杏吧原创

POTTERING around her kitchen on the morning of 31 December, Kate Broderick scrolled through the headlines while she聽waited for her tea to brew. One story caught her eye: a mysterious outbreak of severe pneumonia in Wuhan, China. Nearly overnight, the number of cases seemed to explode. 鈥淚聽knew we didn鈥檛 have time to wait,鈥� she says.

A molecular geneticist at Inovio Pharmaceuticals in California, Broderick was poised for what came next. When Chinese officials published the genetic sequence of the聽new SARS-CoV-2 coronavirus causing the illness just two weeks after the first cases were reported to the World Health Organization, Broderick got to work. Within 3聽hours, her team聽had a prototype vaccine ready for initial testing. It was an unprecedented turnaround, but a moment Broderick and many others had聽long seen coming.

Making vaccines usually takes a decade or more between development, safety testing and聽manufacturing, says , head of聽Gavi, an international group that promotes vaccine use around the world. With global confirmed cases of the new disease, covid-19, surging past 180,000 at the time of writing, time is of the essence.

To speed things up, scientists are turning to聽untested classes of vaccines, and rethinking every part of how they are designed, evaluated and manufactured. If the approach works, we will, for the first time, have identified a new disease and developed a vaccine against it while the initial outbreak is still ongoing.

But speed can come with downsides. 鈥淲e聽could have a vaccine in three weeks, but聽we聽can鈥檛 guarantee its safety or efficacy,鈥� says聽Gary聽Kobinger, a virologist at Laval聽University in Canada.

The hope is to have at least 1 million doses of聽coronavirus vaccine available to the public聽in 12聽to 18 months, according to . She is head of vaccine development and聽research at the , set up in 2017 with funding from the Bill & Melinda Gates Foundation, the Wellcome Trust and several governments. Until now, the fastest we have ever cranked out a vaccine in response to an outbreak was with Ebola 鈥� and that took five years, says Berkley. Eighteen months to make a聽new vaccine widely available is 鈥渘aively optimistic鈥�, says Kobinger. It isn鈥檛 impossible, but it may mean ripping up the rule book.

All vaccines work by tricking the body into believing it has been exposed to a pathogen. This causes the immune system to respond with antibodies and T-cells to neutralise or kill the invader. Afterwards, some of these remain in circulation, ready for action in case you are exposed to the actual infection. In other words, your immune system is primed.

The more closely a vaccine mimics the disease, the more protection it will provide. We聽currently have four main strategies for pulling off this trick. Live-attenuated vaccines use actual viruses or bacteria that have been altered to prompt an immune response but not full-blown illness. Inactivated vaccines are聽exactly what they sound like: they are made by growing huge amounts of the pathogen in vats, which is then inactivated 鈥� or killed 鈥� with heat or chemicals. Both these strategies are used with flu vaccines, for instance.

The third variety, toxoid vaccines, are used against bacteria that cause disease indirectly, by producing a toxin, as is the case with tetanus, diphtheria and botulism. They contain a piece of the toxin that readies your聽body鈥檚 response to the full thing. Lastly, subunit vaccines contain just the small pieces of a pathogen that activate the immune system, which can be polysaccharides (sugars), proteins or a combination of these, called a聽conjugate. These subunits are made by producing the right sugars and proteins in large vats using engineered bacteria or yeast, then painstakingly removing impurities.

These key vaccine types have been around for decades and have an established safety record, but it can still take up to 15 years to go from prototype to general use, says Berkley (see 鈥淗ow to make a vaccine, step by step鈥�). Two main factors are behind long development times: historically, scientists have spent years studying how a pathogen interacts with the body and the immune system before developing a vaccine; and fewer than one in four candidate vaccines that start clinical trials make it through the whole process and get licensed for use, he says.

A head start

In principle, the tried and tested nature of聽these approaches should give them an advantage in the sprint to develop a vaccine against the new coronavirus, says at Baylor College of Medicine in Texas. While these vaccine types typically take years to develop, their established safety profile could mean fewer, shorter trials in people.

