Is it safe? Will it work?

As a number of vaccines come up in record time to combat the covid-19 challenge, a closer look at the safety and efficacy of the various candidates in the fray

Illustration by NILANJAN DAS

AS 2020 DRAWS TO A CLOSE, there is little doubt that it will be regarded as an Annus Horribilis. Not just because of the toll the Covid-19 pandemic took on lives (64 million infected worldwide and 1.4 million dead) but also due to the devastation it caused to livelihoods, plunging the world into an economic trough not seen since the Great Depression. Yet, by the end of the year, amidst all the gloom, there emerged a silver lining that could yet make 2020 an Annus Mirabilis, thanks to the exciting development of vaccines to combat the pandemic.

Vaccines against diseases normally take years, if not decades, to develop. Not anymore. In a major breakthro-ugh, on December 2, just nine months after the World Health Organization (WHO) had declared the Corona-virus disease or Covid-19 a pandemic, the United Kin-g-dom cleared a vaccine developed by US pharma giant Pfizer in collaboration with German firm BioNTech SE for emergency use. Meanwhile, Pfizer, along with Mod-erna, a US-based bio-tech firm, which has dev-el-o--ped a vaccine of its own, applied for an Emergency Use Authorisation certificate with the Food and Drug Admi-nistration (FDA), America’s health regulatory body. Both applicants claimed an effectiveness of treating the disease way above the 50 per cent stipulated by the FDA.

Two candidates in a neck and neck race to defeat a disease would normally be considered an embarrassment of riches in the vaccine business. But the pandemic seems to have triggered an unprecedented burst of innovation in vaccinology with another half a dozen vacc-ines being readied to compete with the frontrunners. Among them is British pharma giant, AstraZeneca, which, in collaboration with Oxford University and the Serum Institute, an Indian firm, has completed the final phase of trials for its vaccine in five countries, including India, reporting a high success rate against the infection. Meanwhile, Russia’s Sputnik-V, developed by its Gamaleya National Research Institute of Epidemiology and Microbiology, has already been cleared for domestic use. The Russian company has now collaborated with Dr Reddy’s Laboratories, an Indian pharma company, and clinical trials of the Sputnik-V vaccine are ongoing in India. China reportedly has already cleared two vaccines, Sinopharm and Sinovac, developed by its research companies for use.

In a welcome change, Indian companies and institutions, which are better known as the manufacturing hub of vaccines for the world, are not just collaborating with the big international names in the business but also have several indigenously developed candidates on trial. The Hyderabad-based Bharat Biotech, in collaboration with the National Institute of Virology, Pune, has developed a ‘traditional’ vaccine, which uses an inert virus to produce antibodies against the disease when injected into the body. The Ahmedabad-based Zydus Cadila has opted for the DNA-based technique for its vaccine that would be a first if it is cleared for use. Both these vaccines are undergoing clinical trials. Five other Indian companies, Gennova Pharmaceuticals, Aurobindo Pharma, Reliance Life Sciences, Mynvax and Serum Institute, are working on Covid vacc-ines that are in the pre-clinical trial stage.

Incredibly, many more vaccines are being developed across the world. According to the WHO, more than 150 Covid-19 vaccines are under development, with around 44 candidates in clinical trials and 11 in the late testing stage. While the surge in vaccine development is welcome, especially as the world struggles to find a silver bullet to end its pandemic woes, the enthusiasm needs to be tempered with a heavy dose of caution and scepticism. “The speed with which the vaccines have been developed is phenomenal. The high efficacy of some of the vaccines is great news. But many unanswered questions remain, particularly about long-term safety, duration of protection, distribution and what this means for future Covid vaccine trials after a particular candidate becomes the standard of care,” says vacc-ine expert Dr Gagandeep Kang, vice-chair of the Coalition for Epidemic Preparedness Innovations (CEPI), the Oslo-based philanthropic foundation. How safe, then, are these vaccines and how effective will they be?


Doubts about the vaccines, especially regarding their safety, have arisen because of the improbable speed of their development. Experts note that in the past 25 years, pharma companies worldwide have developed seven “truly new” vaccines. It took pharma giant Merck four years of research and development to develop a vaccine for mumps and five and a half years to get approval for its Ebola vaccine. In July, as the Covid-19 vaccine quest gathered momentum, Kenneth Frazier, Merck’s CEO, said in an interview, “What worries me the most is that the public is so hungry, so desperate to go back to normalcy that they are pushing us to move things faster and faster. Ultimately, if you are going to use a vaccine in billions of people, you’d better know what it does.” Ironically for Pfizer, its former vice-president and chief scientist, Dr Michael Yeadon, recently published a paper refuting the need for vaccines to bring an end to the pandemic, arguing that it is effectively over as the population in the UK is already close to achieving herd immunity.

