Even as countries and scientists fight against time to find the best and quickest solutions, the coronavirus crisis continues to outmanoeuvre the world. Will we find a magic bullet or will it take us on an exhausting journey to nowhere?
On April 3, a handful of army veterans fired off a letter to Prime Minister Narendra Modi. With the coronavirus pandemic barrelling down, they claimed to have the panacea to save the world: Gangajal. River activists, they called for a probe into the “holy” waters for that special something in its depths that made it pure. In a world frozen by fear and foreboding, the news danced across headlines for a while, before sinking into the bottomless pit of viral pseudoscience, miracle cures and cow-urine parties, on an overdrive since the pandemic started. It’s a mad, mad, mad, mad world.
A tiny virus has brought the planet to its knees and no one knows the way out of it. A race to find a solution has gripped all. Every day is a new surprise, as millions of eyeballs scan the news for a “magic cure”: from please-drink-hot-liquids messages on WhatsApp to the direct-sunlight-and-injected-disinfectants remedy of US President Donald Trump, to scientific jargons—repurposed drugs, convalescent plasma, antibody cocktails, genetic vaccines. In a pandemic characterised by extreme uncertainty, the world is waiting with bated breath for an answer to that million-dollar question: “What will cure Covid-19?
HUNT FOR A MAGIC BULLET
Scientists around the world are working around the clock to figure out new ways to beat the virus. Over 70 groups are at work, 100 vaccine candidates are in the pipeline, over 460 clinical trials are on. Research papers and preprints are being published at a furious pace every day: from 1,245 in the first 80 days of the year to a staggering 26,000-plus now, according to PubMed, a search engine for biomedical research. Countries, pharmaceutical makers, biotech innovators and academic laboratories are going neck-to-neck to produce a therapeutic, a vaccine, a prophylactic or a curative agent that will work. Never before, researchers say, have so many experts in so many countries focused simultaneously on a single topic and with such urgency. “This is like a world war,” writes Bill Gates, the Microsoft founder who has pledged has pledged $100 million toward containing the virus, in his blog post, Gates Notes. “Except in this case, we’re all on the same side.”
A striking feature of the war on Covid-19 is the diversity of platforms being developed by drug companies, researchers, medical institutes, universities and governments. From protein treatments to reduce inflammation and infection to gene therapies that disrupt viral replication, from combinations of repurposed drugs—antivirals, anti-inflammatories, antimalarials, antiparasitic—to shotgun technology, immunotherapy to Artificial Intelligence—all targeting the deadly pathogen. Some has backfired, with serious side effects in users: for instance, the antimalarial hydroxychloroquine advocated by Trump. Some are showing modest benefits—for instance, Gilead Pharmaceutical’s antiviral remdesivir, which has just entered into a licensing pact with five drug firms in India and Pakistan.
PROMISE OF ANTIBODIES
India’s apex body for biomedical research, ICMR, is expending all its energy on something else—something new, that’s also something old—“plasma antibody therapy,” the country’s chosen way to confront and contain the raging pandemic. Will it work? The esoteric world of science is buzzing over this line of treatment where patients who have been infected and recovered hold the key to cure. And the gateway to recovery are the antibodies—protective proteins in the immune system—that patients typically develop in response to the virus. These are called neutralising antibodies, because they can target and neutralise the virus (SARS-CoV-2). “The procedure involves infusing blood plasma from a Covid-19 patient who has recovered to another patient who is critically ill,” says oncologist Dr Vishal Rao of HCG Cancer Centre, Bengaluru, whose team is leading one of India’s first plasma therapy clinical trials on Covid-19 patients, ever since the Drug Controller General of India gave the go-ahead on April 17.
Scientists call it a “passive vaccine”. “In active immunisation you are injected with a weakened or dead form of a virus, which tricks your immune system into creating new protective antibodies,” explains Rao. Here, no virus is injected into the patient. The science can be traced back to late 19th century, when German physiologist Emil von Behring used it for diphtheria treatment and won the Nobel Prize in 1901. Over the years, it has been identified as a potential therapy for a number of viral infections: the influenza pandemic of 1918-1920 to influenza, SARS to avian flu. The 2014 Ebola outbreak has turned the spotlight on its potential as a therapy in infectious diseases for which vaccines, drugs or cures are far off.
How dependable are they? Lav Agarwal, Joint Secretary, Union Ministry of Health, highlighted at a press briefing on April 28 that plasma therapy is an experimental therapy: “So far there is no evidence to support it as a treatment.” Yet neutralising antibodies have ignited hope. “As vaccines and drugs are yet to come, plasma therapy is lining up as the first-choice treatment,” says Rao. “One-fourth of the 400 clinical trials running around the world involve plasma therapy,” he adds. A host of antibody cocktails from global pharma giants—Regeneron, Sanofi, Roche, Eli Lilly—are expected in June.
