Meet the 4 frontrunners in the COVID-19 vaccine race

[Karlston]

Meet the 4 frontrunners in the COVID-19 vaccine race

Safety and immune responses look good, but do these vaccines work?

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Researchers have now reported data from early (and small) clinical trials of four candidate COVID-19 vaccines.

 

So far, the data is positive. The vaccines appear to be generally safe, and they spur immune responses against the novel coronavirus, SARS-CoV-2. But whether these immune responses are enough to protect people from infection and disease remains an important unknown.

 

The four candidates are now headed to larger trials—phase III trials—that will put them to the ultimate test: can they protect people from COVID-19 and end this pandemic?

The challenge

While early trials looking at safety and immune response required dozens or hundreds of volunteers, researchers will now have to recruit tens of thousands. Ideally, volunteers will be in places that still have high levels of SARS-CoV-2 circulating. The more likely it is that volunteers will encounter the virus in their communities, the easier it is to extrapolate if a vaccine is protective. As such, researchers are planning to do a significant amount of testing in the US and other parts of the Americas, which have largely failed at controlling the pandemic.

 

There has been much debate about the use of “human challenge trials,” in which researchers would give young, healthy volunteers at low risk from COVID-19 an experimental vaccine and then intentionally expose them to SARS-CoV-2 in controlled settings. This could potentially provide a clearer, faster answer on vaccine efficacy. It’s certainly an appealing idea given the catastrophic pandemic—and it's an idea that has gained traction in recent weeks. An advocacy group called 1Day Sooner has collected the names of more than 30,000 people willing to participate in such a trial, for instance.

 

But experts remain divided on the idea. The main concern is that there is no “rescue” treatment for COVID-19 that can fully protect a trial volunteer from severe disease and death if an experimental vaccine fails. Though young, healthy people have less risk than older people and those with underlying health conditions, some still suffer severe disease and death from COVID-19—and it’s unclear why. Opponents also note that challenge trials may not be faster or necessary, given the high levels of disease spread in the US and elsewhere.

 

Though the debate on challenge trials is ongoing, it’s unclear if researchers will end up needing or using them. Meanwhile, traditional phase III trials are now underway—and they have generated plenty of enthusiasm from the public. According to a report this week, more than 138,600 people have signed up through the National Institutes of Health to participate in vaccine testing. If all goes well, we could have data from these trials by the end of the year.

 

So how do the four top vaccine candidates work, and what do we know about them?

mRNA-1273: Moderna, NIAID

mRNA-1273 is a messenger RNA (mRNA) vaccine made by the biotechnology company Moderna, which was working with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The idea behind the mRNA vaccine platform is that it delivers snippets of a target virus’s genetic code—in this case, code in the form of mRNA—into human cells. Those cells can then translate that code into viral protein. From there, the immune system can mount a response to the protein, which can be activated if the target virus ever tries to invade.

 

In the case of mRNA-1273, researchers used a fatty nanoparticle to package up mRNA that codes for the SARS-CoV-2 spike protein, which is usually found jutting out from SARS-CoV-2 viral particles.

 

Vaccines using genetic material—RNA or DNA—are new and untested. So far, there are no approved vaccines using this type of platform. It’s unclear if they will be successful here or elsewhere and—if they are—how easy it will be to manufacture such a vaccine on a global scale. (For background on the different types of vaccine platforms, see our vaccine primer.)

 

On July 14, researchers published results from a phase 1 trial, which primarily looks at safety in a small group of people. The study, appearing in the New England Journal of Medicine, included 45 healthy volunteers between the ages of 18 and 55 and tested three dose levels of the vaccine. That is, there were three groups of 15 people, with each group getting either a low, medium, or high dose of the vaccine (25 micrograms, 100 micrograms, or 250 micrograms dose). Each participant got two shots of their dose, 28 days apart.

