Megan Smith was particularly aware of the threat COVID posed to her 6-week-old daughter in October 2021. Megan Smith, now 36, from Buffalo, New York, said she was “doing everything she could to protect her daughter.” But she says it wasn’t her COVID that ultimately sent her baby to the hospital, but a more common virus that infects nearly everyone by her second birthday, the respiratory syncytial virus ( RSV).
Smith’s daughter required hospitalization and intubation for this respiratory virus that infects the nose, throat, lungs and respiratory tract. “I was totally unprepared for this,” said Smith, who was surprised to learn she had no treatment for RSV other than supportive care and oxygen. Her daughter recovered, but Smith hoped a vaccine would help her with her stress and her heartache.
Scientists have been working on an RSV vaccine since soon after the virus was discovered in 1956, but the 1960s saw several disastrous clinical trials and dozens of failed vaccine attempts. , until recently, progress was hampered. The U.S. Food and Drug Administration’s Vaccines and Related Biologics Advisory Committee (VRBPAC) announced on February 28 and March 1 that two RSV vaccines (one from GlaxoSmithKline , another from Pfizer) to recommend FDA approval. The FDA, which normally follows VRBPAC’s recommendations, expects to make a decision by May.
Two other new RSV vaccines, Moderna for the elderly and Pfizer for pregnant women, are moving toward FDA consideration this year. Regulators may also approve nirsevimab, a new long-acting monoclonal antibody that provides vaccine-like protection to infants for up to five months, the length of a typical RSV season. Nirsevimab is already approved in Europe.
This breakthrough in RSV vaccine research came when researchers solved a 50-year-old mystery about the virus by examining the shape of its proteins. This process has ushered in a new era of vaccine development using protein structure-based vaccine design, the same approach that has enabled the rapid development of COVID vaccines.
tragic history
For most people, RSV is just a nasty cold with symptoms like coughing, sneezing, wheezing, runny nose and fever. However, because it poses a risk to young infants, the elderly, immunocompromised individuals, and those with chronic heart and lung disease, it became a target for early vaccines. Elderly people are hospitalized with RSV, resulting in 100-500 children and approximately 14,000 elderly deaths. Costing the United States more than $1 billion annually, the disease is the leading cause of hospitalization for infants.
In 1966, ten years after the discovery of the virus, four clinical trials tested inactivated virus vaccines in children who had never been infected with RSV. To the scientist’s horror, one study found that 80% of vaccinated children were hospitalized when he later became infected with the virus itself, and two infants (a 14-month-old and his 16-year-old) were hospitalized later. month) died. Hospitalization rates for RSV are typically in the single digits, according to pediatrician Ruth Caron, director of the Center for Immunization Research at Johns Hopkins University. Death from RSV can occur in otherwise healthy children, but it is most likely within the first six months of life.
“As you can imagine, this kind of vaccine development has stalled for a very long time,” says Karon. “You took a pathogen that still didn’t kill many children and killed children.”
For the next two decades, RSV vaccine progress stagnated. Researchers needed to know what went wrong in the 1960s. This mystery was not solved until 2008 when Fernando P. Pollack, founder of the Infant Foundation in Argentina, and Johns and his team at Hopkins University published a study. natural medicine It explains that the antibodies produced by the vaccinated child’s immune system did not bind the virus tightly enough. Instead, the antibodies attracted dead viruses, triggering a dangerous cascade of abnormal immune responses, causing severe inflammation in the lungs and making children sicker than they would have been without the pre-existing antibodies.
But big questions remain. Why didn’t these antibodies bind to the virus properly? A chance encounter later that same year led to the final piece of the puzzle needed to make an RSV vaccine a reality.
A tale of two protein shapes
In June 2008, Jason McLellan, now a molecular biologist at the University of Texas at Austin, had just completed his PhD. He earned his doctorate from Johns Hopkins University and began working as a postdoctoral fellow at the National Institutes of Health’s Center for Vaccine Research, where he now works with Bernie Graham, Senior Advisor for Global Health Equities at Morehouse College of Medicine. I met. While Graham has dedicated his career to researching RSV, his McLellan, which specializes in mapping the atomic structure of proteins, is interested in working on something “a little off the radar.” , says Graham. “Well, we don’t have any information about the structure of the RSV yet,” he told his McLellan. Graham was particularly interested in the F protein, which is the primary target for RSV vaccine development. The F protein is an antigen, part of a pathogen that the immune system recognizes as a threat and makes antibodies.
The idea piqued McClellan’s interest. “RSV has emerged as one of the major pediatric pathogens for which no vaccine has yet been developed. I was ambitious,” he says.
Finding the structure of the paired target F protein will be key to a successful vaccine. However, the F protein is not stable: when the F protein fuses with cells, it changes shape when the virus enters and hijacks the cell so that it can replicate. Antibodies against the post-fusion form produced by do not neutralize the circulating form of the virus long before the virus binds to the cell. However, if a vaccine can induce antibodies against the pre-fusion form, it may bind appropriately to the active form of the virus. The trick was understanding what that pre-fusion protein looks like and how it locks into that shape.
