Why we shouldn’t get too excited about a Covid vaccine

It isn’t a silver bullet for the pandemic.

WrittenBy:Ronak Borana
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Nearly eight months into the coronavirus pandemic, new infections in India have finally slowed down, according to official data. But as several countries in Europe again impose lockdowns and the United States records more daily cases than ever, it seems inevitable that India too will be hit by a second wave.

In the meantime, as we swing from needless hygiene theatre to pandemic fatigue, vaccines seem to be the most promising exit plan. But it is illusory to expect a vaccine to reinstate the pre-pandemic normalcy.

Best bets

More than 200 vaccine candidates are currently in trial. But our best bets are the handful in phase three trials that may get approval in the next few months – from Pfizer, Johnson and Johnson, Moderna, AstraZeneca/Oxford, Novavax, and CanSino.

Two of these are undergoing trials in India, according to the IMCR, which is leading the country’s pandemic response. First is Oxford and AstraZeneca’s Covidshield, a billion doses of which are being made in partnership with the Serum Institute of India, half of those for domestic use. This is likely our best bet.

The Serum Institute will also manufacture a billion doses of Novavax’s candidate for low- and middle-income countries, including India.

Then, there’s the indigenous Covaxin, developed by the ICMR and the National Institute of Virology, and manufactured by Bharat Biotech. Though this inactivated vaccine is built on a more reliable platform, it's still in early phase three trial and at least six months behind the frontrunners. ZyCoV-D, a DNA vaccine candidate from Zydus Cadila, is further behind.

Vaccines are more likely to succeed in clinical trials than other therapeutics. Even then, an average vaccine takes 10.71 years to develop and has only a six percent probability of entering the market. Only one in five vaccine candidates that undergo clinical trials succeed, according to WHO. But this volatility is the nature of biopharmaceutical licensing.

Vaccine candidates from Pfizer, Moderna and Zydus Cadila are built on experimental mRNA and DNA platforms that have not been used to make a commercial vaccine before. Similarly, a recent approval from the European regulator EMA aside, the adenovirus vector vaccine platform used by Oxford, Johnson and Johnson, Gamaleya, and CanSino hasn’t yet produced an FDA-approved vaccine. An adenovirus vector vaccine for HIV was abandoned in 2008 after trials showed that it was not only ineffective, but even exacerbated HIV infection in some participants.

Vaccines built on more reliable platforms are months behind in development than the frontrunners and they would likely be overshadowed once first approvals are granted. Novavax has spent $1.5 billion dollars over 30 years developing vaccines. Yet, the company, which was recently awarded $1.6 billion by the US government, does not have a single licensed vaccine in the market.

Given the trials of these frontrunner candidates have been extended, the optimistic timeline of late 2020 for a vaccine has been revised to 2021, and the rollout will likely be more staggered than what we currently assume.

Beyond the gravestone of hydroxychloroquine, this pandemic has seen pharma giants bulldoze their way through regulatory approval. Remdesivir, an antiviral made by Gilead, in spite of falling flat in multiple trials, was approved by the American FDA, and even secured a highly lucrative contract from the European Union.

Indian regulators, under the garb of “restricted emergency use”, approved Biocon’s Itilozumab and Glenmark’s Favipiravir despite unreliable data on their efficacy. This pattern of regulatory authorities bowing to political and corporate pressure makes it easier for a poor quality vaccine to fly under the radar.

For all this scepticism, vaccines absolutely do work. They have a remarkable safety record, have helped save millions of lives, mostly children, and become indispensable to public health. In the past 10 years alone, vaccines have saved an estimated 23 million lives.

Measuring efficacy

For most vaccine candidates, data from phase one and two trials has been promising. They spur immune response and produce healthy amounts of neutralizing antibodies. But virus titer reduction or antibody production tells us little about the efficacy. By what amount the vaccine reduces Covid infection is the critical question. And phase three trials seek to answer that.

Let’s look at what a simplified average phase three trial looks like. We recruit 30,000 people. Half of them are immunised with our vaccine candidate and the rest are given a placebo. We wait for 150 events, each a predetermined endpoint such as an RT-PCR positive test at recurring intervals. We then look at the distribution of the events between vaccine and placebo to calculate its efficacy.

Measuring the events can tell us different things. Depending on what we’re measuring, we can see whether they decrease infection, severity, disease, infectiousness. All trials of the current frontrunners only measure reduction in the risk of mild infection, and tell us little about moderate or severe disease.

Preventing disease in the vaccinated person is direct protection. Preventing the person from transmitting the virus to others is indirect protection. In a country such as India, where vaccinating the majority of the people would take months, indirect protection would be crucial to controlling case surges. Based on trials in apes, it’s unlikely that any of the frontrunners would prevent transmission.

Along with efficacy, phase three trials check for safety and rare adverse events that are only highlighted when there are thousands of participants. All the approvals that we will see granted in the coming months will be based on interim data and most phase three trials, involving Moderna, Oxford, Novavax, Pfizer candidates, won't end before late 2021.

WHO, FDA and Indian regulators have all set a bar of at least 50 percent efficacy in placebo-controlled trials for approval. This means if a moderately efficacious vaccine is licensed, it will end up becoming the benchmark for better candidates, making it more difficult to judge their true efficacy.

Like for repurposed drugs, WHO is running an international, randomised, multisite-trial for several vaccine candidates at once. The WHO Vaccine Solidarity trial aims to recruit 2,80,000 participants across 34 countries. But its results will come only in early 2021, after most of the frontrunners would have been licensed and distributed.

