of such traditional plants can be integrated to harmonise with modern medicine, to ensure its dosage and safety in augmenting disease management.

Keywords

Antibody vaccine, Coronavirus disease 2019, Recombinant vaccine, Traditional medicine

Novel coronavirus, SARS-CoV-2 (COVID-19) a spillover zoonotic virus, has evolved into a pandemic strain infecting human beings leading to fatal respiratory illness (1). The whole genome sequencing of this crown shaped virus (WIV04 strain) is identified as the Beta-coronavirus 2B family. It has 82% sequence similarity with SARS-CoV Tor2, 88% with bat SARS-like coronavirus and 96% with bat-SARSr-CoV RaTG13 (2). Apart from the presence of SARS-CoV proteins such as nucleocapsid protein (N), membrane glycoprotein (M), and spike glycoprotein (S)(3), the special protein that makes COVID-19 more infectious could be the presence of glycoprotein having acetyl esterase and haemagglutination (HE) properties. Currently, there are five variants of the virus which have been first identified- B.1.1.7 (UK), B.1.351(South Africa and US), P.1 (US), B.1.427 and B.1.429 (California, US).

Based on the symptoms, the clinical manifestation of the infection is divided in to five different stages. Stage I is asymptomatic but positive, stage II-positive with mild upper respiratory symptoms like sore throat, dry cough, sneezing, nausea, vomiting, and diarrhoea (4), stage III is an initial stage of pneumonia with chest tightness, fever (5) and palpitation (6), stage IV with an Acute Respiratory Distress Syndrome (ARDS) requiring oxygen therapy, and stage V associated with chronic respiratory distress, kidney failure, septic shock, leading to multiorgan failure and death (8). After the discovery of mutant strains of SARS-CoV-2, information about the characteristics of these variants in causing severe illness and symptoms leading to complications are under investigations.

Inimitable molecular mechanism of infection in the host cells, and the emerging mutant variants of coronavirus is a challenge for the available antiviral vaccine or therapeutics. Symptomatic and asymptomatic infection can provide herd immunity, which could be only on exposure to the virus.

VACCINE DEVELOPMENT AGAINST COVID-19

Vaccine for COVID-19 is in preliminary stage and almost 30 different vaccines are being developed in breakneck pace. They fall into four different categories of vaccines, such as Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA) based vaccine, Antibody based vaccine, Recombinant vaccine and other vaccines which include inactivated vaccines (Table/Fig 1).

1. DNA and RNA based Vaccines

The first human trial for COVID-19 vaccine, Fusogenix DNA vaccine (9) was developed in Seattle, United States of America. It is a Proteo-Lipid Vehicle (PLV) formulation developed by Entos Pharmaceutical, which uses plasmid DNA containing multiple protein epitopes from crucial immunogenic SARS-CoV-2 proteins. This platform applies a novel fusion mechanism to deliver its genetic payload directly inside the cells. Another DNA vaccine, INO-4800 (10), is used for activation immunotherapy, developed by Inovio pharmaceuticals in collaboration with Beijing Advaccine Biotechnology. A smart device called CELLECTRA® delivers the optimised DNA into cells, where it gets translated into proteins that activates an individual’s immune system to generate a robust targeted T-cell and antibody response. A parallel, phase one clinical trial is planned to be conducted in China, by Beijing Advaccine. The RNA based vaccine, mRNA-1273 (11) targets against SARS-CoV-2 encoding for a prefusion stabilised form of the spike (S) protein. ModernaTX, Inc, begins the phase I clinical trial of mRNA-1273 with three dose levels (25, 100 and 250 μg) on a two dose vaccination schedule, with a gap of 28 days and currently, it has been approved for human use. The miRNA-1273 inhibits the severe illness caused by COVID-19 infection with the efficacy rate of 94.1% (Table/Fig 2). Comirnaty (BNT162b2), another approved vaccine has been developed by Germany-based BioNTech proprietary mRNA technology and co-developed by BioNTech (Germany) and Pfizer (Belgium). It is a nucleoside modified RNA formulated in lipid nanoparticles encoding an optimised SARS-CoV-2 full length spike protein antigen. Food and Drug Administration's Emergency Use Authorisation (EUA) has expanded its usage to include people of 12-year-old (Table/Fig 2) (9),(10),(11),(12).

