Healthcare workers write down details of residents in a slum during a check-up camp for COVID-19 in Mumbai, June 2020. Photo: Reuters/Francis Mascarenhas.
Last week, a letter from the Indian Council of Medical Research (ICMR) claiming that India would have a COVID-19 vaccine ready for public use by August 15 was roundly panned by scientists. The letter, written by ICMR director general Balram Bhargava, was addressed to 12 hospitals. Bhargava asked them to begin recruiting participants for human trials for the vaccine by July 7.
Experts familiar with vaccine trials quickly pointed out that both the July 7 and August 15 deadlines were ridiculous, given the vaccine had only been tested on animals thus far.
While most experts agree on the need to expedite vaccine development, the problem, they say, is with shortcuts. ICMR’s August 15 launch date and the letter’s tone suggest the agency doesn’t just want to fast-forward the development; it intends to skip vital stages of it.
“The wording of the letter is absolutely wrong. It would lead to the breaking down of systems you have worked very hard to create. You need to speed up, but you certainly can’t bulldoze people into doing a trial,” Jacob John, a professor of community medicine at the Christian Medical College, Vellore, who was involved in developing India’s first indigenous rotavirus vaccine, told The Wire Science.
Vaccine development typically has multiple stages, including animal studies, followed by phase 1, phase 2 and phase 3 studies in humans. Skipping or shortening any of these phases could lead to a potentially ineffective or dangerous vaccine reaching people.
Animal studies – the first safety net
Animal studies are among the earliest stages of vaccine development. Here, the vaccine is given to different animal species to test for immune responses and potentially dangerous side-effects. But Bharat Biotech, the Hyderabad-based company that’s developing the COVID-19 vaccine in collaboration with ICMR, has shared little information about the animal studies it carried out.
The dates on press releases from ICMR and Bharat Biotech suggest the company conducted these studies in around 50 days – between when it received the SARS-CoV-2 vaccine strain from the National Institute of Virology and when it received approval from the Drug Controller General of India (DCGI) to conduct human trials, based on the animal studies.
Several experts told The Wire Science that in this time, the company could only have conducted a few basic tests out of a range of studies that are possible.
According to Shahid Jameel, a virologist and CEO at the Wellcome Trust-DBT India Alliance, Bharat Biotech would have been able to test whether the animals developed antibodies in response to the vaccine – known as the vaccine’s immunogenicity – but “we don’t have the data to know” if it performed challenge studies: in which an animal receives a vaccine, is infected with the SARS-CoV-2 virus, and is then examined for signs of a COVID-19-like disease.
Challenge studies require animal models of COVID-19: animals that develop a disease that mimics COVID-19 in humans. While most lab mice resist infection by SARS-CoV-2, a type of transgenic mouse called the human ACE2 mouse is susceptible. (Other animal models for COVID-19 research include rhesus macaques and Syrian hamsters.)
Such animals are difficult to procure in India, plus performing a challenge study takes longer than an immunogenicity study, Jameel said. “You need to vaccinate the animal, you want to make sure it has enough antibodies, and then you have to challenge it with a live virus.”
Several vaccine developers are conducting challenge studies to be safe. This is because the studies’ results can help them predict whether their vaccine will worsen COVID-19 instead of suppressing it, a phenomenon known as vaccine-enhanced disease. This could occur in two ways: antibody-dependent enhancement (ADE) and vaccine-associated enhanced respiratory disease (VAERD).
When the vaccine worsens the disease
ADE happens when a person generates antibodies in response to a vaccine, but these antibodies end up hurting instead of helping. In the normal course of events, antibodies triggered by a vaccine are supposed to bind to and counteract any new virus that enters the body later. But during ADE, they achieve the opposite effect: they bind with the virus, and then help the virus attack human cells better, causing a more serious infection.
The most famous example of this phenomenon is the French company Sanofi Pasteur’s dengue-vaccine. After the company admitted in 2017 that the vaccine could worsen disease in some people through ADE, Philippines – which had used the vaccine widely until then – pulled the vaccine out of its markets and pressed criminal charges against some of the researchers who had tested the vaccine’s efficacy.
ADE is a worry for COVID-19 because there is some evidence that this phenomenon occurs with coronaviruses too. In the 1990s, scientists working on a vaccine for a deadly cat disease called feline infectious peritonitis, caused by a coronavirus, found that that the vaccine itself could kill cats by triggering a more severe form of the illness.
This is why COVID-19 vaccine developers are keeping close tabs on ADE. The good news is that when Chinese scientists vaccinated rhesus macaques with an inactivated vaccine candidate and challenged the animals with live viruses, the animals showed no signs of ADE.
That’s a comfort, said Vineeta Bal, a scientist at the National Institute of Immunology, New Delhi, because it means ADE may not be a big worry with COVID-19 after all. “But we cannot guarantee that it will not happen with any other COVID-19 vaccine,” she cautioned.
In the other phenomenon through which a COVID-19 vaccine can hurt – VAERD – the antibodies triggered by the vaccine bind with viruses that enter the body later. But instead of neutralising them, they form a large number of molecules called immune complexes that clog the lungs. A 1969 study of a vaccine against the respiratory syncytial virus, which causes pneumonia in babies, found that vaccine recipients fell sicker than those who didn’t. Some 80% of the infant vaccinees even ended up being hospitalised.
Again, VAERD is a worry for COVID-19 vaccines as well. Some coronavirus vaccines have failed to get past animal trials because the animals showed signs of lung-clogging.
Bharat Biotech has not published any data from its animal trials, so it’s unknown if it conducted studies to evaluate the potential for ADE or VAERD. As a result, it’s more crucial that the phase 1 human studies that follow are conducted with utmost care.
