With the approval of the first vaccines for COVID-19, we can now project a future where this terrible time is behind us and the pandemic is under control. Getting this far, this fast has not been easy. It has meant compressing a decade of vaccine development work into less than 12 months—an achievement that has only been possible because of science and the collaboration between academia, industry, policymakers and funding.
The first emergency use authorisation for Pfizer/BioNTech vaccine, based on data that went beyond the originally projected endpoints, was issued on December 2, just 218 days after the clinical trials started and 326 days after the novel coronavirus sequence was released. For both the Pfizer/BioNTech and the Moderna vaccines, it was a matter of days to design the constructs that resulted in the two mRNA vaccines that have shown 90-95 per cent efficacy in protecting against disease and are now approved under U.S. emergency use authorisations, and in the case of Pfizer, in many other countries around the world.
These achievements, however, did not come from a standing start. The rapid acceleration of development of vaccines was only possible because scientists had been working to prepare for future outbreaks despite policymakers and governments dismissing their forecasts of future pandemics. In the wake of Ebola, the World Health Organisation (WHO) began to publish the Global Research and Development Blueprint which identifies each year the top 10 threats to public health, and always includes Disease X, the unknown pathogen that will come from an unknown place at an unknown time. The experience also led to many international consultations, which resulted in the establishment of the Coalition for Epidemic Preparedness Innovations (CEPI), a grouping of state and non-state actors who were committed to the development of early clinical stage vaccines for outbreaks, which would address the issues of ‘market failure’.
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‘Market failure’ refers to the idea that even though there is a need for certain types of vaccines, the companies that manufacture vaccines are not interested in making them because they do not see any commercial viability in such products. In other words, if a disease affects the poor who cannot afford to pay for a vaccine, who will make it for them? For an infectious disease outbreak, where the timing of the disease is unpredictable, the number of people needing to be vaccinated is unknown and if the disease occurs in a poorer part of the world, finding a company or group who will try to make a drug or preventive product like a vaccine is near impossible.
Experience with Ebola
This was certainly the case with Ebola, where a vaccine candidate had been developed at the National Microbiology Laboratory of the Public Health Agency of Canada a dozen years before the first West African urban outbreak, but there were no companies interested in clinical development. By the time the world got its act together to evaluate the vaccine, and turf wars between countries and agencies that all wanted to conduct vaccine research to control the outbreak were sorted out, Ebola cases were already trending down because of aggressive treatment and infection control measures. While developing vaccines that prevent disease are clearly a superior strategy in terms of lower human costs, we need to remember that with sufficient resources, spread of human-to-human infection can be controlled by separating the infected from the healthy, as we have seen with SARS-CoV2, even with the additional challenge of asymptomatic infections.
A coalition against epidemics
CEPI arose from the idea that an essential part of preparedness for epidemics was to make and keep ready vaccines that could be used quickly in outbreak situations for diseases on the WHO Blueprint and also to try to develop new technologies for rapid response in case disease X emerged. CEPI, supported initially by the governments of Norway, Germany and Japan, and by the philanthropic organisations the Wellcome Trust and the Bill and Melinda Gates Foundation, had India’s Department of Biotechnology as a founding partner, with Dr K. Vijayraghavan, then the Secretary of the Department of Biotechnology and now the Principal Scientific Adviser to the Government of India, chairing the interim Board. CEPI was formally established in Norway in 2017, and it raised about $800 million from governments and philanthropies to target Lassa fever, MERS and Nipah in 2018. In 2019, CEPI expanded its portfolio to also support development of chikungunya and Rift Valley fever vaccines and rapid response platforms, which included mRNA and viral vector technologies. Therefore, in 2020, when SARS-CoV2 clearly emerged as a potential global threat, CEPI was able to fund the first three vaccine candidates in January, and these included support for Moderna and the University of Oxford.
Shortly thereafter, others, particularly multinational companies, with and without vaccine development experience, and governments followed with support for vaccine development at multiple scales, particularly in the United States and Europe. The story of vaccine development during this pandemic, while incomplete, is a remarkable record of great speed, great science and cooperation on a scale we have never seen before. But the world has only been able to make such rapid advances because of years of scientific work and investment in understanding two closely related coronaviruses—SARS-CoV-1 and MERS-CoV. The National Institutes of Health in the U.S. house the Dale and Betty Bumpers Vaccine Research Center, which was established under President Bill Clinton to make a vaccine for the human immunodeficiency virus (HIV). While HIV vaccine development efforts have so far not been successful, the learning gained from understanding HIV has resulted in vaccine candidates against Ebola, the original SARS, chikungunya and many other viruses. That Moderna and Pfizer were able to design highly effective vaccines within days of the viral sequences being released was due to the fact that researchers had invested years in understanding how to target the spike protein that studs the surface of all coronaviruses. Work with SARS has shown that stabilising the structure of the spike in the shape before it fuses with the host cell is more likely to preserve targets for infection-blocking antibodies induced by a vaccine.
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This exceptionally rapid progress on mRNA vaccines seen in 2020 reflects years of patient endeavour by scientists on new vaccine platforms. In all our approaches to vaccines from Edward Jenner onwards, the focus of vaccine development was to deliver the entire infectious agent, or part of it, in order to induce an immune response that was calibrated to protect without inducing disease or side-effects. With new technologies that focus instead on delivering the instructions for making a protein to host cells, scientists are trying to make vaccines that are safer, can be made much more quickly and can be adapted to a range of targets once the infectious agent is known. With viral vectors, RNA and DNA vaccines, the two essential components are the genetic cargo or the sequence that instructs our cells to make a protein, and the delivery vehicle, whether it is a virus that acts as a carrier or vector, a fatty nanoparticle that protects RNA from breaking down, or plasmid DNA that incorporates the sequence for a protein within itself. Once inside the cell, the genetic cargo essentially hacks into the same mechanisms used by SARS-CoV2 to replicate itself, but instead of producing the whole virus, a single protein in its three dimensions is produced. The immune system recognises the protein as foreign and musters all of its components to respond.