 

The vaccine was generally found to be safe. More than half of the participants had mild to moderate side effects, mainly including fatigue, chills, headache, myalgia, and pain at the injection site. Side effects were more common after the second dose, regardless of the strength, but those who received the two higher-dose vaccinations reported more side effects. Two people (one in the 100-microgram group and the other in the 250-microgram group) had severe skin redness at the site of the injection. Two people in the 250-microgram group experienced lightheadedness and fainted.

 

All participants produced antibodies against SARS-CoV-2, with antibody levels jumping up after the second shot. Those who got the higher doses had slightly higher levels of antibodies. The researchers compared participant antibody levels to those seen in 41 people who had recovered from a COVID-19 infection. Those vaccinated all had antibodies in the same range as the recovered people.

 

The researchers also tested specifically for neutralizing antibodies—that is, antibodies that don’t just bind to a virus particle but can completely disable it. Researchers found that the vaccine prompted higher levels of neutralizing antibodies than was seen in most of the people who recovered. For instance, 57 days after the first dose, people in the 100-microgram group had neutralizing antibody titers ranging from 163 to 329, while the range was about 60 to 200 in the patients who had recovered from COVID-19.

 

Last, the researchers looked at responses from T-cells—which can attack cells infected with virus—and found that the vaccine did generate certain types of T-cell responses against SARS-CoV-2.

 

Overall, the results are encouraging but not conclusive. Researchers don’t yet know what immune responses or levels of antibodies are necessary to prevent a SARS-CoV-2 infection and/or disease. And, being only six months into the pandemic, it’s unclear how long any such protective immune responses would last.

 

According to a listing on the NIH’s registry for clinical trials, Moderna plans to begin a phase III trial of mRNA-1273 on July 27. Moderna wants to enroll 30,000 people in the trial, looking at efficacy as well as further safety and immune response data.

AZD1222 (ChAdOx1 nCoV-19): Oxford University, AstraZeneca

On July 20, researchers published results from a phase I/II trial of AZD1222, a candidate vaccine made by researchers at the University of Oxford and the international pharmaceutical company AstraZeneca.

 

AZD1222 (also called ChAdOx1 nCoV-19) is a viral vector-based vaccine. With this platform, researchers can package bits of a dangerous virus into a far less dangerous virus. The mostly harmless viral parcel then gets delivered to the immune system, which can learn to seek and destroy the dangerous virus based on the smuggled fragments.

 

In the case of AZD1222, genetic material of the SARS-CoV-2 spike protein is packaged into a weakened type of adenovirus that infects chimpanzees. Human-infecting adenoviruses normally cause mild infections, often considered common colds. The chimpanzee virus, which doesn’t typically infect humans, is made even more harmless by engineering that prevents it from replicating in human cells. In early tests, AZD1222 protected monkeys from developing pneumonia after researchers exposed them to high doses of SARS-CoV-2.

 

The clinical trial results, published in The Lancet, show that AZD1222 is generally safe and spurred immune responses in humans. The trial involved 1,077 participants (aged 18 to 55), 543 of which were randomly assigned to get AZD1222, and the remaining 534 were given a meningococcal vaccine as a control. Researchers divided the participants into four groups and ran different types of tests on their immune responses. Ten of the participants who received AZD1222 were in a “boost” group that got a second vaccine shot after 28 days. The other participants who received AZD1222 only received one dose.

 

Mild side effects from AZD1222 were common, including pain, feeling feverish, chills, muscle ache, headache, and malaise. Some participants were preemptively given paracetamol (acetaminophen/Tylenol) to lessen these effects. No serious side effects were reported.

 

In 127 participants vaccinated with AZD1222, all produced antibodies against SARS-CoV-2. The levels were within the range seen in people who had recovered from COVID-19. The researchers conducted two separate tests to look for neutralizing antibodies in 35 vaccinated participants. In one test, 32 (91 percent) were positive for neutralizing antibodies 28 days after vaccination and, in the other test, 100 percent were positive. The ten participants who got a booster shot all produced neutralizing antibodies, some which were at levels higher than those typically seen in the COVID-19 recovered patients. The researchers also reported that AZD1222 induced T-cell responses.

