When it comes to the Covid-19 pandemic, the world is tracking data by the minute: the numbers affected, mortality rates, tests to confirm cases, and possible treatments, of course. However, the one news update that humanity is waiting for anxiously—and with billions of fingers crossed—is the approval of a vaccine, with the stamp of being safe and effective for use. The various bulletins on the progress of the vaccine are followed across the board, by individuals, governments, and bodies like the World Health Organization (WHO) which is tracking over 140 companies that are working independently, or in partnership with academia, in a relentless race to exit the pandemic.
The world is restless, but a vaccine was never built in a day.
Vaccine testing is a four-stage process (see box) and has historically taken between two to 12 years. Back in 2009, the H1N1—or swine flu—vaccine was an exception. It took only 93 days to start the clinical trial after identification of the vaccine candidate and it could be deployed while the epidemic was in progress. But that was possible because of the nature of the virus—the vaccine was similar to that used for regular influenza.
Closer to the standard time frame is the development of the Ebola vaccine, which was approved in 2019 by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (USFDA) long after the outbreak was over; the clinical testing had taken five years. Also the severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Zika viruses ended up being geographically localised, and the vaccines are still under clinical testing in phase 1.
However, recognising the havoc—and contagion—created by the Coronavirus, science and governments alike are trying to break the speed barrier with the Covid-19 vaccine. “The Covid-19 global pandemic has led to an unprecedented collaborative effort amongst industry, academia, regulatory bodies, and governments with huge financial investments,” says Amit Dinda, a professor in the department of pathology at AIIMS, and an executive council member at the Global Coalition of Regulatory Science Research.
In India, there are 21 manufacturers of human vaccines. Of these, Serum Institute of India, Bharat Biotech International Limited (BBIL), Zydus Cadila (the listed entity is called Cadila Healthcare), Biological E., and Dr Reddy’s Laboratories are in the Covid-19 vaccine fray, either through original research or partnerships, or both.
One of the lead players is the Adar Poonawalla-led Serum Institute, which is producing Covishield, the vaccine being developed by Oxford University and AstraZeneca. The vaccine platform, based on a chimpanzee adenovirus called ChAdOx, has begun phase 2 and 3 trials in the U.K., as well as phase 3 trials in Brazil, South Africa, and the U.S. Serum Institute is conducting phase 3 trials in India in 18 sites. According to interim data from AstraZeneca, the vaccine candidate is 70.4% effective, and is projected to be available in the first quarter of 2021. Serum Institute also has a manufacturing agreement with U.S. biotech company Novavax for its vaccine, NVX-CoV2373.
The other hopeful is Covaxin, the country’s first indigenous Covid-19 vaccine developed by the Indian Council of Medical Research (ICMR). Hyderabad-based BBIL has partnered with ICMR to take it through development and clinical trials. “The [BBV152] vaccine is derived from a strain of SARSCoV-2 (the Covid-19 virus) isolated by ICMR and the National Institute of Virology, Pune,” says Rajnikant Srivastava, director of Regional Medical Research Centre and head of research management, policy planning, and coordination at ICMR. BBIL has completed interim analysis of the phase 1 and 2 clinical trials and commenced phase 3 trials with 26,000 participants in India. They are pushing for a mid-2021 release of Covaxin, with ICMR asking 12 institutes to fast-track clinical trials.
Another indigenous candidate, Zydus Cadila’s ZyCoV-D, is currently in phase 2 of clinical trials and unlike other vaccines in development, this one doesn’t use live or dead viruses. Instead, it introduces plasmid DNA into the host cells, intended to transmit into the viral protein and create an immune response in the body. Explaining their choice of a DNA-based vaccine, Pankaj Patel, chairman, Zydus Cadila, says, “A clearly defined regulatory pathway for a DNA-based vaccine has been laid out by the USFDA and WHO.” He points out that DNA-based vaccines for SARS 1 and MERS-Cov had successful phase 2 trials even though they were subsequently not taken forward. Also, he says, “in case there is mutation in the Covid-19 virus, a modified vaccine can be produced within three months.” Patel points out that just creating a vaccine is not enough. Developers have to take it through the process of development, transportation, and distribution. “We found that a DNA vaccine is stable and suitable to be transported at 2-8 degrees [Celsius].”
Abroad, there’s the mRNA-based vaccine candidate BNT162b2, produced by BioNTech along with Pfizer and Fosun. Pfizer has claimed that the final results from its phase 3 trials have shown 95% efficacy. Moderna’s vaccine candidate, which is also mRNA-based, is another example. The American firm claims it has shown 94.5% efficacy. This vaccine candidate was prepared in 42 days for human trials once the genetic code of the virus was known. mRNA vaccines work by training the immune system to recognise a virus-like threat and begin producing antibodies to protect itself. While both candidates are yet to reach India, the vaccine race is heating up as there’s a pot of gold waiting for the winner.
Back home, also in the vaccine race is Dr Reddy’s Laboratories, which is conducting phase 2 trials with 100 volunteers before starting phase 3 trials to market Russia’s Sputnik V in India. Like the others, they also expect to get to market in the next few months. And most recently, Hyderabad-based vaccine-maker Biological E. got the go-ahead to conduct phase 1 and 2 clinical trials of the vaccine developed by U.S.-based Baylor College of Medicine. This makes it the fifth vaccine to go into human trials in the country.
