Jaipur: On December 8, 2020, the United Kingdom (UK) began the process of vaccinating its elderly population against COVID-19 with a vaccine made by Pfizer and BioNTech; the Oxford University published the interim results of its human trials of the Oxford/AstraZeneca vaccine in the UK, Brazil and South Africa; and the Indian government said it is considering issuing licenses for three vaccines.

Does this mean we will soon return to our pre-pandemic lives, without physical distancing and masks?

"Not for another six months to one year, depending on how fast we cover the population [with vaccines]," said V. Ravi, a neuro-virologist and public health expert who is also part of the Karnataka COVID-19 task force. "You can't really let your guard down," said Soumya Swaminathan, chief scientist at the World Health Organization. Masking, physical distancing, handwashing, testing, treating and contact tracing will continue to be important in the global campaign against COVID-19, experts told IndiaSpend.

Large-scale immunity is still a distant goal though three vaccines have been declared effective based on their publicly available trial data. The trials do not tell us if the vaccines can block the transmission of the disease from those who are asymptomatic and have been vaccinated. We also do not know how long the immunity from the vaccines will last.

Here's what we do know about the COVID-19 vaccines so far:

When can we expect COVID-19 to be under control in India?

"Vaccinating 100% of the population is a utopian concept. We have never achieved it for any vaccine, nor is it required," said Ravi. The aim of the COVID-19 vaccines is to cut the transmission of the disease by vaccinating at least 60-70% of the population, thus creating 'herd immunity' wherein a majority are protected from the disease. If the aim is to eliminate a disease, over 90% of the population would have to be vaccinated, said Gagandeep Kang, member of the WHO's working group on COVID-19 vaccines and professor of microbiology at the Christian Medical College in Vellore.

To cover 60-70% of the Indian population would take a minimum of 1.4 billion doses of the vaccine, Ravi estimated. And even if an effective vaccine is made available today in India, manufacturers would need 6-8 months to reach that target and then more time would be needed to deliver the vaccines to the people, Ravi said.

The short answer: About a year.

Are vaccines effective against COVID-19?

So far, three vaccine candidates have published the results of large-scale human trials: the US-based Pfizer in collaboration with Germany-based BioNTech, the US-based Moderna, and the Anglo-Swedish company AstraZeneca in collaboration with the UK's Oxford University. Of these, the Oxford/AstraZeneca vaccine has an India arm in its trials, but the data on this are yet to be published.

The Russia-based Gamaleya Research Institute of Epidemiology and Microbiology has published results from 38 trial participants in two studies. More data are needed on this vaccine, said Kang. A large-scale trial is going on--whose interim results published in a press release claim 91% efficacy 28 days after the first dose and 95% after 42 days. India-based trials of the vaccine (named Sputnik V), in collaboration with Dr. Reddy's, will begin soon, the government said at a press conference.

The UK and Canada have approved the Pfizer/BioNtech vaccination for emergency use. In the UK, the vaccine will be first given to the elderly and healthcare workers. Two doses of this vaccine, given over 21 days, have 95% efficacy, including in those over 65 years of age, said a study published by the company. This means, of 100 COVID-19 infections among trial participants, only five were in the vaccine group. The other 95 were in the placebo group. So, the proportion of participants administered a placebo who went on to get COVID-19 was much higher than those who were administered the vaccine. (What it does not mean, however, is that 95 of 100 people vaccinated were protected from COVID-19.)

The Moderna vaccine, in two doses, has 94% efficacy and the company is waiting for emergency use approval in the US. The Oxford/AstraZeneca vaccine has 62% efficacy for those who received two standard doses of the vaccine and 90% efficacy for those who first received a low dose and then a standard dose of the vaccine. These interim results are based on a smaller number of patients than in the other two trials. The low dose combination was accidently given but was then continued as part of the trial.

"I am certain about the results that have been published but it is good to remember that efficacy is highest in the early stages of the trial. It could drop a little bit later but it will still protect against the virus," said Kang.

How long can vaccine-driven immunity last?

"The honest answer is that nobody knows," said Ravi. These vaccines have only been tested for 2-3 months, so protection is guaranteed for that period but there are no data on long-term immunity, experts said.

