The year 2020 will be remembered for the devastation wrought by the COVID-19 pandemic all over the world.
Coronaviruses (CoV) are a large group of viruses that cause a variety of illnesses ranging from the common cold to more serious diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV).
Being zoonotic, coronaviruses are transmitted between animals and humans. SARS-CoV was found to be transmitted from civet cats to humans while MERS-CoVwas transmitted from dromedary camels to humans. However, there are many known coronaviruses in animals that have not yet infected humans.
COVID-19 is caused by a novel coronavirus called SARS-CoV-2; it is a new strain that has not been previously identified in humans. The World Health Organisation (WHO)said that it first came to know of this new virus on December 31, 2019, after reports of many cases of ‘viral pneumonia’ in Wuhan, in the People’s Republic of China.
The COVID-19 is an infectious disease, and the virus spreads primarily through droplets of saliva or discharge from the nose when an infected person coughs or sneezes. It is for that reason that masks have been prescribed and social distancing (though a better term would be ‘physical distancing’) advised.
It is found that most people infected with the COVID-19 virus experience mild to moderate respiratory illness and recover without requiring special treatment. However, it is possible for older people, and those with underlying medical problems like diabetes, chronic respiratory disease, cardiovascular disease,and cancer to develop serious illness.
Symptoms
The WHO lists the most common symptoms of COVID-19 as fever, dry cough, and fatigue. Less common symptoms that may affect some patients include: loss of taste or smell, nasal congestion, conjunctivitis, sore throat, headache, muscle or joint pain, different types of skin rash, nausea or vomiting, diarrhoea, chills or dizziness.
Severe COVID‐19 may lead to shortness of breath, loss of appetite,confusion,persistent pain or pressure in the chest,high temperature (above 38 °C). There may also be other less common symptoms such as irritability,confusion,reduced consciousness (sometimes associated with seizures),anxiety,depression,sleep disorders, and more serious and rare neurological complications such as stroke, brain inflammation, delirium, and nerve damage.
It has been found that some people who have recovered from COVID-19 continue to experience symptoms, especially fatigue, and respiratory and neurological symptoms.
The period that elapses between exposure to the virusand the moment when symptoms show is, usually, 5-6 days, but it can be anywhere from 1 day to 14 days. This is the reason behind advising people who have been exposed to the virus to remain at home and stay away from others for 14 days; it would prevent the spread of the virus. Simple protection methods is through washing hands frequently or using an alcohol based rub and not touching the face.
Tests
RT-PCR TestA commonly used test to detect pathogens and confirm infection is the polymerase chain reaction (PCR) test, which is a molecular test. Samples are collected The test detects the virus in the sample by amplifying viral genetic material to detectable levels. A molecular test is used to confirm an active infection, usually within a few days of a person being exposed to the disease and around the time that symptoms may begin to appear.RT-PCR is a variation of PCR. The two techniques use the same process except that RT-PCR has an added step of reverse transcription (RT) of RNA to DNA, to allow for amplification. PCR is used for pathogens, such as viruses and bacteria, that already contain DNA for amplification, while RT-PCR is used for those containing only RNA that needs to be transcribed to DNA for amplification. PCR test is widely used in detecting diseases such as Ebola, African swine fever, and foot-and-mouth disease.COVID-19 virus only contains RNA, so RT-PCR is used to detect it.
A sample is collected from deep inside the nose and the back of the throatwith a swab. The sample is treated with several chemical solutions that remove fats and proteins and extract only the RNA present in the sample. This RNA is a mix of the person’s own genetic material and, if present, the RNA of the virus. The RNA is now reverse transcribed to DNA using a specific enzyme. The test detects the virus in the sample by amplifying viral genetic material to detectable levels. The test is used to confirm an active infection, usually within a few days of a person being exposed to the disease and around the time that symptoms may begin to appear. The test detects the virus’s RNA, which will be present in the body before antibodies form.
The majority of the tests being conducted in India and worldwide are RT-PCR, which are considered the most accurate of the tests available.The test can detect the virus even in asymptomatic persons, but there is apossibility of showing a false negative in about 30 per cent of cases. Individuals are, therefore, tested twice before being confirmed as non-infectious.
