Dr (Prof.) Sundeep Mishra, Till date, the COVID-19 has claimed more than 13 lakh deaths and infected nearly 5.5 crore people globally; nearly 88 lakh individuals, causing > 1 lakh deaths in India alone. With no etiological cure available yet, the only ray of hope, is development of effective vaccine. Vaccination is among the humanities top ten achievements, resulting in the eradication of smallpox; elimination of poliomyelitis and control of measles, rubella, tetanus, diphtheria, Haemophilus influenzae type b, and other infectious diseases all over the world. Currently, scientists across the globe are working around the clock to find a vaccine against SARS-CoV-2. The Herculean effort means that a fast-tracked vaccine could come to market anywhere from the end of 2020 to the middle of 2021. Several claims and counter-claims regarding various possible vaccines are already there which seem to have created more confusion than any real panacea. There are several issues that have contributed to this confusion and they require a careful look. Some of these concepts which need to be understood are effectiveness of vaccine, fast-tracking of regulatory process, phase III trial, ultra-cold chain and at-risk manufacturing. These issues need to be carefully understood before we can assess the progress in the field of COVID vaccination.
Vaccine Approval Process and Clinical Trials
Clinical development is a three-phase process. During phase I, small groups of people receive the trial vaccine. The idea is to identify the effective dose of a vaccine. In phase II, the clinical study is expanded and vaccine is given to people on whom it would be used in clinical practice (have same characteristics such as age and physical health, similar to those for whom the new vaccine is intended). This phase generally focuses on the safety of the vaccine. In phase III, the vaccine is given to thousands of people and tested for efficacy and safety.
After phase III trial the vaccine developers generally apply for regulatory clearance which may be granted based on data accumulated from pre-clinical development (animal studies) but more importantly from clinical trials particularly phase III clinical trial. After regulatory approval vaccines go for mass production or manufacturing. Many vaccines undergo phase IV formal, ongoing studies even after the vaccine is approved and licensed.
Vaccine efficacy and effectiveness
Vaccine efficacy and effectiveness are measures that compare the rates of disease between vaccinated and unvaccinated people. Efficacy is measured in controlled clinical trials, whereas effectiveness is measured once the vaccine is approved for use in the general population. From these we can identify the proportion of vaccinated people we would expect to be protected by the vaccine. No vaccine is 100% effective (a small percentage of people are not protected after vaccination) and for others the protection may wane over time. A vaccine works by producing something that is also known as herd immunity which means that if enough people are immune, then transmission of the disease is reduced or eliminated. It is estimated that anywhere between 25–50% of the population would have to be immune to the virus to achieve suppression of community transmission (Herd immunity). Thus any vaccine which is ≥ 50% effective, if delivered en-masse to a community, should stop the transmission of virus. As a matter of fact WHO does recommend that successful vaccines should show disease risk reduction of at least 50% (with 95% CI that true vaccine efficacy exceeds 30%). It has been estimated that ‘effective’ vaccine dispatches must reach at least 185 of Indian population within six months.
Cold-Chain Requirement
While effectiveness of vaccine is important, it is equally important that they are stored safely and then delivered safely for mass immunization. WHO has defined cold-chain as a system that is used to store vaccines in a good condition. Depending on the composition of the vaccine (toxoid, live attenuated virus, genetic material etc), they are required to be kept at a particular temperature from the point of manufacture to the point of administration. Based on the relative heat sensitivity of vaccines, they are generally grouped into six categories. The most heat sensitive vaccines are in Group A (oral polio vaccine) and the least heat sensitive vaccines are in Group F (Hepatitis B, HiB, Meningococcal A, Pneumococcal) – other vaccines lie in between. The traditional cold-chain is between 2-8o C for storage as well as transportation. After reconstitution for use, they should be used within a short period of time. Most traditional vaccines cannot be frozen.
Ultra-cold chain; However, when the vaccine is made of genetic material, they may require ultra-cold storage chain ~ – 70 o C. These kind of chains are rare in even US and European hospitals, what to speak of developing countries. In any case this kind of cold chain will be prohibitively expensive.
At-risk Manufacturing
Once upon a time, developing a new vaccine was a step-by-step process that went from concept, to design, to tests in humans, to regulatory approval, to manufacturing. This process could take a decade or more. However, the urgent need for a COVID-19 vaccine has radically changed all that. Now, the hope is that the entire process can be completed in a year or less. The point is that a lot of steps that used to come one after another can take place concurrently. Thus manufacturing can start as soon as the vaccine shows promise i.e. after phase II trial even before / at the time of embarking on phase III trial. But since the actual use would depend on success of phase III, this is essentially at-risk manufacturing. Many COVID vaccines under development are embarking on this strategy like Pfizer, Moderna & even Covishield and SPUTNIK V in India. However, one concerning aspect is that many of these vaccines are already pre-booked by developed countries so there may be no vaccine available in near future for developing countries.
