Indian contribution toward biomedical research and development in COVID-19: A systematic review

Abstract

COVID-19 pandemic led to an unprecedented collaborative effort among industry, academia, regulatory bodies, and governments with huge financial investments. Scientists and researchers from India also left no stone unturned to find therapeutic and preventive measures against COVID-19. Indian pharmaceutical companies are one of the leading manufacturers of vaccine in the world, are utilizing its capacity to its maximum, and are one among the forerunners in vaccine research against COVID-19 across the globe. In this systematic review, the information regarding contribution of Indian scientists toward COVID-19 research has been gathered from various news articles across Google platform apart from searching PubMed, WHO site, COVID-19 vaccine tracker, CTRI, clinicaltrials.gov, and websites of pharmaceutical companies. The article summarizes and highlights the various therapeutic and vaccine candidates, diagnostic kits, treatment agents, and technology being developed and tested by Indian researcher community against COVID-19.

Introduction

COVID-19 pandemic led to an unprecedented collaborative effort among industry, academia, regulatory bodies, and governments, with huge financial investments. Scientists and researchers across the world are working hard to find the best possible treatment modalities apart from following various preventive measures to control its spread. The article highlights the contribution of Indian researchers toward COVID-19 research in the areas of therapeutic and preventive agents, diagnostics, and agents being developed and manufactured by Indian research community and pharmaceutical industry.

Materials and Methods

We utilized Google platform to search for the information related to various treatment agents and devices being developed or tested by Indian researchers to combat COVID-19. Other sources used were PubMed, CTRI, clinicaltrials.gov, COVID-19 vaccine tracker, and WHO website portal dedicated for the vaccine research. The data were searched up to December 31, 2020, without any language restrictions. The websites of Indian pharmaceutical companies and universities featured in various articles were also reviewed to gather information related to various therapeutic, preventive, and diagnostic candidates being developed by them.

Result and Discussion

The findings have been summarized in terms of in silico or drug-designing studies, artificial intelligence and machine learning (AI/ML), in vitro studies, preclinical studies, AYUSH trials, clinical studies, vaccine development and manufacturing, diagnostics, and systematic reviews and meta-analysis.

In silico and drug design

Various studies targeting different binding domains of COVID-19 have been published by Indian researchers suggesting various potential leading drug candidates against the virus.[1,2,3] Out of 496 articles (data searched on December 31, 2020) published in PubMed, 198 articles have been contributed by various Indian researchers. The search was conducted using the keywords COVID-19, SARS-CoV2, in silico, molecular docking, India.DDH2020, a joint initiative of AICTE and CSIR and supported by Government of India, National Informatics Centre, and MyGov India is an open-source platform for drug discovery against COVID-19.The objective of DDH2020 was to identify leading drug candidates against SARS-CoV2 via in silico drug discovery tools.[4] Among academic institutes, the Experimental Pharmacology Laboratory (EPL), PGIMER, Chandigarh, came up as a major contributor in academic in silico drug discovery program against COVID-19.[1,2,3,5,6,7] Other study groups are from IIT, Mandi,[8] and AIIMS, Rishikesh,[9] among major contributors.

Machine learning and artificial intelligence

Out of 1078 articles (data searched on December 31, 2020) published on machine leaning or artificial intelligence (AI) worldwide, 105 have been contributed by India, out of which 65 articles were on ML studies contributed by Indian research community. The results of the phylogenetic characterization of the virus isolated from first three cases from India done using ML techniques were published earlier in March 2020.[10]

In vitro/culture-based studies on SARS-CoV-2

Out of 1214 articles (data searched on December 31, 2020) published worldwide, Indian researchers have contributed about 125 articles to PubMed. Among major contributions, ICMR-NIV, Pune, developed in-house positive control in vitro transcribed RNA for the laboratory diagnosis of COVID-19 samples via reverse transcription polymerase chain reaction (RT-PCR) assay.[11] Tiwari et al. evaluated the in silico and in vitro mechanisms of coagulation in COVID-19.[12] Other novel agents identified against COVID-19 are bisindolylmaleimide IX,[13] VTRRT-13.V2.1,[14] and VTRM1.1.[15] Kumar et al. compiled all cell culture models of COVID-19 for better and comprehensive understanding of the disease.[16] Indian Immunologicals Ltd., in collaboration with their foreign collaborators, developed a reverse genetic system and a coronavirus tool kit for benefits of COVID-19 researchers.[17]