 

Researchers have already begun a phase III trial of AZD1222 at sites in Brazil, the UK, and South Africa. They also plan to test the vaccine in the US soon. AstraZeneca said it will use two doses in trials moving forward in order to maximize immune responses.

 

Ad5-vectored COVID-19: CanSino, Chinese military

Alongside the AZD1222 results published July 20 in The Lancet, Chinese researchers published phase II trial results for their Ad5-vectored COVID-19 vaccine, made by biotechnology company CanSino Biologics and the Chinese military.

 

Like AZD1222, CanSino uses the viral vector-based vaccine based on a weakened adenovirus. However, the adenovirus in this vaccine—Ad5—is one that circulates in humans, not chimpanzees. This is problematic because past exposure to the human adenovirus appears to throw off immune responses to the bit of the vaccine that’s derived from SARS-CoV-2. In earlier published phase I trial data—previously reported by Ars here—researchers noted that those who had already been exposed to the adenovirus did not produce immune responses as robust as those who had not been exposed.

 

Nevertheless, CanSino forged on with a randomized phase II trial, involving 508 volunteers (aged 18 to 83) who received either a placebo or a single injection of Ad5-vectored COVID-19 at one of two dosage levels.

 

Mild side effects including fever, fatigue, headache, or pain at the site of injection were common. Though 24 participants in the high dose group and one in the low dose group had side effects rated as severe, there were no serious reactions.

 

Researchers found that more than 96 percent of participants who received Ad5-vectored COVID-19 developed antibodies against SARS-CoV-2. But researchers detected SARS-CoV-2 neutralizing antibodies in only 59 percent of the high dose group (148 out of 253 participants) and 47 percent of the low dose group (61 out of 129 participants). For those who developed antibodies, the level of those antibodies was only compared with those from the placebo group, not with those found in people who recovered from COVID-19. Finally, around 89 percent developed T-cell responses.

 

The researchers note that 52 percent of participants showed high pre-existing immunity to the human adenovirus, Ad5, used to make the vaccine. They also note that in some populations, immunity to Ad5 is as high as 80 percent. Still, CanSino is now planning its phase III trial, and—as Ars reported previously—the vaccine has already been approved for use by the Chinese military.

BNT162b1: BioNTech, Pfizer

BNT162b1 is an mRNA-based vaccine made by German firm BioNTech and the pharmaceutical giant Pfizer. Like Moderna’s vaccine, BNT162b1 uses a fatty nanoparticle wrapping to deliver a fragment of the genetic code for the SARS-CoV-2 spike protein into human cells.

 

On July 1, researchers released results of a phase I/II trial of BNT162b1 on a preprint server, where scientists can air their study data before it is published in a peer-reviewed journal. The study involved 45 participants (ages 19 to 54), with three groups of twelve. One group got two shots of a low dose (10 micrograms), spaced 20 days apart. A second group got two shots of a medium dose (30 micrograms), also spaced 20 days apart. And the third group got one shot of a high dose (100 micrograms). The remaining nine people in the trial got a placebo.

 

Most participants reported side effects, which were largely mild to moderate. Common side effects included pain at the injection site, fatigue, fever, headache, chills, and muscle pain. The occurrence of side effects increased with dose level and were stronger after the second dose. Researchers decided against giving the 100-microgram group a second injection for this reason. No serious side effects were reported.

 

All vaccinated participants developed antibodies and neutralizing antibodies against SARS-CoV-2. Researchers noted that after the second injection of the low and medium doses, participants developed higher levels of antibodies and neutralizing antibodies than those seen in blood samples from 38 people who had recovered from COVID-19. For example, those given the low dose had 1.8 times the mean level of neutralizing antibodies seen in people who have recovered from COVID-19. And those who received the medium dose had 2.8 times the level.

