Top 5 most promising COVID-19 vaccine candidates

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More than 100 vaccine efforts are currently underway in the global push to stop the COVID-19 pandemic, according to the World Health Organization. Which are most likely to work? And how long will it take? We’ve compiled a list of the top 5 most promising candidate vaccine platforms, with a brief summary of relevant details. We’ll keep this page updated so come back regularly to learn the latest developments.

Top 5, as of May 27:

  1. China’s CanSino adenovirus vaccine currently leads the pack — although there was a notable stumbling block in its May 22 results
  2. Oxford University’s adenovirus vaccine candidate has slipped into second place — but Oxford just attracted a $1 billion bet from BARDA
  3. Moderna’s much-vaunted mRNA platform reported some early results on May 18 — but can future results live up to the hype for what is an entirely new vaccine technology?
  4. Maybe the safest bet is to use the long-proven route of an inactivated virus vaccine — if so, the Chinese company Sinovac is the one to watch
  5. Inovio’s May 20 DNA vaccine candidate results looked highly promising: some have said this is a ‘moon shot’ but that has worked before…

Adenovirus vaccine

How does it work?

Adenoviruses, which exist in the wild in humans and typically cause mild infections such as the common cold, have been genetically engineered to express viral antigens found in SARS-CoV-2, usually those of the infamous spike protein that the coronavirus uses to break into human cells. These engineered adenoviruses, when put into a vaccine, trigger an immune response in the human body, protecting against COVID-19.

This is a new technology: no adenovirus vector vaccines for other diseases are yet widely available, though vaccines for HIV, influenza, Ebola and malaria using this platform are in clinical trials and an Ebola vaccine has been briefly deployed.

Who is doing it?

Probably the highest-profile effort is the ChAdOx1 nCoV-19 vaccine candidate from Oxford University’s Jenner Institute. (ChAdOx1 stands for “chimpanzee adenovirus Oxford 1.”) The Chinese company CanSino Biologics — the medical science arm of the People’s Liberation Army, no less — has completed Phase 1 trials with an adenovirus vector vaccine called Ad5-nCoV.

A big-name corporate player is Johnson & Johnson, via its subsidiary Janssen, which uses a genetically modified human adenovirus technology it calls AdVac. This is a proven platform, which was used to produce thousands of doses of company’s Ebola vaccine deployed in the Congo in November 2019.

Adenoviruses are not the only viral vectors that can be used: pharmaceutical giant Merck says it is working on a potential COVID vaccine using an engineered vesicular stomatis virus, previously used successfully in its Ebola vaccine. Another collaboration Merck is involved in uses an attenuated live measles vaccine.

What’s the latest?

CanSino reported positive results in a Lancet paper on May 22. This is the first Phase 1 COVID vaccine clinical trial anywhere in the world to report full results in a peer-reviewed paper, with 108 healthy adults all showing an immune response to the adenovirus vector vaccine. There was a stumbling block, however. Because the adenovirus (which causes common cold symptoms) is already widespread in the human population, some of those in the trial had already been naturally infected with it, dampening their immune response. Will Oxford’s chimp adenovirus vaccine perform better? Time will tell, but meanwhile CanSino is proceeding to Phase 2 trials with a six-month study of 500 adults in Wuhan.

The Oxford team published a preprint on May 13 showing that ChAdOx1 prevented rhesus macaques monkeys from getting pneumonia when infected with SARS-CoV-19. That’s the good news — the vaccine protected against disease. The bad news was that the vaccinated monkeys still became infected, and nose swabs showed the same amounts of virus in samples taken from both vaccinated and non-vaccinated animals. This means in theory that vaccinated people could still be infectious even if they don’t actually get symptoms of the disease. Still, it would be a massive step forward if we could just “push the disease from pneumonia to a common cold,” in the words of one expert. Phase 1 trials in over a thousand United Kingdom-based human volunteers are ongoing.

Oxford University has partnered with the global pharmaceutical company AstraZeneca. The company is making a big bet on Oxford’s vaccine, which is now being renamed AZD1222. On May 21 it announced an agreement to produce 400 million doses and claims to be able to manufacture 1 billion doses with current facilities. The US government is also betting big on Oxford: its Biomedical Advanced Research and Development Authority (BARDA) put $1billion behind the Oxford/AstraZeneca effort, with a Phase 3 trial involving 30,000 participants now in development.

Johnson & Johnson, while it has the corporate muscle to produce vaccine doses in large quantities, doesn’t expect to start Phase 1 trials until September, which it says could possibly “allow vaccine availability for emergency use in early 2021.”

