Jie Sheng1,†
Jianjian Ji- 1Jiangsu Key Laboratory of Pediatric Respiratory Disease, Jiangsu Provincial Research Institute of Chinese Medicine Schools, Nanjing University of Chinese Medicine, Nanjing, China
- 2Clinical Laboratory, Jiangning District Center for Disease Control and Prevention, Nanjing, China
- 3Department of Infectious, The Affiliated Taizhou People’S Hospital of Nanjing Medical University, Taizhou, Jiangsu, China
Introduction
Respiratory syncytial virus (RSV) remains one of the leading causes of viral acute lower respiratory tract infections (LRTIs) in all regions of the world, with elevated burden among children under 2 years of age and the elderly over 65 (1). Annually, tens of millions of cases of RSV-induced lower respiratory tract infections in children under 5 years of age occur globally, resulting in more than millions of hospitalizations and hundreds of thousands of deaths (2, 3). Deaths and hospital stays owing to RSV show great geographic disparities, most pronounced in low-income and middle-income countries (LMICs)—limited healthcare infrastructure, a lack of diagnostic tools, and delayed access to critical care increasing fatalities (4–6).
Historical setbacks in RSV vaccine development highlight the biological complexity of the pathogen and the ethical challenges of pediatric immunization. The catastrophic 1960s formalin-inactivated RSV vaccine trial, which induced vaccine-enhanced respiratory disease (ERD) in seronegative infants, underscored the perils of immunizing immunologically immature populations (7–10). This failure not only halted pediatric RSV vaccine research for decades but also instilled caution in regulatory frameworks, prioritizing safety over speed. Contemporary efforts remain hamstrung by the dual challenges of ensuring efficacy and avoiding ERD-like outcomes in infants. Infant-targeted strategies face inherent biological limitations, prompting a paradigm shift toward immunizing toddlers and school-aged children (2–12 years) as a transmission-blocking measure. This approach leverages the concept of herd immunity: by reducing viral circulation among school-aged populations—who serve as primary community transmitters—indirect protection extends to high-risk groups, including infants and the elderly.
This article synthesizes interdisciplinary evidence to advocate for accelerated development of RSV vaccines for toddlers and school-aged children. By bridging immunological insights, epidemiological trends, and implementation science, it outlines a roadmap to transform research into equitable global health impact.
Immunological and epidemiological rationale
Currently, prophylaxis is with monoclonal antibodies (Palivizumab, Nirsevimab) and vaccines (RSVpreF, RSVpreF3, mRNA-1345) (11) and these are given to infants and older adults, including preterm infants, low-birth-weight infants, and children with chronic respiratory diseases or congenital heart disease (12–14). However, since these are high-risk populations, it is possible to overlook the chances of vaccines for older children. Immunization of infants is, in theory, ideal, but is hindered by biological barriers that cannot be overcome. The B cell repertoires of the newborn are limited in diversity because of reduced somatic hypermutation and low-affinity antibody responses (15). Moreover, underdeveloped germinal centers fail to generate long-lived plasma cells and memory B cells, making the immunity short-lived (16–19). Maternal antibodies, which are protective in the first few weeks of life, disappear rapidly, and neutralizing titers against RSV are less than the protective levels by 3–6 months (20–23). In addition, the neonatal immune system may be more inclined to the Th2-type of responses (increased IL-4, IL-5, and IL-13), which would predispose infants to eosinophilic inflammation, perhaps one of characteristic of ERD seen in early vaccine trials (24, 25).