 

On July 20, the researchers released a second batch of data from 60 participants, again on a preprint server. The data echoed the earlier findings that the vaccine is generally safe and produces strong antibody responses. In addition, the researchers found that more than 80 percent of those vaccinated mounted strong T-cell responses to SARS-CoV-2.

 

Like the others, Pfizer and BioNtech are moving toward phase III trials for BNT162b1.

That’s not all

While it’s unclear how successful any of these vaccines will be in larger trials, there are plenty of other vaccine candidates following close behind in the pipeline. According to the latest vaccine tracking by the World Health Organization, 20 other COVID-19 vaccines are currently in some phase of clinical trials, with 142 others in preclinical development.

 

 

Meet the 4 frontrunners in the COVID-19 vaccine race

 

[Karlston]

These 4 Covid-19 Vaccines Are Closest to Becoming Reality

There are hundreds of trials currently in the works. Here’s everything you need to know about the ones edging ahead in the global race.

Photograph: NICOLAS ASFOURI/Getty Images

 

 

As the world waits eagerly for a Covid-19 vaccine, several candidates are starting to be put through their paces in clinical trials. More than 100 vaccine candidates are being developed by teams around the world, with more than 20 now in or about to enter clinical evaluation, meaning they are being tested in humans.

 

“When the world got the virus [RNA] sequence through on January 11, we knew pretty well immediately what kind of vaccine one would need and what bit of virus you would need to put in it, so the world of immunology was in a very good state to get going on that,” says Danny Altmann, a professor of immunology at Imperial College London.

 

On July 20, two vaccine candidates published preliminary results from Phase I and II trials showing they induced an immune response and didn’t trigger any major safety concerns, marking a positive step forward. But there’s still a way to go. Inducing an immune response doesn’t necessarily mean that the vaccine will actually protect people from Covid-19. Only a Phase III trial, which involves giving a large number of people the vaccine and tracking if they get the disease, will show this. “They’ve done everything we wanted, so that’s good news,” Altmann says. “Now it’s the difficult bit.”

 

The vaccine candidates currently in development make use of a range of different vaccine technology platforms, some of which are tried-and-tested and others that are really cutting-edge. While some first results have started to come out, it’s not possible to draw direct comparisons, as different labs can test with different doses and populations, and use different assays to measure the immune response. “The question of which one is better cannot be answered at this point,” says Beate Kampmann, director of the Vaccine Centre at the London School of Hygiene and Tropical Medicine.

 

With that in mind, here are some of the vaccine candidates that are currently furthest along:

 

Oxford/AstraZeneca

 

The world has heard a lot about a vaccine being developed at the University of Oxford in partnership with the pharmaceutical firm AstraZeneca. The UK government has already ordered 100 million doses of the vaccine, and it is currently one of the front-runners in terms of testing.

 

The Oxford vaccine is a viral vector vaccine: It is based on a chimp adenovirus (a virus that causes an illness like the common cold in chimpanzees), which has been modified to contain a genetic sequence of the coronavirus “spike protein,” which is thought to play a large role in infecting cells. This is a way of exposing the body to the spike protein without exposing it to coronavirus, so that it creates an immune response. “The chimp adenovirus is kind of the Trojan horse to bring the Covid protein information into the immune system,” Kampmann explains. If the immune system then comes into contact with the actual coronavirus, it’s primed to react.

 

On July 20, researchers published a preliminary report in The Lancet on Phase I and II studies of their vaccine, ChAdOx1 nCoV-19, which they report induced an immune response and didn’t have any major side effects. It is now moving into Phase III trials in Brazil and South Africa.

 

Altmann says the immune response shown in the Oxford data is promising and emphasizes the importance of triggering T cells as well as antibodies. T cells are a type of white blood cell that help B cells create antibodies and kill infected cells to help stop an infection from spreading. “For any good response from a vaccine, you need both on board,” Altmann says. He says that all the data he has seen from vaccine candidates looks good for both—“although I thought the Oxford data had really truly impressive T cell data.”

