Scientists edge closer to develop a vaccine against the SARS-CoV-2 corona virus and Indian pharmaceutical companies are in front and centre of the race to supply the world with an effective product. However India’s experience as a vaccine manufacturer, its companies have to struggle to produce enough doses sufficiently fast to bring its own huge outbreak under control. And, it will be an immense logistical challenge to distribute the doses to people in rural and remote regions.
Indian is a major manufacturers of vaccines distributed worldwide, especially to low-income countries, supplying more than 60 per cent of vaccines to the developing world. As such, they are likely to gain early access to any COVID-19 vaccine that works. Several Indian vaccine makers already have agreements to manufacture corona virus immunizations that are being developed by international drug companies, or are working on their own vaccines. The government has allowed these manufacturers to export some of their supplies as long as a proportion remains in the country. Without India, there won’t be enough vaccines to save the world.
R&D Landscape
The global COVID-19 vaccine R&D landscape includes 321 vaccine candidates as of 2 September 2020. Of these, 32 vaccine candidates are in clinical trials with plans to enroll more than 280, 000 participants from at least 470 sites in 34 different countries. The most advanced clinical candidates are now in phase III trials and data to support licensure are anticipated to be available later this year. For the leading candidates, large-scale manufacturing of vaccine has already been initiated to enable rapid distribution if approved.
Technology Platforms and Targets: The current COVID-19 vaccine pipeline comprises a broad range of technology platforms, including both traditional and novel approaches. Early data are emerging for the most advanced clinical candidates. Although encouraging antibody and T cell responses have been reported for vaccines based on several of the different platforms being used but it is too early to assess their relative potential. Eleven clinical-stage vaccine candidates employ adjuvants.
The majority of vaccine candidates currently in clinical trials target the spike (S) protein and its variants as the primary antigen. However, candidates that target other or multiple antigens are progressing, including candidates that target N protein, attenuated vaccines, inactivated vaccines and peptide vaccines.
Vaccine Developers: The biggest change in the profile of COVID-19 vaccine developers since April has been the increasing engagement of large multinational companies. Of the candidates currently in the clinic, eleven are being developed by Chinese organizations, and seven are being supported by the US Operation Warp Speed programme, which aims to deliver 300 million vaccine doses for COVID-19 by January 2021 and has so far announced funding of more than US$10 billion to advance vaccine development. Eight of the clinical candidates have received funding from the Coalition for Epidemic Preparedness Innovations (CEPI) and are now included in the portfolio of COVAX, a collaboration led by CEPI, Gavi and the WHO that aims to deliver two billion vaccine doses for global allocation by the end of 2021.
Perspectives on Clinical Development
The progression of COVID-19 vaccine candidates into clinical development is beginning to lead to insights that may be useful for informing future COVID-19 vaccine development efforts, as well as vaccine R&D strategies for future outbreaks. The WHO has also released a target product profile for COVID-19 vaccines, which provides guidance for clinical trial design, implementation, evaluation and follow-up and briefly summarized below.
Trial design: An accurate estimate of the background incidence rate of clinical COVID-19 end points in the placebo arm is required for a robust sample size calculation in a conventional clinical trial. However, the rapidly changing epidemiology of the COVID-19 pandemic means that it is challenging to predict incidence rates and trial design is further complicated by the effect of public health interventions to help control the spread of the virus, such as social distancing and quarantine. Thus, an adaptive case-driven trial design, in which power and precision are not determined by the size of the trial but rather by the overall number of COVID-19 cases identified for the primary end point, is worth considering. Recruitment is discontinued when the minimum necessary number of events is reached, resulting in a more efficient, effective and rapid clinical trial.