By contrast, toddlers and school-aged children have a more fully developed adaptive immune system. The lymphoid structures, including lymph nodes and the spleen, become structurally and functionally equipped for children to generate the germinal center reaction. This reaction leads to affinity maturation of B cells and high-titer, high-avidity antibodies to RSV surface glycoproteins. Furthermore, older children have a balanced Th1/Th17 response that is crucial for coordinating cytotoxic T cell activity and mucosal immunity (26–30). The NALT reaches maturity by early childhood and helps in the maintenance of secretory immunoglobulin A (sIgA) secretion after vaccination (31). SIgA is the first line of defense that works by neutralizing viral particles at the respiratory mucosal surfaces; this is lacking with systemic antibody-based therapies (32, 33). Tissue-resident memory T cells (TRMs) that reside in the respiratory epithelium also contribute to protection (34). Antigen design innovations in prefusion F protein vaccines, exemplified by GSK's Arexvy, effectively exploit these immunological advantages (35, 36). Vaccines utilizing the prefusion conformation of the F protein as an antigen have demonstrated superior induction of neutralizing antibodies by exposing key neutralizing epitopes that are lost in the postfusion state. This specifically engineered design can elicit broad immune responses through efficient engagement of diversified B-cell receptors (BCRs) in older children, thus providing enhanced protection—as evidenced by clinical data showing significantly higher neutralizing antibody titers compared to postfusion F vaccines (37). Adjuvant systems such as AS01 (a TLR4 agonist) interact with dendritic cells to enhance cross presentation and priming of CD8+ T cells to combine innate and adaptive immunity (38–41).
Epidemiologically, school-aged children are pivotal drivers of RSV transmission due to their high viral loads, prolonged shedding (7–10 days), and dense social networks (42–46). Cohort studies in Kenya demonstrated that 73% of infant RSV infections originated from school-aged siblings, with 91% of transmission events involving school-aged individuals (47). Similarly, European surveillance data linked 10% of acute respiratory infections in the elderly to contact with preschool-aged children outside their households (48). Sibling transmission studies reveal stark gradients in risk: infants with ≥3 older siblings face a threefold higher likelihood of RSV hospitalization compared to those with one sibling, with 45% of infections attributable to sibling transmission (49). These dynamics position school-aged children as critical nodes in RSV transmission networks. Vaccination of these populations may indirectly protect high-risk groups by reducing viral load and the number of susceptible individuals, thereby lowering the risk of virus transmission to others (50). This requires further verification through real-world testing. Such indirect protection is particularly important in LMICs.
Overcoming challenges and future directions
The development of RSV vaccines for toddlers and school-aged children is fraught with scientific, logistical, and sociopolitical challenges that require novel approaches. Although the immunological and epidemiological basis for this approach is attractive, the theory needs to be unpacked to reflect on the complex barriers specific to biology, infrastructure, and public perception to realize.
The main problem is the perception of the low clinical importance of RSV in school age children. While infants have high hospitalization rates, older children generally have mild or asymptomatic disease. This discrepancy has in the past adversely influenced research funding and regulatory priorities directed towards high-risk groups, and hence school-aged vaccine development has been under-resourced.
This poses a major hurdle to the development of the vaccine because of antigenic diversity. The main vaccine antigen of RSV is the fusion protein in the surface of the virus, but it has strain variation in its pre-fusion and post-fusion conformations. Current pre-F stabilized vaccines like Pfizer's RSVpreF generate potent neutralizing antibodies to dominant strains. The conformational diversity of antigenic site Ø is an intrinsic property of pre-F, with conformational differences centered on the conserved Pro205 residue (Figure 5D) (51, 52). Amino acid variations in this region may affect the recognition efficiency of neutralizing antibodies (51). Although there is currently no direct evidence that such variations have led to reduced efficacy of existing vaccines, from a structural biology perspective, it is inferred that if the virus accumulates mutations at this site, it may increase the risk of immune escape. To this end, the next-generation platforms must incorporate mRNA technology. The use of mRNA platforms for pediatric use—with dose optimization to decrease reactogenicity—may be the key to building RSV vaccines that can withstand the virus' evolutionary capabilities.
