On January 16th, 2021, Prime Minister Narendra Modi launched the world’s biggest COVID-19 vaccination drive.
The government plans to inoculate three crore health officials and frontline workers in the first phase of the rollout, following which people aged above 50 years and those with co-morbidities will be identified and vaccinated. By August 2021, the government plans to vaccinate about 30 crores (about 1/4th of the total population) Indians. For this drive, the government is using two vaccines- Covishield (produced by the Serum Institute of India), which is the Indian variant of the Oxford-AstraZeneca vaccine developed by Jenner Institute, Oxford, and COVAXIN (produced by Bharat Biotech), which is a home-grown vaccine. Both vaccines employ different working methods.
First things first, how are vaccines developed?
In the initial stage, each vaccine must undergo an evaluation to ascertain which antigen must be used to evoke an immune response. This is the pre-clinical stage and does not involve humans. It is first tested in animals, and its safety and potential to prevent disease is evaluated. Then, the three phases of clinical trials begin.
In Phase-I, a small group of young and healthy volunteers is given varying levels of vaccine doses. This is done to determine the highest level of dosage that can be given without inducing any negative side-effects. In Phase-II, several hundred volunteers are tested to determine further whether an immune response is being generated and if the vaccine is safe. Participants in this stage have similar characteristics compared to the group for which the vaccine is intended. Multiple trials are involved in this phase with different groups and combinations of the vaccine. Finally, in Phase-III, a much larger group (thousands of volunteers) is involved. The volunteers are divided into two groups; while one is given the vaccine, the other is given a placebo. Both the scientists and the volunteers are shielded from knowing whether they have been administered a placebo or the vaccine itself. This is known as blinding. Once the trial is completed, the data is ‘unblinded’ and scrutinised for efficacy. The process can be better explained through the example of Pfizer’s vaccine.
Pfizer enrolled 43,661 volunteers for its Phase-III trial, of which 41,135 received a second dose. A total of 170 people got infected with COVID, of which 162 were part of the group which received a placebo, while only 8 belonged to the group which received the vaccine. The variance is large enough to prove that the vaccine was indeed efficacious but by how much? About 0.74 % of those who received the placebo contracted COVID (162/22,000), while only 0.036 % (8/22,000) of those who received the vaccine did so. Using this, we can calculate the relative risk by dividing 0.036 % by 0.74 %, which gives us 4.9%. This means people in the vaccinated group have about 5 % of the risk of contracting COVID than people in the placebo group, implying that the vaccine has a 95 % efficacy.
About the Two Vaccines
Covishield, the Indian variant of the Oxford-AstraZeneca vaccine, is being produced by the Serum Institute of India (SII), the world’s largest vaccine manufacturer. According to SII, it is producing five crore doses of the vaccine every month. The vaccine is made from a weakened version of adenovirus, which is known to cause common cold in chimpanzees. It carries the code to make the spike protein, which the body recognizes as a threat and builds antibodies against it. The Central Drugs Standard Control Organisation (CDSCO) has granted the vaccine approval for ‘restricted emergency use.’ The vaccine has completed Phase-III trials in Brazil and the UK, where its efficacy was found to be 62% and 90%, respectively. The high percentage of efficacy in the UK was obtained despite a dosage error, i.e., volunteers were administered half-dose of the vaccine followed by a full-dose. It has, however, been clarified that it is a two-full dose vaccine. In India, the Phase-III trials have not been completed yet; it began in August last year and is expected to continue till March 2021. However, according to a report by The Print, the SII ‘has now applied for permission from the Drugs Controller General of India (DCGI) to “unblind” the data of its ongoing phase 3 trial.’ Since many of SII’s volunteers are now eligible for the vaccine, they expect to know whether they have been vaccinated already or received just the placebo.
