With dozens of respiratory syncytial virus vaccines and monoclonal antibodies in development, many experts agree that the next decade may finally bring new tools to prevent this major global respiratory pathogen.
Infectious Diseases in Children asked four experts — Pedro A. Piedra, MD, a professor virology, microbiology and pediatrics at Baylor College of Medicine; Jennifer E. Schuster, MD, MSCI, a pediatric infectious disease specialist at Children’s Mercy Kansas City and assistant professor of pediatrics at the University of Missouri-Kansas City School of Medicine; John V. Williams, MD, chief of the division of pediatric infectious diseases at UPMC Children's Hospital of Pittsburgh; and Peter F. Wright, MD, professor of pediatrics at the Geisel School of Medicine at Dartmouth — who would most benefit from an RSV vaccine, and why.
To learn more about RSV vaccine development, read our cover story.
Piedra: RSV is the major global respiratory pathogen affecting children aged younger than 5 years and is the leading cause of pneumonia and bronchiolitis in young children. Almost half of the deaths occur in children aged younger than 6 months, and most RSV-related hospitalizations occur within the first 6 months of life, peaking in the second and third months when maternal antibody is decaying.
Since its discovery in 1956, epidemiological studies quickly identified RSV as an important respiratory pathogen in young children. In the mid-1960s, the first major vaccine trials were conducted with a formalin-inactivated, alum-precipitated RSV vaccine that resulted in enhanced respiratory disease in children aged younger than 2 years upon subsequent infection with RSV. This enhanced respiratory disease phenomenon dampened the enthusiasm to develop RSV vaccines for infants for many years.
Over the ensuing 60 years, there have been major knowledge gains in the epidemiology, pathogenesis, immunology, molecular virology and regulatory science for RSV that has guided vaccinology to new levels. High quantities of RSV-specific neutralizing antibodies administered either as an IV immunoglobulin or monoclonal antibody preparation were shown to be effective against preventing severe RSV infection in infants. These clinical trials provided a road map for immunization strategies that targeted infants during their first 6 months of life by maternal immunization or the use of highly potent monoclonal antibodies.
Pedro A. Piedra
The maternal immunization approach with an RSV-F vaccine is currently completing a phase 3 trial in pregnant mothers to protect infants against RSV lower respiratory tract infection (LRTI) with hypoxemia for at least the first 90 days of life. The results of an interim efficacy analysis are expected early in 2019. In a phase 2b trial, a highly potent monoclonal antibody with an extended half-life is being evaluated in healthy preterm infants who are between 29 and 35 weeks’ gestational age and entering their first RSV season for the prevention of medically attended RSV LRTI.
Other vaccine approaches targeting young infants are in early stage (phase 1) clinical development, with live RSV vaccines or later stage (phase 2) clinical development with a recombinant vector vaccine approach.
These are promising times in that RSV vaccines and highly potent, extended half-life monoclonal antibody have advanced to late-stage clinical development for the prevention of RSV LRTI in infants. There is a high level of enthusiasm that these interventions will be shown to be well-tolerated, safe and highly effective against moderate to severe RSV disease in healthy infants. In addition, these products, if licensed by the regulatory agencies, will need to be made affordable and with equitable access to the global community for the prevention of RSV-related mortality and morbidity in infants.
Schuster: RSV is a leading cause of medically attended acute respiratory illness in both children and adults aged older than 65 years, and the virus circulates annually. Primary infection typically occurs in infants and toddlers, but reinfection can occur throughout life and adults are also at risk of RSV-related morbidity and mortality. RSV is a well-suited target for vaccine development due to annual epidemics, reinfection throughout life and high morbidity and mortality among a broad range of hosts, including young children and older adults. Many vaccines are currently undergoing investigational trials.
The largest impact of RSV disease occurs in young children. In children aged younger than 5 years, RSV causes more than 2 million outpatient visits and greater than 57,000 hospitalizations annually. The majority of infected outpatient and hospitalized children are aged younger than 24 months, with hospitalization rates averaging 5.2 per 1,000 children. Most children hospitalized with RSV infection (66%-79%) were previously healthy, suggesting that an effective vaccine would likely have broad benefit to all young infants, in addition to high-risk infants, such as those with prematurity or underlying cardiopulmonary diseases. However, vaccination would need to start early in infancy to provide optimal protection to young infants.
Jennifer E. Schuster
Maternal immunization is an alternate strategy focused on protecting the youngest infants. Children younger than 6 months have the highest rate of hospitalizations (17 per 1,000 children), and hospitalization rates continue to increase as age decreases. The highest hospitalization rates occur in children aged younger than 1 month — a population that would not benefit from infant immunization but may benefit from maternal immunization. RSV antibody is effectively transferred from mother to infant transplacentally after maternal infection, so passive immunity from maternal RSV immunization, similar to maternal pertussis immunization, may be protective for infants who are too young to receive an infant RSV vaccine series. Additionally, RSV is a leading cause of febrile acute lower respiratory tract infection in pregnant women. Therefore, maternal immunization could be a beneficial strategy by providing both active and passive immunity, to mother and infant respectively.
