Humanity really has only two options to confront the coronavirus pandemic currently sweeping the planet. The first is to mount a rolling program of lockdowns and other drastic social distancing strategies to restrain the pace of the virus epidemic, with a view to gradually building up natural herd immunity among the human population.
That strategy, especially if combined with successful anti-viral drug treatments and a massively upscaled testing effort, should give some relief. But it would come at the likely cost of many millions of deaths and incalculable worldwide economic damage, hitting especially hard in countries with little resilience and limited healthcare infrastructure.
The second approach is to develop a vaccine, and to do so as rapidly as possible. A fully effective vaccine would not just tame COVID-19 but possibly eradicate it altogether — as the world successfully did with smallpox and is on the verge of doing with polio (both also viral diseases).
These two approaches will most likely be concurrent: the first will buy us time, while the second provides an exit strategy from a constant pattern of repeating lockdowns and travel restrictions that could otherwise go on for years.
With the current total of confirmed cases rapidly closing in on one million worldwide, the true picture is most likely that many tens of millions of people have already caught COVID-19. Humanity’s most desperate challenge, therefore, is to find an effective vaccine.
First vaccine trials already underway
Fortunately, science is already stepping up. History was made on March 16, when the first clinical trial volunteer was injected with an investigational vaccine for coronavirus at the Kaiser Permanente Washington Health Research Institute in Seattle.
The volunteer was mother-of-two Jennifer Haller, a 43-year-old Seattle resident who told National Public Radio that she “wanted to do something because there’s so many Americans that don’t have the same privileges that I’ve been given.”
The vaccination was produced by Moderna, with the first batch being delivered to the US National Institutes of Health a remarkable 42 days after the viral genome was first sequenced in China.
This Phase 1 trial does not yet test the efficacy of the vaccine against COVID-19. Carried out over six weeks among a group of 45 healthy adult volunteers aged between 18 and 55, it will test the basic safety of the proposed vaccine and its ability to stimulate an immune response in the human body.
Although the Phase 1 trial will continue with the Seattle-area recruits being monitored for a whole year, the urgency of the global situation means that the collaborators will likely rush to Phase 2 at the same time, testing the ability of the vaccine to prevent infection by the novel coronavirus SARS-CoV-2 that causes COVID-19.
The Moderna vaccine trial is a world first not just for the particular disease target but because it is one of a whole new potential class of vaccines that employ messenger RNA (mRNA) to program human cells to produce the viral proteins that trigger an immune response, rather than injecting proteins or viral particles directly, as have most previous vaccines.
This natural role of mRNA is why Moderna’s approach is so quick. Normal vaccines have to be produced from actual viruses, which are grown within chicken eggs and then refined into sufficient quantities to be directly injected — once weakened or killed — into the human body. This takes months, at a minimum, and is difficult to scale quickly.
For the mRNA approach, all that was needed was the correct viral genetic sequence, which in the case of SARS-CoV-2 encodes for the spike proteins that enable the virus to gain entry into human respiratory cells. This genetic sequence for the viral protein can then be encoded into mRNA synthetically generated in a lab — a rapid process that is easy to scale.
That’s the good news. The bad news is that the mRNA approach, while undoubtedly quick and versatile, is so new that it has yet to be fully proven in any vaccine in either humans or animals. Some tests have shown efficacy against rabies, for example, but others have shown little lasting immune response.
The mRNA approach is therefore a moon-shot rather than a marathon. Even so, Moderna is optimistic enough to already be making plans to produce millions of doses — intended for health workers initially — as early as this fall.
Other mRNA coronavirus vaccines
Other companies and partnerships are also racing to develop a vaccine using the same mRNA approach. One of these, the German firm CureVac, generated so much interest that President Trump reportedly tried to acquire it in order to ensure any potential vaccine would be available to Americans first.
Like Moderna, CureVac’s efforts are supported financially by CEPI — the international Coalition for Epidemic Preparedness Innovations, which has raised over $700 million from governments around the world and philanthropic foundations like the Bill & Melinda Gates Foundation (which also supports the Cornell Alliance for Science) and Wellcome.
While Moderna has been able to restart vaccine projects originally intended for MERS and SARS, CureVac has already achieved some success with an mRNA vaccine against rabies virus in humans. In a Phase 1 trial doses as low as a millionth of a gram of mRNA vaccine were sufficient to fully protect humans against rabies, it reported in January.
Such small doses offer major promise for immunizing huge numbers of people if CureVac is able to achieve the same success with SARS-CoV-2 as it has with rabies and move rapidly into Phase 2 trials to further demonstrate real efficacy.
Also in Germany, BioNTech and Pfizer are racing to shift their mRNA vaccine work from influenza to SARS-CoV-2, and are aiming to start clinical trials as soon as April. As part of a broader collaboration, BioNTech has already demonstrated that an mRNA vaccine protected mice and non-human primates against Zika virus, raising hopes for similar effectiveness against COVID-19.
RNA’s double-stranded cousin, DNA, is also being deployed in a novel but equally promising vaccine system against the coronavirus. The approach is related, but rather than injecting mRNA directly into cells so that it can produce viral proteins, DNA is inserted, which in turn produces mRNA inside cells to do the same job.
This DNA is not intended to integrate into the genome of the target cell in humans – indeed if this happens, damaging mutations might occur. Instead, DNA is formed into circular plasmids which operate separately to the integral genetic material inside a cell’s nucleus. Like genomic DNA however, these plasmids are read and transcribed via mRNA into viral proteins which can then prime the body’s immune system against a later invasion by the real virus.