Rapid antigen testRapid antigen test (or rapid diagnostic test – RDT) detects viral proteins called antigens. (An antigen refers to any toxin in the body that sets off an immune response.) Samples are collected from the nose and/or throat with a swab and tested for antigens, which are found in the SARS-CoV-2 virus. The test relies on These tests perform best when there is more virus circulating in the community and when the sample is taken from a personat a time when they are most infectious. The test is reliant on the amount of virus collected by the swab. The test performs best when there is more virus circulating in the community and when the sample is taken from a person at a time when they are most infectious. Performed outside the conventional laboratory setting, this test enables a quick diagnostic result. However, though cheaper than the PCR, the results are quick but not so accurate.
The Indian Council of Medical Research (ICMR) has approved this test for use in containment zones and healthcare settings.
Rapid antibody testRapid antibody tests, unlike the PCR test or the antigen test, require a blood sample. The test determines whether the person concerned has antibodies for coronavirus. (Antibodies are proteins that the body produces and are used by the immune system to identify and neutralise bacteria and viruses.) The blood sample is examined for two types of antibodies—IgM antibodies, which appear early in an infection, and IgG antibodies, which are more likely to appear later. Comparatively inexpensive, these tests can be used to gauge the extent of infection within a community. But they are not very reliable and can give false positives, so the ICMR has advised that if a person tests positive through a rapid test, they need to take a PCR test before treatment.Antibody tests are only for the purpose of surveillance; they can determine if a patient has previously had the illness.
TruNat testTheTruNat test is commonly used for detecting tuberculosis and HIV. It works on the same principle as RT-PCR and produces faster results. ICMR has approved TrueNat, manufactured by a Goa-based company, for screening and confirmation for COVID-19. It is chip-based machine, small and portable, mostly running on batteries. It is equipped to detect the RdRp enzyme found in the virus RNA in nasal and oral swabs taken from an individual.
The Indigenous Feluda testIndia has developed a test for detecting COVID-19, which gives fast results, similar to a pregnancy test. It has been namedFeluda after the fictional private detective created by Satyajit Ray.Feluda is, however, the acronym for FNCAS9 Editor Linked Uniform Detection Assay. It uses indigenously developed CRISPR gene-editing technology to identify and target the genetic material of SARS-CoV2.
The test was developed by the New Delhi-based CSIR-Institute of Genomics and Integrative Biology (IGIB) and the TATA Group, and received regulatory approvals from the Drug Controller General of India (DCGI) for commercial launch in October 2020. The FeludaCovid test kit, which has been marketed as ‘TataMD’s CHECK’, was launched by the Tata Group in collaboration with the Apollo group of hospitals in November 2020.
According to CSIR, the test matches accuracy levels of RT-PCR tests, considered the gold standard in the diagnosis of the disease, has a quicker turnaround time, and requires less expensive equipment.
The CSIR statement said that the test meets high quality benchmarks with 96 per cent sensitivity and 98 per cent specificity for detecting the SARS-CoV2. (Sensitivity is the ability of a test to correctly identify persons with the disease, while specificity is the ability of the assay to accurately identify those who do not have the disease.)
Feludacan detect even low quantities of the genetic material of the novel coronavirus, based on very minute differences in their RNA. It can differentiate between SARS-CoV-2 and SARS-CoV sequences which differ by just a single nucleotide.
In this method, a protein called FnCas9 and a guide RNA(gRNA) which helps in recognising the viral genes is used. Cas9 protein is derived from Francisellanovicida bacteria. If the sample taken from a person has the viral gene, this gRNA-FnCas9 complex binds to the gene. Using a paper strip this binding can be visualised.In this the Feluda test is similar to a pregnancy test strip: it will show a positive result (in this case the presence of the virus) with a change of colour.
Feluda test is the world’s first diagnostic test that deploys a specially adapted Cas9 protein to detect the virus. Other CRISPR tests use CAS12 and CAS13 proteins to detect the novel coronavirus. A CRISPR-based Covid-19 test called ‘Sherlock’ has been authorised for emergency use by the United States Food and Drug Administration (FDA). The test uses Cas-13 for detecting the virus.
The process is simple and the results fast – in a couple of minutes. The sample from the nose or throat is collected by a swab, and the RNA is extracted. The paper strip is immersed in theFeluda mix which is prepared by incubating the dead FnCas9 protein, guide RNA, and the amplified viral DNA. Gold nanoparticles on the strip bind to the Feluda complex, and a protein called Streptavidin on the test line captures this gold nanoparticle bound-Feluda complex. The unbound gold particles are captured on the control line. One line indicates negative and two lines mean positive, and the indication is through colour.
