Every fall, the arrival of chilly air and red leaves signals the beginning of preparations in pediatric ICUs for the annual RSV virus onslaught. While flu and COVID may dominate the headlines, it is RSV, or respiratory syncytial virus, that remains the leading cause of hospitalization for babies year after year. Inflicting inflammation on their delicate airways, the sickest babies struggle to breathe. RSV is equally deadly for older adults, claiming the lives of 6,000 to 10,000 elderly Americans annually.
In the battle against RSV, a breakthrough has finally been achieved with the approval of three new vaccines. Rapidly gaining FDA approval in recent months, these vaccines promise a new era in RSV prevention. The first, nirsevimab, is an antibody shot for infants designed to provide passive immunization for babies who are too young to receive traditional vaccines. The second, developed by Pfizer, targets both adults over 60 and pregnant mothers, who can then pass on the immunity to their babies. The final vaccine, from GlaxoSmithKline, is specifically aimed at adults over 60. Collectively, these vaccines reveal a newfound hope for combating RSV.
It is no coincidence that these three RSV vaccines are emerging simultaneously. The key to their success lies in their ability to exploit a specific weakness within the virus, identified in 2013. This targeted approach to vaccine development holds tremendous potential for revolutionizing the design of vaccines for a wide range of diseases. In fact, this strategy served as the foundation for developing the highly-effective COVID vaccines from Pfizer and Moderna. Initially perfected for RSV, this innovative approach has finally come full circle to tackle RSV itself.
“After more than 65 years, we are finally in a truly remarkable position,” says Asunción Mejías, an infectious diseases doctor at St. Jude Children’s Research Hospital.
The quest for an RSV vaccine began shortly after the discovery of the virus in 1956. However, an early trial ended in disaster, casting a shadow over RSV vaccine development for decades. Modeled after a successful polio vaccine, the initial RSV vaccine utilized a chemical called formalin to inactivate the virus. Much to everyone’s horror, infants who received the vaccine later contracted the virus at an alarming rate—80 percent of them were hospitalized, compared to only 5 percent in the control group. The vaccine not only failed to offer any protection but also exacerbated the severity of the disease. “It was such a disaster,” recalls Ann Falsey, an infectious diseases doctor at the University of Rochester. Despite years of investigation, scientists could not overcome this hurdle in developing an effective vaccine. Progress was at a standstill.
In a fortunate turn of events, a fortuitous meeting paved the way for a breakthrough in RSV vaccine research. Jason McLellan, a freshly-minted Ph.D. specializing in protein structure, joined the National Institutes of Health in 2008 to work on HIV vaccines. Due to a lack of space in his designated lab, McLellan found himself sharing a workspace with Barney Graham, a virologist who had been grappling with RSV for decades. Graham persuaded McLellan to explore the potential of RSV. By then, scientists had identified a plausible target for an RSV vaccine—the fusion protein (F) used by RSV to attach itself to human cells. F exists in two forms: a highly unstable prefusion state and a much more stable postfusion state. Once F transitions to the postfusion state, it cannot revert back. McLellan remarked, “It can’t come back.”
In the manufacturing of RSV vaccines, all F protein eventually switches to the postfusion state. However, antibodies against postfusion F proved to be minimally effective. McLellan discovered why—extremely potent neutralizing antibodies bind to a specific site at the tip of prefusion F, which is lost during the transition to the postfusion form. Losing this critical site resulted in a tenfold to a thousandfold decrease in potency. To develop an effective RSV vaccine, targeting prefusion F was essential.
Even armed with this knowledge, the researchers faced a practical challenge—how to stabilize F in its prefusion form to be included in a vaccine. McLellan made slight adjustments to the protein, introducing molecular “staples” and filling structural gaps. These modifications effectively froze F in its prefusion shape. When tested on mice, the results were clear—the vaccine elicited the highest levels of neutralizing antibodies ever witnessed in three decades of RSV research by Barney Graham. McLellan recalls thinking, “This is it.”
Pharmaceutical companies quickly came calling, igniting a race to deliver an effective vaccine. Today, both Pfizer and GlaxoSmithKline have gained FDA approval for RSV vaccines that target prefusion F, as has nirsevimab, the antibody shot for infants developed by AstraZeneca and Sanofi. These vaccines and the antibody shot trigger immunity to RSV—vaccines stimulate the body to produce its own antibodies, while nirsevimab provides a direct infusion of antibodies.
Trials for all three vaccines were already underway when the COVID-19 pandemic struck. However, due to the near eradication of RSV during the implementation of social distancing measures, these trials experienced delays. Meanwhile, McLellan and Graham applied a similar molecular technique to stabilize COVID’s spike protein, which Pfizer and Moderna incorporated into their vaccines. While stabilization wasn’t a make-or-break requirement for COVID vaccines as it was for RSV, it still holds potential for addressing other viruses with unstable fusion proteins. McLellan, now at the University of Texas at Austin, is investigating vaccines targeting the prefusion structure of other persistent viruses, such as cytomegalovirus and Crimean-Congo hemorrhagic fever. This structure-based vaccine design approach has the power to revolutionize our ability to combat elusive viruses.
As we approach the fall and winter seasons, the real test for these new RSV vaccines will be how well they perform in the real world. Vaccines alone don’t save lives; it is the act of vaccination that truly makes a difference. Ann Falsey, a specialist in studying RSV in the elderly at the University of Rochester, expresses concern over the limited uptake of the new vaccines among Americans aged 60 and over. While the CDC advisory panel allows elderly individuals to receive the vaccines through shared clinical decision-making with their doctors, it falls short of issuing a full recommendation that would trigger private insurers to cover the cost of the shots under the Affordable Care Act. The out-of-pocket expense for these shots can exceed $300. However, the impact of these vaccines is expected to be significant for infants. The CDC has already endorsed Pfizer’s vaccine for pregnant women, and the antibody shot, nirsevimab, for newborns. Most babies will only require one or the other. The existing RSV antibody shot, palivizumab, which targets a less potent site on both prefusion and postfusion F, will be replaced by nirsevimab. Due to its superior efficacy and the need for only one dose per season (compared to up to five doses for palivizumab), nirsevimab holds promise for wider adoption. According to Mejías from St. Jude Children’s Research Hospital, “It’s going to change the way we manage and treat RSV.” Nirsevimab is expected to be available for babies starting from October, and if everything goes according to plan, pediatric ICUs might experience a quieter winter season.
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