Asunción Mejías sits at a microscope in the lab

Asunción Mejías analyses a sample containing respiratory syncytial virus under a microscope.Credit: St Jude Children's Research Hospital

Mask wearing, social distancing and other public-health measures put in place to thwart COVID-19 also kept other respiratory infections at bay. But by late 2022, most countries had dropped these protections — and with no vaccine available, respiratory syncytial virus (RSV) ran amok in children who hadn’t been exposed to the virus for the previous two years. In the United States alone, RSV-related hospitalizations tripled in November 2022 relative to the pre-pandemic levels three years before.

Paediatricians have bemoaned the absence of an RSV vaccine for decades. “By age three, nearly 100% of children will have become infected with RSV,” says Steven Varga, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. Although many of these cases result only in a few days of wheezing, coughing and worried parents, infection can also be serious. Estimates from April indicate that RSV hospitalizes one in every 56 otherwise healthy infants born in Europe1. And 2% of all deaths in children under the age of five are attributable to this virus2 — with almost all of those occurring in low- and middle-income countries (LMICs). “We suffer a pandemic every year with RSV,” says Asunción Mejías, a paediatric infectious-disease specialist also at St. Jude Children’s Research Hospital.

But good news has finally arrived. Multiple preventive strategies, including both conventional vaccines and antiviral antibodies that act like short-term vaccines, have proved their mettle in phase III clinical trials and should be available at hospitals this year. Several of these strategies have also proved effective for older adults — a high-risk group for RSV-associated pneumonia — and numerous other promising candidates are waiting in the wings.

“RSV has been a major cause of morbidity and mortality around the world, and I think this is going to change dramatically,” says Louis Bont, an infectious-disease paediatrician at the University Medical Center Utrecht in the Netherlands. But he also cautions that these benefits are unlikely to be evenly distributed, with cost and infrastructure issues almost certain to delay access in LMICs. And even in wealthier parts of the world, broader questions have arisen about how to deploy these various preventive strategies in the safest and most effective way.

Second wind

The first attempt at a vaccine for RSV began clinical testing in 1966 (see Nature https://doi.org/b39p6d; 2008), less than one decade after scientists first isolated this pathogen from young children experiencing severe pneumonia. The trial proved to be a disaster and ended up exacerbating the disease. “That really hampered efforts to create a successful vaccine for decades,” says Varga (see ‘Friendly fire’). But over the past decade or so, RSV vaccine development has accelerated.

Friendly fire

The ideal outcome for a vaccine — rarely achieved in practice — is to perfectly fortify the recipient against any future encounters with the pathogen. A more reasonable gauge of a vaccine’s success is whether it can prevent serious disease or reduce transmission. The first vaccine to be tested against respiratory syncytial virus (RSV), however, fell short of even that lower threshold.

Four RSV vaccine clinical trials in the late 1960s provided an example of a worst-case scenario — the vaccine ended up making the vaccinated children’s first encounter with the virus much more severe. In one study10 of 71 infants, 80% of the vaccinated children who acquired RSV were subsequently hospitalized, compared with just 5% of the control group — and two of the hospitalized vaccine recipients ultimately died from the infection.

This alarming outcome was surprising for a few reasons, including the fact that the vaccine design itself was unremarkable. RSV particles were inactivated by treatment with formalin, an agent that chemically locks proteins into place so that they can no longer perform their normal biological function, and then combined them with an immunity-stimulating adjuvant mixture of aluminium salts known as alum. This approach was standard in the 1960s. Indeed, both formalin inactivation and alum adjuvants remain in use for some modern vaccines, according to Steven Varga, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. For example, vaccines for hepatitis B and pneumococcal disease both use alum, and inactivated polio vaccines are made from formalin-disabled viral particles.

It took decades of investigation and debate before researchers clarified the various factors that coalesced to inflict such damage. “It was a perfect storm of events that created the vaccine-enhanced disease that was experienced by those children,” says Varga.

One problem was that this vaccine preparation procedure seemed to lock the viral particles into a structural state that can elicit antibodies that bind to the viral proteins reasonably well, but that were not up to the task of neutralizing infection. In fact, some studies have indicated that the antibodies elicited by RSV infection following immunization with the formalin-inactivated vaccine could accumulate as immune complexes in the lungs, where they could subsequently promote a damaging inflammatory response.

In parallel, the inactivated virus seemed to do a poor job of training killer T cells, which would normally go on to eradicate virus-infected cells in future encounters. That immunological lapse left a crucial gap in the antiviral defences. However, the vaccine did elicit a potent reaction from a subset of helper T cells that subsequently recruited a drove of other immune cells during infection, which could elicit a potent — and damaging — inflammatory response in the lungs.