Any drawbacks?

Live viruses, even if attenuated, can be risky in immunocompromised people. It is also notable that neither Oxford nor CanSino scored full successes with their first attempts.

RNA vaccine

How does it work? 

While conventional vaccines work by presenting the body’s immune system with the inactivated real virus or antigens derived from it, injecting mRNA into cells means that they produce the required viral proteins directly inside the human body. mRNA (the “m” stands for messenger) is the molecule that takes instructions from DNA to the cell’s protein factories (called ribosomes). As Dr. Sanjay Mishra from Vanderbilt University explains: “A big advantage of mRNA vaccines is that scientists can skip the laboratory production of proteins by directly injecting the molecular instructions to make the protein into the human body itself.”

In this case the RNA sequence is taken from the SARS-CoV-2 virus genome, stimulating an immune response that should later stop the COVID-19 disease. One advantage to mRNA vaccines is a cheaper, faster production process, making them potentially the most scalable to tackle a global pandemic.

Who is doing it?

Moderna — a biotech startup now worth tens of billions, though it has yet to sell a single product — is in the lead. Other teams pursuing the mRNA approach include one based at Imperial College, London; the German-based company BioNTech, which is working in alliance with the drugs giant Pfizer; and CureVac, another German-based company. A Chinese consortium from Fudan University, Shanghai JiaoTong University and RNACure Biopharma is employing a second strategy of using mRNA to create “virus-like particles” in the body to activate an immune response.

What’s the latest?

Moderna’s vaccine was the first to be injected into human volunteers, way back in mid-March. Its May 18 announcement that its vaccine candidate had stimulated an immune response with the production of neutralizing antibodies in eight human volunteers in its Phase I trial generated global media coverage and a stock market rally. Others were more skeptical, however, pointing to incomplete data and demanding more context from this “interim” result, which was not yet for the full trial and not published in a peer-reviewed journal.

CureVac announced “positive pre-clinical results” for its lead COVID vaccine candidate on May 14 and aims to start Phase 2/3 clinical trials in human volunteers in June. BioNTech announced on May 5  that volunteers for its Phase 1/2 study have begun taking their first doses of its mRNA vaccine candidate, called BNT162, in the United States and Germany.

Any drawbacks?

No mRNA vaccines have ever been used before, so failure is a big risk. Moderna’s mRNA vaccine did lead to some negative side-effects in some of the trial volunteers. This isn’t unsual, but the fact that so-called Grade 3 reactions were observed – in one case including pain, nausea and high fever – might dampen enthusiasm somewhat.

Related article:  Viewpoint: Only a tiny percentage of children face threat of severe coronavirus complications. That risk isn't high enough to justify lockdowns

Inactivated pathogen

How does it work?

The most traditional vaccine approach — one utilized over many decades — is to inject someone with the inactivated virus. This stimulates the immune system to produce antibodies, while the virus is either killed before injection or weakened sufficiently so that it cannot cause a serious infection. Inactivated viruses are used against influenza, for example, and in the global effort to eradicate polio.

Who is doing it?

Here once again the Chinese are in the lead. The Chinese company Sinovac, in partnership with a number of leading medical research institutes in China, designed a vaccine by isolating SARS-CoV-2 samples from infected hospital patients and growing the virus in cell lines before inactivating it with a chemical agent. It is called PiCoVacc (for “purified inactivated SARS-CoV-2 vaccine”).

An international team has a different approach, using a vaccine that is already widely deployed: the BCG vaccine against tuberculosis. It has been shown to protect against other respiratory diseases, too, so researchers are hoping it might be effective against COVID. (BCG is an inactivated bacterial pathogen, not a virus.)

What’s the latest?

The Chinese team has made impressive progress with its inactivated viral COVID vaccine. In a paper published in Science on May 6, the team reported that their candidate vaccine had “induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates.” It also “provided partial or complete protection in macaques” against deliberate infection with the virus. A Phase 1/2 clinical trial with 744 human participants is underway in China, with the first results predicted for August.

Because BCG already has a decades-long history of safe use as a vaccine, trials to see whether it is effective against COVID have gone straight to Phase 3. Trials are currently underway among 10,000 frontline health workers in Australia, run by Murdoch Children’s Research Institute, and in the Netherlands among a further 1,500 health workers.

Any drawbacks?

Growing large volumes of viruses to use in vaccines is a long and arduous process, so the traditional approach will be the slowest to scale up globally. Believe it or not, most attenuated virus vaccines are made using huge numbers of chicken eggs.