2. Antibody Based Vaccine

Kevzara, a fully human monoclonal antibody (13), is in phase two/three clinical trial in patients with severe COVID-19 infection. A passive vaccine, REGN3048-3051 (14) developed by Regeneron, is prepared by a cocktail of mouse antibody and COVID-19 recovered patient antibody. It was approved to treat rheumatoid arthritis that could block the Interleukin-6 (IL-6) pathway. Another vaccine named, AdCOVID, Intranasal COVID-19 vaccine (15), is being developed by Altimmune on a vaccine technology platform. It is similar to NasoVAX, an influenza vaccine, and it is being tested to validate its immunological response against COVID-19 infection. The EpiVacCorona (DB16439) developed by Vektor State Research Center of Virology and Biotechnology in Russia is a chemically synthesised chimeric peptide vaccine that contributes in developing immunity against SARS-CoV-2 infection following two intramuscular administration spaced 21-28 days apart (Table/Fig 3) (13),(14),(15),(16),(17),(18),(19).

3. Recombinant Vaccine

Vaxart’s VXA-CoV2-1, an oral recombinant vaccine, is based on the published genome of COVID-19 and tested in preclinical models for mucosal and systemic immune responses. It targets both the spike protein (S) and nucleoprotein (N) and triggers mucosal immune responses in humans. Interestingly, Clover Biopharmaceuticals developed Recombinant subunit vaccine based on the trimeric S protein (S-Trimer) of the COVID-19 coronavirus, which is responsible for binding with the host cell and causing a viral infection. This vaccine is in phase I clinical trial to evaluate the safety and the immunogenicity of the S-Trimer with AS03 and CpG1018 plus Alum adjuvants (20). This vaccine will be subjected to clinical trial soon. Also, Tonix Pharmaceuticals designed TNX-1800 to express the spike protein, derived from the virus that causes the SARS-CoV-2 infection and this vaccine at the low dose of one 106 PFU is a perfect dose for a one shot vaccine in humans. Sputnik V (Gam-COVID-Vac) is an adenoviral-based, two part vaccine against the SARS-CoV-2 coronavirus produced in HEK293 cell lines. It reduces the time taken for the actual development of immunity to SARS-CoV-2 infection (21). Covishield otherwise named as Vaxzevria, produced by Oxford-AstraZeneca jab in India works in a similar way as Sputnik V. It is prescribed to be administered in two doses between twelve to sixteen weeks apart (12). A modified coronavirus vaccine, Infectious Bronchitis Virus (IBV) vaccine has been developed to treat poultry coronavirus, which has high genetic similarity to the human coronavirus (22). The vaccine has demonstrated efficacy in preclinical trials conducted by the Volcani Institute. Yet another adjuvant vaccine, BPI-002 developed by beyond spring is a small molecule agent that is indicated for treating various infections including COVID-19. The cocktail of BPI-002 with another COVID-19 vaccine is assumed to generate long term protection against viral infections. Likewise, there are numerous other vaccines which are under developmental stage, either in in-vivo testing or in clinical trials (Table/Fig 4) (22),(23),(24),(25),(26),(27),(28),(29),(30),(31),(32),(33),(34),(35),(36).

4. Inactivated Vaccines

Covaxin (BBV152) is the India’s first indigenous vaccine against COVID-19 infection, developed by Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR) and National Institute of Virology. Being an inactivated vaccine, the pathogen’s ability to replicate will be reduced maintaining the cellular integrity intact, which could be recognised by the immune system and produce the antibodies. It has the ability to target even the mutated strains from UK. It has been approved to use in two dose regimen at four weeks interval (37). It was developed from NIV-2020-770 and a Vero cell platform (CCL-81) with adjuncts of either aluminum hydroxide gel (Algel) or a novel TLR7/8 agonist adsorbed gel. Other inactivated vaccines such as BBIBP-CorV (38), CoronaVac or Sinovac (39), WIBP-CorV (40), CoviVac (41), QazVac (42) are still in phase III clinical trials (Table/Fig 5) (38),(39),(40),(41),(42),(43).