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CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)occurs naturally in bacteria and archaea as a system of defence against viruses.It is a part of DNA with two special characteristics: the presence of nucleotide repeats and spacers. Repeated sequences of nucleotides (the building blocks of DNA) are distributed all over a CRISPR region; spacers are bits of DNA that are incorporated in the repeated sequences. In bacteria surviving a viral attack, the spacers are incorporated from viruses that attacked the organism. They work as a memory bank that enables the bacteria to recognize the viruses and defend themselves from the attack.CRISPR segments are used as a template to create strands of RNA that move on to the corresponding sequence of the viral genome. The CRISPR RNA carries Cas9 – which is a protein–to the target location on the viral DNA and disables the virus by cutting its DNA. Scientists have attempted to use the technique to make precise cuts or ‘edits’ in any DNA. A customised RNA molecule called the ‘guide RNA’ and the Cas9 protein can together bind with the target DNA sequence, which can then be modified, repaired, or deleted. This technique brought about a revolution in gene editing and gene therapy. The CRISPR technique has been applied in the treatment of cancer, sickle cell anaemia, and infectious diseases such as tuberculosis and malaria.
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Vaccines
Efforts to create a vaccine to prevent COVID-19 began soon after the news of the disease spread. Vaccines work by preparing the body’s the immune system to recognize the viruses and bacteria and fight them off. If the disease-causing germs attack the body later, the body is well prepared to destroy them, so the illness caused by those germs is prevented.
Different types of potential vaccines for COVID-19 are in development. All of them are aimed at developing an immune response in the person who takes them in different ways. They work by stimulating an immune response to an antigen, a molecule found on the virus. In the case of COVID-19, the antigen is the characteristic spike protein found on the surface of the virus; the virus normally uses this protein to help it invade human cells. (i) In live attenuated vaccines, a weakened form of the virus that can still replicate without causing illness is used. In inactivated vaccines, viruses whose genetic material has been destroyed are used, so they cannot replicate, but can still trigger an immune response. (ii) Protein-based vaccines use harmless fragments of proteins or protein shells that imitate the COVID-19 virus. (iii) Viral vector vaccinesuse a virus genetically-engineeredso as they will not cause disease, but can produce coronavirus proteins to safely generate an immune response. (iv) RNA and DNA vaccines (nucleic acid vaccines) use genetically-engineered RNA or DNA. The genetic material is used to provide cells with instructions to make the antigen. Once this genetic material enters the human cells, it uses the protein in those cells to make the antigen to generate an immune response.
According to WHO, the organisation is working in collaboration with scientists, business, and global health organisations through the ACT Accelerator to speed up the response to the disease. When a safe and effective vaccine is found, COVAX (led by WHO, GAVI and CEPI) will facilitate the equitable access and distribution of these vaccines to protect people in all countries.
CEPI (Coalition for Epidemic Preparedness Innovations) classifies development stages for vaccines as ‘exploratory’ (planning and designing a candidate, having no evaluation in vivo), ‘pre-clinical (in-vivo evaluation with preparation for manufacturing a compound to test in humans); this is the initiation of Phase I safety studies in healthy people. After Phase I come the Phase II trials which evaluate immunogenicity, dose levels, and adverse effects of the chosen vaccine, usually in several hundred people. This phase is typically done in a random manner and is placebo-controlled, while determining more precise, effective doses. In Phase III trials, many more participants are involved and at multiple sites, besides including a control group. The effectiveness of the vaccine to prevent the disease is tested: it is an interventional or pivotal trial. There is careful monitoring for adverse effects at the optimal dose. Vaccine safety and efficacy in a Phase III trial, such as defining the degree of side effects, infection, or amount of transmission, and whether the vaccine prevents moderate or severe COVID‑19 infection, may vary from company to company.
In December 2020, the Oxford University-Astra Zeneca vaccine was approved following trials that proved to be successful in 70 per cent of the candidates. It is made from a weakened version of a common cold virus from chimpanzees, been modified to not grow in humans.It has the advantage of not needing to be stored at very cold temperatures. Two doses are required.The UK became the first country to give emergency use authorisation to the vaccine.
