What are the Top 5 most promising COVID-19 vaccine candidates?

By Mark Lynas

July 20, 2020

More than 160 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 July 20:

  1. With the strong Phase 1/2 immune response results on 20 July, Oxford University’s vaccine jumps to no. 1 in this list – leading the pack into Phase 3 trials in the UK, US, Brazil and South Africa
  2. Moderna drops to no. 2 with its unproven mRNA platform, even following its successful Phase 1 trial results
  3. China’s CanSino adenovirus vaccine also saw data published on 20 July – showing a rapid immune response and no serious adverse reactions
  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. Novavax got the biggest sum so far from Operation Warp Speed – $1.6 billion, announced 7 July – but has yet to get to Phase 3

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 Phase 2 results in the Lancet on 20 July. According to the authors, these showed that the adenovirus vector vaccine “is safe, and induced significant immune responses in the majority of recipients after a single immunisation”. According to Reuters, the company is in talks with Russia, Brazil, Chile and Saudi Arabia to launch Phase 3 trials.

The Oxford team published results on 20 July in the Lancet. “We are seeing very good immune responses, not just on neutralizing antibodies but of T-cells as well,” Adrian Hill, head of Oxford’s Jenner Institute, told Bloomberg. “We’re stimulating both arms of the immune system.” Oxford’s vaccine leads the global race, and could receive emergency use authorization as early as October. Phase 3 trials are now planned, involving tens of thousands of participants in the UK, US, Brazil and South Africa. These will establish whether the vaccine actually protects against the virus in the real world.

Oxford University has partnered with the global pharmaceutical company AstraZeneca for manufacturing purposes. 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.

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. CanSino’s adenovirus is a human virus, while Oxford uses one from chimpanzees – the latter might be more effective as no-one yet has an immune response to it.

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 (mRNA-1273) was the first to be injected into human volunteers, way back in mid-March. On 14 July it published the results of this Phase 1 trial in a peer-reviewed paper in the NEJM. The news was good: its “mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all [45] participants, and no trial-limiting safety concerns were identified”. Phase 2 trials in 600 participants are underway now, and the company has announced that its 30,000-participant Phase 3 trial will begin on 27 July in the US. Moderna “remains on track to be able to deliver approximately 500 million doses per year, and possibly up to 1 billion doses per year, beginning in 2021”, it says.

CureVac announced “positive pre-clinical results” for its lead COVID vaccine candidate on May 14 and received approval to start a Phase 1 clinical trial on June 17 in Germany and Belgium. More exciting, perhaps, is the reported involvement of tech superstar Elon Musk, who recently revealed that his company Tesla will soon be “building RNA microfactories for CureVac & possibly others”.

BioNTech and Pfizer announced positive results online – on MedRxiv in advance of peer review – on 20 July. This was a Phase 1/2 trial with 60 adults in Germany, and showed strong immunological responses with no ‘serious’ adverse effects (see below). This followed the first results of their US Phase 1/2 trial which were published a MedRxiv preprint published on 1 July. The news was promising there too: the vaccine triggered strong immunological responses among the 45 volunteers who received it, with more antibodies seen even than is typical in recovering COVID patients.

The Imperial College vaccine began first human trials on 24 June in the UK – it also includes an enzyme that triggers the mRNA to make more of itself, meaning smaller initial doses are needed.

Any drawbacks?

No mRNA vaccines have ever been used before, so failure is a big risk. Moderna’s Phase 1 mRNA vaccine lead to some ‘adverse events’, including fatigue, chills, headache and myalgia (these were mild to moderate, and adverse effects are not uncommon with vaccines). BioNTech’s vaccine also saw some adverse reactions “generally mild to moderate, with occasional severe events (Grade 3) of flu-like symptoms and injection site reactions”.

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 was formerly called PiCoVacc (for “purified inactivated SARS-CoV-2 vaccine”) but has now been more simply renamed CoronaVac.

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.  On 9 June a paper in PNAS seemed to suggest that BCG vaccines given earlier in life were reducing death rates in some populations. (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. On June 13 Sinovac posted initial results for a Phase 1/2 trial involving several hundred people: 90% of the volunteers tested positive for protective antibodies. The company inked a deal on 11 June to push on to Phase 3 trials in Brazil, where the disease is still running rampant. It will simultaneously construct a vaccine manufacturing plant capable of producing 100 million doses annually.

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 30 June Inovio announced that 34 out of 36 of Phase 1 trial participants “demonstrated overall immune responses” after two doses of its INO-4800 trial vaccine. However, experts expressed caution, and some were critical of the company’s failure to disclose how many (if any) patients produced antibodies that neutralize the coronavirus, which is the important thing.

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. Inovio has been around for four decades but has yet to develop a single approved product.

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’s hare-and-tortoise approach may soon begin paying dividends. The company was a slow starter, but has brought forward Phase 1/2 trials from December to September. “We are the only vaccine in the race that’s off a proven platform that works in scale,” said its CEO. On 24 June Sanofi said Phase 3 trials could begin by December, and that it expects to have 100 million doses of its vaccine prepared by the end of the year – even before it has been proven to work. If all goes to plan, another 1 billion doses can be manufactured in 2021.

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 began Phase 1 trials on May 26 in Australia in 131 human volunteers, with results expected later 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. It secured the biggest payout so far from the US Operation Warp Speed, with $1.6 billion announced on 7 July. The vaccines – 50 million doses for starters – are expected to be delivered to the US government in February 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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