Feature MICHAEL CLEVENGER/GETTY The first US shipments of the joint Pfizer–BioNTech COVID-19 vaccine were ready by mid-December. making vaccines, such as by using messenger RNA (mRNA), have been validated by the WHAT THE LIGHTNING-FAST COVID-19 response, he adds. “It has shown that the development process can be accelerated QUEST FOR COVID VACCINES substantially without compromising on safety.” The world was able to develop COVID-19 MEANS FOR OTHER DISEASES vaccines so quickly because of years of pre- vious research on related viruses and faster The speedy approach used to tackle SARS-CoV-2 could ways to manufacture vaccines, enormous funding that allowed firms to run multiple change the future of vaccine science. By Philip Ball trials in parallel, and regulators moving more quickly than normal. Some of those factors might translate to other vaccine efforts, par- ticularly speedier manufacturing platforms. But there’s no guarantee. To repeat such hen scientists began seeking That speed of advance “challenges our rapid success will require similar massive fund- a vaccine for the SARS-CoV-2 whole paradigm of what is possible in vaccine ing for development, which is likely to come coronavirus in early 2020, they development”, says Natalie Dean, a biostatisti- only if there is a comparable sense of social were careful not to promise cian at the University of Florida in Gainesville. and political urgency. It will depend, too, on quick success. The fastest It’s tempting to hope that other vaccines might the nature of the pathogen. With SARS-CoV-2, any vaccine had previously now be made on a comparable timescale. a virus that mutates relatively slowly and that been developed, from viral These are sorely needed: diseases such as happens to belong to a well-studied family, sampling to approval, was malaria, tuberculosis and pneumonia together scientists might — strange as it sounds — have Wfour years, for mumps in the 1960s. To hope kill millions of people a year, and researchers got lucky. for one even by the summer of 2021 seemed anticipate further lethal pandemics, too. highly optimistic. The COVID-19 experience will almost cer- Years of advance research But by the start of December, the develop- tainly change the future of vaccine science, The research that helped to develop vaccines ers of several vaccines had announced excel- says Dan Barouch, director of the Center for against the new coronavirus didn’t start in lent results in large trials, with more showing Virology and Vaccine Research at Harvard January. For years, researchers had been promise. And on 2 December, a vaccine made Medical School in Boston, Massachusetts. paying attention to related coronaviruses, by drug giant Pfizer with German biotech firm “It shows how fast vaccine development can which cause SARS (severe acute respiratory BioNTech, became the first fully-tested immu- proceed when there is a true global emergency syndrome) and MERS (Middle East respiratory nization to be approved for emergency use. and sufficient resources,” he says. New ways of syndrome), and some had been working on 16 | Nature | Vol 589 | 7 January 2021 ©2021 Spri nger Nature Li mited. All rights reserved. ©2021 Spri nger Nature Li mited. All rights reserved. new kinds of vaccine — an effort that has now once SARS-CoV-2 was sequenced in January. ‘Vaccine innovation’), with companies running paid off spectacularly. “The fact that people had been paying close efficacy and safety tests on animals and then Conventional vaccines contain viral pro- attention to coronaviruses really allowed this in humans. Human testing requires three teins or disabled forms of the virus itself, whole process to accelerate,” says Dean. phases that involve increasing numbers of which stimulate the body’s immune defences The third vaccine to show efficacy in people and proportionately escalating costs. against infection by a live virus. But the first phase III clinical trials in November, made by The COVID-19 vaccines went through the same two COVID-19 vaccines for which efficacy was the pharmaceutical firm AstraZeneca with the trials, but the billions poured into the process announced in large-scale (phase III) clinical University of Oxford, UK, does not use mRNA. made it possible for companies to take finan- trials used just a string of mRNA inside a lipid Instead, a viral vector (or carrier) holds extra cial risks by running some tests at the same coat. The mRNA encodes a key protein of genetic material that codes for the SARS-CoV-2 time (see ‘A vaccine in a year’). SARS-CoV-2; once the mRNA gets inside our spike protein. This, too, benefited from years With large sums given to vaccine firms by cells, our bodies produce this protein. That of research to select the vector; in this case, public funders and private philanthropists, acts as the antigen — the foreign molecule that the firm chose a modified form of adenovirus “they could do preclinical and phase I, II and triggers an immune response. The vaccines isolated from