Two factors can help us estimate how long vaccine-driven immunity could last--our knowledge of the period of the body's natural immunity when it has actually fought COVID-19 and long-term studies of other vaccines. The worst-case scenario is the influenza virus, which mutates fast and needs a different shot every year but the COVID-19 virus does not seem to mutate so fast, said Ravi.

In the case of COVID-19, most recovered patients have had antibodies for six months after they were infected and even in those who did not have detectable antibodies post-recovery, there are memory cells that remember how to fight the infection, said Ravi, estimating that COVID-19 vaccines could provide immunity for at least a year.

From SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), also caused by coronaviruses, we know natural immunity can last for several years, said Swaminathan. "The hope is that the impact of these vaccines can last for two-three years but that still needs to be studied and there has to be an extensive follow-up," she added.

Even if the immunity lasts only for 1-3 years, it would not mean that everyone needs to be re-vaccinated every few years, said Shahid Jameel, director of the Trivedi School of Biosciences at Ashoka University. As more people get vaccinated and fewer get serious infections, the virulence of the virus is likely to decrease. "It is likely that the disease will become endemic and we will see spikes in cases every some time and then vaccines can be deployed to control it," he explained.

Do vaccines protect all demographics?

The Moderna and Pfizer/BioNtech vaccine trials included participants of all ages and those with comorbidities. Based on the details currently available, the vaccines provide "good protection" to all age groups, said Swaminathan.

But we have not followed people long enough to know how well different groups are protected by the vaccines, said Jameel, adding that several vaccines do not work well in those who are diabetic. Children and pregnant women are yet to be studied because they are usually included in the later stages of a trial.

"Less than 4% of participants were older than 70 years of age, no participants older than 55 years of age received the mixed-dose regimen, and those with comorbidities were a minority, with results for that subgroup not yet available," said an article in the medical journal The Lancet, on the Oxford/AstraZeneca vaccine's interim findings.

Are the vaccines safe?

"Currently all vaccines that are being considered have a good safety profile," said Ravi. However, companies have reported minor side-effects common to vaccines such as pain or inflammation at the site of the inoculation or mild fever, he added. The UK's drug regulator has said that people with a history of severe allergic reactions to medicines, vaccines or food should not be given the Pfizer/BioNtech vaccine. Two healthcare workers with allergies developed a reaction to the vaccine but have recovered, the BBC reported.

"But will there be safety issues that come up when a larger number of people get vaccinated?" Swaminathan asked, pointing out that so far the trials have been small and "rare events" can happen when thousands and millions are vaccinated. "It's important to go carefully over the next 2-3 months," she cautioned.

All vaccine trials measure what are termed as "adverse events", serious medical reactions that patients can experience during the trial. When this occurs, a committee evaluates if it is related to the vaccine. These incidents are also assessed by data safety monitoring boards consisting of independent experts appointed by trial sponsors.

The Oxford/AstraZeneca vaccine trial reported two adverse events that could be related to the vaccine: one case of transverse myelitis--a neurological disorder affecting the spinal cord--and one of high fever that resolved on its own. Pfizer and Moderna have not reported any serious adverse events related to the vaccine yet.

In India, a volunteer in the Oxford/AstraZeneca trial being run by the Pune-based Serum Institute of India sent the company a legal notice after a neurological illness. The company maintained that the illness is unrelated to the vaccine.

It is important to analyse if vaccination caused any adverse event and whether that vaccine can cause the kind of illness that participants might report to trial investigators, said Kang. For instance, in the Oxford/AstraZeneca study, there were four deaths that were related to neither COVID-19 nor the vaccine, including a homicide, a road accident and fungal pneumonia. Similarly, Pfizer/BioNtech eliminated the possibility that some cases of severe appendicitis among participants were related to the vaccine.

But "for anyone who is a part of a trial and suffers from an illness after the vaccination is given, it is difficult to understand that the events are related in time but not in cause", said Kang.

"The US's Food and Drug Administration and other international agencies have mandated at least 70 days between the last dose [in clinical trials] and emergency use of a vaccination because most adverse events are likely to happen within six weeks of administering a vaccine," said Jameel.

"There are likely to be adverse events when a vaccine is given, it is about catching them in time and treating them," said Jameel. For instance, even with the polio virus, one in a million could get vaccine-induced polio but such instances were taken care of in the government immunisation programme, explained Jameel. "Do the risks outweigh the benefits? It all comes down to that," he said.

