Unless you have had cancer or experienced an inflammatory disorder, chances are you have never taken an antibody drug. But Oliver DeLong, a healthy baby from Chicago, Illinois, probably received his first antibody therapy before he was even four months old.
Oliver participated in a clinical trial in 2021 that involved a unique kind of antibody treatment, one designed to prevent, rather than treat, disease. It is called nirsevimab, and studies show that the drug, when given before the start of the first respiratory syncytial virus (RSV) season that a baby will experience, can help youngsters to avoid the types of severe lung infection that often lead to hospitalization and even death.
Antibody drugs are usually given to treat severe diseases. But when it comes to RSV, these drugs have been used for more than 25 years as a preventive measure.
Rather than waiting for babies to contract the virus and get ill, physicians administer antibodies beforehand to stop RSV from taking hold — a vaccine-like approach that provides short-term protection against the worst complications of RSV-associated disease.
Historically, this strategy has been reserved almost exclusively for youngsters that are at the highest risk of dying from RSV — babies born prematurely and those with certain lung and heart conditions. The available antibody drug, called palivizumab, is simply too expensive and inconvenient for widespread deployment, requiring monthly injections that can collectively cost upwards of US$10,000 per child.
A new wave of affordable and accessible antibody therapies could reshape the landscape. Priced well below the cost of palivizumab and requiring only a single injection in the thigh — not the five needed for palivizumab over the course of one RSV season — next-generation antibodies could drastically reduce the burden of RSV.
If adopted widely, these antibodies could cut the rate of RSV-associated hospitalizations almost in half, modelling studies show1. “We’re on the cusp of these incredibly effective preventive interventions for RSV,” says Heather Zar, a paediatric pulmonologist at the University of Cape Town in South Africa, who has worked on trials of different antibody drugs.
Yet, the arrival of these agents comes at a time of increased pharmaceutical options for defending against RSV. Two vaccines for older adults were approved by the US Food and Drug Administration (FDA) earlier this year. And the agency approved another for pregnant people in August as well, offering benefits to newborns accrued through the transfer of maternal antibodies across the placenta (see ‘Complementary care’). Vaccines for young infants might not be far behind either.
This leaves many people contemplating the role that long-acting antibody drugs will assume amid this new array of prophylactic options. Although these antibodies offer distinct advantages compared with conventional vaccination strategies, challenges emerge regarding implementation and parental acceptance.
The universal roll-out of antibody drugs by health-care systems is uncharted territory, unlike the commonplace practice of maternal vaccination against respiratory infections such as influenza and pertussis (whopping cough). And the successful adoption of either immunization approach might hinge crucially on the existing clinical infrastructure.
“Price and ambition will be key,” says Steve Cunningham, a paediatric respiratory-disease specialist at the University of Edinburgh, UK. “There’s going to be a big debate over the next year or two about which is the best coverage option.”
Antibody drugs that target and neutralize the RSV virus function similarly to vaccines, acting as barriers against the harmful pathogen. But there’s a crucial difference. Vaccines introduce pieces of the virus into the body and then rely on the immune system to gradually build its own defensive response, whereas antibody therapies offer immediate protection to recipients.
Prophylactic antibodies of this kind are already approved to deflect infections from SARS-CoV-2, rabies and anthrax. And since 1998, palivizumab has been used in many countries to prevent RSV in high-risk babies. But the drug strategy has never been implemented on a population-wide scale.
The introduction of nirsevimab could change that. Because of a change to the amino acid sequence in the antibody’s backbone, nirsevimab can circulate in the body for an extended period of time, providing prolonged protection against the virus. Studies indicate that recipients maintain high levels of the molecule in their bloodstream for at least five months, and potentially longer2. This persistence eliminates the need for monthly top-up jabs, as is required with palivizumab. And phase III studies show that just one dose of nirsevimab can help youngsters to avoid the severe infections that often lead to hospitalization and even death3,4.
“What we have now is a situation where you can give a single shot of this highly potent antibody to an infant and protect them for an entire season,” says Tonya Villafana, head of nirsevimab’s clinical development at AstraZeneca, a drug firm based in Cambridge, UK. The company is now co-developing the drug with the pharmaceutical firm Sanofi, based in Paris.
On 17 July, the FDA approved nirsevimab for use in neonates and infants, who can be given the drug before or during their first RSV season, and for children up to two years old who remain susceptible to severe RSV disease. Regulators in the European Union, the United Kingdom and elsewhere have granted similar authorizations.
Notably, pharmaceutical companies have committed to offering nirsevimab and other long-acting antibodies at the same price as conventional vaccines. In high-income countries, analysts estimate that the antibodies will be priced between $300 and $500 for newborns — not much higher than the $200 or so expected for RSV vaccines. Prices in resource-poor settings should be even lower.