DNA vaccine

How does it work?

As we recently told Reuters in an interview, “No, DNA vaccines will not lead to genetically engineered humans.” However, the technique does involve injecting a fragment of circular DNA, called a plasmid, into human cells. This introduced DNA codes for SARS-CoV-2 viral proteins that are then expressed by the cell and help prime the immune system to fight off an attack by COVID-19. Like mRNA, this is a new technology — no DNA vaccines have ever been fully developed and utilized in humans to prevent disease.

Who is doing it?

The leading developer is Inovio, which worked with a DNA candidate vaccine against MERS. Several other teams are also working on DNA vaccine candidates for the novel coronavirus, including one at the Harvard Medical School.

What’s the latest?

On May 20, Inovio scientists published trial results in the journal Nature Communications for its COVID candidate DNA vaccine, INO-4800. This showed “robust binding and neutralizing antibody as well as T cell responses in mice and guinea pigs,” according to the company, raising hopes that INO-4800 might also stimulate a strong immune response in humans. Inovio’s vaccine is already in human trials, with a Phase 1 study testing on 40 volunteers in Philadelphia and Kansas City — results are expected in late June. After that, Inovio plans a large, randomized Phase 2/3 clinical trial this summer.

Separately, the Harvard-led team announced in a paper published in Science on May 20 that various DNA candidate vaccines expressing different forms of the SARS-CoV-2 spike protein had succeeded in immunizing rhesus macaque monkeys. This adds further to hopes that at least some of these DNA vaccines will also work in humans. Some have called this a ‘moon shot’, but hey, that’s worked before…

Any drawbacks?

As with mRNA, there have never yet been DNA vaccines – and the chance that this will work first time is anyone’s guess.

Viral proteins

How does it work?

This is another traditional method for vaccinations: genes that code for proteins from the pathogen — in COVID’s case, mostly the notorious spike protein — are spliced into different viruses, which are then mass-produced. The approach has been used successfully in the HPV vaccine, for example. Virus-like particles can also be produced in plants.

Who is doing it?

Sanofi Pasteur, the vaccines division of Sanofi, is repurposing its earlier SARS vaccine efforts into COVID. Its recombinant DNA approach in cell lines has already been licensed to produce an influenza vaccine, distributed since 2017 in the US under the brand FluBlok. This should produce a quicker and more stable product than vaccines traditionally produced in chicken eggs.

This approach is also being used by a team at the University of Pittsburgh, whose members had already worked on SARS and MERS and quickly repurposed their spike protein vaccine to target SARS-CoV-2. Its purified protein can be delivered in a “microneedle array,” a fingertip-sized patch of 400 tiny soluble needles that affixes to the skin like a Band-Aid.

Separately, Novavax has developed a way to package SARS-CoV-2’s spike proteins into nanoparticles that should enhance the immune response by better mimicking the virus. In Canada, Medicago began producing virus-like particles of the coronavirus — expressed in leaves of Nicotiana benthamiana, a wild relative of tobacco — just 20 days after the viral genome was published.

What’s the latest?

Sanofi says its candidate vaccine “is expected to enter clinical trials in the second half of 2020 and to be available by the second half of 2021,” making it a backup perhaps if quicker mRNA and DNA vaccine approaches prove to be duds.

The Pittsburgh team won the race to produce the first peer-reviewed paper on a COVID vaccine trial, reporting in mid-March that its microneedle vaccine had “elicited potent antigen-specific antibody responses” when tested in mice. However, Phase 1 human trials have not yet begun, and the scientists warn that getting results “would typically require at least a year and probably longer.”

Novavax has received investments totalling $388 million from the Coalition for Epidemic Preparedness (CEPI) to advance clinical development of its candidate vaccine NVX-CoV2373. Phase 1 trials began on May 26 in Australia in 131 human volunteers, with results expected in July. The company is developing scaled-up production that could potentially deliver 100 million vaccine doses by the end of 2020, and 1 billion doses starting in 2021.

Medicago announced positive results for a trial of its COVID candidate vaccine in mice on May 14, and aims to start human trials in the summer. It can already produce 120 million doses of the vaccine per year in its current facilities, and aims to scale up to 1 billion per year by 2023.

Any drawbacks?

As with growing viruses directly, growing large amounts of viral proteins takes time. Cell lines may be quicker than chicken eggs but scaling up to the billions of doses will take a lot longer than the mRNA/DNA approach.

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