What's Next in Development of RSV Vaccines for Children?
How much progress have we made in developing therapies to treat this common childhood respiratory disorder?
Acute respiratory infections caused by human respiratory syncytial virus (RSV) are widespread and cause significant morbidity and mortality for children worldwide. A recent analysis suggested over 33 million worldwide RSV infections in children annually and that RSV-attributed illnesses account for 2% of all-cause mortality in children under 5 years.1 The development of preventive therapies has been a priority since the virus was first identified in the 1950s. While the science underlying RSV vaccines has progressed substantially, that progress is only now starting to bear fruit.2 Arexvy, the first ever RSV vaccine in 50 years of vaccine development, was authorized by the FDA in May 2023 for use in older adults. Fortunately for families of children at risk for RSV, a pediatric vaccine may soon follow. This article will explore the current landscape of RSV vaccines in development for pediatric patients; candidates for adult vaccination, as well as monoclonal antibodies and passive immunization will not be discussed, although monoclonal antibodies remain a valuable target for prevention of RSV infections in infants and children.
Impact of COVID-19 on RSV epidemiology
RSV typically follows a seasonal epidemic pattern of transmission, with spikes in the fall/winter in temperate regions such as North America.3 The typical epidemiological pattern of RSV infections was disrupted during the COVID-19 pandemic when rates of RSV infections dropped by as much as 90% in some regions and the seasonal peaks failed to materialize.4 This decline has been postulated as resulting from secondary effects from COVID-19 related nonpharmaceutical interventions such as social distancing and masking.5 The effects of rolling back these non-pharmaceutical interventions and other public health measures on RSV transmission are becoming clear. In 2022, transmission of RSV peaked earlier than previously seen and maintained high levels of transmission through late 2022.5 This early and prolonged period RSV activity may be attributable to an “immunity gap” of low RSV exposure during the pandemic years. It’s unclear whether these temporal shifts in RSV transmission will remain, but countries who loosened restrictions earlier and saw the “summer spike” in 2021 already have returned to winter seasonality in 2022.
Roadmap for RSV pediatric vaccination
The return to higher levels of RSV infection makes the development of viable RSV vaccines even more urgent. The World Health Organization’s strategic roadmap for RSV vaccines in infants and children prioritizes 2 approaches: (1) maternal immunization (MI) to protect neonates and young infants and (2) active pediatric immunization of infants and young children.6 Current vaccines in development follow this roadmap and utilize different technologies (eg, live-attenuated viruses, sub-unit particles, or vector-based vaccines) to produce immunity. Candidates for MI are closer to approval and will be discussed first.
Maternal immunization
RSV is more dangerous to neonates and infants than older children: of deaths attributable to RSV in children aged less than 5 years, 45% occur in infants under six months.1 The risk to neonates and infants is compounded by multiple factors: immature immune systems with an inability to generate lasting response to vaccination, potential inhibition of vaccine response by maternal antibodies, as well as concern for vaccine enhanced disease in unexposed infants. MI leading to placental transfer of antibodies sidesteps these problems and offers protection during the period of highest risk during infancy. MI has effectively reduced tetanus, pertussis, and influenza infections in young infants. There are two recent RSV vaccines candidates for MI; both target a stabilized pre-fusion F protein, a surface glycoprotein used to mediate fusion with host cells.