Preclinical studies against COVID-19

Using the keywords COVID-19 AND animal model AND India, there were only 42 articles (PubMed, up to April 15, 2021). However, none of the studies represented an original study evaluating different therapeutic or preventive agents against COVID-19. Majority of the preclinical studies were centered against vaccine development. However, there were few reviews regarding selection of animal models.[18] In zebrafish model (humanized, xenotransplanted with epithelial cell from lung), SARS-CoV-2 spike protein induced damage and associated cytokine surge was prevented by coronil (herbal medicine).[19] Scientists from Institute of Life Sciences, Bhubaneswar, evaluated the tissue distribution of angiotensin-converting enzyme 2 receptor in Syrian golden hamster.[20]

Preclinical studies on vaccines against COVID-19

Although preclinical trials are less frequently reported, the WHO draft on COVID-19 vaccine candidates recorded 172 vaccine candidates worldwide. Out of these potential candidates, about 14 potential candidates are currently being developed by Indian companies or in collaboration with others.[21]

Indian Immunologicals Ltd. has collaborated with Australia's Griffith University to develop vaccine candidate against SARS-CoV2 based on codon deoptimized live-attenuated virus.[21]

A recombinant deactivated rabies virus containing S1 domain is being evaluated against SARS-CoV2 jointly by Bharat Biotech (BBtech) and Thomas Jefferson University.[21]

In collaboration with University of Wisconsin, Madison, and vaccine manufacturers, FluGen and BBtech have begun animal testing of vaccine called CoroFlu against COVID-19.[21,22] It is an intranasal vaccine that has been developed by inserting gene sequences from SARS-CoV2 into M2-deficient single replicon influenza vector (M2SR), a unique form of flu virus so as to result in immunity against coronavirus. M2SR lacks gene M2 and the resultant virus can undergo only a single round of replication in the cells. As it is single replicon, so the virus has the ability to enter the cells but cannot leave, thereby tricking the body to assume being infected with virus, thereby triggering an immune response. BBtech has also completed preclinical testing of their novel chimp adenovirus, single-dose intranasal vaccine candidate against COVID-19.[23,24] BBtech has also collaborated with Washington University, USA, and Phase 1 for the intranasal vaccine will be conducted in 2021 at Saint Louis University's Vaccine and Treatment Evaluation Unit after approval.[23]

A live-attenuated recombinant virus-vectored vaccine against SARS-CoV2 by CHL is under preclinical development. The recombinant measles virus produced by reverse genetics is expected to express proteins of the novel coronavirus (nCoV) that will in turn induce long-term specific neutralizing antibodies, thereby protecting from infection.[25]

An adjuvanted protein subunit receptor binding domain (RBD) developed by Biological E Ltd. (BE) is under preclinical evaluation.[21] Similarly, SII-Covax being developed by Serum Institute of India (SII) in collaboration with the University of Pittsburg, USA, is also currently under preclinical developmental phase.[21]

Vaccine based on avian paramyxovirus-based vector platform against SARS-CoV2 is under early phases of development by IIT, Guwahati, in collaboration with the Hester Bioscience.[26]

Reliance Life Sciences, a subsidiary of Reliance Industries, has developed a recombinant protein-based vaccine candidate against COVID-19, which is currently under preclinical testing and is expected to enter human trials by 2021.[27]

Auro Vaccines, wholly owned subsidiary of Aurobindo Pharma, are developing vaccine candidate against SARS-CoV2[28] based on attenuated, replication-competent, recombinant vesicular stomatitis (VSV, VesiculoVax) vaccine delivery platform.[21]

Gennova vaccine candidate HGC019 being manufactured in partnership with HDT Biotech Corporation, USA, has completed its preclinical trial and is set to enter into Phase 1/2 clinical trials soon.[29,30] The preclinical testing has demonstrated safety, immunogenicity, and neutralization antibody activity in rodents as well as in nonhuman primate models. Gennova's self-amplifying vaccine candidate based on m-RNA against COVID-19 has been provided seed funding by Department of Biotechnology (DBT). HGC019 conveys the crucial information needed to direct the host cells in the production of antigen-spike protein of virus, utilizing LION as delivery vehicle.[29,30]