This is not exclusively an RSV-associated phenomenon — similar issues arose with a formalin-inactivated vaccine against measles during the same decade. Formalin-inactivation does not seem to be an issue for other vaccine preparations, however. Therein might lie a clue to what went wrong. Varga points out that both measles and RSV belong to the same family of paramyxoviruses. “I think it’s a common issue with that particular group of viruses,” he says.

Fortunately, subsequent instances of vaccine-enhanced disease have been exceedingly rare. And Louis Bont, an infectious-disease paediatrician at the University Medical Center Utrecht in the Netherlands, thinks that the vaccine-development community is now much better situated to intercept such outcomes before they emerge in humans. “Back in the 1960s, we thought we could make a vaccine for everything overnight,” says Bont. “The preclinical and early clinical development pathway is much more regulated today.”

This includes the identification of a suitable antigen for eliciting a potent antibody response that can neutralize infection and prevent severe disease. RSV relies on a surface molecule known as the fusion (F) protein to bind to and penetrate host cells, and virologists quickly recognized this as a promising target. However, not all F antigens are created equal. This protein fluidly transitions between a compact ‘pre-fusion’ and an extended ‘post-fusion’ structure. The pre-fusion form, which aids viral penetration of cell membranes, can be readily neutralized by antibody binding, making it an excellent target for vaccines. However, early RSV vaccines tended to elicit a response against the post-fusion conformation of the F protein, which is much more stable than the pre-fusion structure. The antibodies produced by such vaccines generally bind to their viral target in a way that is insufficient to thwart infection. In the early 2010s, however, researchers led by Barney Graham and Peter Kwong at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, made crucial headway in determining the structure of the pre-fusion F protein. They subsequently engineered versions of this protein that are essentially locked into this conformation. The resulting F variants could be used to trigger a much more potent neutralizing response3.

Another big leap was the notion of focusing on vaccinating pregnant people rather than infants, and relying on protection from maternally-generated antibodies that cross the placenta and enter the fetal bloodstream. This is crucial, because newborns lack the capacity to produce a meaningful immune response in their first few months of life. Indeed, most RSV hospitalizations occur in those aged 3–4 months, according to Heather Zar, head of the department of paediatrics and child health at the University of Cape Town in South Africa. She highlights a 2020 trial4 of an F-protein-based maternal vaccine from the biotechnology company Novavax, based in Gaithersburg, Maryland, as an important early proof of concept. The study failed to meet its endpoints in terms of disease prevention — probably because the vaccine did not rely on the pre-fusion antigens that are now standard. “But it actually performed reasonably well — and much better in low- and middle-income country settings,” says Zar, who was part of the research team. The reasons for these results are unclear, but they could be because wealthier nations have lower levels of RSV infection and a greater tendency to hospitalize children with less-severe infections.

Federico Martinón-Torres listens to an infant’s breathing via its back with his stethoscope.

Paediatrician Federico Martinón-Torres checks on an infant in an intensive care unit.Credit: Rita García Fernández

In April, researchers led by a team at the pharmaceutical company Pfizer in New York City demonstrated the magnitude of protection that could be achieved by combining the use of the stabilized pre-fusion antigen and maternal vaccination5. The study involved more than 7,000 pregnant people in 18 countries — including Argentina, Gambia and the United States. The researchers demonstrated that incidence of severe RSV disease in the first three months of life was reduced by almost 82% in children born to mothers who were vaccinated with Pfizer’s RSVpreF vaccine. Although the vaccine failed to meet another trial goal of generally preventing respiratory infection that required medical attention, Zar is still excited about the results. “Preventing severe disease is very important because of the health-care costs and associated mortality,” she says. In August, the US Food and Drug Administration (FDA) approved the shot.

Prophylaxis preparation

As of this year, many parents already have another option: a single-dose antibody drug, called nirsevimab, that targets a key site on the pre-fusion F antigen. Developed by the pharmaceutical companies AstraZeneca and Sanofi, nirsevimab is engineered to achieve prolonged stability in the body. As such, newborns dosed with the drug can achieve roughly the same level of protection against RSV as they would from antibodies elicited by maternal vaccination. In April, a team of researchers published results from a phase III study6 showing that the administration of nirsevimab before the onset of RSV season reduced hospitalizations by nearly 77%. Both the European Medicines Agency (EMA) and the FDA have now approved nirsevimab for use in infants.

