To fight a war and win, Sun Tzu, the 6th century BCE Chinese military strategist and author of The Art of War, advises that you first know your enemy well. So, first let’s get to know Covid-19, the world’s Enemy No. 1 that has afflicted over 12 million people in 213 countries and territories and caused more than half a million deaths, at last count. In India alone, there are 700,000 cases with over 20,000 dead, putting us in the unenviable position of being No. 3 in the list of countries with the biggest toll of Covid cases, behind only Brazil and the United States. A recent study by MIT predicts that given the size of India’s population, we may have as many 270,000 cases a day by February 2021. This could eventually make us the worst-affected country in the world if no vaccine is found to treat the virus by then.
The micro-organism responsible for the pandemic is a formidable opponent that can rapidly fell humans a zillion times its size in huge numbers. To get an idea of how small this silent, insidious assassin really is, think of this: a thousand of them could fit into a grain of salt with ease. With the virus first being reported in Wuhan, China, in late 2019, the World Health Organization (WHO) termed it Coronavirus Disease 2019 or Covid-19 because of its descent from the corona family of viruses, which have a zoonotic origin (passed on from animals to humans). The ancestor of the corona viruses was first discovered in the 1960s and got its name from its crown-like shape when viewed through an electron microscope. Seen through more powerful diagnostic viewing tools now, the virus appears spherical, and is studded with distinctive spikes known as peplomers. Multiplying rapidly in the sea of humanity, the virus has in just six months wreaked enormous havoc and distress on the world.
The battle against the Covid-19 pandemic is proving to be more daunting than policy-makers and medical researchers had initially imagined. For decades, the milder cousins of Covid-19 caused about a quarter of the common colds in the world and were relatively harmless. In recent years, however, they have mutated into more deadly forms. In 2002, the Severe Acute Respiratory Syndrome Coronavirus (SARS-Cov) afflicted 8,098 people, mostly in China and Southeast Asian countries and killed 774. While the death rate was high, 1 out of 10 people died, the outbreak was brought under control in a year by isolating the afflicted.
Test phase: A scientist at the Bharat Biotech lab in Hyderabad
Ten years later, the virus mutated again, striking the Middle East, mainly Saudi Arabia, this time. The Middle East Respiratory Syndrome Coronavirus, or MERS-Cov, afflicted only 2,494 people, but the case fatality rate was a high 37 per cent, which meant that one out of three people who got the disease died. In its newest avatar, Covid-19 is proving to be less fatal, killing less than two people out of every 100 afflicted, but it has been far more virulent, widespread and resilient than its predecessors. “It’s a 21st century virus, smart, savvy and tough, and the challenge it poses should not be underestimated,” says Pankaj Patel, chairman, Zydus Cadila, the Ahmedabad-based pharma major that is researching ways to combat it.
Despite unprecedented total lockdowns of nations across the world, including in India, which shut down for three months, the virus shows no signs of peaking yet. On the contrary, there has been an alarming surge of fresh cases as countries remove restrictions on movement of people and allow them to return to business as usual. With the affliction and death rates continuing to mount and no proven drugs to cure the disease so far, medical institutions and pharmaceutical companies across the world are working at a feverish pace to find other ways of arresting its rapid spread. Their current best bet: a global vaccine to inoculate people and help them build immunity against the virus.
In an encouraging bit of news, the WHO reports that there are currently 136 potential candidates for a Covid-19 vaccine that research institutions across the world are testing, with 21 of them having reached the human clinical trials stage. Three of them, AZD1222 developed by the British-Swedish biopharma firm AstraZeneca and Oxford University, mRNA-1273
by the American biotech firm Moderna and CoronaVac by China’s Sinovac Biotech, are at the final stage of human clinical trials, with results expected by the end of this year. Last week, two Indian companies, the Hyderabad-based Bharat Biotech and Zydus Cadila, joined the global quest, with the Indian government clearing their respective vaccines, the COVAXIN and ZyCOV-D, for the early phases of human clinical trials.
