What were you doing on 10 January 2020? It was a Friday, so chances are you were arranging to meet up with friends. The days of completely unrestricted normality seem a distant memory. But it’s the date that the race to create a coronavirus vaccine began. That day, the Chinese government released the genetic sequence of the virus – SARS-CoV-2 – responsible for the pandemic. It enabled researchers around the world to start building bits of the virus in their labs, with the aim of developing a vaccine that will make us immune. There are around 35 research teams around the world now working on a vaccine. Millions of pounds are being pumped into vaccine development by organisations and wealthy individuals, including Microsoft billionaire Bill Gates, who has pledged to build factories for the seven (as yet unannounced) leading candidates. Meanwhile, a handful of teams, including US biotech businesses Novavax and Moderna, and a team at the University of Oxford, are supported by a foundation called the Coalition for Epidemic Preparedness Innovation (CEPI). The University of Oxford’s team is one of the furthest along the path to a vaccine. “I got the sequence on 10 January and then we spent the weekend deciding what to put in our vaccine,” says immunologist Dr Teresa Lambe, who is one of the vaccine team leaders at the university’s Jenner Institute. Since then, the work has been intense. “I haven’t had a weekend off. I’ve worked through gastro [a stomach bug]. I’ve worked through birthdays. I haven’t seen my children. It’s been exhausting.” Since the pandemic took hold, there’s been a question that not even the experts can answer – when will it end? Given how widespread the virus is, it seems unlikely that it will just disappear. Even if one country eliminates it entirely, it could just take one infected person travelling from another country to reignite the virus’s spread. To stop it for good, we need immunity. So the sooner we have a vaccine, the quicker certainty can return to our lives. The path to COVID immunity SARS-CoV-2 belongs to a broader group of viruses called the coronaviruses. Many just cause mild symptoms – nothing more than a cold. But a handful have caused serious disease outbreaks: SARS in 2002-2003, MERS from 2012 onwards, and now COVID-19 – the disease caused by SARS-CoV-2. We don’t yet have an approved vaccine for any coronavirus. But the urgency of this pandemic means that SARS-CoV-2 is now the top priority. The basic principle of any vaccine is to fool the body into thinking that it’s been infected by the virus (or bacterium) that causes the disease. In response, the immune system creates proteins called antibodies. If you get infected by the real virus, memory cells in the immune system called ‘B lymphocytes’ produce the antibodies again, helping you to fight the infection. All of the potential COVID-19 vaccines fundamentally achieve this in the same way, by exposing the immune system to the club-shaped protein spikes that cover the virus’s spherical shell. (This shell, made of fatty lipid molecules, encloses the virus’s genetic material.) When the virus invades our body, the spikes connect with a receptor on the surface of cells lining the throat and lungs to gain access to these cells, allowing the virus to enter and replicate. But exposing the immune system to these spikes, which are harmless on their own, trains our body to quickly churn out antibodies that smother the spikes and stop them from connecting. Each team has its own twist on this approach. The Oxford coronavirus vaccine involves injecting the genetic sequence (the DNA) of the protein spike into the blood. Our cells will use this DNA to manufacture the spike, triggering the immune response. Moderna’s approach, meanwhile, involves injecting the spike’s genetic material in a different form (RNA instead of DNA). And a vaccine being developed at the University of Pittsburgh injects the spike protein itself on a patch of microneedles – the patch would be stuck on like a plaster, and the tiny needles would dissolve once they’d pierced the skin. Researchers from the University of Pittsburg say their fingertip-prick system can be mass-produced and the vaccine can sit at room temperature until needed To deliver the spike’s DNA to our cells, the Oxford researchers are packaging it inside a ‘viral vector’ – essentially a delivery virus. This is a modified chimpanzee virus belonging to a group of viruses called the ‘adenoviruses’. “The vector has been crippled,” says Lambe. “It doesn’t replicate and it doesn’t cause disease.” At the time of writing, three vaccine developers have launched human trials: Moderna, China’s CanSino Biologics (CanSino also use an adenovirus-based viral vector), and the Oxford team. Testing the coronavirus vaccines After receiving the virus’s genetic sequence in January, the Oxford team’s first step was to identify the spike’s DNA. This DNA was then cloned and used to create a vaccine for pre-clinical tests. “Before it goes to clinical trial, every vaccine or drug has to be assessed in animal models,” says Lambe. The pre-clinical tests have shown that the vaccine is effective at producing antibodies that stop the SARS-CoV-2 virus from binding with cells. The vaccine also boosts levels of a type of white blood cell called T cells – another weapon in the immune system which kill virus-infected cells, slowing the virus’s replication. Meanwhile, the University of Oxford’s Clinical BioManufacturing Facility is making a