Status of COVID Vaccine Development
While more than 100 COVID vaccines are in various stages of development, so far 10 vaccines have reached phase III trial which means that their dose has already been found (phase I) and its limited safety has been established (phase II).
Table 1 shows summary of these phase III trials
| Candidate | Mechanism | Sponsor | Cold Chain Requirement | At-risk Manufacturing | |
| 1 | BNT162 | mRNA-based vaccine | Pfizer, BioNTech | -70 o C | Yes, stock-piles available |
| 2 | Ad5-nCoV | Recombinant DNA vaccine (adenovirus type 5 vector) | CanSino Biologics | Not Required | – |
| 3 | AZD1222 | Replication-deficient chimpanzee adenovirus vector vaccine | The University of Oxford; AstraZeneca; IQVIA; Serum Institute of India | 2-8 o C | Yes, stock-piles available with Serum Institute of India |
| 4 | CoronaVac | Inactivated vaccine (formalin with alum adjuvant) | Sinovac | 2-8 o C | – |
| 5 | Covaxin | Inactivated vaccine | Bharat Biotech; National Institute of Virology (ICMR) | 2-8 o C | – |
| 6 | JNJ-78436735 (formerly Ad26.COV2.S) | Non-replicating viral vector | Johnson & Johnson | 2-8 o C | – |
| 7 | mRNA-1273 | mRNA-based vaccine | Moderna | -20 o C | Yes, stock-piles available |
| 8 | No name announced | Inactivated vaccine | Wuhan Institute of Biological Products; China National Pharmaceutical Group (Sinopharm) | 2-8 o C | – |
| 9 | NVX-CoV2373 | Nanoparticle (antigen subunit) vaccine | Novavax | 2-8 o C | Yes, stock-piles available |
| 10 | Sputnik V | Non-replicating viral vector | Gamaleya Research Institute, Acellena Contract Drug Research and Development | -18 o C | Yes, stock-piles available |
Regulatory Approval
To date, just two coronavirus vaccine has been approved. Sputnik V – formerly known as Gam-COVID-Vac and developed by the Gamaleya Research Institute in Moscow – was approved by the Ministry of Health of the Russian Federation on 11 August without a phase III trial. A second vaccine, EpiVacCorona, also from Russia has also been granted regulatory approval, also without entering phase III clinical trials. Giving trials approval without conducting phase III trials has raised considerable concern about the vaccine’s safety and efficacy of an “under-cooked” vaccine. Another vaccine BNT162 from Pfizer / BioNTech has reported a successful “interim result” and will request regulatory approval by the end of November 2020. Many vaccines are hoping for fast-track regulatory approval and have already undertaken at-risk manufacturing Table
Vaccines to Watch
- BNT162 – Pfizer / BioNTech. Recently, Pfizer Inc in a breaking news announced the interim data on phase III clinical trial of their vaccine (mRNA) against COVID-19, involving 44.000 participants, finding that it was more than 90% effective with no major side-effects (some minor side-effects were aches and fever) making it the first drug makers to release highly successful data, from a large-scale clinical trial of a coronavirus vaccine (earlier vaccines had approached only 50% success with concerns of serious side-effects in some of them). The dose is 2 injections, spaced 21 days apart. The only down-side for this vaccine seems to be the requirement for ultra-cold storage. The company has already at-risk manufactured and stock-piled 10 crore doses (In year 2020), hoping for an early emergency-approval.
- Covishield / AZD1222 – The University of Oxford / AstraZeneca / IQVIA / Serum Institute of India. The AZD1222, the most widely globally tried vaccine, is really a weakened version of a common cold virus (adenovirus that causes infections in chimpanzees, but has been genetically modified to make it impossible for it to grow in humans) to which genetic material (ChAdOx1 construct) is added which is used to make Spike glycoprotein (S), found in SARS-CoV-2 coronavirus. Immunity generated against this protein affords protection when actual infection happens. The phase1/2 study published on July 20, 2020, showed a single dose of AZD1222 resulted in a 4-fold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants one month after injection with an “acceptable safety profile.” Phase III clinical trial is globally enrolling with a target to enroll up to 50,000 participants. There has been 1 death & two neurological events (transverse myelitis and multiple sclerosis) which put the trial on hold but it has now re-started with results expected by the end of year.
