Covid-19 Vaccines: The India Challenge
The three tests that the Covid-19 vaccination program has to pass, to be successful. By public health expert Dr K Srinath Reddy.
If 2020 is the year of Covid-19, with the SARS-CoV2 virus still tirelessly doing its laps across the world, will 2021 be the year of vaccines that will upstage the virus and win the race for humanity? With over 150 vaccines in different stages of development and evaluation, there is an expectation that some winners will emerge by early next year after a regulatory review of trial data that will be reported by the end of this year. Recent news reports of interim results suggest that the expectation is not mislaid.
A vaccine has to pass three tests to be successful – quality, ease of delivery, and public acceptance. Quality, in turn, has three attributes – safety, efficacy, and duration of protection. These are initially assessed in animals, then in humans through rigorously three-phased clinical trials involving thousands of persons, followed by post-marketing surveillance of several thousands more.
Safety And Efficacy
It is essential to assess safety as the vaccine will be administered to healthy persons. It is a concern because some candidate vaccines have previously been known to have serious adverse effects. A vaccine intended for the SARS-1 virus did not take off because it exhibited Antibody-Dependent Enhancement or ADE where the antibodies elicited by the vaccine paradoxically enabled the virus to enter and infect more cells. The Dengue vaccine is a prime example of ADE posing danger.
Efficacy too needs to be demonstrated in terms of protection. The vaccine may succeed in preventing infection or in preventing an infected person from developing severe disease. Or, it may fail to stimulate the immunological responses needed to protect a person against the viral entry or disease. Due to a phenomenon labelled as the Original Antigenic Sin, the vaccine may only elicit antibodies against the modified viral elements that are used in it but not against the actual virus itself due to ‘repertoire freeze’. Even when antibodies are produced against the real virus, they may not be neutralising antibodies that can bind it down. The neutralising antibody response may be weak and T-cell immunity, the other and more durable component of the immune response, may not be stimulated. With so many reasons to fail, a trial must demonstrate convincing success of protection.
The vaccines which are now ahead in clinical trials have to be injected into the body and the immune response they elicit may not prevent the virus from entry into the nose or throat (‘infection’) but may be able to prevent the subsequent impact on the body (‘disease’).
By preventing disease but not the infection, can they still leave the vaccinated persons capable of infecting others?
Mucosal vaccines, which elicit secretory antibodies that barricade against the virus even intruding into the respiratory tract, are in the early stages of evaluation and may arrive later as the second generation of vaccines. Future use may even see the combined use of systemic and mucosal vaccines.
Given the challenges of passing the quality test, it is heartening to note high levels of efficacy and safety being claimed by interim reports from three ongoing trials. The Pfizer-BioNTech, Sputnik-V, and Moderna vaccines have just reported over 90% efficacy rates from interim analyses of ongoing Phase three trials. Several national regulators and WHO had set a bar of at least 50% demonstrated efficacy, with the lower 95% confidence limit of the estimate not falling below 30% (as the lower bound of a range of true efficacy values the observed result may represent). The claimed interim results of ongoing trials are promising far better results. Scientific scrutiny eagerly awaits the publication of these interim results and completion of the trials. Other vaccines, which are lined up in the parade, will also soon walk the ramp seeking to claim the winner’s crown or a congeniality prize. Affordability and ease of administration may outweigh superior quality in driving choices by the countries.
Delivery Dynamics
It is possible that more than one vaccine will cross the finish line of regulatory approval after passing the trials. The earliest to do so need not be the best in quality or most suited to mass administration. Beyond the comparative quality measures, operational issues of vaccine production, procurement, supply chain, prioritisation for sequenced administration in the population, and monitoring of impact will pose major challenges.
- Will it be a single dose or a two-dose vaccine that has to be administered 21 to 28 days apart?
- How will it be priced?
- What are the cold chain requirements?
- Will there be an adequate number of trained health personnel who can administer the injections?
- Will delivery to rural populations prove difficult?
- How constrained in time and quantity will the supply chain be?
Vaccines for Covid-19 are using different platforms that vary in the cold chain requirements and the number of doses. The innovative two-dose mRNA vaccines that are ahead in the trials have stringent freezer requirements for storage and transport. The Pfizer-BioNTech vaccine requires to be stored and transported at -70 degrees Celsius, while the Moderna vaccine needs storage at -20 degrees Celsius. These are daunting even for rural areas of the United States. For most of India and many low and middle-income countries, vaccines that require such severe sub-zero temperatures for storage and transport are impractical. Other candidate vaccines, which use more conventional platforms for vaccine development, can be preserved and transported in less stringent cold chain systems that are already available for ongoing routine immunisation programmes involving other vaccines.
The universal immunisation programme in India has well established and time-tested vaccine distribution systems. The cold chain for those vaccines does not require super-freezing sub-zero temperatures but functions well at +2 to +8 degrees Celsius.
The Covid-19 delivery system will use the UIP platform, with the innovative Electronic Vaccine Intelligence Network enhancing efficiency and diligence.
This is a smartphone application that helps to monitor vaccine stocks and cold chain efficiency. Even though super-freezers exist in several research laboratories in India, vaccines that require sub-zero temperatures will not find favour for the national rollout.
A group of scientists, led by Raghavan Varadarajan at the Indian Institute of Science, has recently developed a warm, dry, lyophilised vaccine that can withstand up to 100 degrees Celsius and is easy to store and transport at 37 degrees Celsius. It is still to enter the clinical testing arena. Its evaluation will take time but, if successful, would be most suitable for the long run. Keep those hopes alive!
Access And Cost
Even when an approved vaccine becomes available, countries will have to prioritise the order in which different population groups will receive the vaccine as supply will be limited for several months. People will also wait to see the initial experience with the vaccine. Open, frequent, and accurate public communication on the vaccines will help to overcome legitimate concerns. As public confidence in the vaccines grows, the demand would rise and supply chains need to keep pace. Most countries will follow a mix of essentiality and demography as the criteria for guiding the initial selection of vaccines recipients. Essential workers (especially health, security and transport personnel) as well as the elderly are likely to be the first recipients. Persons with co-morbidities and economically essential occupations will probably follow. Others in the population will be vaccinated later, moving down the age groups. These are choices that countries will make, weighing priorities based on the availability of vaccines over time.
Global manufacturing capacity will be put to test by the demand for vaccines. India will be a major contributor to vaccine production, whether indigenously developed or internationally licensed. That should provide early and high volume access to affordable vaccines. Other vaccine manufacturing hubs too are expanding their capacity. The cost of vaccines will be a challenge to many countries. The COVAX partnership promises globally equitable and affordable supply. We have to see how it will manage the competition with high-income countries when the initial production levels are low. It will greatly help if multiple vaccines qualify, with diverse manufacturing platforms, supply chain requirements, and cost structures.
In the meanwhile, we collectively invest in hope, while relying on the strength of science for research and development to trustworthily tell us if we will soon have a safe, effective, and easily-deliverable vaccine. As Louis Pasteur advised his research fellows, “keep your enthusiasm but let strict verification be its constant companion”.
Dr. K Srinath Reddy is a cardiologist and epidemiologist. He is President, Public Health Foundation of India, and the author of 'Make Health in India: Reaching a Billion Plus'. Views are personal.
The views expressed here are those of the author, and do not necessarily represent the views of BloombergQuint or its editorial team.