REPURPOSING OF DRUGS AGAINST COVID-19

Currently, allopathic medicines are being repurposed in various countries to battle COVID-19 infection, since it has entered the stage beyond containment. Repurposing drugs is an emergency contingency strategy which was already being tested and found to be safe for humans and so, does not require a clinical trial period. Retasking the drugs that are intended for other diseases may or may not bring complete clinical cure for the COVID infection, hence combinatorial or cocktail of drugs could be considered effective for the present scenario.

Specifically, HIV protease inhibitors that functions as an antiviral drug like Darunavir, Nelfinavir, Saquinavir, lopinavir/ritonavir (Kaletra) (44) are under investigation against COVID-19 infection. Combination of Kaletra with Arbidol, a drug that prevents the virus from attaching to the host is also been tested against COVID-19 infection. Another combination of Kaletra with anti-influenza drug, Oseltamivir (Tamiflu) showed promising effect within 48 hours of treatment in COVID-19 patients.

Notably, Remdesivir (45), an adenosine analog interferes with the copying machinery of viral RNA polymerase produces premature termination of viral RNA. It is used for treating Ebola virus disease and Marburg virus infections and found to be more effective against Middle East Respiratory Syndrome (MERS). The antimalarial drug and broad spectrum antiviral drug, chloroquine and its derivative, hydroxychloroquine, is currently redirected as a promising drug for treating coronavirus. It is found to change the pH level of the endosome, interferes with the glycosylation of cellular receptor of coronavirus, thus preventing the endosome from releasing the virus into cytoplasm. Remdesivir and chloroquine combination are highly effective in the control of COVID-19 infection, in vitro (46).

Japanese flu drug named Favipiravir (47), selectively inhibits viral RNA-dependent RNA polymerase and has been found to be effective with the patients with mild to moderate symptoms. However, Japanese health ministry suggested the drug as ineffective against patients with severe lung infection. A similar effect was also observed when the patients treated with the cocktail of the HIV antiretroviral drugs, lopinavir and ritonavir. In addition, APN01 (48), ACE2 protein decoy, which was designed to treat SARS, is now being redirected to decoy the SARS-CoV-2 from entering the cells. Although the drug crossed the phase I and phase II clinical trials, a few reports reveal that the drug does not protect people with ARDS. As discussed, various combinations of drugs seem to be more promising in reducing the symptoms of COVID-19 infection (Table/Fig 6) (49),(50),(51),(52),(53),(54),(55),(56),(57),(58),(59),(60),(61),(62),(63).

Challenges Encountered in Vaccine Development and Drug Repurposing

The major concern with respect to vaccine development is the timely response to the pandemic or epidemic situation. However, the effective development of vaccine is merely dependent on the coordination of policy makers, researchers, funding agencies, manufacturers and regulators. Time to complete the pre-clinical testing in cell culture systems, animal models and in humans, financial support, postlicensure monitoring of vaccine, is quite challenging in the vaccine development. The development of vaccine put forth various challenges such as its ability to target the specific variants of SARS-CoV-2, its efficacy against mutant strains, and its ability to provide herd immunity to the population.

Considering all these factors in a pandemic outbreak like SARS-CoV-2, the overall time and money taken to complete the process of production of vaccine till the approval by Food and Drug Administration (FDA) will take a minimum of 1 to 1.6 years, charging loss of huge human lives. Despite the advances in using the de-risked compounds for SARS-CoV-2, there are numerous technological and regulatory challenges that need to be addressed for the approval. Repurposed drugs do not always succeed and mostly they fail to pass the phase III trial. Barriers at patent considerations, regulatory and organisational restrictions must be encountered. Legal and intellectual property barriers also need to be addressed. The time and the efforts taken to overcome all these hurdles during an epidemic disaster delays the drug discovery.

