Vaccines take years to develop. But mere months after the novel coronavirus that causes Covid-19 was first spotted, a team at the University of Oxford is already recruiting for human clinical trials for its vaccine against the disease, while researchers at Imperial College London took just two weeks from receiving the sequenced genome of the virus to producing a candidate vaccine. The Coalition for Epidemic Preparedness Innovations (CEPI) believes one of the eight projects it is backing can create a vaccine within a year; that includes work led by American firm Moderna, which is already partway through its first clinical trial.
The Covid-19 pandemic is accelerating the slow, safe vaccine development process, but even the most aggressive predictions don’t see us getting protective jabs until next year at the earliest. There are safety risks to cutting corners, which may see trials run concurrently rather than carefully waiting for results before continuing, but somehow the biggest hurdle may be a lack of funding, with researchers saying they lack the money to keep trials running beyond March.
Despite those challenges the virus’ unprecedented spread has sparked a rush to find a vaccine. According to the World Health Organisation (WHO) there are two vaccines in clinical trials — one from the pharmaceutical firm Moderna, plus another from CanSino and the Beijing Institute of Biotechnology — with a further 42 candidate vaccines under clinical evaluation, including Oxford’s, which is recruiting for clinical trials.
Those 44 vaccines use a wide range of delivery platforms and techniques to trigger the necessary immune response to protect our bodies from Sars-CoV-2. Generally, vaccines work by mimicking a disease with parts of a virus or a deactivated virus to generate an immune response from the body.
The traditional, classical technique – think smallpox and cows – involve deactivating the pathogen so it can be used to trigger the immune system in a person without making them sick. That can include chemically inactivating the virus or live-attenuating it, meaning the vaccine uses a live but weaker version of the virus, which may be mutated until it’s no longer a threat, explains Nicola Stonehouse, a professor in molecular virology at the University of Leeds. “There are still people thinking about developing a coronavirus vaccine in those very classical ways — but they do take time,” Stonehouse says. One example is the Serum Institute of India, which is developing a live-attenuated vaccine for the Sars-CoV-2 based on existing TB vaccines; that company is fast-tracking the work and hopes to begin human trials within six months.
Another technique uses pieces of a virus, such as proteins, to trigger that immune response. Known as recombinant vaccines, they’re easy to produce because the virus proteins can be made in labs; researchers don’t need to grow the virus, and work well with coronaviruses because the spikey proteins on the surface of such viruses are easily recognised by our immune systems. Pharma giant Sanofi is repurposing a Sars protein vaccine to fight Sars-CoV-2 – the virus that causes Covid-19 – while Novavax is hoping to begin human testing on such a vaccine by the end of spring.
The other Covid-19 vaccine in human trials is from CanSino in Hong Kong. It uses a different technique, hiding genetic codes for the novel coronavirus’ proteins inside a virus that isn’t dangerous to humans; in this case, an adenovirus. That sneaky trick worked on Ebola.
There’s a new technique that’s turned the industry’s head: RNA vaccines. This uses a messenger RNA (mRNA) – a specific type of nucleic acid molecule – to introduce to the patient antigens in the form of proteins from the virus to kickstart the immune system’s response. RNA vaccines are faster to develop than classical vaccines, as researchers don’t need to grow large amounts of the virus, but there’s a catch: none have yet been approved. “This is very new,” Stonehouse says. “So we don’t know how they’re going to work, and we don’t know if they’re going to be safe.” Moderna’s vaccine uses this technology, which means it could be the first RNA vaccine to be approved as well as being the first approved against Sars-CoV-2 – but that, of course, assumes it works.
But even then, trials for the Moderna vaccine may continue into next year, taking a year to 18 months, despite clinical trials of its mRNA based vaccine already happening with 45 adults; the first participant was given the vaccine on March 16. The initial goal was to start trials three months after announcing the vaccine. “We managed to do that in 63 days, so we already demonstrated the ability to move a little faster than expectations,” Moderna president Stephen Hoge told Time. “We have an ethical responsibility to build the data and show the vaccine is safe and effective, and to do that in a sequential way. Still, every chance we have to continue to demonstrate that we can pull the timeline in, we will take.”
Testing takes time. First the vaccine has to be proven to work on cells in a lab, then they’re tested on animals for toxicity. Then there are three phases of tests on humans: phase one is safety tests on small groups; phase two expands the cohort to test whether it works and study side effects; phase three sees it doled out to hundreds or thousands of people to see if it works in the real world. “18 months is actually pretty much as quick as you can do it,” Stonehouse says. “The only way you can speed that up is to run those trials side by side. Once a successful, safe vaccine is created, there are further challenges, including setting the dosage, setting up manufacturing, packaging and properly stored.
Still, there are ways to speed up the process, beyond shaving days off with faster trials and using new techniques such as mRNA. Oxford has repurposed a vaccine it was developing for the similar Middle East Respiratory Syndrome (MERS) virus, for example. Such repurposing is a good idea because it means development is further along – it’s the “here’s one I made earlier” of vaccines. However, those vaccines already in development haven’t been proven to work. “Most of these approaches haven’t actually got far enough to generate a vaccine for the diseases they were working on,” Stonehouse says. Oxford doesn’t know if its vaccine works on MERS, let alone Sars-CoV-2. “A lot of it is really unproven, not only the technology but the efficacy,” Stonehouse says. “But in times of great challenge, great advances can be made.”