This affordability could pave the way for administration of protective antibodies to all infants, regardless of geography, health status or whether babies were born preterm. That is a cause for celebration for Anna Banerji, an infectious-disease specialist at the University of Toronto’s Dalla Lana School of Public Health in Canada, who studies the well-being of Inuit children, a population with some of the highest rates of RSV complications anywhere in the world.
For more than a decade, Banerji has advocated for unrestricted access to palivizumab for Inuit babies born in remote northern communities, irrespective of gestational age. However, her appeals have gained limited traction.
Health authorities in one part of the Canadian Arctic — in the Nunavik region of northern Quebec — launched a pilot programme in 2016 in which they expanded eligibility for palivizumab from high-risk babies to include healthy, full-term newborns. But the programme was discontinued after just four years, in part because of limited health-care resources and a lack of cost-effectiveness in all but the most severe RSV seasons.
Things should be different with nirsevimab. As a one-time, lower-cost option, nirsevimab should streamline the administration process, while also being “highly cost-effective or cost-saving as compared to the pilot strategy in Nunavik”, according to a 2021 modelling study led by researchers at York University in Toronto5.
In April, Canadian regulators granted approval for the antibody’s use in all newborns and young infants, including those born at full term with no underlying health conditions. Banerji’s long-standing vision of providing universal antibody treatment to Inuit babies now stands poised to become a reality. “This should save a lot of lives,” she says.
Vaccine versus antibody
Those babies could also be helped through maternal vaccination, which enhances immunity for both the mother and the baby. Doubling up on both approaches — vaccines and antibodies — would offer even greater protection. But, with limited budgets, public-health officials might be forced to choose between offering jabs to expectant mothers or giving synthetic antibodies to babies to prevent severe RSV infection in their first months of life.
If disease prevention were the only consideration, then — shot for shot — antibodies would be the better option, says Louis Bont, a paediatric infectious-disease specialist at University Medical Center Utrecht in the Netherlands.
As chair of the non-profit ReSViNET Foundation, an international RSV research consortium, Bont has worked with AstraZeneca and other pharmaceutical companies to evaluate most of the RSV vaccines and antibodies being considered for widespread roll-out. Although the two strategies have never been tested head-to-head, the antibody seems to be both more effective and potentially safer, he says.
In clinical trials, the maternal vaccine offered around 50–60% protection against RSV infections that required medical attention or hospitalization6. That’s a meaningful benefit — but not as good as nirsevimab, which offered protection in the 70–80% range3,4,7. Some maternal RSV vaccines have also been linked to a modest increased risk of preterm birth, whereas studies of nirsevimab have not raised any major safety concerns.
What’s more, all babies can benefit from antibody treatment, whereas the same is not true of maternal vaccination.
Those born prematurely to immunized women might be insufficiently protected because they will acquire fewer maternal antibodies in the womb than would babies who were born at full term. Infants born a few months ahead of the RSV season might have lost much of their transferred immunity by the time they face the viral threat. Antibodies, by comparison, can always be given right before or during an active RSV season. They can also be routinely administered in a hospital maternity ward or at an early paediatrician visit, rather than relying on pregnant people to seek out vaccines at the appropriate time in their late second to third trimester.
“It can be operationalized,” says William Muller, a paediatric infectious-disease physician at Northwestern University Feinberg School of Medicine in Chicago, Illinois, who has been involved in Oliver DeLong’s care as an investigator in the nirsevimab trial. “Then you know that babies are protected for the next five months or potentially longer.”
Of course, it doesn’t have to be one or the other. “Each strategy has its own benefits,” says Catherine Weil-Olivier, a paediatric infectious-disease specialist at Paris Cité University — offering both could achieve maximal population coverage, especially considering the variations in health-care systems, public acceptance of medical interventions and unique socioeconomic factors across different countries.
Offering a diverse array of RSV-preventing drugs could also help health-care providers to stay one step ahead of RSV evolution because, as the virus mutates, new variants might emerge that render some antibodies obsolete.
Researchers at Regeneron, a pharmaceutical company in Tarrytown, New York, learnt this the hard way. The company’s antibody candidate suptavumab looked to be highly potent against dozens of RSV strains collected over the span of 20 years. And historical records indicated that the target of this antibody, part of RSV’s fusion protein that is involved in aiding entry into host cells, did not vary between viruses isolated from one season to the next.
