Prevention is better than cure for Indigenous infants

RSV prevention in underserved regions: a global effort to fund and provide vaccines for children in low- and middle-income countries

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.”

The data suggest that nirsevimab has an advantage in terms of ability to last for a long period of time. When it was first introduced, the efficacy of the vaccine was only shown in people who were up to 3 months old. 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.

Vaccination and prevention of respiratory infection in the early stage of vaccination: The case of GSK, Pfizer, and Varga

If we are truly committed to reconciliation as the Canadian government states, then things need to change. If we can make progress on this, it shows the world that the burden of health disparity shouldered by Indigenous people is not unsolvable. We need to act.

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.

The vaccine preparation procedure locked the particles into a structure that could cause some antibodies to bind to the virus, but that wasn’t good enough for the job of neutralizing it. The immune complexes that can be produced in the lungs as a result of the receipt of the immunization with the formalin-inactivated vaccine may be related to the activity of the anti-RSV antibodies.

After decades of investigation and debate researchers are able to say what factors coalesced to cause such damage. “It was a perfect storm of events that created the vaccine-enhanced disease that was experienced by those children,” says Varga.

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. A potent response from a subset of T cells that subsequently recruited a drove of other immune cells was elicited by the vaccine, which could lead to an inflammatory response in the lungs.

This also includes identification of a suitable antigenic for triggering a potent immune response that can help prevent infections and cases of disease. The fusion (F) proteins is a surface molecule used to bind and penetrate host cells, and Virologists recognized it as a promising target. Not all F antigens are created the same. A compact pre-fusion and extended post-fusion structure is fluidly transitions between. The pre-fusion form can be easily taken out by the human body’s immune system, making it an excellent target for vaccines. The post-fusion structure of the F protein is more stable than the pre-fusion structure, which is why 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. Barney Graham and Peter Kwong led the research at the US National Institute of Allergy and Infectious Diseases in Maryland that made important progress in determining the structure of the pre-fusion F molecule. They subsequently engineered versions of this protein that are essentially locked into this conformation. The resulting F variant could cause a more potent neutralizing response.

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.

It is obvious that the arrival of two effective preventative therapies is a cause for celebration but unanswered questions remain.

There is also some uncertainty around aspects of safety for the maternal vaccines. There were small increases in the rate of premature births in women who received the vaccine from Glaxosmithkline. It isn’t yet clear what caused these premature births and they might ultimately be linked to non-trial-related factors. Despite the small increase in the vaccine cohort during the pivotal trial, Pfizer seems to have little cause for concern. Zar doesn’t think there is a real concern with prematurity. She recognizes that mothers want to know if a vaccine is safe, and that post market supervision is needed to keep an eye on this risk.

If you’ve ever had cancer or inflammatory disorder, you’ve probably never taken a drug that protects against it. But Oliver DeLong, a healthy baby from Chicago, Illinois, probably received his first antibody therapy before he was even four months old.

Many people are considering the role that long-acting drugs will have in this new array of prophylactic options. Although these antibodies offer distinct advantages compared with conventional vaccination strategies, challenges emerge regarding implementation and parental acceptance.

“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.”

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. The modelling study found that irsevimab could be a one-time, lower-cost option and also save a lot of money.

Louis Bont, a specialist in infectious diseases at University Medical Center Utrecht in the Netherlands, says shots for shot would be better for disease prevention.

Bont is chairman of the ReSViNET Foundation and has worked with pharmaceutical companies to evaluate most of the RSV vaccine and Antidote 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.

Babies who were born at full term might be less protected than those who were born early, because they’re less able to acquire maternal antibodies in the womb. 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.

Perspectives on nirsevimab in the light of Recent Advances in Research in Low-Income Diseases

It’s not clear what the 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. Dunne says that they will get the price down as low as possible.

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.

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.

We are pleased to acknowledge the financial support of Moderna in producing this Outlook. As always, Nature retains sole responsibility for all editorial content.

The effects of the RSV infections may linger long after the initial one has been treated; studies are beginning to uncover links between the infections and 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 have encouraged optimism, but there are still substantial hurdles to overcome. Access to existing RSV interventions is already unequal, leaving people in low-income countries especially vulnerable. These communities could be exposed despite recent progress if policies in place to ensure equity are not in place.

Efforts to prevent infections and keep vulnerable people out of hospital are beginning to pay off, but new challenges arise when deployment is done.

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