In February 2020, just as a new coronavirus was triggering the global COVID-19 pandemic, structural biologist Jason McLellan and his team published the structure of the key protein it uses to invade human cells ¹ . Immediately, scientists began using that protein’s structure to develop COVID-19 vaccines .

But that wasn’t the first time McLellan, now at the University of Texas at Austin, had solved a structure and spurred on a new wave of vaccines. In 2013, he was focusing on a different killer — respiratory syncytial virus, or RSV ² .

RSV causes a respiratory tract infection that affects 64 million people per year worldwide. It hospitalizes 3 million children under 5 years old and approximately 336,000 older adults annually (see ‘Common scourge’). The global health-care costs of RSV-associated infections in young children in 2017 were estimated to be US$5.45 billion ³ .

Researchers have been trying for decades to develop a vaccine, and have had some particularly devastating failures — including the deaths of two participants in a trial in the 1960s.

Solving the protein structure revived the RSV field. McLellan, then a postdoctoral researcher at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and his colleagues looked at a protein that the virus uses to fuse with cells and infect them, called the F protein, and found a way to stabilize it in its prefusion form — the shape it adopts when ready to grab on to cells. The structure of the prefusion F protein unveiled the best target for making vaccine-induced antibodies that could prevent the virus from entering human cells.

Now, an effective RSV vaccine is nearly within reach: four candidates and one monoclonal antibody treatment are in late-stage clinical trials.

“It’s been 8 years since the prefusion F protein conformation was elucidated and now we’re all in phase III trials based on that fundamental discovery,” says Christine Shaw, vice-president of early-development programmes in infectious diseases at messenger RNA therapeutics company Moderna in Cambridge, Massachusetts.

The quest for RSV vaccines has not escaped the effects of the COVID-19 pandemic. The pandemic has complicated the trials, but it also helped spur developments that might finally protect against this childhood killer.

Rough start

RSV infects most children by age three, and most adults many times over, but natural immunity to it is not long lasting. Infections are usually most severe in infants under two months old, who are encountering the virus for the first time. A vaccine or treatment would drastically reduce hospital and intensive-care admissions for this most vulnerable group, says Rabia Agha, a paediatric infectious-disease specialist at Maimonides Children’s Hospital in New York City. And because of the acute medical need for vaccines and treatments for RSV, regulatory agencies in the United States and Europe are prioritizing them for review.

These candidates have been a long time coming. In the late 1960s, a series of vaccine trials tested a vaccine made from inactivated RSV in children in the United States. Tragically, the shot did the opposite of what it was meant to — it made disease worse in vaccinated children when they were later naturally infected with RSV. This caused severe lung disease that hospitalized most of the children in the trial and killed two.

Steven Varga, a viral immunologist who studies RSV at the University of Iowa in Iowa City, says that early vaccine was “the culmination of a perfect storm of events”: it evoked too few virus-blocking antibodies and simultaneously caused an overactive inflammatory response. Researchers now know more about the science of both RSV infection and vaccinology, and Varga says there is no concern that the current crop of vaccine candidates could provoke a similar response.

Vaccine researchers soldiered on, but were targeting the wrong viral proteins — or the wrong forms of these proteins — for decades. “People have tried to make RSV vaccines since the 1970s, but it had been one failure after another,” says Rino Rappuoli, senior vice-president and chief scientist for vaccines at GlaxoSmithKline (GSK) Vaccines, based in Siena, Italy. “Things changed completely when we began to understand the main viral protein, protein F.”

In a very similar fashion to SARS-CoV-2 and its spike protein, RSV uses the prefusion form of the F protein (preF) to wedge its way into human cell membranes and fuse with them. Once that happens, the protein undergoes a major conformational shift to its more stable postfusion form (postF). Many of the earlier failed vaccines targeted postF.

The tangled history of mRNA vaccines

By contrast, preF induces potent neutralizing antibodies that have been found to block the virus from entering human cells, Varga says.

To solve the structure of preF in a way that would make it useful for vaccine design, McLellan’s team made a version of it in which the protein was fixed in a particular shape, so that its vulnerabilities were on display. To stabilize the protein in this shape, the team added a crucial chemical bond that acted like double-sided tape, keeping the protein folded in the preF shape, with its key antibody-target sites exposed. Vaccines that use this stabilized form prompt a much stronger antibody response from the immune system. All the current RSV vaccine candidates involve this stabilized form of preF, and healthy adults produce high levels of neutralizing antibodies against it.

Vaccines work by presenting the immune system with key bits of a pathogen, which induce the production of antibodies and immune cells that can recognize and fight the whole pathogen when the person is re-exposed to it. Many RSV vaccines use a similar array of technologies to those in development or use for COVID. Of the four RSV vaccines in phase III trials, two, from GSK and Pfizer, contain the stabilized preF protein itself. Another, from Janssen, uses a modified adenovirus that produces preF after delivery into the body, plus a dose of the pure protein, in the same shot. The fourth, from Moderna, delivers modified mRNA that produces preF once the RNA is inside cells.

Promising trials

Once approved, an RSV vaccine will be most useful for the very young and the very old. But to simplify clinical trials, all four companies in the race are initially testing their shots in people older than 60.

So far, early-stage data from phase II trials, some in older adults and some in younger adults, suggest that the vaccines will be safe and effective. Both Janssen and Pfizer have run small-scale challenge trials, exposing vaccinated younger adults to RSV, and have shown that their vaccines protect against infection. The Janssen, Moderna and GSK vaccines increased levels of neutralizing antibodies 9–15-fold.

GSK, Janssen, Moderna and Pfizer now each have global phase III trials under way in tens of thousands of older adults. GSK leads the pack, and Rappuoli says he expects to have interim results in early 2022.

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