Although RSV is commonly thought of as a childhood disease, adults have high rates of morbidity and mortality, with 177,000 hospitalizations and 14,000 deaths occurring annually in adults aged 65 years or older. In older and high-risk adults, the burden of disease in hospitalized patients rivals influenza A; in a large cohort, 15% of RSV-infected patients required intensive care and 8% died. Thus, older and high-risk adults remain another group that may benefit from an RSV vaccine.
This is an exciting time in the field of RSV. With many new vaccines in the development pipeline, we are getting closer to having an effective agent against this disease. However, further epidemiological studies are needed to determine the optimal target populations for these preventive measures.
Williams: The most severe disease resulting from RSV occurs in very young infants and high-risk children, such as those who were born prematurely or have asthma or heart disease, adults older than 65 years who may have underlying health conditions and immunocompromised patients.
There are several different patient populations that suffer from severe and fatal RSV disease, but part of the challenge is that one vaccine type cannot protect all of these different groups due to different immune responses.
The peak age of hospitalization for RSV of otherwise healthy infants in the United States is around 2 to 3 months of age. These infants would be a key group to protect. The best approach is probably maternal vaccination, as is done for tetanus and pertussis. In these cases, we do not immunize the babies; we immunize the mothers during pregnancy.
Older infants and children with risk factors including heart and lung disease, congenital heart disease, asthma and cystic fibrosis might receive different vaccines later during the first year of life. This group would begin vaccinations between 2 and 6 months of age.
John V. Williams
The other major risk group who should be a target of a vaccine are older adults with underlying health problems like emphysema and heart disease. This is a growing group as the baby boomers retire and we get more and more older adults.
Although different vaccines may be needed for these different groups, there is precedent for this. An example is the shingles vaccine for older adults that has been marketed for several years. It is essentially a more potent version of the childhood chickenpox vaccine.
It is likely that the vaccine for older adults would be different than what would be developed for children and is quite possible that there could be two or three different vaccines.
To protect the youngest infants, you need a vaccine that can be used late in pregnancy. Safety is extremely important because of pregnancy. Live vaccines are typically not used in pregnant women.
However, in older infants or adults, a live vaccine might be more effective than a non-live or a killed vaccine.
Older adults might need a more potent, stronger vaccine than the younger infants and children, similar to the shingles vaccine. The other challenge in developing a vaccine for older adults is that this population has been infected with RSV throughout their lifetime, so there is some immunity developed but not necessarily enough to protect them. This could affect the development of a vaccine for this population.
In summary, key target groups of RSV vaccine have significantly different immune responses and safety concerns; therefore, it is likely that two or three different vaccines and vaccination strategies may be needed.
Several companies are conducting vaccine trials right now, with several in phase 1 and 2 and at least one in phase 3 development. It is possible that a licensed vaccine could be on the market within 5 years, but it is likely that a vaccine will be available within 10 years
Wright: Who should be targeted? It depends on the ultimate formulation of the successful vaccine. We do not have any vaccines that have been proven to work at this point.
For a universal vaccine strategy, several scenarios are being studied. One is maternal immunization alone. Another is infant immunization, and a third is a combined maternal and infant immunization.
One strategy might be maternal immunization alone to try to enhance the level of antibody in the infant after birth and prevent more serious disease. The second would be to immunize infants directly at a fairly young age, because most of the hospitalizations for RSV occur within the first 6 months of life, and many of them within the first 3 months of life.
The third would be to combine maternal and infant immunization, in which a mother would be immunized in the third trimester of pregnancy so that her antibody level at the time of birth would, in turn, transfer to the infant across the placenta. The infant’s antibody levels would be higher in the first 2 months of life, which is thought to provide protection against more serious RSV disease. A vaccine would then be given to infants to further boost their immunity.
Peter F. Wright
The universal vaccine strategy would be based on which approach is the most effective.
There could be room for more than one vaccine or one strategy, but ultimately, one of these vaccine strategies would be proven to be the most effective. And that would become the vaccine approach of choice.
It will probably be at least 10 years before we have a vaccine that is licensed and is in regular use. We will learn considerably earlier if one of these vaccine approaches is really going to be effective. But, subsequent steps, including larger trials to determine safety and manufacturing capacity in in the U.S. and perhaps globally will take time.
Because RSV illness is almost universal in young children, with roughly 50% of children becoming infected in the first year of life, a very substantial number of them present with illness in one of three ways. They require a visit by their pediatrician, they come to EDs or they are hospitalized.
This is an illness that quite predictably occurs in a very seasonal basis, during the winter months in the U.S. Elsewhere in the world, the RSV season may vary. There are recognized risk factors, including prematurity and underlying cardiovascular disease that influence the risk of more serious disease.
Although RSV is not a common cause of mortality in the U.S., it has a substantial economic and medical burden on the basis on the frequency of the illness.
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Disclosures: Piedra reports receiving grant support and serving as a scientific adviser for Novavax; receiving grant support from Janssen; being a member of the data and safety monitoring board of Pfizer; serving as a scientific adviser for AstraZeneca and Sanofi-Pasteur; and serving as an adviser for Merck. Schuster reports that she expects to receive research support for RSV-related clinical trials from Janssen and Merck. Williams reports being on the scientific advisory board for Quidel Corporation and serving on an independent data monitoring committee for GlaxoSmithKline. Wright reports serving as a consultant on the scientific boards of several companies working toward developing an RSV vaccine, including GlaxoSmithKline and Sanofi Pasteur.