The US-based Inovio Pharmaceuticals announced on 12 March that it had received a grant of $5 million from the Bill & Melinda Gates Foundation to accelerate the testing of a DNA vaccine for COVID-19, with a view to starting Phase 1 clinical trials in April.
Inovio has another advantage: its DNA vaccine INO-4700 was the only vaccine candidate against MERS to progress to Phase 2 trials — demonstrating, at least initially, the potential feasibility of the DNA approach. The US Department of Defense — with an eye to protecting its military personnel all over the world against COVID-19 — has pumped another $11.9 million into INO-4800. The company has also demonstrated protection in early trials using its DNA vaccine against Chikungunya, Zika and influenza viruses.
A role for genetic engineering
CEPI is not putting all its eggs in one basket, however. As well as DNA and RNA systems, another promising approach for a COVID-19 vaccine is to use a genetically engineered measles vaccine — a strategy supported by a $5 million CEPI grant split between collaborating institutions Themis in Vienna, Institut Pasteur in France and the University of Pittsburgh’s Center for Vaccine Research.
This takes the live attenuated measles virus vaccine — a vaccine with a long history of safe use, having been used to immunize billions of children over the last 40 years — and uses reverse genetics technology to insert new genes coding for proteins expressed by other viruses. These then induce an immune response against the new virus whose genetic material has been introduced.
The research team aims to have a COVID-19 candidate vaccine ready for animal testing as soon as April, with wider tests in human volunteers by the end of the year.
Measles virus is not the only candidate for the vector approach. Chinese scientists have reported that they are about to proceed to Phase I human trials with a vaccine candidate starting at the pandemic’s epicenter in Wuhan. The scientists have genetically engineered a replication-defective adenovirus type 5 (Ad5) as a vector to express the SARS-CoV-2 spike protein, with the resulting vaccine candidate named Ad5-nCoV.
This is perhaps the easiest approach, as all that has to happen is for the engineered harmless adenovirus to infect patients in order to trigger the production of antibodies which should be effective against invading novel coronavirus too. The Chinese company CanSion Biologics has successfully demonstrated this approach with another fully completed vaccine against Ebola, Ad5-EBOV, which is already on the market in China.
Host plants and genetically engineered insects
A more tried-and-tested approach — already widely used to produce flu vaccines — is to grow viral proteins directly: these are then injected as a vaccine into human patients so that the immune system is already primed against the real pathogen when it attempts to infect the body. Usually chicken eggs are used, but to speed things up insect cell lines are becoming the preferred option for the coronavirus pandemic.
Here genetics is again an important component: the company Novavax uses a baculovirus vector to genetically engineer an insect cell line originally isolated decades ago from the ovaries of the fall armyworm. The baculovirus transports genes into the insect cells, which program them to manufacture viral proteins that are correctly folded and biologically active, more reliably enabling the human immune system to produce antibodies against them.
According to Novavax, its resulting recombinant protein nanoparticles then self-assemble into a structure that approximates the actual virus, helping enhance the immune response. It claims to have already tested this system in RSV virus, a recalcitrant pathogen that has so far resisted attempts at a vaccine. This approach looks promising enough that CEPI has pumped $4 million in so far with a view to launching Phase I trials by late spring 2020.
In a similar way, the company Sanofi is taking a snippet of genetic code from SARS-CoV-2 and splicing it — also via baculovirus — into insect cell lines. Its advantage, made in a pitch to the US government that resulted in a big cash injection, is that it already has an FDA-approved facility that could make 600 million doses a year of any resulting vaccine.
Plants can also be engineered to produce viral proteins. The company Medicago is working with Nicotiana benthamiana, a close relative of tobacco that grows wild in the Australian outback, with this aim in mind. To speed things up, instead of adding new genes to the nucleus of cells and regenerating entire plants from these single cells (as happens with conventional plant genetic engineering), it uses the Agrobacterium vector in a vacuum to transfer recombinant DNA directly into the nucleus of fully-grown leaf cells. This DNA enables the production of the desired viral proteins without ever being integrated into the genome, enabling proteins to be harvested from transiently transformed leaves within a matter of days.
Using this system, Medicago claims to have produced a virus-like particle of the coronavirus within just 20 days of the SARS-CoV-2 genetic sequence becoming available. The government of Canada quickly put millions of dollars behind the effort as a result.
More money needed
Astonishingly, given that the coronavirus pandemic is now threatening to devastate societies and economies around the planet on a scale second only to a world war, this effort is still short of cash. CEPI has issued an urgent call for funding, seeking to raise $2 billion: it says just $375 billion by the end of March would enable four-to-six vaccine candidates to move rapidly towards phase 2/3 trials.
Scientists are also hoping desperately that SARS-CoV-2 does not rapidly mutate as influenza viruses tend to do, which would likely reduce the effectiveness of any single vaccine. So far, according to researchers studying 1,000 samples of the virus from around the world, this seems not to be the case.
This means that the race to find a vaccine, and to do so in sufficient time to salvage the situation before the world tips into an economic depression and millions of people die, has a decent chance of success — and that any successful vaccine would likely confer lasting immunity.
Meanwhile, all of humanity is waiting. And if the scientists do succeed in this urgent challenge, it will very likely be due to modern genetics. Though “genetic engineering” was once a dirty word, it now could literally help save the world.