Mynvax Pvt. Ltd. in collaboration with IISc, Bangalore, has developed highly thermotolerant and immunogenic recombinant subunit vaccine.[31] Vaccine can be easily stored for up to a month at 37°C without losing its ability to fight against virus. The vaccine candidate uses a specific part of the RBD, a string of about 200 amino acids, instead of utilizing the entire spike protein.[31]

Premas Biotech has developed world's first triple antigen VLP vaccine candidate Saccharomyces cerevisiae-based D-Crypt™ platform against COVID-19.[32] D-Crypt platform has been optimized for the high yield production of “difficult to express proteins” singularly or in combination.[33] The D-Crypt platform allows the expression of surface proteins (spike, envelope, and membrane proteins).[33]

Preclinical evaluation of a lipid-encapsulated mRNA-based vaccine candidate against SARS-CoV2 is underway at CMC, Vellore.[34]

Translational Health Science and Technology Institute (THSTI) has developed human MAb against the RBD of SARS-CoV2.[35] THSTI has also filed patent for immunogenic peptide-based vaccine candidates targeting spike domain of SARS-CoV2. These synthetic peptides target neutralizing B-cell or T-cell epitopes for the development of antibodies against SARS-CoV2, which further lead to blockage of viral invasion. The preclinical studies involving mice have yielded promising results. It also reduces antibody-dependent enhancement or pulmonary immune pathology, a hallmark of SARS-CoV2 infection.[35]

Clinical studies involving new and repurposed drugs

On searching the keyword “COVID-19” displays a total of 751 trials (date of search: December 31, 2020) which includes randomized trials and observational studies using various candidates against COVID-19.[36] Out of 751 trials registered in the CTRI portal, there are 335 observational studies, 413 interventional trials, and 3 studies based on postmarketing surveillance.[37]

Sarma et al. were the first to postulate the possible use of povidone iodine eye drop in COVID-19–associated conjunctivitis,[38,39] and an IND was also applied to Drug Controller General of India (DCGI) office. Kaur et al. postulated that the relative failure of hydroxychloroquine in clinical trials of COVID-19 could be due to wrong placebo selection as many of the studies used folic acid as placebo and low folic acid level in the blood itself is associated with severe COVID-19.[40,41]

Itolizumab, an anti-CD6 humanized immunoglobulin G (IgG) 1 MAb developed by Biocon, India, binds to domain 1 of CD-6 and interferes with the induction of cytokine storm.[42] The drug has already been approved for use in the treatment therapy of severe plaque psoriasis since 2013 in India and is being repurposed as a treatment modality for COVID-19. The drug is currently undergoing Phase 4 trial (CTRI/2020/09/027941) across various centers in India.

Zydus Cadila has received approval from COFEPRIS, Mexico, to study Desidustat in the management of COVID-19, and Phase 2b trials (NCT04463602) involving mild, moderate, and severe COVID-19 patients are currently underway in Mexico.[43] Desidustat is a drug originally developed to treat anemia associated withchronic kidney disease (CKD). ZYIL1, a novel oral small molecule NLRP3 inflammasome inhibitor developed by Zydus, has received node to initiate Phase 1 trials in India.[44] The trial is aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers. ZYIL1 selectively suppresses inflammation caused by the NLRP3 inflammasome and is expected to show benefit in cytokine storm associated with COVID-19.

Trials involving herbal products

CSIR in collaboration with the Ministry of AYUSH has undertaken safety and efficacy trials of AYUSH prophylactics and therapeutics involving plant-based compounds. Clinical trials involving Withania somnifera, Andrographis paniculata, Piper longum, Arsenicum album 30, Tinospora cordifolia, Adhatoda vasica, Glycyrrhiza glabra, and AYUSH-64 formulation are undergoing safety and efficacy trials. The CTRI portal displayed around (date of search: December 31, 2020) 101 registered trials based on Ayurveda, 7 trials on Unani, 4 trials based on Homeopathy, 19 trials based on Siddha, and 18 trials on Yoga and Naturopathy. One trial each based on phytopharmaceutical and nutraceutical was also registered on the CTRI portal.

Phytopharmaceuticals

AQCH, India's first phytopharmaceutical drug, has successfully completed Phase 2 clinical trial on moderately ill COVID-19 patients (CTRI/2020/05/025397) by Sun Pharmaceuticals Ltd. in collaboration with DBT.[45,46] AQCH is extracted from the tropical creeper, commonly known as Patalgarudi (Sanskrit) or broom creeper, native to India, Pakistan, and Africa. AQCH was originally being developed for dengue and has shown broad antiviral effect in in vitro studies and hence being tested as a potential agent for COVID-19. Sun Pharmaceuticals Ltd. had applied for emergency use authorization with the DCGI which was not approved on the grounds of safety and efficacy.[47] However, the Phase 3 trials are expected to begin soon.