The mucosal immune deficit poses another challenge. Although systemic IgG responses are important in preventing viremia, they fail to prevent completely upper respiratory tract disease or transmission. Mucosal IgA and tissue resident memory T cells (TRMs) in the nasopharynx inhibit the transmission chain by significantly reducing viral load (rather than complete clearance) (53, 54). Intranasal vaccines such as trivalent live attenuated intranasal influenza vaccine (CAIV-T) appear to mimic natural infection in order to induce mucosal immunity (55). It should be noted that natural RSV infection fails to induce sterilizing immunity, whereas optimized vaccine design is expected to overcome this limitation and achieve more long-term and effective immune protection.
In LMICs, where the vast majority of RSV mortality occurs, cold-chain dependency is a key bottleneck. Vaccines should always be stored at 2°C–8 °C during the period of manufacture until administered to the beneficiary. More than 25% of vaccines are discarded each year. One of the main reasons for this is the absence of a continuous cold chain in low-income areas where electricity is scarce (56, 57). Attempts could be made to develop freeze-dried RSV vaccines suitable for distribution in rural areas. Furthermore, patches that have been tested to be effective for measles and polio can provide needle free, cold chain independent administration of the vaccine (58–60).
Vaccine hesitancy and sociocultural perceptions further impede uptake. In LMICs, RSV is often misclassified as “mild flu” or paired with malaria, which reduces the demand for prevention (61). A survey conducted in Kenya in 2021 showed that only 39.4% of non-KENITAG (not the members of the Kenya National Immunization Technical Advisory Group) Health Care Workers had heard of RSV disease, and only 1.9% were aware of RSV prevention products because of cost and unawareness (62). To this end, combining with existing platforms such as combining RSV vaccines with routine measles or Human papillomavirus (HPV) immunization could help improve coverage.
Mechanisms for funding have also to change. Sustainable funding needs Public-Private-Partnership (PPP). The African Vaccine Manufacturing Accelerator (AVMA) launched in 2024 to build capacity in the region for vaccine manufacturing, which expected to provide up to $1.2 billion in funding over 10 years (63). At the same time, tiered pricing models, under which high income countries pay more to make the vaccine available to LMICs at lower prices, could help achieve equity while fulfilling profit motives.
The COVID-19 pandemic accelerated the development of infrastructure and technological innovations that can be applied to RSV: The mRNA manufacturing hubs launched in South Africa can be adapted for RSV vaccine production; Artificial intelligence-based surveillance systems provide real time RSV epidemic surveillance (64–66).
Discussion
The push to create vaccines for RSV in children is driven by a paradox. The most at risk (infants and older adults) are not easily vaccinated directly which leads to a focus on indirect protection using methods that block transmission of the virus instead. School-aged children play a role in spreading RSV within households and communities due to their extended period of shedding the virus and close interactions with others. Immunizing this group could help stop the circulation of the virus to how flu vaccination programs, for kids have been successful (67, 68).
This change in approach encounters obstacles on scientific grounds as well as in terms of practicality and public perception. An important issue revolves around the necessity of safeguarding non-targeted groups from harm. Although vaccinating school age children is mainly intended to protect infants and senior citizens, it involves procedures for a demographic that receives minimal direct advantages. This situation prompts discussions about obtaining consent through information and ensuring fair distribution of healthcare resources especially in regions, with limited resources where parental decisions may clash with government health directives. The experiences gained from HPV vaccination initiatives offer insights: in Rwandas case study demonstrated that reaching a 93% coverage rate was possible through school based distribution by highlighting vaccines as essential for “community well-being” rather than just individual prevention measures (69, 70). With RSV campaign aiming to resonate with cultural values should focus more on the altruistic aspect such as promoting protection for younger siblings, like baby brothers or sisters.
Building trust and dispelling myths are crucial for gaining approval in this matter. To address this issue effectively, approaches like the Centers for Disease Control and Prevention's (CDC's) “Vaccinate with Confidence” campaign, which operates in three dimensions—Protecting Communities, Empowering Families, and Stopping Myths—working collaboratively with local partners and trusted messengers to increase confidence in vaccines (71). In LMICs, incorporating RSV education into maternal healthcare initiatives could foster better acceptance of vaccinations.