The outcome of a trial also depends on the prevalence of the virus in the place where the vaccine is being tested. More the Covid cases, the faster the trial ends. But as Covid cases have begun to decline, so has the speed of some trials. Low attack rates because of immunity building, masking, and physical distancing will slow and maybe even halt some of the trials.

Another problem with the ongoing trials is that they are not diverse enough. For instance, older people who are at greater risk from Covid can’t mount a strong immune response. More data on tolerability and dosage is therefore required for this population. Other disadvantaged people such as those who are obese, HIV positive, immunocompromised, or pregnant women are underrepresented in the trials as well.

The longevity of protection against Covid is still unknown for the vaccines in development, and we will likely need booster shots every few years, or less.

Safety concerns

Reactogenicity is the body’s reaction to the administration of a vaccine, and usually involves some physical discomfort such as headache, fatigue, and fever. While these are manageable symptoms and signs, a vaccine with a poor tolerability profile might discourage some patients from taking it.

Of the frontrunners, the Oxford vaccine has the worst profile. In their phase one and two trials, Oxford scientists had to add newer arms where the participants receiving the vaccine were also given paracetamol every six hours for a day to manage the symptoms. Still, reactogenicity was significantly high as compared to the placebo, which was a vaccine but for another pathogen.


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Percentage of participants that experienced some adverse effects. Source: The Lancet

Moderna’s vaccine had similar reactions in about 80 percent of the participants. While this isn’t unexpected for new vaccines, it’s imperative such risks are communicated well and not brushed off, otherwise the public could grow distrustful.

Sometimes, vaccines can cause serious reactions, such as Guillain-Barré syndrome, that may require hospitalisation, even cause death. Both Oxford and Johnson and Johnson were compelled to pause their phase three trials to evaluate such rare extreme reactions. Most recently, SinoVac’s trial in Brazil was suspended after some of the participants showed serious adverse reactions.

There’s also the fear of a vaccine making the disease worse. Vaccines for respiratory syncytial virus, dengue, SARS CoV-1 were abandoned or restricted for use for this reason. While current research and data suggest the risk of a Covid vaccine exacerbating the disease is no more than for any other viral vaccine, careful monitoring of phase three data is essential.

Vaccine hesitancy

The rise of anti-maskers has inflamed the risk of vaccine hesitancy prolonging this pandemic. Since the pandemic started, the number of Americans willing to take a Covid vaccine has decreased to almost half. For candidates with less efficacy, more coverage will be required, which would be jeopardised if certain groups do not trust vaccine science.

In the last couple of years, unlike in Pakistan, South Korea, Indonesia, confidence in vaccination has increased in India.

Anti-vaxxers as a group are nascent and unorganised in India. Some older instances of vaccine hesitancy involve the claims about MMR vaccine being an infertility-inducing tool. Similar rumours about Covid vaccines have been busted by Alt News, still repeat offenders such as Biswaroop Roy Chowdhury are having a field day dismissing Covid and potential vaccines for it. Given India’s history of flirting with fake news and anti-science rhetoric, there’s a fertile cyberspace for spreading misinformation about Covid immunisation.

Percentage of population that believes vaccines are safe. Source: The Lancet

Rolling out

From Bihar to the United States, politicians have made the supply of a Covid vaccine a wedge issue. Given the world is holding its breath for a vaccine, there is a genuine risk the regulators may approve a substandard vaccine or, worse, a poorly tested one. The FDA, in many ways the regulator of the world, felt pressured to approve convalescent plasma therapy and remdesivir for Covid treatment, despite evidence against their effectiveness.

To complicate the situation, there’s “vaccine nationalism”. During the H1N1 pandemic of 2009, the US and European countries allowed 10 percent of their vaccine stocks to be sold only after ensuring they had enough for themselves. The recent news about the Pfizer vaccine’s success reminded us of this global disparity once again.

Covax, a collaboration between WHO, Gavi, and the Coalition for Epidemic Preparedness Innovation, is a promising remedy to this disparity, a partnership to buy and equitably distribute vaccines around the world. Funding and procuring shortage, blurry details, possible export restrictions, and several other challenges fret Covax, however.

The main bottleneck in procuring a vaccine is the cost. Back of the envelope calculations suggest the cost of immunising India will be Rs 70,000 crore, a bit more than the central government’s annual health expenditure. This is without accounting for manpower, syringes, logistics, cold storage, and other peripherals. Covax may bring down the cost but there is still a lot of uncertainty.

Next come transportation and logistics. Oxford’s Covidshield and Novavax’s vaccine require specialised cold chain storage. In fact, without significant investment, which has been absent until now, any potential vaccine can’t ride on the existing cold chain logistics reserved for maternal and infant immunisation.

India plans to immunise 200-250 million people by July 2021. Most candidates require two doses, each a month apart. This means administering 400-450 million doses by mid-2021. The frontrunners all require intramuscular delivery and, therefore, skilled practitioners to administer. Even if all this is provided for, the country would cover barely a fifth of the population, far from the 60 percent coverage needed for herd immunity.

Vaccination will have to be followed by monitoring the people for adverse reactions and ensuring they get booster doses. So, it will likely take a few years before everyone is vaccinated.

All these dominos, from phase three trials to the eventual jab in the arm, are stacked uncomfortably close to each other. So, every delay may extend the timeline.

Vaccines are incredible public health tools. For a dollar or less, they protect us against the most ferocious diseases. But they are not silver bullets. Until they slowly push us out of this pandemic we will have to stick to the fundamentals – test widely, wear masks, practice physical distancing, and have compassion.


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