Phase 1 trials – the importance of slow and steady
Now that the company has completed animal studies, phase 1 trials – in which the vaccine is given to healthy human adults to evaluate its safety – will begin. Despite ICMR’s dramatic claim about an August 15 launch date, which effectively gives investigators 38 days to recruit participants and finish all studies, the trial’s registration on the Clinical Trial Registry of India (CTRI) suggests even phase 1 trials won’t be complete by then.
This is because the trial must first enrol 375 people starting July 7 (this could take weeks), vaccinate each of them twice with a 14-day gap, and then review the data 28 days after the first vaccination. That’s more than 38 days already.
The bigger question is: can the 12 participating institutions named in the ICMR letter begin recruiting people by July 7? The letter says any non-compliance in this matter “will be viewed very seriously”.
According to bioethicist Anant Bhan, this demand makes little sense. Phase 1 trials is the first time a new vaccine will be given to humans, which means that a hospital doing such a study must be prepared to handle unexpected and life-threatening events like anaphylactic shock.
“You need to have 24/7 monitoring of participants,” he said. This is why the ethics committees overseeing the trials in the 12 institutions must thoroughly review whether they have the infrastructure and expertise to do so.
Urmila Thatte, a clinical pharmacologist and bioethicist at the Seth G.S. Medical College and KEM Hospital, Mumbai, quoted the example of a 2006 study of a rheumatoid arthritis drug in the UK. The drug, known as TGN1412, had been tested on animals and seemed safe. But when six humans received it in the phase 1 trial, they suffered violent immune reactions and multi-organ failure. It took the patients several days to recover; one of them lost the tips of his fingers and toes in the tragedy.
“No animal studies had shown any danger before that trial,” Thatte said. This shows how animal studies can never fully predict what will happen in humans. And this is why investigators in phase 1 trials usually give a new drug to just one or two people on the first day and wait for adverse effects before moving on to the rest, according to Thatte. “However much you are in a hurry, you have to be careful.”
Other common phase-1 trial precautions include admitting all participants to the hospital for a few days when the drug or vaccine is administered for the first time. Studies should ideally be run by investigators who have prior experience in running such trials.
Both Thatte and Bhan expressed concerns over whether the 12 hospitals chosen to run the Bharat Biotech trial have this experience. And if they don’t, an ethics committee may either refuse permission or ask the institute for further data. This makes ICMR’s demand that the 12 institutions begin recruiting participants by July 7 a strange one — because it presumes the ethics committees will be okay with the study.
“You cannot tell an ethics committee to give approval. You can only ask them to review the proposal,” Bhan said.
Can phase 2 be shortened?
Once phase 1 is complete, Bharat Biotech will move to phase 2. Trial investigators will first recruit 750 new participants. Then, over at least 194 days, according to CTRI data, the investigators will study whether these participants develop antibodies to the virus and, if so, their levels.
The CTRI entry isn’t clear on what kind of antibodies Bharat Biotech will look for. The entry talks about neutralising antibodies in the context of the phase 1 trial but doesn’t mention the type of antibody in the description of phase 2. People exposed to the novel coronavirus develop many kinds of antibodies. Of them, only the neutralising antibodies can fight off an infection by inactivating a virus.
So if investigators find during phase 2 that a large number of people developed high levels of neutralising antibodies after vaccination, compared to those that weren’t vaccinated, does it mean the Bharat Biotech vaccine is effective?
Scientists cautioned that this isn’t an obvious conclusion. While high levels of neutralising antibodies are expected to protect against disease, the only way to prove that the vaccine really does protect is to show exactly that: that vaccinated people developed the COVID-19 illness less often than unvaccinated ones.
The reason neutralising antibodies can’t predict efficacy with certainty, said Bal, of the National Institute of Immunology, is that we don’t yet know how long these antibodies last or exactly how much they can protect.
“Antibodies decay in the body. Some vaccine recipients may destroy antibodies at a higher rate during infection”.
Then there is the prospect of ADE and VAERD, which could make the disease worse – neutralising antibodies or not.
Research into the behaviour of novel coronavirus antibodies is still ongoing. A study by Chinese researchers published on June 18 found that neutralising antibodies dropped to very low levels within 2-3 months of exposure among asymptomatic people. Other studies have shown that they last longer. And we still don’t know the level at which they protect.
This means neutralising antibodies are at best a surrogate endpoint of vaccine efficacy. In other words, they are a likely predictor but not unambiguous evidence. For this reason, the WHO recommends that all vaccine manufacturers conduct phase 3 trials (which can include as many as 30,000 people), measure rates of actual disease and can take years.
Unless the Bharat Biotech vaccine’s safety is ascertained in the first two phases, it can’t begin phase 3.
How are others shortening trials?
Given the unprecedented nature of the pandemic, many countries are looking to shorten the course of vaccine development that can otherwise take decades. But these strategies don’t involve skipping phase 2 or 3, even if this is the only way Bharat Biotech can meet ICMR’s deadline.
Instead, their strategies involve defraying the financial risk that manufacturers take on while developing a vaccine and speeding up manufacturing. For example, as part of the US’s Operation Warp Speed, vaccines found to be efficacious in phase 3 studies will get help to quickly scale up production.
While we urgently need a COVID-19 vaccine, experts are agreed that the urgency doesn’t justify sacrificing scientific rigour to get the vaccine to the market. So the haste communicated in ICMR’s letter to hospitals is just unscientific as well as unethical, Jameel argued.
“We should not rush into this. Our aim should be to give a safe and efficacious vaccine for public health. It is the credibility of the scientific world, the government, and the company developing the vaccine that are at stake. We should not cut corners.”
Priyanka Pulla is a science writer.
The reporting for this story was funded by a public health journalism grant to Priyanka Pulla from The Thakur Family Foundation.