Although, vaccine development and drug repurposing are considered as a promising area in drug discovery and therapeutics, value added herbal medicine is recommended as an immediate source of alternative medicine for viral diseases like SARS-CoV-2. Potential herbal medicines that are ethnically practiced as an antiviral drug could be possibly used to treat the different stages of COVID-19 infection, which will be discussed in the following section.

ALTERNATIVE BIOMEDICINE FOR CORONAVIRUS

During COVID-19 infection, the immune system provides defense just like it does to any other infectious organisms and other foreign invaders. But, the coronavirus virus employs different evasion mechanisms to escape the host immune system (64). The strategies of immune evasion are directed towards humoral, cell-mediated and effector mechanisms. It is also noted that immune pathogenesis is associated with uncontrolled immune response leading to pulmonary tissue damage, functional impairment, and reduced lung capacity. Immune insufficiency or misdirection may increase viral replication and cause tissue damages (65). Thus, an effective alternative medicine is vital to curb the viral multiplication and prevent the disease. Application of the traditional medicine along with modern medicine might boost the immune system to fight against the deadliest coronavirus.

Despite the advancement in the vaccine or drug development, many viruses escape the conventional therapies due to the generation of viral mutants with enhanced virulence. Re-emerging viruses or virus variants like SARS-CoV-2 remains a threat to public health especially when there is no efficient vaccination or antiviral therapies. It is observed that only a few antiviral drugs approved by FDA are repurposed against COVID-19 infection, and limited vaccines are in clinical trials. The usage of specific viral enzyme specific inhibitors lead to the development of multidrug resistant mutants of SARS-CoV-2 (66). Hence, there is an urge to identify an alternative strategy for the control of COVID-19 infection especially, when standard vaccines or therapies are still under clinical trials. Herbal medicines are the richest source of novel antiviral compounds and many countries especially in Asia prefer traditional medicines than the conventional medicines or the combination of both (67). Here, we have systematically reviewed several herbal plants; these plants with antiviral property can be gainfully used in the management of COVID-19 infections such as fever, pneumonia, cold and cough, asthma and bronchitis, kidney dysfunction.

Antiviral and Antibacterial Activity of Traditional Medicine, Aegle Marmelos

Commonly called as ‘Vilvam’ in vernacular Tamil, it has been widely used in indigenous systems of Indian medicine. It possesses antiviral activity against human coxsackie viruses B1-B6. It appears to inhibit the viral replication with the least host cytotoxicity than the modern viricidal drug ribavirin, that usually acts in later stage of viral replication (68). Shorea robusta, one of the most important traditional Indian medicinal plant, also named as ‘Venkungiliyam’ is found to exhibit antiinflammatory, antipyretic activity (69) and antiviral activity against herpes simplex virus (70). Earlier, Nilavembu kudineer (NVK) has been used to cure the epidemic outbreak caused by Dengue, by Flavivirus (DENV) and Chikungunya by an alphavirus, (CHIKV) (71). As per Siddha medicine, the regimen of medication of NVK (otherwise called as neem of ground) is used as an antiviral concoction. It is a polyherbal concoction with Andrographis paniculata as the chief ingredient that controls fever in a comprehensive manner through its healing effects of temperature regulation, inflammation control and body pain relief and thus boost the immunity (72). Allium sativum, commonly called as ‘Garlic’ is widely used as a spice in Cameroon and has been found to have antimalarial activity (73). Indian folklore of Achyranthes aspera (Nayurivi) is used in treatment of cough, bronchitis and rheumatism, malarial fever, dysentery, and asthma (74).