chimpanzee stool. Advances in III trials, as well as manufacturing, in parallel made by Pfizer and BioNTech and by the US instead of sequentially”, says Rino Rappuoli, pharmaceutical company Moderna both use “If SARS in 2002 had spread chief scientist at GlaxoSmithKline’s vaccines mRNA that encodes the spike protein, which division in Siena, Italy. This meant that com- docks to human cell membranes and allows like this, we wouldn’t have panies could gamble on starting large-scale the coronavirus to invade the cell. had the vaccine technology testing and manufacturing of candidates that “A lot went into the mRNA platform that we or the coordinated systems.” might not work out. “It was totally de-risk- have today,” says immunologist Akiko Iwasaki ing the entire development process,” says at the Yale School of Medicine in New Haven, Kampmann. Connecticut, who has worked on nucleic-acid conventional vaccines such as these have also The vaccine science would not have pro- vaccines — those based on lengths of DNA or come from research on SARS, MERS, Ebola and duced such fast results without this funding, RNA — for more than two decades. The basic malaria, says Beate Kampmann, director of the she says. “It didn’t happen with Ebola, which research on DNA vaccines began at least Vaccine Centre at the London School of Hygiene was devastating communities in Africa [in 25 years ago, and RNA vaccines have benefited & Tropical Medicine, and such approaches 2014–16]” — and Ebola vaccines accordingly from 10–15 years of strong research, she says, remain cheaper than using mRNA. took longer to develop. The money only some aimed at developing cancer vaccines. Vaccine researchers were fortunate with materialized this time because all countries, The approach has matured just at the right SARS-CoV-2 in many respects, says Iwasaki. including wealthy ones, faced economic dev- time; five years ago, the RNA technology would The virus doesn’t mutate a lot or have effec- astation: suggesting that the development of not have been ready. tive strategies for foiling the human immune future vaccines, including for existing diseases For instance, researchers at the US National system, she says, unlike HIV, herpes or even such as malaria, will not be as speedy. “Unless Institute of Allergy and Infectious Diseases influenza. The herpes virus, by contrast, has you put in the money, there’s no way to accel- (NIAID) in Bethesda, Maryland, knew from more evasion capability — it actively blocks erate,” says Rappuoli. their research on MERS and SARS that it was antibodies from binding, which makes it harder Virologist Peter Hotez at Baylor College of best to tune the RNA sequence to stabilize the to find an effective agent against it. And the Medicine in Houston, Texas, suggests that resulting spike protein in the form it adopts fast mutation of flu viruses requires a different large pharmaceutical companies might have before it docks with a host cell. “If you can trap vaccine formulation for every flu season. been motivated not just by the desire to stop it in its original pre-fusion state, it becomes a the pandemic, but also by the opportunity for much better vaccine antigen,” says Barney Supercharged with funding governments to fund their research and devel- Graham, deputy director of NIAID’s vaccine The slowest part of vaccine development opment. With public investment of around research centre. That work gave the NIAID isn’t finding candidate treatments, but US$10 billion, the US Operation Warp Speed team, which worked with Moderna, a head start testing them. This often takes years (see vaccine programme “represents the largest VACCINE INNOVATION Most vaccines take years to develop, but scientists created multiple vaccines for SARS-CoV-2 within a year. Year in which pathogen Year in which US was linked to disease vaccine was licensed Typhoid fever Meningitis Whooping cough Polio ANALYSIS Poor vaccine New vaccine Mumps developed development started NATURE Measles Hepatitis B Ebola SARS-CoV-2 SOURCES: OUR WORLD IN DATA; IN DATA; OUR WORLD SOURCES: 1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 Nature | Vol 598 | 7 January 2021 | 17 ©2021 Spri nger Nature Li mited. All rights reserved. ©2021 Spri nger Nature Li mited. All rights reserved. Feature A VACCINE IN A YEAR The drug firms Pfizer and BioNTech got their joint SARS-CoV-2 vaccine approved less than eight months after trials started. The rapid turnaround was achieved by overlapping trials and because they did not encounter safety concerns. ANALYSIS Preclinical Phase II/III clinical Some countries approve studies commence trials begin vaccine for emergency use NATURE SARS-CoV-2 Phase I/II clinical Rolling submission genome released trials begin of data to regulators Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2020 BIONTECH/PFIZER; SOURCES: government stimulus package the pharma disease were patchy, with peaks in some areas can be chemically synthesized in a few days, companies have ever seen”, says Hotez.