Vaccine development and manufacturing/ marketing

As per the WHO draft on vaccine candidates, 61 candidates are currently under clinical development compared to 172 candidates under preclinical development.[21] Out of 61 potential vaccine candidates in clinical trials, six are being developed by or in collaboration with Indian companies.

India's first indigenous COVID-19 vaccine, BBV152 or COVAXIN™, which is a whole virion-inactivated SARS-CoV2 vaccine being developed by BBtech in collaboration with ICMR-NIV and IQVIA, has entered Phase 3 trials in India (CTRI/2020/11/028976 and NCT04641481). The Phase 1 and Phase 2 results have shown promising safety and immunogenicity profile.[48] BBV154, another COVID-19 vaccine candidate based on adenoviral vector platform developed by BBtech, is underdoing Phase 1 trial for the evaluation of safety and immunogenicity.[49]

Zydus Cadila (Cadila Healthcare) has submitted Phase 1/2 clinical trial data (CTRI/2020/07/026352) of ZyCoV-D, a DNA vaccine seeks node to start Phase 2 Clinical Trials in India from the DCGI. Plasmid DNA upon introduction into host cells would get translated into the viral protein, thereby eliciting a strong immune response which will further play a role in protection from disease and viral clearance. Zydus has also received approval from the DCGI to commence Phase 3 clinical trials with pegylated interferon alpha-2b, “PegiHep™” in India. Pegylated interferon alpha-2b with or without arbidol has been found to significantly reduce the viral load (inflammatory markers interleukin-6 and C-reactive protein) and reduce the need for supplemental oxygen in moderate COVID-19 patients.[50] The Phase 2 trial (CTRI/2020/06/026087) to evaluate safety and efficacy has been completed.

Sepsivac (Mw), a vaccine candidate being developed by Cadila Pharmaceuticals Ltd. in collaboration with the CSIR led by Indian Institute of Integrative Medicine, Jammu, has entered into Phase 3 clinical trials. The clinical trials are being conducted at PGIMER, Chandigarh, AIIMS, Delhi, and many other sites across India (CTRI/2020/04/024846, CTRI/2020/12/030085, CTRI/2020/05/025271, and CTRI/2020/05/025277). It was a novel drug developed to treat Gram-negative sepsis and contains heat-killed bacteria of the species Mycobacterium indicus pranii (previously known as Mycobacterium w or Mw). It is an immunomodulator with the property to inhibit cytokine storm. The cytokine storm in COVID-19 is quite similar that generated by Gram-negative sepsis, and hence, it is anticipated as a potential agent for the treatment of critically ill COVID-19 patients.

SII is set to launch five COVID-19 vaccines by 2021: COVISHIELD, COVOVAX, COVIVAXX, COVI-VAC, and SII-COVAX.[51] SII in collaboration with Dynavax has jointly announced the enrollment of participants in the Phase 1 part of Phase 1/2 clinical trial involving the vaccine candidate based on the RBD of SARS-CoV-2 delivered as VLP along with Dynavax's advanced adjuvant CpG 1018 plus alum.[52,53] The trial will be enrolling 39 healthy volunteers in Phase 1 and 216 subjects in Phase 2 depending upon the decision poststudy.

BE in collaboration with Dynavax Technologies Corporation (NASDAQ: DVAX) and BCM has initiated Phase 1/2 clinical trial (CTRI/2020/11/029032) in India.[54] The COVID-19 vaccine candidate is based on the RBD of the spike protein of SAR-CoV2 along with an antigen in-licensed from BCM Ventures, along with adjuvant CpG 1018 from Dynavax. The vaccine candidates being evaluated in the trial are BECOV2A, BECOV2B, BECOV2C, and BECOV2D.[55] BE has also initiated Phase 1 trial of its COVID-19 therapeutic agent in November last year (CTRI/2020/11/028779). It is an open-labeled, randomized trial aimed to evaluate the safety and efficacy of Equine Antiserum Immunoglobulin (Purified F[ab] 2 fragment) in patients with moderate COVID-19 disease.