“For all we knew, when we started the clinical programme with [suptavumab], we thought it was a very potent antibody that was binding to an extremely conserved site,” says Christos Kyratsous, a senior vice-president of research at Regeneron. But over the course of two years, just as Regeneron was running a clinical study across 18 countries and involving more than 1,150 preterm babies8, a new strain of RSV popped up that compromised the ability of suptavumab to neutralize one subtype of the virus.
This strain rapidly spread around the world. As a result, the drug fared no better than a placebo at preventing the hospitalization of preterm babies.
“You can call it extremely bad luck,” says Kyratsous. But he also sees a valuable lesson in the experience: “You cannot predict virus evolution.” And for that reason, it will be important to have multiple RSV antibodies on the market, with a diverse range of binding specificities, to increase the likelihood of maintaining effective options for if and when new mutations arise. Then, says Kyratsous, “even if one of them stops working, we will have alternatives”.
One potential alternative could be clesrovimab, a long-acting antibody candidate from the pharmaceutical company Merck, based in Rahway, New Jersey. According to data presented at an RSV conference earlier this year, its drug provided up to 81% protection against RSV complications in initial clinical testing. Late-stage trials are continuing.
Notably, clesrovimab has several design features that make it distinct from, and complementary to, nirsevimab. One key distinction is its target location on the RSV fusion protein. Nirsevimab binds to a spot on the protein’s apex — one that is only present in the protein’s pre-activation state, before it undergoes a structural change necessary for viral entry into host cells. But, clesrovimab latches on to the protein’s flank, on an area that remains consistent across different conformations of the protein.
In molecular surveillance studies9,10 mutations to the site targeted by clesrovimab seem to be less common than are changes to the site targeted by nirsevimab. These observations have led Kevin Russell, an associate vice-president of global clinical research at Merck, to think that his company’s antibody might have the upper hand when it comes to thwarting resistance. “It’s a highly conserved site,” he says, “so we think there’s much less chance for escape variants of RSV to develop” against clesrovimab.
The few mutations observed so far have reduced the potency of nirsevimab11. Still, the potential for resistance remains an area of concern — one that requires close monitoring, says Octavio Ramilo, a paediatric infectious-disease researcher at St. Jude Children’s Research Hospital in Memphis, Tennessee. “We need to watch the mutations, watch the outcomes, and see what happens,” he says.
Access and affordability
At least two other long-acting antibodies are also in the early stages of clinical testing for RSV prevention. One, from the Trinomab Biotechnology company in Zhuhai, China, is being evaluated in healthy infants; the other, which originated at the biotechnology firm Adimab in Lebanon, New Hampshire, has completed safety and pharmacology testing in healthy adults.
On a molecular level, the Adimab agent — called RSM01 — and nirsevimab are fairly similar. The antibodies bind to adjacent sites on the RSV fusion protein, and they demonstrate comparable potency in laboratory experiments, according to Laura Walker, former head of antibody sciences at Adimab. “The differences are pretty minor,” she says. RSM01, however, has an important potential advantage. A non-profit biotechnology arm of the Bill & Melinda Gates Foundation plans to advance the drug and offer it in low- and middle-income countries for as little as manufacturing costs will allow.
It is not clear what that price will be yet. But Michael Dunne, chief medical officer and head of development at the Bill & Melinda Gates Medical Research Institute in Cambridge, Massachusetts, expects it to be well below the $300 or more that drug companies will probably charge in Europe and North America for nirsevimab. “We’re going to get the price down as low as we can,” Dunne says.
Zar welcomes the focus on health equity: “Globally, we need to advocate for access and affordability,” she says.
In a commentary published earlier this year, Zar and Cunningham called for a concerted global initiative to fund and deliver RSV preventative treatments to all infants everywhere, particularly in underserved regions, where rates of RSV-related illness and death are greatest12. “It’s absolutely a key issue now to get these products out to low- and middle-income country settings,” Zar says. “This is where children are dying from RSV.”
As with most medical interventions, however, the first beneficiaries of nirsevimab will invariably be in wealthier parts of the world — that is, children such as Oliver.
Two years ago, when the now-toddler was just four months old, he attended his first Thanksgiving dinner, at which family members who later tested positive for RSV coddled him in their arms. However, Oliver never contracted the virus — and he might have nirsevimab to thank for that.
Although his parents do not yet know whether Oliver got a placebo injection or the active drug, one thing they can be sure of is that his participation in the nirsevimab trial helped to usher in the antibody’s approval. “I’m just proud and excited that we could be part of that in a very small way,” says his mother, Hillary DeLong.
Now, as the next RSV season approaches, millions more families can safely gather together, with the knowledge that these virus-thwarting antibody drugs will help to ensure joyful and worry-free celebrations during the holiday season and beyond.