And getting out of the starting blocks has become easier. New approaches to vaccine development allow us to dramatically shorten the first step in the process. For the new coronavirus, researchers like Annie De Groot, co-founder of the biotech company in Rhode Island, used computational models that can jump directly from the genetic sequence to聽a potential vaccine by zooming in on those parts of the virus颅 that would be good vaccine targets. As soon as SARS-CoV-2 was sequenced, researchers at labs around the world were able to jump in and get to work figuring out what made it tick and how to fight it, says , an infectious disease and vaccine specialist at Mount Sinai School of Medicine in聽New York. Like Inovio, many had mock-ups of prototypes ready within hours. Such advances have been a long time coming. 鈥淚t took us 21 years of work to be able to develop a聽vaccine in 3 hours,鈥� says De Groot.

at Hong Kong University of Science and Technology is one of those taking advantage of such leaps. He and his team looked at genetic similarities between the new virus and another, earlier coronavirus that shares up to 90 per cent of its DNA: SARS鈥慍oV, the one that caused a SARS outbreak in 2003. Their work on SARS showed that the human immune system responded most strongly to the protein spikes that form the crown, or corona, surrounding the virus and to the proteins that envelop its nucleus. McKay鈥檚 team also found that one in five of the sites that the immune system could recognise, known as epitopes, were identical between the new coronavirus and the earlier SARS one. His team . 鈥淭his says these appear to be important targets for a vaccine,鈥� says McKay. An last week.

鈥淚t took us 21 years of work to be able to develop a vaccine in 3 hours鈥�

This initial flurry of work has yielded at least聽, six backed by CEPI. In the wake of earlier epidemics such as Ebola, MERS and SARS, CEPI was created to help us respond better 鈥� and faster 鈥� by having rapid response systems at the ready.

Many of these use the well-established vaccine types, but hope to accelerate the usual timelines by streamlining each step in the process, most notably prototype development. For example, CEPI is funding a collaboration between EpiVax and the University of Georgia to use the results of the company鈥檚 computer modelling to genetically engineer a segment of聽the virus into a subunit vaccine, like the one used for hepatitis B worldwide. Bottazzi鈥檚 team at Baylor is developing a similar vaccine.

Janssen, a pharmaceutical company owned by Johnson & Johnson, has begun work on a possible vaccine using a harmless, genetically engineered adenovirus. That is the same strategy the firm used for Ebola.

Another CEPI-funded initiative uses in Australia to stabilise the coronavirus protein subunit that would be used in a vaccine and so improve its ability to generate an immune response. The university already has its vaccine in animal trials, according to Saville.

But the tried-and-tested vaccine types aren鈥檛 the only game in town this time. Inovio, for example, aims to use nucleic acids like RNA or DNA in its vaccine. Although neither DNA nor messenger RNA (mRNA, which helps the body translate genes into protein) create an immune response directly, these vaccines get cells to make the proteins that will create a response.

鈥淚nstead of producing viral proteins in a factory, we鈥檙e injecting RNA and letting your cells be the factory,鈥� says , head of Arcturus Therapeutics, one of the companies using this approach.

Once the DNA or mRNA enters a cell, the person鈥檚 own protein-making machinery takes over. DNA vaccines must be converted by cells into mRNA first, whereas mRNA allows you to skip this stage. Depending on the genetic code used, the resulting viral protein made in the body can be secreted from muscle or skin cells,聽displayed on the cell鈥檚 membrane, or be聽embedded in the membrane itself. These strategies trick the immune system into thinking the body has been invaded by a pathogen, which leads to the creation of T-cells and antibodies 鈥� or so the theory goes. So far, no such vaccines have been approved.

A major hurdle with these vaccines is getting the DNA or RNA into cells, as our blood is filled with enzymes that can chop these substances into bits within seconds. Each company pursuing this approach has developed its own聽technology to circumvent this problem. Arcturus and a Massachusetts-based biotech firm called Moderna are enveloping the vaccine鈥檚 genetic material in a protective core, while Inovio is administering a tiny electrical current at the injection site to encourage nearby cells to swallow DNA whole. All three have said they will be able to rapidly scale up production. Moderna has already recruited people in Seattle for an . The trial, which will include 45聽healthy volunteers, began on聽16聽March.

鈥淚t鈥檚 a crazy, awesome speed, beyond what we聽saw with Ebola,鈥� says Kobinger.

The safety and efficacy of these new types of聽vaccines remain unknown, and there are concerns that DNA-based vaccines might affect our own genes or somehow spur harmful immune reactions. As of 17 March, none of the companies had released detailed data about the immune responses generated in animal models or any potential adverse events.

Moderna is also taking its RNA-based vaccine, mRNA-1273, directly to human trials before completing standard toxicological testing in animals. The firm is relying on safety testing already completed for its other mRNA vaccines in development.