Four other Indian institutions, including the Pune-based Serum Institute of India, the world’s largest vaccine manufacturer, are in an advanced stage of vaccine research and are likely to apply for permission to start human trials soon. In Geneva, WHO chief scientist Dr Soumya Swaminathan told INDIA TODAY, “It’s excellent that Indian R&D is coming up with vaccine candidates because earlier it was considered only a manufacturing hub of generic pharmaceuticals. The more participants we have, the better. Along with the many other participants across the world, they would help in finding out a vaccine or vaccines that will have lasting immunity and are safer for use.” (See accompanying interview.)
However, controversy broke out over the Indian effort when an overzealous Indian Council for Medical Research (ICMR), the country’s premier medical research agency, sent out a note telling the two Indian firms and their collaborators to ensure that Phase 1 and 2 trials were completed by August 15, India’s Independence Day. Bodies of experts, such as the Indian Academy of Science, protested strongly against the imposition of such deadlines to rush through critical research. K.I. Varaprasad Reddy, chairman, Shantha Biotechnics, Hyderabad (now a subsidiary of the French Sanofi), warns: “You cannot gloss over protocols and forego sequential safety in developing a vaccine. We cannot make a mockery of science. It will take at least 18 months to two years even in an emergency-like situation. What is dangerous is the practice of drug controllers shortchanging on procedures to unveil a vaccine in a hurry.” The ICMR was forced to clarify that the deadline was not binding but only “envisaged” and that the respective institutions should take all precautions to ensure that the trials are carried out with all the stipulated protocols.
The pushback from the Indian scientific community was important. While there was reason for both speed and optimism, vaccine development has always been a game of hits and misses. Some like those for polio and small-pox were revolutionary in their impact, while others like the flu vaccine flattered only to deceive (see Nearly on Target). A few resulted in complications in those who were administered the vaccine, forcing governments to withdraw them and, in some cases, even pay heavy compensation. One such case is the influenza vaccine, which is the closest we have for a disease like Covid-19. Over a hundred laboratories worldwide monitor this virus under the WHO Global Influenza Surveillance Network and recommend the mixture of strains to be used in a vaccine in the coming flu season. It started in 1918, after the Spanish influenza pandemic broke out, claiming almost 12 million lives in India alone.
In 1976, fearing a recurrence of the Spanish flu, the US government under President Gerald Ford launched the National Influenza Immunisation Program, or NIIP, and drew up plans to vaccinate the entire population. But after reports came in of one in every 100,000 vaccinated people developing a serious neurological disorder, the programme had to be shut down. Every year since then, an effective influenza vaccine has to be made afresh based on virus surveillance data and strict monitoring by the WHO.
More recently, in 2009, Norway reported complications in those who were administered a vaccine for the H1N1 pandemic when 1 in every 100,000 people who took the vaccine and were under 30 years of age developed narcolepsy, a debilitating sleep disorder. On the plus side, however, the vaccine reduced the risk of contracting influenza from those who were afflicted by as much as 70 per cent. There were similar contradictory results for the vaccine administered for dengue in 2017. While one study showed that it enhanced the disease by a statistically significant number in those that took it, others demonstrated that it did provide protection. Swaminathan acknowledges that there may be complications in the efficacy and safety of a vaccine and it is critical that countries using a vaccine have a vigilant safety monitoring system and educate the public about such complications. “There are always benefits and risks associated with such things, and countries have to be transparent and open about it, apart from [having] a proper testing, evaluating and monitoring system.”
Despite the ICMR’s push for a vaccine for Covid-19, many doubt we will have a vaccine before early 2021. That’s because after trials on rodents and other animals, a vaccine, typically, has to go through three phases of human trials, a process that can take anywhere from six to nine months. Phase 1 of the trials focuses on the safety of the vaccine on a small group of respondents. Phase 2 tests efficacy, determining the required dosage for an effective immune response. Phase 3 puts the vaccine to test on a larger scale across age and population groups. On occasion, during emergencies, the last two phases are clubbed together. But the final stage does take time as it involves testing between 30,000 and 40,000 randomly selected people and a placebo group. Adar Poonawalla, CEO of the Serum Institute, says: “We should not be rushing through any of these stages. Nor should we be focusing on who is the first to bring out a vaccine; rather, it should be which candidate vaccine is the safest and most efficacious.”