Because the vaccines have only been tested for a maximum of 2-3 months, their long-term safety cannot be estimated. For instance, 50% of the 37,706 participants in the Pfizer/BioNtech vaccine trial were followed for about two months after the second dose and before the results were made public.

It is almost impossible to estimate the long-term effects of the vaccines, said Ravi. "Will all vaccinated people get cancer after 15 years? I don't know. But the technology that is used is time-tested, and we also know that none of these approaches [for making COVID-19 vaccines] have ever resulted in cancer, so we presume it is safe," he said.

What exactly can the vaccines do?

For vaccine development, a disease is seen in three stages: infection, disease and transmission. Take the example of the common cold. You could be infected by a common cold virus but because the body has had the virus before and knows how to fight it, it might not develop into a disease with clear symptoms. If the body cannot fight the virus, symptoms will emerge, such as a headache and blocked nose. The infection could be transmitted by someone who is just infected or someone who has a full-blown cold.

Currently, little is known about what all the COVID-19 vaccines can do--prevent the infection itself or stop it from deteriorating. Even those vaccinated may have to continue to wear masks so that in case they are asymptomatic carriers, they will not spread the infection.

"No vaccine actually is ever initially tested for its ability to prevent infection. The primary endpoint of a phase III clinical study is to prevent the disease caused by that organism," Kang said. Companies do this by testing those who show some symptoms of the disease. "If that vaccine prevents disease, then you can ask it to do more," Kang said.

Very few vaccines induce sterilising immunity--which means they can prevent the virus from repeatedly entering the body and multiplying. For instance, vaccines for measles, rubella and hepatitis B are sterilising but those for BCG, diphtheria, pertussis are not.

If companies were to repeatedly test participants for infection, it would become an expensive, impractical process. "You can't do that for 30,000 people," said Kang. Pfizer/BioNtech and Moderna will reportedly test a subset of the trial participants for infection but have not yet done so.

In the Oxford/AstraZeneca UK trial, a small number of participants were asked to self-swab two times a week and send the swabs for testing. From the results currently available, the vaccine provided low efficacy (59%) against asymptomatic infection in the lower/standard dose combination and very low efficacy (4%) in the standard dose trial.

Even if the vaccines cannot prevent infection, they might prevent transmission in two ways: One, a vaccinated individual who gets infected sheds less of the virus than an unvaccinated person or less than someone who develops symptoms. For instance, if you earlier put out a million viruses every time you exhaled, post-vaccination the number could go down to 400,000 and the disease transmission would be limited, explained Kang.

The other method is through secondary prevention, which means that if fewer people are falling sick overall because of being vaccinated, there is a lower threat of infection in the community, said Kang.

Should the vaccines be given to those who have recovered from COVID-19?

Trials have shown that those who have had the disease and were given the vaccination did not suffer any adverse effects, experts said. "In the absence of clear evidence that infection gives you lifelong immunity, I would suggest that people who have had infection previously should get the vaccine," said Kang.

Jameel disagreed. "Vaccines are probably unlikely to provide any extra immunity to those who have recovered from infection," he said, but agreed that it would be too cumbersome to test and then deliver the vaccines only to those who do not have antibodies.

"When you are talking about mass vaccination and you say that COVID-19 infected people need not receive the vaccines, you are adding a huge layer of complication," said Ravi. "When you want to protect people quickly, these kinds of layers in public health do not work." He suggests that everyone, even if they have recovered from COVID-19, be vaccinated.

Which are the strongest contenders in India?

In India, three companies have applied for a license: Pfizer/BioNtech, the Serum institute (running trials of and manufactures of the Oxford/AstraZeneca vaccine) and Bharat Biotech. Of these, Bharat Biotech is yet to publish results from its trials of its vaccine called Covaxin and only began its Phase III trials that determine the vaccine's effectiveness on November 16, 2020. Moderna has not yet applied for a license in India.

Three vaccines are being considered for licensing, said V.K. Paul, a member of the government think-tank NITI Aayog and its central COVID-19 task force, at a press conference on December 8. "There is a hope that an early license is possible for all of them or for one of them."