Covaxin, developed by Bharat Biotech, is an ‘inactivated’ vaccine. It uses a killed SARS-CoV-2 virus, which cannot replicate or infect. However, it can be used to generate an immune response. Bharat Biotech plans to produce about 70 crore dosages of the vaccine by the end of this year. At present, it already has an arsenal of 2 crore dosages. Covaxin has been approved for ‘restricted use in emergency situation in public interest as an abundant precaution, in clinical trial mode.’ Phase-III trials of the vaccine began in November 2020 with 25,800 volunteers, and efficacy data is expected to be released by March. On 21st January, The Lancet, a leading medical journal, published the Phase-I data for Covaxin ‘giving it a green light for safety and stating that it generates adequate immune response, but said further efficacy trials were warranted.’
Why the ‘vaccine hesitancy’?
India is facing a unique problem in its inoculation drive- it has an abundance of vaccine shots, but not many people are willing to take them. As of last week, only 56 % of people who are eligible to get the vaccine stepped forward. Hesitancy is much higher for Covaxin; in Tamil Nadu, only 23.5 % of people allocated Covaxin received the shot on January 19 compared to 56 % for Covishield. Much of this can be attributed to the fact that both the vaccines have not completed Phase-III trials in India to prove safety and efficacy on a large scale. The fact is compounded for Covaxin as Covishield does have efficacy data from the UK and Brazil.
The approval granted to both the vaccines is couched in vague and uncertain language; it uses terminology absent from the relevant drug laws, i.e., the Drugs and Cosmetics Act, 1940 (D&C Act), the Drugs and Cosmetics Rules, 1945, and the New Drugs and Clinical Trials Rules, 2019 (NDCT Rules). The NDCT Rules do allow for expedited approval based on Phase-II clinical trial data, but tremendous leeway is given to the ‘Central Licensing Authority’ (CDSCO) to specify terms of post-approval use. For Covishield, such terms were specified in the 134th Meeting of the Subject Expert Committee (SEC) of the CDSCO. There were conditions that the vaccine shall be administered to people above the age of 18, the SII should submit safety and efficacy data from ongoing clinical trials both nationally and internationally at the earliest, and data on any possible adverse effects of the vaccine with due analysis every 15 days for the first two months and monthly thereafter. For Bharat Biotech, the SEC in its 135th Meeting specified that it had to submit Phase-III trial data as and when available. It also formulated an implementation plan titled “Restricted use of COVAXIN under clinical trial mode,” pursuant to which the vaccine was approved for rollout in clinical trial mode with a factsheet, informed consent form, and adverse event form.
The government has been trying to bolster people’s confidence surrounding the vaccines, but lack of Phase-III data and adverse effects following immunisation (AEFIs) have acted as significant impediments. Nine people who received the Covishield vaccine have died since the drive began on 16th January. While it is unclear whether the deaths were caused by the vaccine, further investigation is underway. Further, the government’s inability to provide a choice between the two vaccines has been questioned since Covaxin was to be used only as ‘abundant precaution’ to have more options for vaccinations. However, at present, the government is procuring and distributing both the vaccines to different states (110 lakh doses of Covishield and 55 lakh doses of Covaxin), effectively treating both equally.
Until Phase-III data is available in the public domain, it is unlikely that the government efforts to develop public confidence in the vaccines will be of much avail.
What is Vaccine ‘Maitri’?
India has been using its massive vaccine production capacity to aid not just its own people but several other countries. Vaccine Diplomacy, or Vaccine Maitri, as it has been popularly termed, is being used to generate goodwill with various countries around the globe. Consider the following excerpt from The Financial Express–
“Over the next few days, India is planning to give more vaccines to countries across the globe. Oman will get one lakh, CARICOM countries will receive 5 lakh, and Central American nation Nicaragua will get 2 lakh and Pacific Island states around 2 lakh doses…
…From January 20, 2021, India has given around 55 lakh doses of vaccines to the neighbourhood and the supplies made were based on the requests from these countries.
Seychelles (50,000), Sri Lanka (5 lakhs), Bhutan (1.5 lakh), Maldives (1 lakh), Nepal (10 lakh), Bangladesh (20 lakh), Myanmar (15 lakh), Mauritius (1 lakh), and Bahrain (1 lakh).”