Indian drug maker company Aurobindo Pharma has collaborated with the US firm COVAXX to develop, commercialize, and manufacture COVID-19 vaccine for India and UNICEF. The Phase 1 clinical trial for UB-612, the vaccine candidate, by COVAXX is underway. Phase 2/3 trials are expected to begin early in the first quarter of 2021 in Asia, Latin America, and the US.[21]

Phase 1/2 randomized trial jointly sponsored by the Accelagen and SII is currently underway (ACTRN12620000817943). The trial is aimed at evaluating the safety as well as immunogenicity of RBD SARS-CoV-2 HBsAg-VLP vaccine in healthy adults.[56] The Serum Institute has partnered with SpyBiotech that uses its proprietary SpyCatcher/SpyTag protein “superglue” technology to produce a potent immune response.

The Phase 2/3 trial of the oxford vaccine COVISHIELD is being conducted in India by the SII (contact manufacturer for COVISHIELD), co-sponsored by the ICMR (CTRI/2020/08/027170). The ChAdOx1 nCoV or AZD122 has been co-invented by Oxford University and its spin-out company Vaccitech and the Jenner Institute. It is a replication-deficient chimpanzee adenoviral vector expressing the SARS-CoV2 spike protein. Oxford University has collaborated with AstraZeneca for the global production and distribution across the world that further collaborated with the SII, GAVI, and CEPI to provide global equitable access to vaccine by low- and middle-income group countries. The recruitment for the Phase 3 trial has been completed in November and the results of the trial will be available soon.

Another vaccine candidate, COVI-VAC, a live-attenuated virus against COVID-19, is undergoing first-in-human trial by hVIVO in London, UK (NCT04619628). This intranasal formulation is being developed by Codagenix in collaboration with the SII.[57,58]

Dr. Reddy's Laboratories Ltd. (DRL) has commenced the multicentric, adaptive Phase 2/3 clinical trials (CTRI/2020/11/029234 and NCT04640233) to assess the safety and immunogenicity of Sputnik V or Gam-COVID-Vac combined vector vaccine for SARS-CoV2. Sputnik V vaccine developed by GNRIEM, Russia, is the world's first vaccine candidate based on adenoviral vector platform against COVID-19.[59] DRL has also partnered with BIRAC, DBT, to use BIRAC's clinical trial centers for the vaccine. Based on the safety profile, the vaccine has been approved for the emergency use authorization in India.[60,61]

SII in collaboration with Max Planck Institute for Infection Biology and Verity Pharmaceuticals is currently enrolling participants in Phase 3 trial (NCT04439045) being conducted in Toronto, Ontario, Canada. The trial is being sponsored by University Health Network, Toronto, and the vaccine candidate under study is VPM1002 which is a recombinant BCG.

OSIF has licensed novel live-attenuated measles virus-vectored vaccine candidates against COVID-19 being developed by OSUCVM exclusively to BE. BE will further develop and commercialize the vaccine candidate. The attenuated recombinant measles viruses have been shown to express the recombinant S antigens and have demonstrated production of antibodies against SARS-CoV2 in proof-of-concept trials involving various animal models.

SII has entered into agreement with Novavax to produce the antigen component of NVX-CoV2373, a SARS-CoV2 vaccine candidate, thereby increasing Novavax's global production capacity.[62] NVX CoV2373 is a stable, prefusion protein formulated using recombinant protein nanoparticle technology including Novavax' proprietary Matrix M™ adjuvant. The SII will be gaining approval to conduct Phase 3 trials in India involving COVOVAX.[63]

Equity in vaccine distribution: A global initiative

COVAX is a global initiative of 190 participating economies to ensure equitable access to SARS-CoV2 vaccine candidates across all countries, irrespective of their income level to protect the most vulnerable groups. It involves 98 high-income and 92 low-income economies and funded by GAVI COVAX AMC. COVAX in partnership with SII has agreed to provide 200 million doses with alternative option to provide more 900 million doses of either Novavax or AstraZeneca/Oxford vaccine candidates, or a statement of intent to provide 200 million doses of vaccine candidate by Sanofi/GSK.[64] The SII has collaborated with GAVI and Bill and Melinda Gates Foundation for the delivery of 100 million doses of future vaccine for low- and middle-income group countries in 2021, if demonstrated safety and efficacy.[65] As per the UNICEF estimate, 22% of the share of COVAX alliance would be from India.