Clinical end point: It is crucial to choose an end point that is likely to reflect the desired relevant public health benefit. Possible end points for consideration in COVID-19 vaccine trials include clinical disease of varying severity and/or asymptomatic infection. Vaccines for respiratory and other mucosal viruses historically have greater efficacy against more severe rather than milder disease and are less likely to affect asymptomatic infection. In addition, use of asymptomatic SARS-CoV-2 infection as an end point may be operationally challenging and result in a large number of false-positive tests results and possibly even failure to demonstrate vaccine efficacy. By contrast, use of a clinical end point requiring signs or symptoms of pneumonia may result in earlier demonstration of vaccine efficacy, as this limits the number of cases of vaccine-induced disease attenuation (that is, people with SARS-CoV-2 infection but only mild, residual clinical symptoms following vaccination) included in the primary efficacy analysis. Thus, the rate of occurrence of the end point in the population under consideration, the importance of the vaccine’s impact on the end point and the reliability in measuring the end point should be considered when defining an end point.
It is important to maintain some flexibility in the clinical end point definition in a pandemic situation involving a novel pathogen because there is limited knowledge of pathogen-specific disease presentation and underlying path physiology. This flexibility enables the collection of clinical case data in early-stage clinical trials, with vaccine efficacy being established in later-stage trials using an evolved case definition based on emerging knowledge. Infection or disease end points not included to address an efficacy trial primary objective should, however, be assessed as secondary end points.
Correlates of protection: What constitutes protective immunity for those exposed to SARS-CoV-2 remains unclear? However, emerging data are indicating that both neutralizing antibodies and cell-mediated immune responses are important in the response to SARS-CoV-2, and potential vaccines should induce both of these responses.
Target population: Relaxing the eligibility criteria to broaden the trial population is of key importance for advanced-stage COVID-19 vaccine trials. The population studied should be representative of the wider population in which the vaccine will be used, and every effort should be made to recruit strategically to demonstrate vaccine efficacy as early as possible. Thus, adequate representation of populations at risk of SARS-CoV-2 infection and/or severe consequences — such as frontline health-care workers, elderly people and those with underlying health conditions — is encouraged, as they may benefit most from a safe and effective vaccine. Vaccine construct-specific characteristics should be taken into account.
Safety considerations: Development of an adequate safety database is crucial for regulatory approval and public acceptance of any new vaccine, especially one using a novel technology platform. Harmonization of safety data collection across vaccine candidates maximizes their comparability and value. Towards this end, the following tools, many recommended by the WHO, are or will be available soon: >60 standardized case definitions for adverse events following immunizations (AEFI); a list of potential adverse events of special interest (AESI) for COVID-19 vaccines, their case definitions, implementation tools and some background rates; standardized templates for collection of key information for benefit–risk assessment of vaccines by technology, including nucleic acid, protein, viral vector, inactivated viral and live viral vaccines; and outcomes from a consensus meeting on vaccine-mediated enhanced disease.
The traditional standards for sample size, duration of follow-up and heterogeneity of study populations in pre-licensure trials may have to be adapted, in close coordination with regulators to ensure safety and efficacy, to meet the unprecedented need for rapid development of COVID-19 vaccines. Furthermore, near-simultaneous global introduction of multiple vaccines, many with novel technologies, is planned. Hesitancy to receipt of COVID-19 vaccines is also emerging and so planning for and implementation of a robust global community engagement and post-introduction pharmacovigilance system is urgently needed.
Local Requirement
A vaccine is essential to combat India’s huge corona virus outbreak. To reduce the number of people dying from COVID-19, those most at risk of exposure or severe infection will need to be immunized first. This includes first responders, people with other illnesses and older adults amounting to nearly 400 million people (nearly one third of the population). This requires a huge number of vaccine doses to be made and distributed. The government has assembled a task force headed by Dr. Vinod Paul of NITI Ayoog with representatives from state and central government agencies to determine how best to distribute the vaccines. The government is also working with vaccine makers to speed up clinical trials and regulatory approvals.