Time is of the essence
But why is it all taking so long, is an oft-repeated impatient query. Covid-19 may have normalised the use of the word vaccine in everyday conversation, but here’s a quick reminder of how it works. A vaccine typically provides the immune system with harmless copies of an antigen: that portion of the surface of a bacterium or virus that the immune system recognises as foreign. A vaccine may also ingest a non-active version of a toxin—a poison produced by a bacterium—so that the body can devise a defence against it.
This is why vaccine testing follows higher safety standards than other drugs, says Mahesh Bhalgat, chief operating officer of Syngene (a sister company of Biocon), a contract research organisation which has joined the global consortium to accelerate clinical testing in India. “Because they are given to millions of healthy people as a prophylactic.”
Apart from the high stakes of safety in vaccine development, Covid-19 has presented contract research organisations—which conduct clinical trials for pharma companies—with logistical challenges. Take the case of Parexel International, which currently has 2,000 trials—in different therapeutic areas— going on across the world and in India; of these, 120 are Covid-19 related. The lockdown and restricted movements led to site closures and they had to rethink operational strategy. “We moved to a decentralised CRO format and that shift allowed us to continue our critical work,” says Sanjay Vyas, senior vice president, India country head, and MD and global SBU head-clinical trial supplies and logistics, Parexel. The company started at-home screening and shipping samples directly to their patients’ houses; site monitoring was done using Covid-19 social distancing guidelines and video conferencing.
Parexel also created a central repository— a Covid-19 clearing house of publications, information, and data—which patients and physicians in their network had access to. This is because real-world evidence and credible information is needed to expedite trials. Normally, it takes about three-six months to get the research site started. “Using the normal SOPs required and all the information needed by regulators, we went live in three weeks for Covid-19 trials,” says Vyas.
Regulators in each country review trial results and decide whether to approve of a vaccine or not. However, during a pandemic, a vaccine may receive emergency use authorisation (EUA) before getting formal approval even as researchers continue monitoring people to generate additional data. For instance, China and Russia have not waited for phase 3 trials, and begun vaccinating their populations under EUA.
“It is important to get approval for vaccines while the outbreak is actively spreading in the community,” says Srivastava of ICMR. “The combined collaborative effort for SARSCoV-2 has significantly accelerated vaccine development through the discovery phase, lead candidate optimisation, preclinical studies, and starting of clinical trials within two months of the onset of the pandemic.”
Companies can combine phases 1 and 2, though satisfactory phase 2 data is needed for permission to conduct large-scale trials in phase 3. “Data generation in the human body cannot be fast-tracked,” says Bhalgat of Syngene. Two windows are critical, he adds: The first 24-48 hours for any serious adverse event and data over two-three months to assess how the vaccine is acting in the body, how it metabolises, and what kind of effect it has on vital organs. Phase 3 trials are generally large enough to discover any side-effects that may have been missed earlier.
A promising vaccine candidate, from discovery to ready-for-use, needs detailed documentation of quality, safety, and efficacy. “In the emerging regulatory science paradigm, the implementation of evidence-based regulatory practices is becoming more important; this helps evaluate a novel product according to the innovation pathway, with more flexibility,” says Dinda of AIIMS. But what is non-negotiable is that data has to be generated to ensure that the product is safe and effective to use.
In India, there are 21 manufacturers of human vaccines. Of these, Serum Institute of India, Bharat Biotech International Limited (BBIL), Zydus Cadila (the listed entity is called Cadila Healthcare), Biological E., and Dr Reddy’s Laboratories are in the Covid-19 vaccine fray.
Regulators like the USFDA and the EMA as well as India’s Central Drugs Standard Control Organisation (CDSCO) are monitoring data remotely. At the same time, use of electronic health records (EHRs) has become critical. Because of the current circumstances, USFDA as well as CDSCO are willing to accept 50% efficacy. It means that at least 50% of the people who receive the vaccine should get protection.
Also, due to the need of the hour, there is an emphasis on DNA and RNA platform-based vaccines which can be quickly developed by synthetic processes and do not need culture or fermentation. The new sciences of application of reverse genetics and next-generation sequencing can also reduce the development time as against conventional platforms.
After the vaccine, what?
But even though the wait may seem unbearable, adopting it may not be universal once it is actually available. The politics over vaccine development—take Operation Warp Speed (initiated by the Trump administration in the U.S.) and the use of EUA—is causing some unease. Many doctors, though not openly critical, are wary of recommending the use of a vaccine till enough data is generated.
The Vaccine Confidence Project—a nonprofit research and vaccination support organisation which works towards raising awareness and conducting research on why people do not take critical vaccines—has its hands full trying to create confidence in the Covid-19 vaccine.
A case for the urgency of the vaccine was recently made by a team of scientists which was asked to create a mathematical model for projection of the pandemic under the direction of the Department of Science and Technology. They showed the progression of Covid-19, nationally and state-wise, using public data. They even factored in the large number of asymptomatic patients who spread the infection without being tested. Based on their findings, a panel of experts set up by the government—which comprises scientists from IITs, IISc Bangalore, ISI Kolkata, and CMC Vellore—claims that the pandemic has peaked in India and that the intensity will lessen by February 2021, since 30% of the Indian population will have antibodies. There is a caveat, though: social distancing norms, masks, and hand hygiene must continue. This is because the model cannot factor in the aberrations driven by religious and community gatherings, the panel says.
In this context, the vaccine, even at 50% efficacy, is the most viable safety net, though no one can predict the protection it will offer. However, Dinda of AIIMS is hopeful that “with 11 vaccines [candidates] in phase 3 trials, we hope there will be a few good vaccines by early next year”. After all, for the first time in modern history, the entire world is working towards a single goal.
(This story originally appeared in the December 2020 issue of the magazine)
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