By 2010, McLellan had determined the structure of the post-fusion protein using a structural imaging technique called X-ray crystallography. He then turned to the pre-fusion structure so that he and his team could compare the pre-fusion and post-fusion structures and understand how to keep the morphology unchanged. Working with Chinese researchers, McLellan and Graham tested over 2,000 mouse antibodies that effectively neutralize or deactivate the pre-fusion F protein without binding to the post-fusion F protein. (thereby eliminating the risk of hyperinflammatory reactions caused by the RSV vaccine). court in the 1960s). The winning antibody was approximately 50 times more potent than the only existing FDA-approved antibody against RSV. The researchers then used a recently discovered human antibody that closely resembles the murine antibody to determine the pre-fusion structure of the F protein and how it is chemically maintained.
“Once we had that structure, everything worked really well,” says Graham. “Suddenly we have a new, highly vulnerable target for the virus to make a vaccine for.”
His team spent the next three years learning how to grow the cells that produce the pre-fusion protein and purify it. His first Phase 1 trial began in 2017, with promising results two years later.
By then, the pharmaceutical industry had taken over development, so “the RSV vaccine had a life of its own,” says Graham. McClellan, on the other hand, focused on the coronavirus. RSV’s research eventually paved the way for determining the spike protein structure of his SARS-CoV-2, the virus that causes COVID, and allowed Moderna, Pfizer, and other companies to test his COVID-19 in record time. enable vaccine development. Beginning with elucidating the protein structure of pathogens and building vaccines around them, the era of protein structure-based vaccine design began.
A vaccine on the horizon
The fruits of that effort are becoming apparent as the FDA begins reviewing several applications for RSV prevention products. At present, there are only two ways to prevent RSV. Palivizumab, a short-acting monoclonal antibody that provides passive immunity to infants, along with normal hygiene practices (such as wearing a mask, washing hands, and avoiding sick people) used to prevent the common cold. Up to 1 month at a time. Passive immunity refers to protection from antibodies made outside the individual’s body, such as drugs such as palivizumab or antibodies transferred from a pregnant woman to the fetus during pregnancy.
However, palivizumab is expensive, costing about $1,844 per dose in the United States. Also, multiple doses are needed as one dose he only lasts a month (a typical RSV season he lasts 5-6 months). Although the drug is licensed for preterm infants born before 35 weeks and under 6 months of age at the start of the RSV season, cost-effectiveness studies suggest that the American Academy of Pediatrics recommends antibody use among these infants. It is recommended to limit to the most vulnerable state in . .
In March 2022, AstraZeneca and Sanofi announced that their long-acting antibody nirsevimab was 75% effective and protective in RSV cases requiring medical attention in infants under one year of age with no history of RSV. announced that it will last for 5 months. A similar long-acting monoclonal antibody, clesrovimab, manufactured by Merck, is in Phase 3 trials.
Shortly after the March 2022 announcement, news broke about several vaccine trials. Pfizer said in August that a single-dose vaccine currently approved by VRBPAC was 86% effective against severe disease with at least 3 symptoms in adults aged 60 and older, and was 86% effective against symptomatic disease (at least 2 reported to be 67% effective against symptomatic illnesses). old. Pfizer also announced last November that the maternal RSV vaccine (intended to be administered during pregnancy so that maternal antibodies provide passive immunity) is effective against severe RSV in newborns by up to three Pfizer’s vaccine is pending priority review by the FDA, and unspecified safety concerns have prompted GlaxoSmithKline to initiate a maternal vaccine trial. It is the only vaccine for adults during pregnancy since it was discontinued.
GlaxoSmithKline announced last October that its vaccine is 94% effective against severe disease and 83% effective against symptomatic disease in adults over 60 years of age. Most recently, Moderna announced in his January that his mRNA-based RSV vaccine was 84% effective against symptomatic disease in adults over the age of 60. His two other vaccines for the elderly, manufactured by Bavarian Nordic and Janssen, are in Phase 3 trials.
None of these vaccines are for neonates, but there are very few neonatal vaccines, Karron notes. And his two of these interventions, the antibody nirsevimab and Pfizer’s maternal vaccine, will be used as long as health officials can determine the most appropriate way to recommend infants when they are most at risk. You can protect your baby.
“You don’t need both to protect your baby,” Karon says. However, it is unclear what the CDC recommends if infants may be protected by vaccines during pregnancy or postnatal antibody drugs. “In our fragmented health care system, he can’t easily swap between these two products offered by different providers,” he says.
Another challenge is ensuring the protection of children from low-income families. These children are already more vulnerable to worse outcomes from RSV. The U.S. Children’s Vaccines Program ensures that all eligible children receive her CDC-recommended vaccines, but the program does not include adult pregnancy vaccines or prophylactic monoclonal antibodies. Is not … “The last thing you want to do is exclude VFC-targeted babies from protection from maternal vaccines and monoclonal antibodies,” he says.
Still, by the end of 2023, for the first time in half a century since scientists began working, it is very likely that older adults and infants will have at least one highly effective option to reduce their risk of RSV. . That possibility is meant to ease the minds of parents like Smith, who says he would have been happy to get his mother’s vaccine if it had been available, as his daughter contracted her RSV. About this, Smith says:
