‘Extremely satisfying’: Scientist’s insight powers new RSV vaccine for infants | Science
Barney Graham, a former scientist at the U.S. National Institute of Allergy and Infectious Diseases (NIAID), was thrilled yesterday when Pfizer announced encouraging results from an experimental vaccine that could protect against a major childhood killer. In a press release, the company said immunizing pregnant women* with its vaccine against respiratory syncytial virus (RSV) protected their babies from severe disease for 6 months. If the full results of its clinical trial bear out that promise, the vaccine could spare millions of infants worldwide from RSV-related hospitalization, reduce lasting lung damage from the virus, and help prevent some of the estimated 120,000 childhood deaths the viruses cause annually. The Pfizer news represents a personal milestone for Graham because his NIAID team made a fundamental discovery about vaccine design that’s used in its RSV shot, as well as in approved or potential vaccines for COVID-19 and other infectious diseases.
Vaccine development for RSV was derailed after a trial of a candidate in 1966 led to two deaths and the hospitalization of 80% of the infants who received the product, which contained an inactivated version of the entire virus. But Graham, who began working on RSV in 1985 when he was a 32-year-old clinician, created a safer, more potent vaccine that only contains the RSV surface protein known as F.
The F protein rearranges its structure when the virus infects and fuses with a cell. Graham, who is now at the Morehouse School of Medicine, led an NIAID team that designed a molecular strategy to lock F into its original, “prefusion” configuration, stimulating the most powerful antibody responses. Graham’s NIAID group made a similar modification to the SARS-CoV-2 surface protein, spike, which was adopted by Moderna, Pfizer, and other companies in their designs of COVID-19 vaccines.
In Pfizer’s trial, which is taking place in 18 countries, 7400 pregnant people received one dose of “RSVpreF” or a placebo shot during their late second or third trimester. Mothers naturally transfer the RSV antibodies stimulated by the vaccine to their fetuses. An independent committee monitoring the data recommended the trial stop enrolling people because the study had met one of two of its primary endpoints, but Pfizer will continue to track their infants, some 7000 so far.
In the interim analysis, within a newborn’s first 90 days, the vaccine had an efficacy of 81.8% against severe lower respiratory tract illness that required medical care. At 6 months, the efficacy dropped to 69.4%. The shot did not have a significant impact on infant doctor visits related to respiratory disease: Efficacy was 57.1% at 90 days and 51.3% over 6 months. Still, Graham says, “Those are the best data for RSV vaccines and babies.” (Graham has a patent on the RSV F design and stands to receive royalties if the vaccine reached the market. After leaving NIAID last year, he also began consulting with Pfizer and several other vaccine companies.)
Pfizer will reveal more when it publishes the results, and it plans to file for approval for the vaccine from the U.S. Food and Drug Administration (FDA) before the end of the year.
Both Pfizer and GSK this year have also reported positive results with RSV vaccines given to elderly people, also based on Graham’s innovation. Those data are at various stages of being reviewed by FDA, as well as regulators in Europe and Japan. A recent study of the global impact of RSV infections in older adults estimated it leads to 336,000 hospitalizations and 14,000 in-hospital deaths.
Graham spoke yesterday with Science about the RSV prevention field. In addition to vaccines, a monoclonal antibody, palivizumab, is now on the market to prevent infections in high-risk infants and another, called nirsevimab, is not yet approved but may be even better based on phase 3 trial data. All told, he’s excited at the prospects of helping curb this devastating disease, which is now surging around the world after a lull because of COVID-19 lockdowns and precautions. This interview has been edited for brevity and clarity.
Q: What’s a big picture overview of the RSV vaccine field?
A: The big things that are happening are that the F glycoprotein vaccines, the ones that we first described in 2013, are finally coming through the system and finishing phase 3 trials for both maternal immunization and for elderly immunization. [The 2013 paper made Science’s list of top 10 breakthroughs that year.] It’s extremely gratifying for me to see how basic research can lead to products if it all makes sense biologically. It’s a fun time.
Q: What percentage of children in the in the world get RSV in their first year of life?
A: Probably a little over half, and virtually everyone is infected by their second year of life and everyone is definitely affected by the third year of life. The most severe diseases are very young, under 6 months of age. So both this type of vaccine and the new nirsevimab antibody from AstraZeneca and Sanofi, which would be given at birth, will have a major impact on overall lung health.
Q: What’s the promise of the maternal vaccination strategy that may not be obvious just from looking at Pfizer’s raw efficacy data?
A: We think the goal of RSV vaccines in this country is to keep babies out of the hospital, and in low- and middle-income countries that don’t have the kind of support we do, to keep them from dying. But the bigger goal is to improve overall lung health of infants. If they’re infected with RSV very early in life and develop severe disease, that affects their lung development and overall lung health probably for their lifetime. So the goal here is to really improve overall lung health and that is something that’s hard to calculate until you’ve seen it evolve over several years.
Q: How do you compare the nirsevimab efficacy with the report from the maternal Pfizer vaccine?
A: When you give antibody directly to the infant, the results are similar.
Q: Social distancing and masking led to big drops in RSV transmission during the pandemic. Do you have any concern about this study taking place in this time frame, which meant the mothers had less exposure to RSV—and therefore fewer natural boosts to immunity—which could have exaggerated the impact of the vaccine? The babies also had fewer infections.
A: It certainly made the trials more difficult to do for the companies. It was a difficult set of adjustments all the companies were making to keep the trials going until they had enough cases to actually make a judgement. The mothers probably weren’t exposed to as much RSV as they ordinarily would have been, but these women have already been infected at least a half dozen times probably.
Q: How do you compare vaccinating the mother to vaccinating the infant? And what do we know from studies that have vaccinated infants directly?
A: Active immunization of young children has been complicated. The old vaccine in the mid ’60s caused vaccine-enhanced disease that really prevented and delayed vaccine development for many, many decades. There are other products coming along that are going to be targeting the 6- to 12-month-old infant, but the current vaccines have just not gotten there.
Q: Your work with the prefusion design of the F protein was to prevent the enhancement, right?
A: The enhancement is a complicated story and we think we understand parts of it. It’s like looking through a mirror darkly type of understanding. There is an antibody problem and a T cell problem. The antibody problem was that you were making a lot of antibody that didn’t have very good functional activity at blocking or neutralizing the virus. And that led to a deposition of immune complexes and activation of complement [an immunologic cascade of proteins and chemical messengers] that damaged the airways. The vaccine also triggered a T cell problem that added to airway obstruction and lack of clearance of the virus. The F protein in its prefusion form takes care of the antibody problem because now you’re making very high-efficiency, high-potency antibodies that neutralize well. The T cell part of the equation is not as well established in humans. And so that’s why it’s taken longer to get back into the young infants.
Q: Why aren’t these potential side effects caused by the T cell response a major concern in the elderly, who also are a vulnerable population?
A: The elderly have been infected so many times with RSV already that they’re already primed. So you’re really just boosting them with the vaccine, and that’s safe. The same is true of the maternal immunization.
Q: How does the vaccine response compare in the mother with a natural exposure to RSV that boosts their antibodies?
A: The vaccine boosts way, way higher than a natural exposure to the live virus.
Q: How long do the vaccine-induced antibodies last after maternal transfer?
A: You get at least an additional 4 to 5 months over what mothers normally would have. We think that would give protection for around 6 months.
Q: I imagine that at this point in your career, you’re feeling a lot of satisfaction that your life’s work is paying off and actually doing something as opposed to just publishing papers.
A: I think the RSV successes are even, in many ways, more special to me than the coronavirus one because this is where everything started from.
Barney Graham, a former scientist at the U.S. National Institute of Allergy and Infectious Diseases (NIAID), was thrilled yesterday when Pfizer announced encouraging results from an experimental vaccine that could protect against a major childhood killer. In a press release, the company said immunizing pregnant women* with its vaccine against respiratory syncytial virus (RSV) protected their babies from severe disease for 6 months. If the full results of its clinical trial bear out that promise, the vaccine could spare millions of infants worldwide from RSV-related hospitalization, reduce lasting lung damage from the virus, and help prevent some of the estimated 120,000 childhood deaths the viruses cause annually. The Pfizer news represents a personal milestone for Graham because his NIAID team made a fundamental discovery about vaccine design that’s used in its RSV shot, as well as in approved or potential vaccines for COVID-19 and other infectious diseases.
Vaccine development for RSV was derailed after a trial of a candidate in 1966 led to two deaths and the hospitalization of 80% of the infants who received the product, which contained an inactivated version of the entire virus. But Graham, who began working on RSV in 1985 when he was a 32-year-old clinician, created a safer, more potent vaccine that only contains the RSV surface protein known as F.
The F protein rearranges its structure when the virus infects and fuses with a cell. Graham, who is now at the Morehouse School of Medicine, led an NIAID team that designed a molecular strategy to lock F into its original, “prefusion” configuration, stimulating the most powerful antibody responses. Graham’s NIAID group made a similar modification to the SARS-CoV-2 surface protein, spike, which was adopted by Moderna, Pfizer, and other companies in their designs of COVID-19 vaccines.
In Pfizer’s trial, which is taking place in 18 countries, 7400 pregnant people received one dose of “RSVpreF” or a placebo shot during their late second or third trimester. Mothers naturally transfer the RSV antibodies stimulated by the vaccine to their fetuses. An independent committee monitoring the data recommended the trial stop enrolling people because the study had met one of two of its primary endpoints, but Pfizer will continue to track their infants, some 7000 so far.
In the interim analysis, within a newborn’s first 90 days, the vaccine had an efficacy of 81.8% against severe lower respiratory tract illness that required medical care. At 6 months, the efficacy dropped to 69.4%. The shot did not have a significant impact on infant doctor visits related to respiratory disease: Efficacy was 57.1% at 90 days and 51.3% over 6 months. Still, Graham says, “Those are the best data for RSV vaccines and babies.” (Graham has a patent on the RSV F design and stands to receive royalties if the vaccine reached the market. After leaving NIAID last year, he also began consulting with Pfizer and several other vaccine companies.)