These revolutionary technologies have, for mRNA and viral vectors, been validated by phase 3 and give the world powerful new tools to radically accelerate the response to future disease threats. Even as we hear news of new variants, and the very real threats they pose, we have hope because we now have the tools that will enable us to respond effectively and rapidly.
These are landmark shifts in vaccine development. If a range of viral vectors can be validated, we will have options to choose from, depending on the rapidity and durability of the immune response to be induced, and whether it is to a single protein or multiple proteins. While the vector will remain the same, the genomic message they carry can be easily switched based on need. Viral-vectored vaccines can be easily and cheaply made, holding real promise for their use in low- and middle-income countries. The potential for much more distributed vaccine-manufacturing capabilities, at regional and country level, will promote future security of supply.
The mRNA approaches are even more of a paradigm shift. Unlike traditional vaccines which are dependent on biological manufacturing, which is often tricky and temperamental, mRNA vaccines are actually chemical compounds and the processes for chemical synthesis are well understood and easily replicated. While we still have to work through regulatory processes that have not yet dealt with platform technologies, there is at least hope of a future rapid response strategy.
A long haul, still
In the meantime, though, we still have a long way to go to defeat COVID-19. As an example, the U.S., which is the country most hit in terms of lives lost and the burden borne, is also the country with greatest access to vaccines because it invested $10 billion in making and testing candidates. While vaccine development is usually a risky process, with up to 90 per cent of the candidates failing, the availability of the best science, testing technologies, manufacturing methods and clinical testing platforms meant that the U.S. was able to mitigate the risk of failure for vaccine companies and able to deliver on both speed and scale. Vaccines are now being rolled out in high-income countries, in small numbers at the moment but expanding rapidly. Although other prevention strategies of masking, distancing and re-aligning to prevent congregations may need to continue, high-income countries have a light at the end of the tunnel.
In less well-endowed parts of the world, CEPI, the Gavi Alliance, the WHO and other partners have come together for Access to COVID-19 Tools (ACT) Accelerator that is seeking to make available at least 2 billion doses of vaccines for countries that participate in the COVAX facility. The COVAX facility has over 190 countries participating and is the largest multilateral undertaking after the Paris Agreement on Climate Change. Vaccines provided through COVAX are calculated to be sufficient for the participating countries to vaccinate at least 20 per cent of their populations. This is much better than what the world was able to do for H1N1, the last pandemic, but it is also clear that for most countries access will be slower than for countries that have made bilateral deals with vaccine manufacturers or countries like India, Brazil and Indonesia that have their own vaccine-manufacturing capability.
We need to understand that in a connected world and with a virus capable of asymptomatic spread, no country is safe until everyone has a chance of protection. The failure to promote access to vaccines around the world will ensure many more unnecessary deaths, further suffering and disruption of essential health services, and a slower global economic recovery.
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It is estimated by the RAND Corporation that high-income countries would lose about $119 billion a year if the poorest countries are denied COVID-19 vaccines. RAND also estimates that the high-income countries that paid for vaccines would get back about $4.8. for every $1 spent.
We are in a good place now, but our work is not done. We have proven products, but they are insufficient for the global need and have challenges of storage, supply and distribution. For example, it is unlikely that mRNA vaccines can be widely used in India because of their requirements for cold- and ultra-cold storage. We will need vaccines more suited for all parts of the world, with less cold chain requirements, single dose and with long-term protection. Further, while India’s immunisation programme is the largest in the world, it has no experience of adult immunisation. The logistics support, training, documentation strategy and safety monitoring systems are being built by the government by repurposing or building on existing strategies, but how well they will do, will be known only when vaccines are rolled out.
Although the acute phase of the pandemic may end in a year or so, SARS-CoV2 is likely to be here to stay. It will continue to circulate and evolve. If long-term protection is feasible, then we may not need booster doses, but otherwise we will have to vaccinate and update vaccines regularly. We need to be investing now in research and development so that we can plan for the long-term management of SARS-CoV2. This is actually a huge opportunity for investments in health and in vaccines for India because we have many viruses in our own and the global landscape, such as influenza, dengue, chickenpox and chikungunya that are all vaccine-preventable but have been largely unaddressed so far.
Known and unknown viruses will continue to be a threat. The COVID-19 pandemic will be repeated, even if we do not know when. We were lucky that that SARS-CoV2 is not a virus that has as high a fatality rate as SARS-CoV1 or MERS. With collaboration and incredible efforts, the world has developed vaccines that hold the promise of rapid control, even though there is much to be done for their manufacture and delivery. India may not have been the first to develop vaccines, but what matters more is that we are likely to be very large suppliers to the world, with the vaccines that will become available in 2021.
Looking to the future, in the wake of COVID-19, many countries will make national or regional investments in pandemic preparedness, and India should not be left behind. With investment in research, scientific solidarity, industrial partnerships and an enabling environment, we can develop vaccines for ourselves and the world at scale and speed.
Professor Gagandeep Kang is with Christian Medical College, Vellore.