A constellation of factors has seen the time taken to develop a Covid vaccine compressed into months rather than years. Topmost among them is the collaborative global effort to work on the vaccine and funds for researchers to produce quick results. The WHO was able to mobilise $5 billion for its ‘Access to Covid-19 Tools Accelerator’ to help researchers and companies develop the vaccine. US President Donald Trump announced Operation Warp Speed to provide 200 million doses to Americans by January 2021, and set aside $9.5 billion for the purpose. The European Commission-led initiative is expected to raise $4 billion. CEPI brought in close to $2 billion donated by philanthropists. In India, the Modi government launched Mission Covid Suraksha and put aside over $1 billion for R&D in the vaccine. Virander Singh Chauhan, emeritus scientist at the International Centre for Genetic Engineering and Biotechnology in Delhi, points out, “If the vaccine against Covid-19 has moved very fast, it is mainly because of the tremendous scientific collaborations, push from governments, international agencies like the WHO, CEPI and many philanthropic donors.”

What made the difference was the way government institutions and the regulatory structure responded to meet the challenge. In India, the Department of Biotechnology (DBT) was made the nodal agency for vaccine research and it brought together 30 groups in both academia and industry, as collaborators in development and for trials. The DBT provided facilities for researchers to not just develop the vaccine but also to conduct trials. Dr Renu Swarup, secretary, DBT, says, “We worked on a war footing and cut down red tape to enable funds and establish facilities without delay.” Adds Dr Priya Abraham, director of the Pune-based NIV, which played a major role in both developing and providing testing facilities apart from research on the vaccine, “Everything was done on top priority. In the past, a lot of time would go on travel and personal meetings. But now we conducted most of our discussions in webinars. We cut down on paper documents and enabled digitisation, including for mandatory signatures, to get things moving fast. And we facilitated public-private partnership in record time with the full backing of the ICMR (Indian Council of Medical Research).”

What helped speed up the vaccine development was the structure of the virus itself. A nasty piece of work, no doubt, that could replicate with astonishing speed and overwhelm the human immune system rapidly, it was also in many ways a known devil. Researchers had first encountered its forefathers in 2002 with the outbreak of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), which afflicted 8,098 people and killed 774 of them. The virus lay quiescent for a while till it reappeared as the Middle East Respiratory Syndrome (MERS-CoV)—a related coronavirus—in 2012, infecting 2,994 people and having a high fatality rate that proved self-limiting. By then, researchers had homed in on a particular feature of the coronavirus called the spike protein, which could bond with human cells to multiply. It could also be thwarted by a vaccine that could build antibodies against it.

When SARS-Cov-2, which causes Covid-19, surfaced on the scientific radar in December 2019 in Wuhan, China, with its spherical shape and its distinctive spikes known as peplomers, researchers knew which part to target to strike it down. Importantly, barring a mutation from the original Wuhan virus, Covid-19 has not changed much. Unlike the flu virus that mutates rapidly, making a single vaccine to combat it near impossible, Covid-19 is a relatively stable virus enabling specialists to evolve multiple techniques, including gene technology, for vaccines to tackle it (see The Vaccine Quest). Chauhan says, “DNA and RNA vaccines are relatively easier to develop and scale up, but these are newly developed technologies and have not yet been used in humans. That said, they are backed by solid scientific rationale. How good, viable and successful in the long term they will be will only be known after they have been administered to humans on a large scale.”


Apart from the use of new technology, the unseemly haste with which the vaccines have appeared has led many to wonder whether companies and their research collaborators have jumped through the necessary safety hoops. Most vaccine experts vouch for the strict protocols laid down by the WHO and regulatory bodies in individual countries, whether the USFDA or the Drugs Controller General of India (DCGI). Dr Balram Bhargava, director-general, ICMR, points out, “We have the Central Drugs Standard Control Organisation, which is the national regulatory authority and is respected the world over for the stringency of its protocols and its professionalism.” Apart from pre-clinical trials, where the vaccine is tested for toxicity and efficacy in animals, the trials involving humans follow a strict three-phase process to test safety and efficacy, with independent committees monitoring their progress at every stage. Virologist Shaheed Jameel, director of the Trivedi School of Biosciences at Ashoka University, says, “The compression of the vaccine cycle had nothing to do with compromising on quality or safety. The fast tracking happened largely on the regulatory front, where decisions would take years. Also, many of the phases, instead of being done sequentially, were allowed to run parallelly, but without impacting safety.”

Concerns, however, were raised that since gene technology like DNA and RNA strands was being used for the first time for vaccines, the older safety protocols may have become outdated. There were also complaints that many of the companies had not published the findings of their clinical trials in peer-reviewed journals as per the standard practice, opting instead for public releases without revealing full details. Says well-known health activist Mira Shiva, “Regarding the safety and efficacy of the vaccine, we still don’t know anything about the design or protocol of the study. So how do you expect people to make an informed choice? Years ago, a medicine called Thalidomide was given to pregnant women for morning sickness, which led to a series of ‘seal babies’, children without hands or legs. This is the danger of providing medication or a vaccine without inter-generational or long-term safety data.”