Pfizer will reveal more when it publishes the results, and it plans to file for approval for the vaccine from the U.S. Food and Drug Administration (FDA) before the end of the year.
Both Pfizer and GSK this year have also reported positive results with RSV vaccines given to elderly people, also based on Graham’s innovation. Those data are at various stages of being reviewed by FDA, as well as regulators in Europe and Japan. A recent study of the global impact of RSV infections in older adults estimated it leads to 336,000 hospitalizations and 14,000 in-hospital deaths.
Graham spoke yesterday with Science about the RSV prevention field. In addition to vaccines, a monoclonal antibody, palivizumab, is now on the market to prevent infections in high-risk infants and another, called nirsevimab, is not yet approved but may be even better based on phase 3 trial data. All told, he’s excited at the prospects of helping curb this devastating disease, which is now surging around the world after a lull because of COVID-19 lockdowns and precautions. This interview has been edited for brevity and clarity.
Q: What’s a big picture overview of the RSV vaccine field?
A: The big things that are happening are that the F glycoprotein vaccines, the ones that we first described in 2013, are finally coming through the system and finishing phase 3 trials for both maternal immunization and for elderly immunization. [The 2013 paper made Science’s list of top 10 breakthroughs that year.] It’s extremely gratifying for me to see how basic research can lead to products if it all makes sense biologically. It’s a fun time.
Q: What percentage of children in the in the world get RSV in their first year of life?
A: Probably a little over half, and virtually everyone is infected by their second year of life and everyone is definitely affected by the third year of life. The most severe diseases are very young, under 6 months of age. So both this type of vaccine and the new nirsevimab antibody from AstraZeneca and Sanofi, which would be given at birth, will have a major impact on overall lung health.
Q: What’s the promise of the maternal vaccination strategy that may not be obvious just from looking at Pfizer’s raw efficacy data?
A: We think the goal of RSV vaccines in this country is to keep babies out of the hospital, and in low- and middle-income countries that don’t have the kind of support we do, to keep them from dying. But the bigger goal is to improve overall lung health of infants. If they’re infected with RSV very early in life and develop severe disease, that affects their lung development and overall lung health probably for their lifetime. So the goal here is to really improve overall lung health and that is something that’s hard to calculate until you’ve seen it evolve over several years.
Q: How do you compare the nirsevimab efficacy with the report from the maternal Pfizer vaccine?
A: When you give antibody directly to the infant, the results are similar.
Q: Social distancing and masking led to big drops in RSV transmission during the pandemic. Do you have any concern about this study taking place in this time frame, which meant the mothers had less exposure to RSV—and therefore fewer natural boosts to immunity—which could have exaggerated the impact of the vaccine? The babies also had fewer infections.
A: It certainly made the trials more difficult to do for the companies. It was a difficult set of adjustments all the companies were making to keep the trials going until they had enough cases to actually make a judgement. The mothers probably weren’t exposed to as much RSV as they ordinarily would have been, but these women have already been infected at least a half dozen times probably.
Q: How do you compare vaccinating the mother to vaccinating the infant? And what do we know from studies that have vaccinated infants directly?
A: Active immunization of young children has been complicated. The old vaccine in the mid ’60s caused vaccine-enhanced disease that really prevented and delayed vaccine development for many, many decades. There are other products coming along that are going to be targeting the 6- to 12-month-old infant, but the current vaccines have just not gotten there.
Q: Your work with the prefusion design of the F protein was to prevent the enhancement, right?
A: The enhancement is a complicated story and we think we understand parts of it. It’s like looking through a mirror darkly type of understanding. There is an antibody problem and a T cell problem. The antibody problem was that you were making a lot of antibody that didn’t have very good functional activity at blocking or neutralizing the virus. And that led to a deposition of immune complexes and activation of complement [an immunologic cascade of proteins and chemical messengers] that damaged the airways. The vaccine also triggered a T cell problem that added to airway obstruction and lack of clearance of the virus. The F protein in its prefusion form takes care of the antibody problem because now you’re making very high-efficiency, high-potency antibodies that neutralize well. The T cell part of the equation is not as well established in humans. And so that’s why it’s taken longer to get back into the young infants.
Q: Why aren’t these potential side effects caused by the T cell response a major concern in the elderly, who also are a vulnerable population?
A: The elderly have been infected so many times with RSV already that they’re already primed. So you’re really just boosting them with the vaccine, and that’s safe. The same is true of the maternal immunization.
Q: How does the vaccine response compare in the mother with a natural exposure to RSV that boosts their antibodies?
A: The vaccine boosts way, way higher than a natural exposure to the live virus.
Q: How long do the vaccine-induced antibodies last after maternal transfer?
A: You get at least an additional 4 to 5 months over what mothers normally would have. We think that would give protection for around 6 months.
Q: I imagine that at this point in your career, you’re feeling a lot of satisfaction that your life’s work is paying off and actually doing something as opposed to just publishing papers.
A: I think the RSV successes are even, in many ways, more special to me than the coronavirus one because this is where everything started from.
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