Poonawalla has plenty of skin in the game, apart from developing two possible vaccines in his laboratory, he has tied up with the AstraZeneca/ Oxford group to manufacture over 1 billion doses by 2021 if their vaccine is cleared. He has invested close to $100 million in getting production lines ready to meet the requirement, but says it is important that researchers follow all protocols and go through the routine regulatory hoops. He is planning manufacturing tie-ups with two other groups that are developing vaccine candidates. Ask him the basis on which he selects a group and he says, “I look at safety, proven track record and scalability of manufacturing of the vaccine. If you tick all these three boxes, you enter my gate. If not, you stay outside my factory till you do.”
Poonawalla is right about safety being the top concern. Exposing a vaccine candidate to the disease to check if it works, also known as the human challenge study, is a subject of intense research on ethics. The consensus is that this can only be done in a crisis situation and if an effective cure is available. “During the trials of a malaria vaccine, people were exposed to the disease, but there was a very good cure for it at hand. Covid does not have the kind of guaranteed treatment needed for a human challenge study, even though there is a sense of urgency,” says Dr Shahid Jameel, virologist and CEO of the grants body DBT/ Wellcome Trust India Alliance. Ethics also involves taking the public and the medical community into confidence, as well as data-sharing. “A good study design and peer review are essential if a vaccine is to be taken seriously,” says Partha P. Majumder, director, Indian Academy of Sciences. DBT, or the department of biotechnology, the nodal agency for the Indian vaccine initiative, was quick to play down the disquiet over the ICMR’s initial circular. Renu Swarup, DBT secretary, told INDIA TODAY, “We have a very strong regulatory system and are very proud of it. We have detailed guidelines for trials that match the best in the world. Apart from being scientifically and ethically very strong, they are rigorous too and we have the best experts for peer review.” Swarup says the DBT is facilitating speeding up of the process by identifying in advance areas where the Phase 3 trials could be conducted but without any compromise on quality of the research.
So, given the complications and the long gestation period required to develop a vaccine, should we be enthused by the flurry of global activity to find one? Yes, for several reasons. The only good news about Covid-19 is that it is a comparatively simple and stable virus which makes the task of developing a vaccine for it relatively easier. “Covid is mutating almost a thousand times slower than the influenza virus and India now has the strain which most companies in the West are also developing a vaccine for,” says Dr Rakesh Mishra, director of CSIR-Centre for Cellular and Molecular Biology. Past failures in vaccine development, he adds, need not cloud the future of a Covid-19 vaccine. Both tuberculosis and malaria pathogens are far more complex. TB, for instance, lurks in the body, making an immune response difficult to mount even in a vaccine.
Other researchers remain sceptical. Dr Jayaprakash Muliyil, chairman of the Scientific Advisory Committee of the National Institute of Epidemiology, argues that we need more than one study to confirm whether a vaccine stimulates immunity against Covid-19. “There are also questions of how long the immunity will last and, most importantly, ensure that it does not cause any harm to those who take it,” he says. Muliyil is a firm believer in natural herd immunity as the best way to halt the spread of the disease, and was not in favour of the lockdown that India opted for. We can build herd immunity if the virus spreads rapidly and infects a majority of the world’s population, until it has no new hosts to spread to.
Swaminathan disagrees with this postulation and says that antibody surveys in most countries show that only 10 per cent of the population has been exposed. Even in India, studies show that only 0.7 per cent of the population in rural areas has developed antibodies. This means a majority of the population remains susceptible and vulnerable to Covid-19 and there is no question of their developing natural herd immunity for years. As Swaminathan puts it, “Herd immunity through natural infection will come only at a huge cost that people will have to pay in terms of lives and the economy.” Social distancing and lockdowns, too, cannot be long-term strategies. Recent reports are also warning of the long-term damage the virus inflicts on vital organs even in those who experience relatively mild symptoms. Nor are drugs like Remdesivir, currently being used to treat serious Covid-19 patients, devoid of harmful side-effects.
