Covid-19: The vaccines most likely to work

By Mark Lynas
in the UK

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 ones are the most likely to work? And how long will it take? Here are the top five most promising candidate vaccine platforms as of May 26.

China’s CanSino adenovirus vaccine currently leads the pack — although there was a notable stumbling block in its May 22 results.
Oxford University’s adenovirus vaccine candidate has slipped into second place, but Oxford has just attracted a $1 billion (Sh106.8 billion) bet from BARDA.

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?

Maybe the safest bet is to use the long-proven route of an inactivated virus vaccine and if so, the Chinese company Sinovac is the one to watch.

Inovio’s May 20 DNA vaccine candidate results looked highly promising: some have said this is a ‘moon shot’, but that has worked before…

1. 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 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 the company’s Ebola vaccine deployed in the Congo in November 2019.

What is the latest?
CanSino reported positive results in a Lancet paper on May 22. This is the first Phase 1 Covid-19 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. CanSino is proceeding to Phase 2 trials. The Oxford team published a preprint on May 13 showing that ChAdOx1 prevented rhesus macaques monkeys from getting pneumonia when infected with Sars-Cov-2. That is 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. 

2. 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 they produce the required viral proteins directly inside the human body. In this case, the RNA sequence is taken from the Sars-Cov-2 virus genome, stimulating an immune response that should later stop Covid-19. mRNA vaccines have a cheaper, faster production process, making them potentially the most scalable to tackle a pandemic.

Who is doing it?
Moderna 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 is the latest?
Moderna’s vaccine was the first to be injected into human volunteers in mid-March. Its May 18 announcement that its vaccine candidate had stimulated an immune response generated global media coverage and a stock market rally. Others were more skeptical, however, pointing to incomplete data and CureVac aims to start phase two and three clinical trials in human volunteers in June.

3. Inactivated pathogen

How does it work?
The most traditional vaccine approach is to inject someone with the inactivated virus. This stimulates the immune system to produce antibodies. 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.
An international team has a different approach, using a vaccine already widely deployed: the BCG vaccine against tuberculosis, which has been shown to protect against other respiratory diseases.

What is the latest?
The Chinese team has made progress with its inactivated viral vaccine. In a paper published in Science on May 6, the team reported that their candidate vaccine had “induced Sars-Cov-2-specific neutralising 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 has a decades-long history of safe use, trials on Covid-19 have gone straight to phase three.

4. DNA vaccine

How does it work?
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 introduces 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.

Who is doing it?
The leading developer is Inovio, which worked with a DNA candidate vaccine against the Middle East Respiratory Syndrome. Several other teams are also working on DNA vaccine candidates, including one at the Harvard Medical School.

What is the latest?
On May 20, Inovio scientists published trial results in the journal Nature Communications for its candidate DNA vaccine, INO-4800. This showed “robust binding and neutralising antibody as well as T cell responses in mice and guinea pigs,” according to the company, raising hopes it might also stimulate a strong immune response in humans. The vaccine is in human trials, with a phase one study testing in Philadelphia and Kansas City. Results are expected in late June. After that, Inovio plans a large, randomised 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 had succeeded in immunising rhesus macaque monkeys.

5. Viral proteins

How does it work?
This is another traditional method for vaccinations: genes that code for proteins from the pathogen. In Covid-19’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-19. 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 repurposed their spike protein vaccine to target Sars-Cov-2. 
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.

What is 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-19 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.
Novavax has received investments totalling $388 million from the Coalition for Epidemic Preparedness to advance clinical development. Phase 1 trial results are expected in July.
Medicago announced positive results for a trial of its candidate vaccine in mice on May 14, and aims to start human trials in the summer. It can 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.
race against time »  over 100 efforts underway as china’s adenovirus vaccine takes the top slot