The Pfizer-BioNTech vaccine has been claimed to be up to 95 per cent effective. It is given in two doses, three weeks apart. A disadvantage is that the vaccine needs to be stored at a temperature of around -70C, thpugh it can be stored at higher temperatures for five days. It has to be transported in a special box, packed in dry ice.The UK became the first country in the world to approve the vaccine for widespread use in December 2020. It is an RNA vaccine. It may be noted that an RNA vaccine has never been approved for use in humans before, although they have been tried out on peoplein clinical trials for other diseases.
Moderna uses the same approach as the Pfizer vaccine, and it is claimed to have succeeded in protecting 94.5 per cent of candidates in trials. It is given in two doses, four weeks apart. It is easier to store than Pfizer’s, because it stays stable at -20C for up to six months.
The Rusian vaccine, Sputnik V, is claimed to be 92 per cent efficient.
Sinopharm is a vaccine from the Wuhan Institute of Biological Products, China, and Russia’s Gamaleya Research Institute.
India’s Vaccine OptionsAs of December 2020, applications of three vaccine candidates were pending with the DGCI for emergency use authorisation. These were the Oxford-AstraZeneca-Serum Institute’s adenoviral vector vaccine,Covishield; the Pfizer Biontech mRNA vaccine; and the inactivated virus, Covaxin, the vaccine developed indigenously by Bharat Biotech and the Indian Council of Medical Research (ICMR).
Pfizer-BioNTech’s vaccine is priced quite high and requires ultra-low-temperature for storage, which factors pose a huge challenge for a large-scale immunisation. So, even if the vaccine gets regulatory approval, it may not be part of the government’s programme.
Bharat Biotech-ICMR’s Covaxin will probably be the next one to be available in the country after
Oxford-AstraZeneca’s vaccine. Both these vaccines require storage temperatures of 2 to 8 degrees Celsius, respectively. They are both two-dose vaccines.
Some concerns have been expressed as to whether these vaccines will be effective against the mutated variant of the COVID-19 virus that was first observed in the UK, but companies and several experts believe that vaccines will be effective, though further scientific investigation may be warranted.
Around March-April 2021, Sputnik V, an adenoviral vaccine developed by Russia’s Gamaleya National Center and Russian Direct Investment Fund (RDIF), could be available; it will be distributed in India by Dr. Reddy’s Laboratories. Also likely to be available isZyCoV-D vaccine being developed by Cadila Healthcare, which is a plasmid DNA vaccine.
Serum Institute has also tied up to manufacture US-based Novavax’s vaccine. After conducting trials for this vaccine, Serum Institute will be able to supply it in India sometime in the second half of 2021.
Several other Indian companies, including Biological E, Gennova Biopharmaceuticals, Panacea Biotech, and Aurobindo Pharma, among others, are working to develop COVID-19 vaccines.
Besides indigenously developed vaccines, India will also get access to certain international vaccines through the COVAX facility of the WHO.
Though India is likely to have a wide range of vaccine options, it will be a challenge to immunise the huge population.
The immunization blueprintin IndiaThe Indian government has drawn up a comprehensive immunisation plan, which includes phase-wise vaccination, identification of beneficiaries, management of logistics and storage, improving the infrastructure and human resources, training, engaging with states, several ministries and private sectors, and propagating awareness programmes for citizens.
In the first phase, expected to go one until August 2021, India plans to inoculate a priority group of 300 million people, which includes healthcare workers, and frontline workers such as police personnel, people in the armed forces, municipal workers, and disaster-management volunteers.It also includes people above 50 years of age and those people under 50 years who have co-morbidities. The people aged 50 years or more will be identified from the latest electoral roll for the Lok Sabha and Assembly elections.The remaining adult population will be part of the subsequent phase.
The health ministry has said that vaccination will be voluntary.
The Covid Vaccine Intelligence Network (Co-WIN) system, a digitalised platform, will be used to track the enlisted beneficiaries for vaccination and Covid-19 vaccines on a real-time basis. Only pre-registered beneficiaries will be vaccinated at the vaccination site, in accordance with the prioritisation; there will be no provision for on-the-spot registrations.
According to experts, COVID-19 shots could be available in the private market as well. As per a report from FICCI, against the requirement of 100,000 inoculators, the public sector can potentially provide 60,000-70,000. This could lead to capacity constraints, especially in key states such as Odisha, Bihar, Jharkhand, West Bengal, Uttar Pradesh, and Madhya Pradesh. The private sector can adequately supplement the physical and human infrastructure supply in these regions, the report said.