THE VACCINE rush
Nowhere is the race for cure as intense or evident as in the vaccine landscape. A striking feature is the range of vaccines that are being developed now: DNA, RNA, virus-like particles, peptides, viral vector, live attenuated virus, inactivated virus, to recombinant protein vaccines. Leading the race is a whole new type of vaccines, genetic vaccines, where the patient is given the genetic code needed to produce the virus. Explored so long in cancer gene therapy, the DNA and mRNA vaccines would be the first of
its type. No such vaccines have ever been used.
The vaccine race, however, has locked up countries in one-upmanship. Questions of national security, geopolitical crosscurrents, scientific pride and profit have led to a diplomatic breach between US and China. Tension is brewing between Germany and the US, over allegations that Trump tried to poach German biotech firm CureVac for its research on coronavirus vaccine. From week to week, one country or the other is leading the rush for a magic bullet against Covid-19. China, Europe, the US, Israel have all set off at a sprint. And everybody is saying: “We are the first.” It’s the story of a world in deep crisis.
China is leading the race with 1,000 scientists and more vaccine candidates approved for human testing than any other country.
But with the Academy of Military Medical Sciences of China leading from the front, the vaccine has already been militarised. “[We] will not be slower than other countries,” China has declared. Trump has recently said, “We’re so far ahead of any vaccine ever in history.” Israel has just claimed a “significant breakthrough” in developing the “first vaccine”. The project is under Israel Institute for Biological Research, the defence biological research institute that is controlled by the Prime Minister’s Office, and often described as “secretive” or “shadowy” by the Israeli press. A day later, the same claim has been made by Italy. The quaintly named ChAdOx1 nCoV-19 vaccine by Oxford University scientists, has now shot ahead to become “the most promising” potential candidate, with British drug maker AstraZeneca pitching in to develop, produce and distribute it.
THE COVID-19 RIDDLE
What makes the race for cure particularly challenging is that Covid-19 is proving to be a disease of uncertainty. Coronaviruses are difficult to work with in a laboratory setting, hard to grow and isolate, clone or manipulate. There are very few virologists in the world who specialise in coronaviruses and the field has suffered from lack of funding for years. This explains why some of the most important questions about the current virus have been hard to pin down: why do some people get really sick, but others do not? Why do some mild cases turn into life-threatening emergencies? What explains the startlingly low blood oxygen in some patients who nonetheless are not gasping for breath? None of this variability really fits with any other disease.
Scientists are fitting together puzzle pieces, joining the dots and making all possible connections. New evidences are emerging, challenging the old. Here are the big takeaways: first, the virus does not only attack the lungs, it attacks the lining of blood vessels all over the body—in the heart, brain, intestine, liver, kidney, everywhere. It can cause pneumonia without symptoms, until the blood oxygen levels drop dangerously low, increasing the chance of death. There have been substantial mutations in the virus, making it harder to create a long-lasting vaccine. A high rate of abnormal blood clotting in Covid-19 patients, leading to death and unexpected stroke among healthy younger people. None of this really fits with any other infectious diseases the world has seen.
DISEASE OF IMMUNE SYSTEM
The World Health Organization (WHO) has sounded out a warning that having antibodies to the disease confers immunity. This has brought the whole issue of immune system at the front and centre of the Covid-19 dialogue. It is increasingly clear that SARS-CoV-2 is spreading by exploiting the human immune system—the very defence mechanism of the body.
If you think of the immune system as an army, then its main troops are the T-Cells and B-cells, the ammunition consists of antibodies and the first line of defence is the signalling protein, interferon. Whenever viruses, bacteria, fungus, parasites, chemicals enter the body, the interferons mount alert. Antibodies arrive and neutralise pathogens, while killer T-cells eliminate infected cells. The immune system then winds down, but not before keeping a record of the microbe it has just defeated, so that you don’t catch it again.
Using new sequencing methods, researchers have found that SARS-CoV-2 adopts surprising strategies to trick and avoid our immune system. And it does so by exploiting our own defence mechanism, explains a study by 49 researchers across the world, led by the Harvard Medical School and MIT (published in Cell, April 27).
Consider this: the nose is the main portal of initial infection. Here, a protein in the spikes of the virus masquerades as a glue (that binds cells) and misleads the chemical doorway of cells, unlocks and enters; once inside, it hijacks cell machinery, replicates and starts infecting new cells, transmitting more rapidly than the time taken for the immune response to emerge; it makes the “first responder” ineffective by entering more when it mounts alert; it infects with its spikes lying low, unlike most other pathogens, hiding effectively from antibodies; it can kill the powerful T cells that are supposed to kill the virus instead.
Scientists are worried, because the current coronavirus can sometimes behave like some of the most notorious viruses that directly attack the human immune system. Least understood is why some critically ill patients experience overreaction of the immune system, called “cytokine storms,” when the body attacks its own healthy cells. Or, why—as the WHO points out—antibodies often do not seem to confer immunity, as some recovered Covid-19 patients suffer relapse. A team of researchers from Shanghai and New York have just found that SARS-CoV-2 can damage the immune system in ways that are similar to HIV patients.