COVID-19 vaccine administration program by Government of India

The honorable Prime Minister of India launched the world's largest vaccination drive against COVID-19 at pan-India level involving 3006 sites across all the states and union territories in India on January 16, 2021.[66]

Manufacture and distribution of important antivirals against COVID-19

Zydus entered into agreement in August 2020 with Gilead Sciences Inc. to manufacture and sell Remdac™ (remdesivir) at economical prices in India.[67] Other medicines being marketed by Zydus are ivermectin and favipiravir. DRL, Appili Therapeutics, and Global Response Aid (GRA) entered into agreement with FUJIFILM Toyama Chemical under which they have been granted exclusive rights to develop, manufacture, advertise, and sell REEQONUS™ is also known as Avigan^® (favipiravir) tablets for the treatment of mild-to-moderate COVID-19.[59,68] Following the agreement, Dr. Reddy's launched Avigan^® 200 mg tablets in India with the exclusive rights to manufacture, sale, and distribute the same in India. Dr. Reddy's in partnership with GRA and Appili Therapeutics has filed an application to import, sale, and advertise the Avigan for COVID-19 in Canada. Sun Pharma launched favipiravir as FluGuard^® in India at economical price of Rs. 35 per tablet.

Rapid diagnostic kit development/diagnostics

Gujarat Biotechnology Research Centre (GBRC) has decoded whole-genome sequences of SARS-CoV-2 genome.[69] GBRC has signed an agreement with Neuberg Supratech Reference Laboratory to look for immune markers using its in-house high throughput sequencing mechanisms and the development of recombinant vaccine against COVID-19 and diagnostics.

FNCAS9 Editor-Limited Uniform Detection Assay (FELUDA), the world's first diagnostic assay to deploy specifically adapted Cas9 protein to detect SARS-CoV2, has been given nod for its commercial launch by the DCGI.[70] FELUDA paper strips have been developed by CSIR-IGIB and jointly validated by DAE–NCBS and TIFR, Bengaluru, and have shown 96% sensitivity and 98% specificity.

Ultra-low-cost molecular diagnostic machine-COVIRAP developed by researchers at IIT-Kharagpur has been validated for its efficacy by the ICMR.[71] The testing process takes up to 1 h via this new machine. The test displayed over 93% sensitivity and almost 98% specificity in its results.

Aptamer-linked immobilized sorbent assay is a detection assay using DNA aptamers against SARS-CoV2 developed by the THSTI. Aptamers do not display batch-to-batch variation as it is a synthetic molecule.[72]

An innovative SARS-CoV2 diagnostic kit named Chitra Gene LAMP-N has been developed by SCTIMST, Thiruvananthapuram.[73] It is one of the few confirmatory diagnostic tests in the world for N-gene of SARS-CoV2 virus involving RT-LAMP technique.

To combat the shortage of diagnostic kits that were earlier being imported from other countries, Government urged the local manufactures to develop the same indigenously in India. Global™ diagnostic kit (based on RT-PCR technique) has been developed by Equine Biotech, a startup by IISc and is approved by ICMR to be used as diagnostic measure against COVID-19.[74] The indigenous multiplex kit has shown 100% specificity. Pathocath, a rapid antigen test kit manufactured by Mylab Discovery solutions approved by the ICMR, is the first indigenously developed kit in country against COVID-19.[75] Mylab has also developed PathoDetect™ CoVID-19 detection kit[76] and ViroTrap Molecular Transport Medium for SARS-CoV2.[77] On similar terms, IIT, Guwahati, developed self-check kiosks, diagnostic kits, spray-based anti-viral coating, personal protective equipment, drones for spraying disinfectants, and low-cost UVC LED systems for disinfectant sprays.