The phase III trials of Covishield vaccine are also being carried out on 1,600 participants at 15 centers in India. The vaccine has been developed receiving master-seed from Oxford University / Astra Zeneca by Pune-based Serum Institute of India (SII) and Indian Council of Medical Research (ICMR). 40 million doses of the vaccine under the at-risk manufacturing and stockpiling license from DCGI.
- COVAXIN is the government of India backed COVID 19 vaccine developed by collaboration between National Institute of Virology, ICMR and Bharat Biotech. It has demonstrated safety and efficacy in animal studies as well as phases I & II trials and has now entered phase III clinical trial, taking place at 25 centers across India with a total of 26,000 participants.
The vaccine is likely to be available for clinical use in February 2021 but based on its early efficacy and safety and in view of worsening pandemic, Government of India may consider granting an emergency authorization for at least elderly and in people in high-risk work-places.
- JNJ-78436735is a non-replicating virus vaccine. Interim analysis from Phase1/2a First-in-Human trial demonstrated that a single dose of JNJ-78436735 induced a robust immune response and was generally well-tolerated. Based on this data the company has now embarked on a single-dose of our COVID-19 vaccine candidate versus placebo, the ENSEMBLE Phase3 study. In addition it is also doing a 2-dose study. Recently, the ENSEMBLE was put on hold due to an adverse event in one of the participants but now J&J has been cleared to resume the trial in the US & Brazil.
- mRNA-1273 is an mRNA vaccine candidate against the novel corona virus SARS-CoV-2 encoding for a prefusion stabilized form of the Spike (S) protein, which was selected by Moderna in collaboration with investigators at the NIAID Vaccine Research Center. After NIH-led phase I study which selected an appropriate dose (100 μg), 25,296 participants have been enrolled in the “COVE,” phase III clinical study. Like Pfizer, Moderna has already kept a certain stock of vaccine ready, in case it gets an early approval.
- Sputnik V is the world’s first registered vaccine, based on a well-studied human adenoviral vector-based platform. Results from 2 small phase I / II trial revealed that the vaccine induced strong humoral and cellular immune response, a good safety profile and an efficacy of 92%(among 20 participants).The ongoing Sputnik V post-registration clinical trial in Russia involves 40,000 volunteers. Clinical trials of Sputnik V have been announced in the UAE, India, Venezuela and Belarus. The novel concept for ensuring lasting immunity is to use two different types of adenovirus vectors (rAd26 and rAd5) for the first and second vaccination, boosting the effect of the vaccine. Dr Reddy’s Laboratories is conducting phase III clinical trial in India and RDIF shall supply 100 million doses of the vaccine to Dr Reddy’s upon regulatory approval in India. However, the down-side is that this vaccine also requires a ultra-cold storage facility of < -18O C).
Vaccines Available in India
About 20 vaccines are in the different stages of developments in India. Two of them are in the most advanced stage of development; phase III clinical trial – COVAXIN developed through ICMR-Bharat Biotech collaboration and COVISHIELD from the Serum Institute of India. Dr Reddy’s Laboratories, is another company that is conducting final-stage human trial on SPUTNIK V, the Russian vaccine and will distribute in India after receiving regulatory approval.
ZyCoV by Zydus Cadila is a plasmid DNA vaccine candidate for COVID-19 that targets the viral entry membrane protein of the virus. The company has launched an adaptive phase1/2 dose escalation trial and plans to enroll about 1,000 healthy volunteers. The company announced that phase1 was complete and the candidate is in phase II trials and is likely to enter phase III, the final phase trial by December, among 30,000 volunteers, which will be the largest COVID-19 trial in India. The cold-chain required is usual (2-8O C). The company has created an in-house manufacturing capacity of 100 million doses per year and has roped in a contract manufacturer to make additional capacities to make about 150 million doses a year. Regulatory agencies worldwide, including the Indian regulator the Drug Controller General of India (DCGI), are expected to clear COVID-19 vaccines with an ’emergency use authorization’ to start immunization, once the vaccines successfully undergo trials.
However, vaccine development is one aspect, managing logistics is quite another. Fortunately, all the vaccines being developed in India; COVAXIN, COVISHIELD & ZyCoV require standard cold-chain of 2-8O C. It is estimated that India will have 50 crore vaccine doses (25 crore recipients) by July 2020. Furthermore, besides doses India will also require >16,000 adequate cold-chain storage.
Department of Cardiology, AIIMS, New Delhi
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