Another major factor in pushing for a vaccine is that there has been a quantum leap in vaccine technology and genome sequencing in the past two decades. All vaccines work on the basic principle of first defanging the virus and then injecting it into the human body to produce the desired antibodies to build immunity against the virus. The classical approach is what Bharat Biotech is using for its COVAXIN, an inactivated Covid-19 virus being injected into a person to produce antibodies and act as an immunity-booster. Inactivated vaccines have a well-proven and accepted track record against diseases such as polio and rabies. Bharat Biotech has tied up with the National Institute of Virology (NIV) in Pune to isolate the virus and produce the vaccine. Krishna Ella, its chairman and managing director, says, “Our research and development and manufacturing teams worked tirelessly to deploy our proprietary technologies towards this. We are hoping that the human trials will validate our efforts.”
However, inactivated vaccines come with their own limitations. For one, you need booster doses, and two, even as experts argue that inactivated vaccines are an established approach, doubts have been raised about their safety and efficacy. Inactivated vaccines used against SARS and MERS had led to poorly-regulated inflammatory responses or cytokine storms in which the immune system overreacted. That is why in the past decade many vaccine developers have moved towards decoding the genetic sequence of the virus and manipulating its DNA and RNA to render it harmless before injecting the vaccine. With ZyCOV-D, Patel of Cadila claims to have successfully established the DNA vaccine platform in the country. “We mimicked the DNA of the Covid-19 virus but without its harmful proteins to get the body to build immunity to it after it is injected. We are 100 per cent made in India, Atmanirbhar Bharat.” DNA vaccines are stable and do not require cold-chain storage. They can also be manufactured with minimal bio-safety requirements.
Poonawalla, whose partner AstraZeneca is using a replication-deficient viral vector based on a weakened version of the common cold virus, points out how these technologies are now like proven rocket launchers in a space programme. They can be safely used to test newer payloads, in this case, viruses. They can also be rapidly used to modify the vaccine in a couple of weeks in case the virus mutates to ensure that it still provides protection. There has also been tremendous progress in the synthetic production of RNA genes. The mRNA vaccine that Moderna, Pfizer and BioNTech are developing is said to cut down on manufacturing time as well as develop a stronger immune response against a virus. The vaccine uses synthetically-produced RNA of a virus which, when administered, prompts the body’s own muscles to produce the virus proteins that stimulate immune response. However, experts say that there are concerns that since it has never been tried on humans before, the risks are higher. Each vaccine technology, therefore, comes with comparative advantages and disadvantages.
Should any of these vaccines, Indian or foreign, prove successful, they are likely to raise issues of equitable distribution and pricing, something many global health organisations are concerned about. At present, the worldwide capacity for producing an influenza vaccine is about 6 billion doses year. Assuming the same for Covid would be a challenge for mass vaccination. Many countries, such as the US, have tied up with manufacturers to buy up the vaccines. “Middle-income countries will be at the greatest risk if we don’t ensure equitable distribution and collaborate on a global level. Even in India, questions remain on how much will be pledged domestically and how much will be exported,” says Dr Leena Menghaney, South Asia head of Medecins Sans Frontieres.
India is already preparing to not only block-book vaccines but also develop the logistics and cold chains required to deliver them swiftly to the public. Poonawalla says he has the capacity to make 700 million doses a year and could beef it up if needed. He plans to price his vaccine at Rs 1,000 a dose. Ella says his company can make 300 million doses and is looking for collaborators to up the capacity. Patel is also scouting for tie-ups to make his vaccine. NITI Aayog member Dr V. K. Paul, who is spearheading the government’s task force on vaccine development, says since they may not be able to deliver the vaccine to the entire population at the same time, priorities are being drawn up to see who should be given it first. “The obvious priority is health professionals who are at the frontline of the battle and those with high risk of mortality from Covid-19, like people above 65 years of age and those with co-morbidities like diabetes and heart diseases,” he says. For once it may be better to cross the bridge before you reach it.