"To approve a vaccine, what should you consider enough data?" asked Kang. For instance, she said, since India is fighting a health emergency, its drug controller could say that local clinical trials can be waived because they have been conducted elsewhere, as is the case with Pfizer. "Emergency use would have to be closely monitored," she said. But ultimately, a full license in India will need local bridging studies or smaller supplemental trials showing the vaccine's efficacy for the Indian population, she said.

In the case of the Oxford/AstraZeneca vaccine, known as Covishield in India, no country has approved it yet and results are not available from Serum Institute's India trials.

At this point, Bharat Biotech should not be a contender for a license because it is yet to publish Phase III results, said Kang and Ravi. In an emergency, the regulator could say that the data from the Phase III trial can be waived but that would not be appropriate because some efficacy data is needed to establish that the product works, said Kang.

On December 9, 2020, India's drug regulator asked the Serum Institute of India to provide updated safety data from the trial in India and more data from the UK trial. It has also asked for the assessment of the UK drug regulator on this vaccine. The Indian regulator also said that it will wait for safety and efficacy data from Bharat Biotech's Phase III study before taking a decision on its emergency use.

In India, given the challenges of storing, transporting and vaccinating a large population, especially in rural areas, if proved effective, the vaccines from Oxford/AstraZeneca and Bharat Biotech would be more feasible, said Kang. The Pfizer/BioNtech vaccine has to be stored at -70 degrees celsius and costs about $40 for two doses. The Oxford/AstraZeneca vaccine is likely to cost $2-3 per dose. "The Pfizer vaccine could be used in a limited way in urban areas," said Kang.

How were COVID-19 vaccines developed so fast?

In the past, it has taken up to decades to produce effective vaccines. But in the case of COVID-19, a combination of money, luck, technological advances and collaborations has facilitated the formulation and trials of vaccines in less than a year, experts said.

All vaccines are based on introducing what is called spike protein--the part of the virus that latches on to a cell and allows the virus to enter. [These spikes are also what give the coronavirus its "crown"-like structure and name.] A version of this protein is either introduced into the body or the body is instigated to make it, in order to trigger an immune response that fights off the virus, explained Jameel. "It is the delivery of this protein which is different in the case of the vaccines."

An illustration of the SARS-CoV-2 virus that causes COVID-19.

The Pfizer/BioNtech and the Moderna vaccines, known as mRNA vaccines, use a small Ribonucleic Acid (RNA), which is injected into the cell with the blueprint of the protein. "And no, these cannot change the DNA of a human being and create mutated humans," said Gang of a common misconception about the vaccines using this technology.

The Oxford/AstraZeneca vaccine has altered an adenovirus (which causes a cold in chimpanzees and does not impact humans) so that the body creates the spike protein when the vaccine enters the body. The Bharat Biotech vaccine uses the SARS-CoV-2 virus, grown to large amounts and inactivated with a chemical, which produces an immune response in the body.

On August 7, 2020, the Indian government created a National Expert Group on Vaccine Administration for COVID-19 (NEGVAC) with ministry representatives and technical experts. They guide the government on which population groups should be vaccinated first, procurement and selection of the vaccines and its delivery. India's health secretary has said that the NEGVAC has recommended health workers (10 million), other necessary workers such as police and municipal workers (20 million) and those over 50 years and those with comorbidities (27 million) be targeted initially, but the government is yet to take a decision on this.

Other Vaccines Undergoing Trials In India

Source: Government Press Conference on December 8, 2020.

Note: One vaccine being developed by Aurobindo Pharma is in the initial stages of development.

Traditionally, government approvals for vaccines have taken a long time, experts said--even approvals for another phase of a vaccine trial could take weeks. In the case of COVID-19, regulators have sometimes given approvals for more than one phase in one go, and companies have run these phases parallelly too, Jameel said. Financial investment too has come readily and companies have made manufacturing commitments even before testing was complete or a vaccine was approved, said Swaminathan.

Compare this to the HIV vaccine, Jameel said: "When the cause of the disease was discovered in the early 1980s, the US health secretary said in a press conference that now that the virus has been identified we will have a vaccine in to years." Forty years on, there is no HIV vaccine yet.

"We were just very very lucky that the first things that were tried worked for COVID-19. We may not be so lucky the next time," cautioned Jameel.

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