larger volume of the vaccine that will be safe to go into humans, ready for the first clinical trials. An illustration of the coronavirus, created at the Centers for Disease Control and Prevention (CDC), showing its proteins spikes In phase I of the trials, the focus will be on the vaccine’s safety. “You inject a volunteer with a dose you know is safe from other clinical trials [with similar vaccines],” says Lambe, “and you monitor them carefully for the next two to three days.” As well as checking the vaccine is safe, by looking for side effects such as muscle aches and headaches, the researchers will measure the levels of T cells and antibodies in the volunteer’s blood. By the end of phase I, the plan is to have injected 510 people aged 18-55. If the vaccine looks to be safe and functional, then it’s on to phases II and III. Phase II will extend phase I to those aged 56 and over, as well as a small number of children. Phase III will involve 5,000 volunteers aged 18 and over, with half of them receiving the COVID-19 vaccine. This phase will test whether the vaccine offers protection in the real world, by monitoring the vaccinated individuals and comparing their COVID-19 infection rate to that of those who don’t receive the vaccine in the trial. Vaccine testing takes time It’s impossible to rush the watching, the measuring and the waiting that is the stuff of clinical trials. Regulatory bodies also need time to check the safety and effectiveness of new vaccines, and even once a vaccine is approved, there’s the potential for a delay while vaccine manufacturers ramp up production. “You don’t want to start manufacturing stuff until you know it is actually going to work,” says Dr John Tregoning, an expert in respiratory infections and vaccine development at Imperial College London. The Oxford team is trying to smooth the path to mass production. “In parallel to the trials, we are working really hard on scaling it up so that we are in a position, probably by the end of the year, to have a lot of doses available, probably in the millions,” says Lambe. The vaccine would not initially be freely available, but would be given to those identified as a priority. The other frontrunners are working to similar timescales. Most estimates put COVID-19 vaccines as being available in a year to 18 months – an incredible feat as it typically takes 10 or more years to develop a vaccine and get it approved. The race may ultimately end with several vaccines by several developers in production. “When you get to the point where the world needs to scale up vaccine production to billions of doses, it will be better not to be using just one technology in one factory,” says Tregoning. “You want dispersed, local manufacturing, and a process that’s quick and easy to replicate. So the more different vaccines there are, the quicker you can get a vaccine to people.” Who will get the coronavirus vaccine first? When a vaccine for SARS-CoV-2 is developed, it will initially be in limited supply as production is ramped up. So priority is likely to be given to healthcare workers who are in contact with COVID-19 patients. Older people and those with underlying health conditions would also be a priority, as they are most likely to become seriously ill. If you don’t fit into one of these categories, you will have to wait a little longer. “I doubt that in a year we’re going to see this given to you and me,” says Dr Maria Bottazzi, part of a team developing a COVID-19 vaccine at Baylor University in Texas. Taking a global view, there’s also the question of how evenly the COVID-19 vaccine will be distributed between countries. During the 2009 H1N1 (swine flu) pandemic, rich countries placed advance orders with vaccine manufacturers, leaving poorer nations less well supplied. There are also concerns that vaccine makers in developing countries will struggle to make COVID-19 vaccines if the first ones to be approved use newer technologies. These are all questions that will have to be addressed as we get closer to an approved vaccine. What happens after once we’re vaccinated? But when this is all over, and we’ve got a vaccine, where does it leave us? Deadly coronaviruses have a nasty habit of appearing out of nowhere. Might we just be faced with another vaccine race when the next one emerges? Dr Shibo Jiang at Fudan University in China says he has a solution. Working with colleagues in China and the New York Blood Center in the US, he has developed a type of molecule called a peptide that can latch on to a specific region of the SARS-CoV-2 protein spike, stopping the virus from getting into cells. The director-general of the World Health Organization, Dr Tedros Adhanom Ghebreyesus, has been overseeing the management of the COVID-19 pandemic The research is published in the journal Cellular & Molecular Immunology. Crucially, this region of the protein spike is similar in other coronaviruses, so it means that this molecule could potentially work as a vaccine or treatment for future coronaviruses, too. “This treatment is not injected; it would be inhaled,” Jiang tells BBC Science Focus. “You could use this in your home – you wouldn’t need to go into hospital.” He says the one thing holding up the research at the moment is the money needed to do the pre-clinical research. But if the money becomes available and the research pays off, it might mean that scientists won’t be confronted with another frantic battle against a coronavirus again. And neither will we. Source