REPURPOSED DRUGS
As the wait for a vaccine continues, a strategy of using drugs that are already approved or under investigation for some other medical indication is evolving, to bring down the severity of the pandemic. Scientists are focusing on three main lines of compounds: antivirals, anti-inflammatories and antibody-based treatments. Antivirals, to stop the virus from replicating; anti-inflammatories, to counteract the high inflammations that attack the body; and antibody treatments, to neutralise the pathogen and rev up the immune system.
There’s a buzz over antivirals, but they are not the resounding success many had hoped for, including the much talked-about remdesivir, Gilead Sciences’ Ebola drug. Although it is the first to be approved by the US Food and Drug Administration for emergency use in seriously ill Covid-19 patients, clinical trials show it reduces death rate and duration of the disease slightly. A report from Hong Kong (The Lancet, May 8) shows a combination of multiple antiviral drugs, including HIV drug lopinavir-ritonavir (Kaletra), to be more effective in patients with high viral load.Hope is running high over anti-inflammatories, too. The medical community now believes the worst effects of SARS-CoV-2 infection occur when the immune system goes into overdrive, damaging organs fatally. Six clinical trials are currently assessing anti-inflammatory agents. As governments seek urgent treatments for the new disease, there has been a global surge in demand for anti-malaria and anti-parasitic drugs—Hydroxychloroquine to Ivermectin—although there is no definitive evidence they work on their own. There has also been reports of serious side effects.
A TOUGH CALL
The WHO is using its global reach to fast-track and scale up randomised clinical trials around the world to find a treatment for Covid-19, at a rate that aims to be 80 percent faster than any traditional trial. Through its Solidarity Clinical Trial, the WHO has enrolled an unprecedented number of patients across about 100 countries—to test four possible treatment options faster, with stronger evidence—as doctors around the world dedicate themselves full-time to the task.
“These are the kinds of trials that are demanded now,” says Dr Ambrish Mithal, chairman and head of endocrinology and diabetes at the Max Super Speciality Hospital at Saket, Delhi, and Gurugram. Right now, the world is holding on to hope, lockdowns and social distancing, while the global economy is on the verge of collapse. Unproven therapies and drugs are being touted as potential treatments for Covid-19. Half-baked studies are producing misleading results. The trade-off between scientific rigour and speed for the sake of a medical emergency is real. Administrators, too, are brushing away rules that otherwise would not be permitted. “The race for cure is a race against time,” says Mithal. “People need to find some confidence somewhere.”
the ticking clock
A magic bullet vaccine would undoubtedly be the best bet, but when will they come out? Vaccines take time—10 years on an average—the fastest-ever the world has seen is the mumps vaccine, developed over just four years. Given the pressing need for speed, the traditional vaccine development modalities will most likely give way to novel paradigms. In February, American biotech company Moderna clocked the fastest ever timeline for creating a Covid-19 RNA vaccine ready to be tested in humans in just 42 days. But how will it pan out ultimately?
Bill Gates is optimistic that a strong Covid-19 vaccine would be ready in “as little as nine months or as long as two years.” To Dr David Nabarro, envoy for the WHO on Covid-19 and professor of global health at Imperial College, London, the wait will be longer—if a vaccine comes out at all: “Don’t expect a vaccine to come to the rescue in the short term. Some viruses are very, very difficult when it comes to vaccine development.”
“This is going to be a long haul,” says Dr Jayaprakash Muliyil, former principal, Christian Medical College, Vellore and one of India’s leading epidemiologists. The pattern of the novel coronavirus is still not clear as yet. It is exploding in different places at a different pace. “The virus is likely to come back. That’s what happens in the normal course of epidemics, until a vaccine develops or it runs its course.” While the race for cure is on, let us keep the elderly safe. “That will be half the battle won,” he points out. Meanwhile, the message from the Union Ministry of Health in India is stark and clear: “We will have to learn to live with this virus.”
WHAT THE WORLD IS TALKING ABOUT
Front-running Phase II vaccines
Harmless viral vector, genetically tweaked, by CanSino Biologics, China
Convalescent plasma
Infusing blood plasma from
recovered patients; investigational; India has started clinical trials
Monoclonal antibodies
Mimic the immune-system response to the virus, develop neutralising antibodies that block the virus. Injections to dermal patches. At least 50 candidates in development.
Repurposed drugs
Already in use for something else. Antivirals like Remdesivir (Ebola), Favipiravir (influenza), Kaletra (HIV); anti-inflammatories like Actemra and Kevzara—both anti-rheumatic drugs
Challenge trials of Covid-19 vaccine Deliberately infecting healthy volunteers with coronavirus, an infection with no cure, to accelerate research on vaccines, raises ethical questions; WHO has just issued a 19-page “key criteria for the ethical acceptability of Covid-19 human challenge studies”.