Vaccination for respiratory syncytial virus (RSV) and its associated paramyxoviruses: Where did the vaccine go wrong?
The affordability could lead to the administering of protective immunity to all infants, regardless of geography or health status. Anna Banerji is 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, who have the highest rates of respiratory syncytial virus (RSV) complications anywhere.
Doctors have used vaccine-like approaches to prevent the disease from taking hold, rather than waiting for baby to get sick, so that they can prevent the most serious aspects of the disease.
If we are truly committed to reconciliation as the Canadian government states, then things need to change. If we can make progress on this, then it shows the rest of the world that the pernicious burden of health disparity shouldered by Indigenous people is not unsolvable. We need to act.
A new wave of cheaper and more accessible drug therapies can make a huge difference. 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.
This is not exclusive to an RSV-associated phenomenon, but it is also related to a vaccine against measles during the same decade. Other vaccine preparations don’t seem to be affected by formalin-inactivation. Therein might lie a clue to what went wrong. Varga said that both diseases are part of a family of paramyxoviruses. He says it is a common issue with that particular group of viruses.
It took decades of research before researchers explained the factors that caused the damage. “It was a perfect storm of events that created the vaccine-enhanced disease that was experienced by those children,” says Varga.
The in activated virus did not do a good job of training T cells, which are normally trained to destroy virus cells in future encounters. That immunological lapse left a crucial gap in the antiviral defences. A surge in the number of T cells that were recruited by the vaccine could lead to a potent inflammatory response in the lungs.
The identification of a suitable antigen and the eliciting of a potent immune response are some of the components that comprise this. The fusion (F)protein, a surface molecule utilized to bind to and penetrate host cells, was quickly identified as a promising target by virologists. Not all F antigens are created the same. TheProtein fluidly transitions between a pre-fusion and an extended structure. The pre-fusion form is an ideal target for vaccines since it can be readily neutralized by antibody binding. The post-fusion structure of the FProtein is much less stable than the pre-fusion structure, so earlyRSV vaccines elicited a response against it. 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.
“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.
After years of disappointment, the arrival of two preventive therapies is cause for celebration, but unanswered questions remain.
There is also some uncertainty around aspects of safety for the maternal vaccines. There was a halt to trials for the vaccine after rates of premature births increased in women who had received it. Bont says it isn’t yet clear what caused the premature births and that they might be linked to non-trial-related factors. The safety profile of the vaccine seems to offer little worry, although the study did show a slight increase in abortions, but it is not considered significant. “I personally don’t think that there is a real concern with prematurity,” says Zar. She understands mothers want to know that the vaccine is safe, and that postmarket observation is needed to monitor the risk in the general population.
Unless you have had cancer or experienced an inflammatory disorder, chances are you have never taken an antibody drug. Oliver was a healthy baby from Chicago and most likely received his first therapy when he was four months old.
Maternal vaccine against respiratory infections, such as influenza and whooping cough, is commonplace, unlike the universal roll-out of antibody drugs. 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 will be a big debate about which is the best coverage option over the next year or two.
In order to make it possible for healthy, full-term babies to be treated with palivizumab, the health authorities in the Nuna Inuit region of northern Quebec launched a pilot programme in 2016 that included high-risk babies. The programme was stopped after four years due to limited health-care resources and lack of cost-effectiveness in the most severeRSV seasons.
Things should be different with nirsevimab. The modelling study said that nirsevimab should simplify the administration process and be very cost-effective as compared to the pilot strategy in Nunavik.
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 a chair of the ReSViNET Foundation, Bont has worked with companies to evaluate the effectiveness of most of the vaccines being considered for widespread roll-out. The two strategies have never been tested against one another and so he says that the antibody is more effective and safer.
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. Babies born several months before the start of the season for the Respiratory syncytial virus might lose much of their immunity by the time they encounter the disease. During an active RSV season, antibodies may be given before or during that time. 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.
The Prospects for the Treatment of RSV in Low-Income Countries: The Case for nirsevimab
There is still no idea what that price will be. 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.
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. His mother says she is proud to be part of that in a small way.
Two years ago, when the now-toddler was four months old, family members who later tested positive for RSV coddled him at his first Thanksgiving dinner, even though he was four months old. However, Oliver never contracted the virus — and he might have nirsevimab to thank for that.
We are pleased to acknowledge the financial support of Moderna in producing this Outlook. Nature remains solely responsible for all editorial content.
It is believed that the effects of aRSV can be seen after the initial infection has been eliminated, with studies starting to show a link to respiratory problems in later life. Other research is beginning to unpick how other pathogens in a host might collaborate or compete with RSV.
These developments engender optimism, yet there are still a lot of hurdles. People in low-income countries are particularly vulnerable because of the unbalanced access to existing interventions. These communities could be left exposed regardless of the recent progress if policies were not put in place to ensure equity.
Infections and vulnerable people are being kept out of the hospital but new challenges are presented by implementing these strategies.