Besides, countries like Morocco and Brazil were given 20 lakh doses each under commercial agreements. The UK, Belgium, Saudi Arabia, UAE, and South Africa have also shown interest in buying vaccines from India. This is not surprising, given that Indian vaccines are cost-effective (Covishield, for instance, costs only $6 compared to Moderna’s vaccine priced at $ 30), and India has a large number of vaccine production plants, catering to 50 % of the global vaccine demand.
Which are the other vaccine candidates in India?
Apart from Covishield and Covaxin, there are some other vaccine candidates in India. Zydus Cadilla’s vaccine, ZyCoV-D, has been granted approval for proceeding towards Phase-III trials by the CDSCO. Russian vaccine Sputnik V’s Phase II and III trials are underway at Dr. Reddy’s Laboratories. The vaccine has been in use in Russia since August 2020, and India plans to manufacture 30 crore doses of it by the end of this year. NVX-COV-2373 is another vaccine produced by the SII in collaboration with American company NovaVax. Its Phase III trials are under consideration. Similarly, Bharat Biotech is also producing another vaccine with Thomas Jefferson University, US, and it is still in the pre-clinical stage. Other vaccines include- Biological E Ltd. vaccine, which will start its late-stage trial in April, HGCO19 by Pune-based Gennova Biopharmaceuticals, which will begin its Phase 1 clinical trial with 120 participants; and Aurobindo Pharma vaccine, which is in its pre-clinical stage.
Phase-II of the Inoculation Drive (Updated on February 28, 2021)
The Government has announced the second phase of the COVID-19 vaccination drive from 1st March 2021. In this phase, people above the age of 60 and above the age of 45 (with co-morbidities) will be eligible for the vaccine. In the 1st phase, the Government had planned to vaccinate three crore people, but it could achieve only 48 % of its target. As of today, 1,43,01,266 people have been vaccinated. This is not surprising, given the vaccine hesitancy as explained above. The Government has tried giving it a positive spin by focussing on absolute numbers instead of vaccinations per million population as it did for cases and deaths.
In the second phase, the Government plans to inoculate 27 crore people. It has identified 20 co-morbidities for people between the age of 45 and 59 (like ‘congenital heart disease that leads to pulmonary arterial hypertension, end-stage kidney disease, or cancers such as lymphoma, leukaemia and myloma, decompensated liver cirrhosis (deterioration of liver function due to scarring), primary immune deficiency conditions, and sickle cell anaemia’). People with co-morbidities will have to produce a one-page certificate signed by a medical practitioner. Also, they can register themselves in three ways- on the Co-WIN 2.0 App, on-spot registration, and facilitated cohort registration.
The most significant development is that the Government has finally decided to involve private players in the inoculation drive. The slow rate of vaccination has compelled the Government to leverage their capacities. “The Government has allowed states to use around 10,000 hospitals under Ayushman Bharat-PMJAY and 687 hospitals under CGHS as Covid-19 vaccination centres (CVCs). There would also be government health facilities which will be used as CVCs such as medical college hospitals, district hospitals, sub divisional hospitals, CHCs, PHCs, health sub centers and health and wellness centers and geo reference maps with GPS coordinates of all these health facilities have been prepared that will serve as CVCs, the Union ministry of health and family welfare said in a statement.”
However, the Government has capped the price of each dose at Rs. 250. As per The Print, on 25th February 2021, an official from the Health Ministry confirmed that the estimates presented to them by the private hospitals envisaged a price of Rs. 400 per dose, including an administration cost of Rs. 100. The price cap can be counter-productive, as shown by past experiences. Just last year, the ICMR fixed a price cap of Rs. 4,500 on COVID-19 (RT-PCR) testing, but later allowed the states to fix prices on a mutually acceptable basis. However, states paid the private testing facilities even lesser (Rs. 2,300 on average), making it unfeasible for many private facilities to invest in testing kits. As per a report in the Hindustan Times, ‘Capping the price of coronavirus tests at ₹800 has forced some private labs to use inexpensive and less sensitive kits with lower limit of detection to keep the cost of testing low, which raises the risk of false negatives and compromises data coming out of India, say experts.’ Thus, a price cap will only decrease the pace of vaccination and defeat the very purpose the private players were included in the first place.
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