Yet with any new vaccine, there are concerns聽about something called 鈥渋mmune enhancement鈥�. This can happen when a prior vaccination or infection inadvertently facilitates a virus鈥檚 ability to enter cells and make copies of 聽itself. It means that instead of protecting you,聽the vaccine could make you vulnerable to聽more severe infection. Harmful immune enhancement was seen in early animal trials of聽SARS vaccine and in human trials of a vaccine for a respiratory virus called RSV.

These types of concerns, and the track record of very few vaccines making it from clinical testing through to approval for use in humans, are what make lengthy clinical trials so necessary, says , head of infectious diseases and vaccines for Janssen. Older vaccine technologies have an advantage as they have already been vetted. 鈥淚t gives a certain level of comfort that you can use these [older] vaccines in an emergency and you already have a solid safety database,鈥� he says.

Striking the balance between speed and safety is always going to be a challenge. If a vaccine takes too long to develop, the initial outbreak may be over, which creates its own set of problems. For example, by the time clinical trials of an Ebola vaccine were under way during a large outbreak that began in West Africa in 2014, disease transmission had slowed so much that researchers couldn鈥檛 treat enough people to gather the robust data needed for regulatory approval. Only after a larger outbreak and a bigger trial was there enough evidence to prove safety and efficacy, says Kobinger, who worked on that vaccine, called Ervebo. It was finally approved by the European Medicines Agency in November 2019.

Left in limbo

None of the other vaccine candidates for Ebola聽made it as far. The rest, says Greg Poland at the Mayo Clinic in Minnesota, were stored in聽freezers, unable to find funding quickly enough to even begin testing. No SARS vaccine made it beyond phase I safety trials before the disease vanished and funding dried up.
Money is also critical to vaccine development. 鈥溞影稍�创s need to be assured of聽research funding. Science is not a spigot you聽can turn on聽and off,鈥� says Poland.

In part, it was the stark realisation during聽the聽West African Ebola outbreak that Big Pharma could no longer be relied upon to聽solely underwrite expensive vaccine research 鈥� especially for diseases with little聽chance of recouping the outlay 鈥� that prompted governments and NGOs to seek an聽alternative. 鈥淭he formation of CEPI has been聽a paradigm shift,鈥� says Broderick. 鈥淏efore that, everything was completely reactive.鈥�

CEPI鈥檚 strength isn鈥檛 only funding research, but also pairing small, innovative biotech firms with the might of established drugs companies. The coalition has funded efforts to聽develop vaccines against Lassa fever, Zika and Nipah, and even to prepare for 鈥淒isease X鈥�, the World Health Organization name for any聽unknown infection that may yet emerge聽鈥� precisely the situation that arrived with the new coronavirus. CEPI-funded scientists also聽worked on vaccines against MERS, a coronavirus spotted in 2013 and closely related to SARS, both of which can cause pneumonia.

So when the first reports of severe pneumonia caused by the new coronavirus began trickling out of China, CEPI was ready for聽action. But it, too, needs a steady supply of聽funds. Saville estimates that $350聽million will be required in just the next few months to聽meet the accelerated timeline of creating a聽vaccine for covid-19 within 12聽to 18 months.

Given the all-consuming nature of the current pandemic, there is good reason to believe CEPI will get the money it needs. From there, it is a matter of seeing which vaccine options make it through the many steps to eventual regulatory approval. When one does, then the final challenge will be to rapidly scale up manufacturing to produce millions of doses to exacting medical standards.

All these steps are hard enough when there isn鈥檛 an outbreak, says De Groot, and no one can say how the pandemic will affect supply chains and labour pools related to vaccine development. It is also possible that, by the time a vaccine is ready for late-stage clinical trials, there won鈥檛 be enough virus circulating to provide firm answers about its efficacy.

So how realistic is the 12 to 18-month timeline? 鈥淚t鈥檚 still fairly aspirational,鈥� says Saville. It is based on everything going well and faster-than-ever progress through each step in the process. In other words, it is a long shot.

The teams making vaccine candidates know every minute counts. Broderick says the rising number of cases and deaths rattle through her head from the moment she wakes up.

She and others have no doubt that we will eventually have a vaccine against covid-19. It is just too early to say which candidate will be ready first, or what problems we may hit along the way. It could be a bumpy ride, says Poland. 鈥淲e鈥檙e building the plane as we鈥檙e flying.鈥