THE CONCERN GREW after a participant in the Astra Zeneca/ Oxford University/ Serum Institute vaccine trial in India complained of having developed a neurological issue after being administered the trial dose and threatened to file a suit for damages worth Rs 5 crore. As part of the trial protocol, volunteers are not informed whether they are given placebos or the actual vaccine. Such adverse events are investigated by the independent monitoring committee. At a press conference on December 1, Union health secretary Rajesh Bhushan stated that the initial findings of the event by the monitoring committee of the drug regulator did not necessitate halting of the trials. Meanwhile, the Serum Institute threatened to counter-sue the volunteer for Rs 100 crore for defamation. “All such issues,” says Jameel, “should be dealt with transparency. The company should not have come back with a Rs 100 crore suit. It erodes confidence in the entire process.” Malini Aisola, co-convenor of the All India Drug Action Network, agrees. “If emergency use is granted, then the public needs to know more about the vaccine,” she says. “There should be transparency and accountability in the regulatory process for vaccines as also in distribution.”

Transparency and accountability are crucial in reassuring the public that they are not being made guinea pigs in big pharma’s pursuit of profit and in the political leadership’s desire to win brownie points. There have been several incidents in the past when vaccines cleared the clinical trials stage and were given licences only to have anomalies creep in when deployed on a mass scale. In 2017, for instance, when the vaccine for the dengue virus was administered to schoolchildren in the Philippines, a few deaths were reported. Investigations of the deaths led to the possibility of a condition called antibody-dependent enhancement, which occurs in natural infection with the virus, where the second attack of dengue is worse than the first. The WHO had initially recommended that the vaccine be used only in places where dengue was common so that such events would be rare, but then revised its recommendations to state that each person who gets the vaccine should be tested and shown to have had natural dengue at least once before, so that there is no antibody-dependent enhancement.

In 2009, when the H1N1 influenza vaccine was given in Europe, more than 30 million doses were administered, and over 100 people developed narcolepsy, a debilitating sleep disorder. A subsequent investigation revealed that it may have been the adjuvant, the ingredient that enhances the immune response of a vaccine, and not the vaccine itself that was causing the illness, and that it occurred only in individuals with a certain genetic background. The vaccine continues to be in use, but now without the adjuvant. These examples show that the real test of safety will come when the vaccine is administered to the population at large. But the trade-off between risks and benefits are a part of the process. Kang points out that one in 2.7 million babies administered the polio vaccine may go on to develop the disease because the vaccine virus reverts to being able to cause the disease. But the use of the vaccine also saw polio being almost eradicated globally. As Jameel puts it, “In medicine, there is nothing really 100 per cent safe or 100 per cent effective, including a paracetamol that you take to control ordinary fever. You will always have to balance the benefits over the risks involved.” The key is to make the decision to take the vaccine an informed one, and voluntary, so that the onus lies on the person taking it.


Apart from safety, the effectiveness of the vaccines is the other big issue. An ideal Covid-19 vaccine, says Kang, should prevent three things. The first is to prevent the disease itself. The second is to prevent infection. The third is transmission, which means that if you do get infected, you shed less virus than if you had not been vaccinated. Regarding the current crop of vaccines, Kang’s assessment is as follows: “What we know of these individual vaccines is that they prevent the disease, which is a good thing. But we need more data and studies to define the potential impact of the vaccine, when they work, in whom they work, what aspect of the disease and infection they prevent. Then only will we get a more refined picture of what can be done and decide the best approaches towards vaccination.”

While we do know that these vaccines can help prevent illness despite infection, what we do not know is how long the immunity lasts. ICMR’s Bhargava says, going by respiratory viruses such as flu and pneumonia, vaccines would have to be repeated, though the periodicity remains unclear. Whether this holds true for Covid-19 as well remains to be seen as the virus is less than a year old. We still do not know if a person who has been infected once can be reinfected. According to Jameel, of the 64 million Covid-19 cases reported so far, there have been only 25 reported cases of reinfection, which he describes as a “minuscule number”. That is somewhat reassuring. Yet none of these detract from the value of the vaccines that have been developed so far. Jameel cites his own example saying that for years he would get the flu virus twice every season that would knock him out for a week. But since he has been taking the vaccine, even if he gets the flu, the symptoms last only a day. That, he says, “is the true value of a vaccine”.

Taking stock, Prime Minister Narendra Modi on a visit to ZydusBiotech Park in Ahmedabad, November 28

Finally, there is the issue of building the capacity to vaccinate India’s billion-plus population. India may have the world’s largest infant-immunisation programme but it has never rolled out adult vaccines at this scale. At our current vaccination capacity of 4 million doses a month, it would take decades to vaccinate the entire population. The government will also have to ramp up delivery facilities significantly (see accompanying report: India’s Billion Problem). Bhargava says ICMR studies indicate that the entire population may not have to be vaccinated, the hope being that “vaccinating a critical mass of people would constrain viral transmission and result in a win-win situation that would need just a minimum number to be vaccinated”. That could happen if we break the viral chain and stop the transmission in its tracks or if we reach herd immunity, where the virus cannot find new recipients. Till then, Bhargava emphasises, prevention will continue to lie in masks and Covid-appropriate behaviour. It’s worth the inconvenience if it can save us from the Covid monster.