 

CanSino

 

China’s CanSino Biologics reported results from its Phase II trial, which was conducted in Wuhan, on the same day as the Oxford group, also in The Lancet. It similarly reported that its vaccine was safe and induced a significant immune response.

 

The CanSino vaccine, which is being developed with the Beijing Institute of Biotechnology, also uses an adenovirus as a viral vector to deliver the coronavirus spike protein, but in this case it is a common cold virus that infects humans. One potential downside to this, Kampmann says, is that, as the virus circulates in human populations, some people may already have antibodies to it, which could affect the immune response. “It could be that people with preexisting antibodies against that adenovirus won't make as much of an immune response to the adenovirus Covid vaccine,” she says.

 

The vaccine has been approved for use by the Chinese military.

 

Moderna

 

The US company Moderna is one of several groups working on an RNA vaccine, a new type of vaccine that involves making a synthetic version of the coronavirus spike protein’s RNA—the genetic instructions that tell cells how to make the protein. This tricks the body into making the spike protein itself, which induces an immune response.

 

On July 14, preliminary results from a Phase II trial of the Moderna vaccine were published in The New England Journal of Medicine and stated that the vaccine had induced an immune response and raised no major safety concerns. Moderna began Phase III trials on Monday.

 

The advantage to the RNA approach is that you don’t have to make lots of material, as the body essentially creates the vaccine itself. This could make it easier to scale and cheaper to produce. “You can get away with very, very small quantities,” Kampmann says. However, it is relatively new in the world of vaccine technology; no RNA vaccine has previously been licensed.

 

Other groups working on RNA vaccines include Imperial College London and the German company BioNTech; the latter is working with pharma giant Pfizer and has an agreement with the UK government to supply 30 million doses.

 

Sinovac

 

Beijing-based Sinovac Biotech’s vaccine candidate, called CoronaVac, is an inactivated vaccine—a comparatively old-fashioned type of vaccine that consists of virus particles that have been killed or inactivated and so no longer cause infection. The immune system still recognizes the virus, provoking an immune response that it can call upon if the recipient later comes into contact with the real thing.

 

In June, the company said in a press release that preliminary results from its Phase I and II studies in humans showed that the vaccine induced neutralizing antibodies and had no severe side effects. It is now moving on to Phase III studies in Brazil.

 

One advantage of the inactivated virus approach, says Altmann, is that it is tried and tested; the same technique has been used for decades to make vaccines to protect against diseases such as polio. “I like that logic,” Altmann says. This also means we already have the infrastructure to make this kind of vaccine.

 

A disadvantage, however, is that making the vaccine requires growing the material in vast quantities, which may make it harder to scale than other vaccine types—an important consideration given the scope and urgency of demand for a Covid-19 vaccine.

 

China’s SinoPharm is also developing an inactivated vaccine and is conducting a Phase III trial in Abu Dhabi.

 

A Long Way to Go

 

There are of course many other vaccines being worked on, and picturing the quest for a Covid vaccine as a “race” may be misleading. “This isn't actually a quick sprint, this is a marathon,” Kampmann says.

 

Being first doesn’t necessarily mean being best, and there are other issues beyond just making a vaccine that works. We will need to manufacture and distribute the vaccine at great scale, and we won’t know how long a vaccine protects a person from Covid-19 until later down the line. A vaccine that takes longer to develop may prove more effective, longer-lasting, cheaper, or easier to scale. Or different vaccines may prove more effective in different geographies or age groups. “It might well be there’s going to be more than one vaccine,” Kampmann says. “I would be very surprised if there was only one vaccine that came through.”

 

For now, Altmann says, it’s important to invest in lots of different platforms and candidates rather than put all our eggs in one basket in a rush to back a single “winner.” “It’s an argument for trying to be slow and wise and careful, and not jumping at it as if it was the Eurovision Song Contest of vaccines,” he says.

 

This story originally appeared on WIRED UK.

 

 

These 4 Covid-19 Vaccines Are Closest to Becoming Reality