Current Status:
The world’s largest vaccine maker- the Serum Institute of India of Pune - has an agreement to manufacture one billion doses of a corona virus vaccine being developed by scientists at the University of Oxford, UK, and UK pharmaceutical company AstraZeneca if approved. Currently, the vaccine is undergoing phase III clinical trials in Brazil, the UK and the US to test its effectiveness. If the vaccine works, the Serum Institute and the Indian government have committed to reserve half the company’s stock for India, and to supply half to low-income nations through GAVI - funder of immunizations for low-income nations. The company has invested 11 billion rupees (US$200 million) to manufacture the vaccine and has produced about 2 million doses for use in regulatory clearances and testing, even before the trials have ended. Two factories that were producing other vaccines have been redirected to this effect, and the company can make 60 to 70 million doses a month at full capacity. The decision to stockpile the Oxford vaccine has been solely taken to have a jump-start on manufacturing, to have enough doses available if successful. If the vaccine doesn’t work, Serum will shift its attention to other candidates.
The company is also developing and testing four other COVID-19 vaccines — two developed through in-house initiatives and two being developed in collaboration with biotechnology companies Novovax in Gaithersburg, Maryland, and Codagenix in Farmingdale, New York. Drug firm Biologicals E, of Hyderabad, India, has also entered into a partnership to manufacture a vaccine candidate - developed by Beerse, Belgium based Janssen Pharmaceutica and is currently going through early-stage safety trials. Biologicals E might also manufacture a candidate being developed by Baylor College of Medicine in Houston, Texasq. And Indian Immunologicals of Hyderabad is working with Australia’s Griffith University in Brisbane to test and manufacture the university’s vaccine. Two other Indian companies — Hyderabad-based Bharat Biotech and Zydus Cadila in Ahmedabad — are working on vaccines that are in phase I and II trials.
Distribution Challenges
Scientists have applauded the Indian government for allowing the country’s pharmaceutical companies to export some of their vaccine stocks to other nations. The decision to share supplies contrasts with nations such as the United States and the United Kingdom, which have pre-ordered hundreds of millions of doses of corona virus vaccines under development, enough to supply their respective populations many times over.
But even with manufacturer's commitment to supply a portion of their vaccines locally, scientists say that making the required 400 million doses for people who are most at risk of contracting severe COVID-19 will still take time. And by that point, the brunt of the epidemic, which is currently in major cities, will probably have shifted to rural areas, where health services are weaker.
The biggest hurdle will be getting vaccines to people across India – a huge country having and remote areas, like the Northeast and Ladakh in the Himalayas. It is a huge challenge. The immunization programme will probably take years. One of the country’s largest vaccination campaigns so far — delivery of the measles–rubella vaccine to 405 million children, starting in 2017 — has taken 3 years.
Innovative approaches will be needed to distribute vaccines in rural and remote regions. During National election campaigns of 2019, 11 million poll workers journeyed across India to set up polling stations, so that people didn’t need to travel more than 2 kilometers to vote. The network reached 900 million voters, including those in the most remote areas, in just over 6 weeks. A similar network of health officials to give vaccines could cover much of the country. But it’s not as simple as getting the vaccine to people. The vaccine has to be kept cold, people have to be trained. It will also be expensive to buy syringes and needles, to train people to vaccinate, and to purchase the vaccine. Oxford vaccine has been priced at 225 rupees (US$3) a dose by Serum Institute implying the cost of vaccinating 400 million people will be at least $1.2 billion. It’s unlikely that the Indian government will bear the entire cost of immunizing its people. Probably, it will pay for the poorest citizens, and ask everyone else to buy their own vaccines.
Epilogue
No doubt, COVID-19 vaccine leader candidates have progressed to advanced stages of clinical development at exceptional high speed; many uncertainties remain due lack of robust clinical data. Because of highly unusual circumstances associated with developing a vaccine during the evolution of a novel global pandemic, probability of success benchmarks for traditional vaccine development are likely to under represent the risks associated with delivering a licensed vaccine. The most advanced candidates are expected to begin reporting data from pivotal studies over the coming months, which if positive will be used to support accelerated licensure of the first COVID-19 vaccines. Such data will also provide valuable insights for the field and inform ongoing and future development activities aimed not only at controlling the current global pandemic, but also for effective long-term immunization strategies against the disease.