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Emergency approval of vaccinesIn December 2020, it was reported that Modernaand Pfizer had applied for emergency use authorisation for the vaccines they have developed.In India, hree vaccine developers have now made applications to the Central Drug Standard Control Organisation (CDSCO), India’s drug regulator, seeking emergency use approval for their vaccines.
The approval of a regulatory body is required for vaccines and medicines, and even diagnostic tests and medical devices, before they can be administered.
Approval is granted after an assessment of their safety and effectiveness, based on data from trials. In fact, every stage of the trial requires to be approved by the regulator. It is a long process, aimed at ensuring that a medicine or vaccine is absolutely safe and effective.
In emergency situations, like in the wake of the COVID-19 pandemic, regulatory authorities around the world have developed mechanisms to grant interim approvals if there is sufficient evidence to suggest a medical product is safe and effective. Final approval is granted only after completion of the trials and analysis of full data; until then, emergency use authorisation (EUA) allows the medicine or the vaccine to be used on the public.
In the US, the Food and Drug Administration (FDA) grants an EUA only after it has been determined that the “known and potential benefits outweigh the known and potential risks of the vaccine”. For COVID vaccines, the FDA has specified that it would consider an application for EUA only if Phase III data showed it was at least 50 per cent effective in preventing the disease. This data needed to be generated from well over 3,000 trial participants. These participants needed to be followed up for any serious adverse effects for at least one month after all dosages had been administered.
In India, the Central Drugs Standard Control Organisation (CDSCO) is the regulatory body. Within the CDSCO, the Drug Controller General of India (DCGI) regulates pharmaceutical and medical devices, under the aegis of the Union Ministry of Health and Family Welfare.
The three vaccine candidates seeking approval of the CDSCO are:
COVAXIN by Bharat Biotech, a Hyderabad-based company in collaboration with National Institute of Virology, an ICMR institute in Pune, which has started Phase-III trials only recently. It has based its application mainly on the safety data from first two phases.
BNT162b2 from US pharmaceutical major Pfizer. Clinical trials of the vaccine have not been carried out in India, it has still sought an approval to use it in India based on the results of the trials conducted in the US.
The Serum Institute of India in Pune has sought approval for its version of the vaccine developed by Oxford University and AstraZeneca, COVISHIELD, which it has been testing in India. The vaccine candidate is undergoing Phase-III trials in India. Serum has submitted the safety data from the trials in the first two phases, while the effectiveness data has been sourced from Phase-III trials of the same vaccine in the UK and Brazil.
It has been pointed out by experts that India’s drug regulations do not have provisions for an EUA, and the process for receiving one is not clearly defined or consistent. However,clinical trials of new drugs and vaccines, and their approvals, are governed by the New Drugs and Clinical Trials Rules of 2019. Though these rules do not use the term ‘emergency use authorisation’, it does not mean that the Indian regulatory system does not have provisions for emergency situations like the current one. There is a provision in the 2019 rules for ‘accelerated approval process’ in several situations in which approval may be granted to a drug that is still in clinical trials, “provided there is a prima facie case of the product being of meaningful therapeutic benefit”. A relevant provision of the rules says: “Accelerated approval may also be granted to a new drug if it is intended for the treatment of a serious, or life-threatening condition, or disease of special relevance to the country, and addresses unmet medical needs.” A vaccine is included under the definition of new drug in the 2019 Rules. The rules also specify that a new drug, or a vaccine, can be considered for approval if even Phase II trials report‘remarkable’ effectiveness. However, the approval granted to drugs or vaccines that are still in clinical trials is valid only for one year.
The 2019 Rules are silent on whether data from a trial conducted in another country can be considered while assessing an application for accelerated approval to a drug or vaccine to be used in India.
It may be recalled that the CDSCO has been granting emergency or restricted emergency approvals to drugs for COVID-19 during this pandemic, for example, remdesivir, favipiravir, and itolizumab.
On December 31, 2020, the WHOlisted the Comirnaty COVID-19 mRNA vaccine for emergency use, making the Pfizer/BioNTech vaccine the first to receive emergency validation from WHO since the outbreak of COVID-19 a year ago. This approval opens the door for countries to expedite their own regulatory approval processes to import and administer the vaccine. As a consequence of the listing, UNICEF and the Pan-American Health Organization will be able to procure the vaccine for distribution to countries in need.
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