Alternative Medicine for Respiratory Diseases and Fever

Albizia lebbeck, otherwise called as ‘Vagai’, is highly recommended in Ayurvedic system for bronchial asthma (75). Stem bark decoction has been found to decrease the histamine induced bronchospasm, thus, protective against bronchial asthma (76). Another important folk medicine, Justicia Adathoda, popularly called as ‘Adathodaiillai’ is widely used for the treatment of respiratory diseases as well as inflammation like arthritis and rheumatism (77). Two glycoside compounds from yet another species, Justicia reptans displays a clear viricidal effect on HIV (78). ‘Catechu’, extract from Acacia catechu effectively been used for treating fever and the presence of tannins and polyphenols imparts astringent activity for curing throat infection (79). Similarly, Coleus aromaticus is traditionally used in medicinal system especially for severe bronchitis, asthma, fever, common cold and cough (80). Ethno medical use of Plectranthus amboinicus or ‘Karpuravalli’, has been found to treat common cold (81).

Combinations of Traditional Plants against COVID-19 Infection

Combination of traditional medicine on top of the standard modern medicine is found to be a life supportive system preventing the symptoms of COVID-19 infection. Earlier, SARS clinical data in China have shown that about 40-60% of the infected individuals have received Chinese traditional medicine along with the modern medicine, that helped in decreasing the mortality rate (82). Similarly, Ministry of Ayurveda, Yoga and Naturopathy Unani, Siddha, Sowa-Rigpa and Homeopathy (AYUSH), Government of India with the recommendations (D.O.No.S 16030/18/2019-NAM; dated 06th March, 2020) from the Research council has announced a combinatorial formulation of 15 different plant sources in the name of “Kabasura Kudineer” for symptom management of COVID-19 like illness (83). It makes the body resistant against the viral infection, and also found to be effective against the treatment of swine flu. The decoction includes the combination of the following plants (84), Nilavembu (Andrographis paniculata), Kanduparangi (Clerodendrum serratum), Chukku (Zingiber Officinale), Thippili (Piper longum), lavangam (Syzygium aromaticum), Adathodaiver (root of Justicia beddomei), Cirukancori Ver (Tragia involucrate), Seenthil (Tinosporia cordifolia), Karpooravalli (Anisochilus carnosus), Koraikizhangu (Cyperus rotundus), Kostam (Costus speciosus), Akkara (Anacyclus pyrethrum), Vattathiruppi Ver (Sida acuta), Mulli Ver (Hygrophilla auriculata) and Kadukkaithol (Terminalia chebula). Apart from the above mentioned formulation, there are other plant sources and formulations available (85), which might be in practice specific to each region/ country. In the present pandemic outbreak caused by SARS-CoV-2, the only immediate alternative that we can look as a preventive measure rather than treating the disease, could be the use of plant based medicines.

Conclusion

Intense knowledge on the pathogenic characteristics, immune response and epidemiology of SARS-CoV-2 virus is needed to combat the challenges faced in strain specific drug discovery. Although many Research and Development (R and D) companies in collaboration with academic institutes are striving to develop vaccine and drugs against this pandemic disease, an approximate period of 1 to 2 years is essential to complete the clinical trial and secure the FDA approval before it reaches the common man. The challenges encountered in the vaccine and drug development allow us to look for the better solution with an alternative medicine. Various plant sources of Asian origin, which could be possibly used for the symptoms of COVID-19 infection, are described in this review. Likewise, country specific ethnic usage of plant sources might be therapeutically investigated to find out the optimal mix with the modern medicine, that could either help in increasing the immunity against the virus or control the symptoms of COVID infection.

Acknowledgement

The authors thank Prof. Chellam Balasundram for the critical review and comments, Bharathidasan University, India. The authors also thank ICMR-DHR, India for providing fellowship support to AK.

Note: For economy of space supplemental file for reference number 74, 81, 83 is available at: https://jcdr.net/articles/supplementarydata/15342/Supplementalfile.docx.

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DOI and Others

10.7860/JCDR/2021/49523.15342

Date of Submission: Mar 20, 2021
Date of Peer Review: Apr 26, 2021
Date of Acceptance: Jul 31, 2021
Date of Publishing: Sep 01, 2021

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval Obtained for this study? No
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

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