Some of the accelerated development is simply hard graft. The work at Imperial College London has also happened quickly, with a candidate prepared just two weeks after getting the genetic sequence of the virus. The RNA-style vaccine triggers an immune response by injecting genetic code into a muscle to make a protein found on the surface of the novel coronavirus. Initial experiments in mice have been positive, with human trials set for early summer, if subsequent animal trials are successful and funding can be found, with the potential for the vaccine to be available next year, according to team leader Robin Shattock.
Being first to trial doesn’t mean the vaccine will work, of course. But the pandemic means the race to create a vaccine is happening on many fronts. Alongside the efforts at Moderna and Oxford, CEPI is funding work at Inovio on a DNA vaccine used against MERS, the University of Queensland for its molecular clamp platform, and Institut Pasteur for its measles-vector technology, among others. In the US, pharma giant Sanofi Pasteur is working with the US Biomedical Advanced Research and Development Authority (BARDA) on developing a library of potential vaccines to be piloted using its DNA platform that’s already been used to create the Flublok vaccine; the company expects to start lab tests this year, with human trials next year. Johnson & Johnson’s Janssen vaccine development division has also partnered with BARDA on a similar project, with the same technologies it used to make vaccine candidates for Zika and HIV.
While we desperately wait for those vaccines to be developed, trialled and manufactured to stop the spread of the virus, there are other drugs being considered to treat Covid-19. As with the vaccines, these largely look to repurpose existing treatments already used on other diseases, which is ideal as they don’t require the same rigorous safety tests as a novel drug. “They’re well established and already approved for use in humans. It’s an attempt to see whether they have any effect on this virus,” says Mark Harris, a professor of virology at the University of Leeds. If they do, they can be rolled out on a large scale without as many safety tests.
The WHO announced on March 22 a global trial involving thousands of patients called SOLIDARITY, which will study how effective four drugs are at treating Covid-19 by collaborating on randomised trials. “Multiple small trials with different methodologies may not give us the clear strong evidence we need about which treatments help to save lives,” WHO Director-General Tedros Adhanom Ghebreyesus during a briefing in Geneva.
There are four being considered by the WHO trial, the first of which is Remdesivir, a drug developed by US pharma giant Gilead Sciences to fight Ebola that prevents a virus from replicating. A report in The New England Journal of Medicine describes the drug helping a coronavirus patient in Washington state recover, but larger trials are needed.
“I think it’s the most promising,” says Harris. When a virus grows, it makes new copies of its own genetic material, he explains. Remdesivir induces errors in that process. “It makes the virus make mistakes when it’s making a copy of its new genetic material,” he says. The hope is those errors will make the virus non-functional, and the virus will stop being able to grow. Remdesivir worked in the lab against Ebola, but not in the real world, but Harris notes that Ebola affects the whole body, while this coronavirus focuses on the lungs. “Ebola causes a much more dramatic disease, so I think there was an issue with the type of virus it was targeting,” he adds.
Whether Remdesivir works or not remains to be seen, as trials are on-going, but pharma Gilead raised concerns by seeking “orphan drug status”, which not only would speed it through regulators but give the company a monopoly selling it; the request has since been dropped after backlash. “You would hope that any company that found a compound was working to help patients would… make that available at a reasonable cost,” Harris notes.
The second treatment being considered is chloroquine and the related hydroxychloroquine. If they sound familiar, it may be because Donald Trump has tweeted about them, saying the combination of those drugs with another has “a real chance to be one of the biggest game changers in the history of medicine”. The former is used to treat malaria and arthritis, while the latter is used on lupus, but that doesn’t mean anyone with a supply should be self-medicating, as it can be dangerous; it’s also used to clean swimming pools. A man in Arizona died after trying to use the drug himself.
According to a report in Science Mag, the WHO team wasn’t going to include chloroquine, which works by blocking cells from taking up material from outside itself, in the SOLIDARITY trial, but added it after media attention. It hasn’t worked with other similar viruses in clinical trials, but researchers in China have suggested it worked on 100 patients. The attention on hydroxychloroquine was sparked on March 16 by the results of a small French trial led by Didier Raoult, a well-regarded infection specialist.
The third option studied by the trial is Ritonavir/lopinavir, which is used to treat HIV. It’s been tested in animals against MERS, and in humans against Sars, but research into the use of the combination on Covid-19 patients in China suggested it didn’t help, though there are caveats that the patient test group was too far along with the disease to recover.
The last treatment adds to those drugs a molecule called interferon, a combination that is already being tested on MERS. When you get a fever, part of that is your body responding to a virus, raising the temperature to slow the virus from growing. “Part of that is induced by producing this molecule called interferon,” Harris explains. “It’s the body’s own natural antiviral. By treating it with interferon, you’re bypassing the need for the body to make its own, you’re trying to stimulate the body’s own antiviral responses.” But he notes that’s a nonspecific treatment – “it’s likened to hitting a cell with a sledge hammer.”
There are dozens of other drugs being considered, according to a Covid-19 tracker released by the Milken Institute. We have libraries of drugs, the challenge is picking which one to use. Harris says there are 13,000 compounds to consider, complicated by the fact treatments may use multiple drugs. If a drug or treatment seems like it could work, it is tested first in the lab before being used on patients. “There’s a lot of difference in putting a drug into a petri dish and seeing if that affects the virus growing in the lab compared to administering that to a patient,” Harris says. Then, we need to work out how to administer it – orally, via a nebulizer, or intravenously – before figuring out manufacturing and supply chain. “All of those things need to be worked out.” Researchers are working faster than ever before, but time still isn’t on our side – so stay inside to buy them time to make these drugs and vaccinations work.
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