Pfizer published phase 3 data for its RSVpreF product in early 2023, citing an 82% (99.5% confidence interval [CI], 40.6-96.3) reduction in medically attended severe RSV-associated lower respiratory infection within 90 days of birth.7 Pfizer presented the safety and efficacy data to the Center for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) in February 2023 and will present its cost-effectiveness analysis to ACIP in June.8 The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) will meet on May 18, 2023 to discuss Pfizer’s application with a Prescription Drug User Fee Act (PDUFA) action date of August 2023. If licensed, a final decision by ACIP regarding Pfizer’s RSVpreF for MI is expected in October 2023. Of note, Pfizer’s RSV vaccine for older adults, which uses the same dose and formulation as the maternal vaccine, received a favorable review by the FDA’s VRBPAC in February 2023, has a PDUFA action date in May of this year, and will be voted on by ACIP in June.9
GlaxoSmithKline (GSK) also developed a pre-F RSV vaccine for maternal use that entered phase 3 trials in 2020 and has since been discontinued. Enrollment and ongoing vaccination were stopped in February 2022 after an internal safety review found an increased rate of preterm birth (6.81% vs 4.95%; RR 1.38 (95% CI 1.08-1.75; p-0.0090)) and increased, but not statistically significant number of neonatal deaths in the vaccine arm. No prior concerns were identified in Phase 1 or Phase 2 studies.10 GSK reported that, on review of individual cases, the imbalance in neonatal deaths was a consequence of the preterm birth imbalance rather than an independent safety signal.10 Ongoing monitoring of already enrolled study participants and a detailed safety review is underway.
Vaccination in older infants and children
Protection from maternal antibodies wanes after 6 to 12 months, limiting the potential impact of MI for older children. Furthermore, although neonates are at higher risk compared to older infants and children, 50% of the overall burden of RSV infections and mortality occurs in patients older than six months.1 As such, direct pediatric vaccination after the first 6 months of life remains a key target for RSV vaccine candidates. Fortunately, vaccine researchers have more potential approaches to pediatric vaccination compared to neonatal vaccination, which is reflected in the increased number and variety of candidates being developed.
Live attenuated vaccines
Live attenuated vaccines, while inappropriate for neonates and younger infants, may offer a pathway towards durable immunity in pediatric patients while avoiding the risk of vaccine-enhanced respiratory disease that can occur with non-replicating vaccines.11 Finding the balance between enough attenuation to ensure safety for patients without reducing immunogenicity remains difficult, and vaccine developers are trialing multiple vaccine platforms, delivery systems, and attenuation strategies to achieve this goal. Many of these needle-free candidates are in the early stages of development where trials are not large enough nor designed to assess efficacy. However, researchers are hopeful; a pooled estimate of pediatric Phase 1 data from five promising intranasal live attenuated candidates suggested efficacy of 66% for medically attended RSV infections (95% CI, 24-85).11
Meissa’s MV-012-968 is an intranasal live attenuated vaccine that attenuates virulence without attenuating replication to achieve a better efficacy/safety profile. Phase 1 data for RSV seronegative children aged 6-36 months showed stimulation of neutralizing antibody responses in 78% of 66 patients with no safety concerns identified.12 Codagenic, Inc.’s CodaVax-RSV candidate and Blue Lake’s BLB201 candidate, which are both intranasal live attenuated vaccines enrolling patients in Phase 2 studies, were approved for Fast Track designation by FDA, which combines increased regulatory support and accelerated review for promising candidates.13,14 Intravacc's intranasal candidate, which attenuates attachment of RSV to host cells, showed tolerance in healthy adults, and is awaiting further study in children.15 Investigators at the National Institute of Health (NIH), through separate collaborations with both Sanofi and MedImmune, have developed candidate vaccines that attenuate RSV viruses by removing different genes involved in viral replication: RSV/ΔNS2/Δ1313/I1314L (Sanofi) and LIDΔM2-2 1030s (MedImmune). Both candidates have demonstrated promising results from Phase 1 trials in young children.16,17 Researchers at Pontificia Universidad Catolica in Chile are also exploring a recombinant BCG vaccine expressing an RSV protein (rBCG-N-hRSV) with promising Phase 1 results in adult patients.18 BCG vaccination has been used to prevent tuberculosis meningitis in infants and may allow for immunization of younger patients.
mRNA vaccines
During the COVID-19 pandemic, novel messenger RNA (mRNA) vaccines were developed to prevent SARS-CoV-2 infections and were shown to be safe and effective in pediatric patients. Researchers are hoping to capitalize on this new vehicle for vaccine development as well as the public health investment in mRNA supply chains, storage, and distribution to develop a novel RSV vaccine. Moderna’s mRNA vaccine against RSV (mRNA-1345) successfully reduced infections in adults by 87%.19 The company will submit the vaccine for regulatory approval for adult patients in early 2023 and has fully enrolled Phase 1 studies to evaluate mRNA-1345's tolerance and safety in children.