ICMR-NIV has developed first indigenous IgG test “COVID KAVACH ELISA” for antibody detection against COVID-19.[67] The ELISA kits are being manufactured in collaboration with Zydus Diagnostics and has the advantage of testing 90 samples together in a single run of 2.5 h.[67]

Systematic reviews and meta-analysis

As of December 31, 2020, around 130 systematic reviews and 58 meta-analyses were published in PubMed by Indian researchers compared to 658 meta-analyses and 1585 systematic reviews published by researchers worldwide on PubMed platform. The first meta-analysis evaluating hydroxychloroquine as an antiviral agent against COVID-19 was published by researchers from EPL, PGIMER, Chandigarh.[78] The group also published meta-analysis evaluating antiviral effects of lopinavir/ritonavir,[79] favipiravir,[80] and steroids[81] against SARS-CoV2. The first systematic review on the drug targets against SARS-CoV2,[7] structure of SARS-CoV2,[6] and role of AI[82] in COVID-19 by Indian researchers was contributed by the very same group. The meta-analysis by Sarma et al. came up at the topmost 98 percentile (within top 5%) of all articles ever tracked by altmetric.[78] AIIMS, Delhi, also contributed significantly through this domain in evidence generation.[83,84,85,86] Other areas covered by Indian researchers are neurological outcomes and consequences,[87] hepatic manifestations,[88] ocular manifestations,[89] and other organ systems. Overall, Indian researchers played a significant role in evidence generation in the battle against COVID-19.

Contribution from regulatory field

Following the declaration of COVID-19 pandemic, the National Task Force was created which further suggested establishing “India COVID-19 Clinical Research Collaborative Network” coordinated by the ICMR. The goal of the network was to develop specific clinical management protocols and further R&D for therapeutics. The Government of India formed National Expert Group on Vaccine Administration for COVID-19 who created strategies on the vaccine procurement, international manufacturing, and guiding principles on prioritization of population groups for vaccination. ICMR issued various guidelines in relation to diagnosis, treatment, and management of COVID-19.

Indian Pharmacopoeia Commission (IPC) and DCGI are actively involved in reviewing clinical trial of new drugs and vaccines against COVID-19. In view of COVID-19, to promote the quality of new drugs used in the management of COVID-19 in India, IPC is setting the standards for new drugs and formulations such as remdesivir active pharmaceutical ingredient (API) and its injection, favipiravir API and its tablets and ivermectin tablets. National Coordination Centre-Pharmacovigilance Programme of India (NCC-PvPI), IPC has designed a customized suspected adverse drug reaction (ADR) reporting form to report the adverse reactions associated with the drugs used for prophylaxis and treatment of COVID-19.[90] Regarding adverse events following immunization (AEFI), the COVID-19 vaccination guideline highlighted that AEFI was to be reported as per the national AEFI guidelines and are also being incorporated to VigiFlow (NCC-PvPI) and all union territories and states should have at least one AEFI management centers in each block.[91]

Contribution in the field of bioethics

ICMR issued National Guidelines for Ethics Committees Reviewing Biomedical and Health Research during COVID-19 pandemic in April 2020.[92] Apart from these, guidelines issued on other important issues like liver transplantation, management of pregnant women during pandemic, guidelines on use of diagnostics among many other were issued from time to time. ICMR also played a role in the validation of diagnostic kits. ICMR has networked with DBT, CSIR, and DST institutes for the evaluation of novel claims related to COVID-19.[93] ICMR Bioethics Unit and Central Ethics Committee on Human Research have also released standard operating procedure (SOP) for ethical review for biomedical research during the COVID-19 pandemic.[94]

Sero-surveillance

National Sero-Surveillance Programme of India was launched by the ICMR to monitor the COVID-19 infection trend among the Indian population. It is a sero-epidemiological survey whereby antibody levels were proposed to be evaluated across 60 districts from India.[95] A study on sero-surveillance was conducted in Kerala involving health workers and found to have seropositivity (8.75%) comparable to that in countries such as the USA and Wuhan, China.[96] Another study wherein sample collection was done between August and September 2020 found seroprevalence of SARS-CoV-2 IgG antibodies in children aged 10 years and above to be 6.6% as compared to adults (7.1%).[97]

Clinical research in different health domains

Regarding psychological component of COVID-19–associated lockdown and the disease, Hazarika et al. remained one of the pioneers (which is widely appreciated and also received a mention by prestigious Journal Nature).[98,99,100] Other domains addressed by Indian researchers are COVID-19–related socioeconomic issues,[101] healthcare and national health programs,[101] domestic violence against woman,[102] and impact of COVID-19 on national health policies.[103]

Conclusion

The contribution of Indian scientists/researchers toward understanding and management of COVID-19 is huge, all the details of which cannot be covered in a single article. Indian researchers have contributed significantly in the global platform in COVID-19 research in each and every sector from basic science and disease biology understanding, network biology, AI/ML-based study, clinical research, preventive and therapeutic approach development, diagnostics, and ethics.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.