After decades of disappointment, the arrival of two effective preventive therapies is clearly a cause for celebration — but unanswered questions remain.

Trial data suggest that nirsevimab has an edge on durability, because it achieved stable protection against severe disease for up to five months. Whereas the RSVpreF vaccine’s efficacy dropped from 82% in those aged up to 3 months to only 69% at 6 months5. But even a brief window of protection during that most-vulnerable period of early childhood could make a big difference, says Federico Martinón-Torres, a paediatrician at the University of Santiago de Compostela in Spain. “We are talking about 75–80% of the total burden in infants, which is huge,” he says, noting that first infections occurring after the earliest months of childhood are generally less likely to result in severe disease or death.

Weighing the options

There is also some uncertainty around aspects of safety for the maternal vaccines. In February, the pharmaceutical firm GlaxoSmithKline (GSK) halted trials for its vaccine after observing modestly increased rates of premature births in women who had received the shot. Bont, who helped to analyse preterm-birth data, says it isn’t yet clear what caused these premature births and that they might ultimately be linked to non-trial-related factors. The safety profile of Pfizer’s conceptually similar RSVpreF vaccine seems to offer little cause for concern, although their pivotal trial did show a slight — but not statistically significant — increase in preterm births in the vaccinated cohort. “I personally don’t think that there is a real concern with prematurity,” says Zar. But she also recognizes that mothers will want thorough reassurance of the safety of any vaccine, and postmarket surveillance will be needed to carefully monitor this risk in the general population.

Steven Varga and Stacey Hartwig in conversation standing in the lab

Immunologist Steven Varga talks with laboratory manager Stacey Hartwig at St. Jude Children’s Research Hospital in Memphis, Tennessee.Credit: St. Jude Children’s Research Hospital.

Finally, there is the question of economics. In February, Philippe Beutels, a health economist at the University of Antwerp in Belgium, reported on a cost-effectiveness analysis of the nirsevimab antibody versus maternal vaccination in six European countries7. “When they’re equally priced, it’s quite clear the antibody is dominating,” Beutels says. The scales might tip the other way, however, if the cost of buying and administering a dose of nirsevimab rises to above double that of the vaccine — an entirely realistic possibility (price negotiations are still under way). Antibodies might also have an edge in wealthy countries because of the generally poor uptake of existing maternal vaccines. In LMICs, where health-care funds are more precious than in high-income countries, vaccines might be more cost-effective. Beutels collaborated with a team led by Mark Jit at the London School of Hygiene and Tropical Medicine to evaluate the economics of RSV prevention in Kenya and South Africa. The study8 found that both preventive approaches would save lives and avert hospitalizations, although vaccines generally prevailed from an economic perspective.

Unfortunately, it remains unclear how soon these products will arrive in less-advantaged parts of the world. The RSV community hopes to avoid a repeat of the inequitable global access to COVID-19 vaccines; in September 2022, for example, the Bill & Melinda Gates Foundation gave Pfizer a US$27.5-million grant to support the deployment of the RSVpreF vaccine in LMICs. However, in April, the news agency Reuters reported that it might be several years before the Pfizer begins shipping significant quantities of the vaccine to these parts of the world. In parallel, the Bill & Melinda Gates Medical Research Institute is working on a pre-F-targeting antibody that is very similar to nirsevimab, with the goal of providing a cost-effective alternative, but this is still in early clinical development.

A turning point

More options for prevention are also on the horizon. Even if the highest risk from RSV comes in the earliest months of life, severe disease can still occur in the year or two that immediately follows. Several vaccine candidates are targeted at protecting toddlers, including an mRNA-based candidate from the biotechnology firm Moderna that has already proved efficacious in older adults9.

In fact, there is now a growing recognition that individuals over the age of 60 are also at heightened risk of developing potentially fatal pneumonia as a consequence of RSV. Despite the setbacks in its maternal vaccination programme, GSK won FDA approval in May for the same vaccine formulation in adults over the age of 60. Its trial, with 25,000 participants, showed 94% efficacy in protecting against severe lower respiratory disease in this demographic. Shortly thereafter, Pfizer also won FDA approval for its vaccine in older adults on the strength of strong efficacy data.

None of the current vaccines seems likely to confer one-and-done protection against RSV, a virus that has honed a variety of strategies to elude immunity and therefore returns to haunt most people at some point in their lives. But a brief window of protection when it matters most could have a tremendous public-health impact. Varga is enthusiastic about the future. “This is an important first step and an exciting one, because it’s taken us almost 60 years to get to this point,” he says. “And I’m sure it won’t end here — we’ll continue to work to improve things.”