Vector- based vaccines
Adenovirus vectors encoding genes for RSV proteins (specifically pre-fusion F protein) are thought to generate both humoral and cellular immune responses needed for durable protection against infection. The Adv26.RSV.preF vaccine developed by Janssen/ Johnson and Johnson showed promising results in older adults and generated safe, yet effective immune responses in pediatric patients in Phase 1 and 2 trials.20 However, in March 2023, Janssen and J&J discontinued their adult RSV vaccine program and discontinued the Phase 3 trial of Adv26.RSV.preF in adults following an internal review of their vaccine portfolios.21 If research into the use of Adv26.RSV.preF for pediatric patients continues, there will be increased focus on potential adverse effects: the adenovirus vector vaccine against SARS-CoV-2 developed by Janssen and J&J was associated with the rare but serious complication of vaccine-induced immune thrombotic thrombocytopenia and is not recommended for patients younger than 18 years.22
Cost effectiveness and global reach
Researchers have additional steps to prove safety and efficacy of these candidates for infants and children. Integrating a licensed vaccine into clinical practice will further require assessing a candidate’s cost-effectiveness and thoughtful, complex policy decisions. Will RSV vaccines be recommended for all children (like influenza vaccines) or limited to high-risk patients—the way palivizumab (Synagis) is used? Will RSV vaccines be deployed as adjuncts to existing preventive agents such as monoclonal antibodies or as replacements? Models suggest that cost-effectiveness will be determined by characteristics of individual vaccines (including product costs and delivery costs), disease burden in different regions, and willingness-to-pay thresholds for regulatory agencies – all factors that vary within and between countries. Universal vaccination in pregnancy for other infectious diseases such as influenza or tetanus remains elusive, so passive immunization against RSV through long-acting monoclonal antibodies such as nirsevimab will likely remain vital to comprehensive RSV prevention strategies in infants.
Importantly, most RSV infections and RSV-related deaths in children occur in low-and-middle-income countries (LMICs) where the only licensed preventive medicine is often prohibitively expensive and the general health infrastructure limits opportunities for supportive care.1 Included in the growing RSV vaccine landscape is a focus on the development of therapies and delivery mechanisms specific to LMIC settings. Many RSV vaccine studies references above were multicountry with specific recruitment goals for LMICs. Proving efficacy, however, is not enough; reducing the impact of RSV infections in LMICs requires a commitment to studying all stages of vaccine development including vaccine delivery and cost-effectiveness.23 Researchers funded by a collaboration between the Bill and Melinda Gates Foundation and Pfizer are studying a multi-dose vial that would make their maternal vaccine more affordable in LMIC.24 Gavi, the Vaccine Alliance, a global health partnership that work on increasing access to immunization in poor countries, is leading modeling on the cost-effectiveness of RSV vaccination strategies using data from over 133 LMICs; early results regarding MI suggest cost-effectiveness is achievable with care regarding targeted vaccination and delivery strategies.25
Conclusion
Successful vaccination against RSV infections appears to be a question of “when,” not “if.” This optimism should be tempered by the recognition that moving from the current RSV vaccine candidates to effective and equitable vaccine access will depend not only on continued research and development, but also on investment in the distribution of vaccines and implementation in resource poor areas and LMICs. The transition to structure-based vaccine design has led to promising candidates for RSV vaccination with great potential for protecting children infected with RSV.
BIO
Samuel McAleese, MD, is a neonatal-perinatal medicine fellow, Division of Neonatology, department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