In addition to advancing policies in the realm of healthcare accessibility and innovation is paramount well. Drafting school regulations reminiscent of those implemented for measles control in the United States could significantly boost vaccination rates for children. Tax breaks offered to firms engaged in research and development for pediatric RSV could spur creative solutions and breakthrough discoveries. The European expediting the approval process, for vaccines targeting overlooked diseases (72, 73).
Despite nirsevimab achieving high coverage rates and significantly reducing hospitalization rates in infants, its protective effect is limited by an age window (≤1 year) and duration (single dose provides ∼5–6 months of protection) (74, 75). Additionally, targeting a single epitope (the F protein) poses a risk of viral escape (76). Real-world data from Spain showed that after the introduction of nirsevimab in infants <6-months-old, children admitted to Catalan hospitals were older than in the previous season, indicating a shift in viral transmission to older children (77). Therefore, active immunization of school-aged children remains a critical strategy to bridge protective gaps and address viral evolution. Developing RSV vaccines for infants and older children are complementary rather than competitive.
The development of RSV vaccines reflects the evolution of health—from facing crises to embracing opportunities and moving towards inclusivity and fairness in healthcare access for all people worldwide. The experiences gained from dealing with the COVID-19 pandemic shed light on how we can progress in the future by learning from both successes and setbacks. As mRNA vaccines revolutionized vaccination schedules, RSV immunization has the potential to transform the way we control diseases. It is a decision to make: either vaccinate school-age children now or continue to witness unnecessary loss of life in the future.
Author contributions
JS: Writing – original draft. KT: Writing – original draft. CZ: Writing – original draft. AZ: Writing – review & editing. YL: Writing – review & editing. JJ: Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Key R&D Program of China (2023YFC2308200), Funded by the Key Research Project of Jiangsu Provincial Academy of Chinese Medicine Schools 2025 (LPZD2025012), and the National Natural Science Foundation of China (82374524).
Acknowledgments
We thank the Nanjing University of Chinese Medicine and Professor Jinjun Shan for providing the experimental facility for the successful conduct of this study.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. (2012) 380(9859):2095–128. doi: 10.1016/s0140-6736(12)61728-0
2. Li Y, Wang X, Blau DM, Caballero MT, Feikin DR, Gill CJ, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet. (2022) 399(10340):2047–64. doi: 10.1016/s0140-6736(22)00478-0
3. Stein RT, Bont LJ, Zar H, Polack FP, Park C, Claxton A, et al. Respiratory syncytial virus hospitalization and mortality: systematic review and meta-analysis. Pediatr Pulmonol. (2016) 52(4):556–69. doi: 10.1002/ppul.23570
4. Srikantiah P, Vora P, Klugman KP. Assessing the full burden of respiratory syncytial virus in young infants in low- and middle-income countries: the importance of community mortality studies. Clin Infect Dis. (2021) 73(Supplement_3):S177–9. doi: 10.1093/cid/ciab486
5. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet. (2010) 375(9725):1545–55. doi: 10.1016/s0140-6736(10)60206-1
6. Geoghegan S, Erviti A, Caballero MT, Vallone F, Zanone SM, Losada JV, et al. Mortality due to respiratory syncytial virus. Burden and risk factors. Am J Respir Crit Care Med. (2017) 195(1):96–103. doi: 10.1164/rccm.201603-0658OC
7. Chin J, Magoffin RL, Shearer LA, Schieble JH, Lennette EH. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol. (1969) 89(4):449–63. doi: 10.1093/oxfordjournals.aje.a120957
8. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. (1969) 89(4):422–34. doi: 10.1093/oxfordjournals.aje.a120955
9. Fulginiti VA, Eller JJ, Sieber OF, Joyner JW, Minamitani M, Meiklejohn G. Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol. (1969) 89(4):435–48. doi: 10.1093/oxfordjournals.aje.a120956
10. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol. (1969) 89(4):405–21. doi: 10.1093/oxfordjournals.aje.a120954
11. Terstappen J, Hak SF, Bhan A, Bogaert D, Bont LJ, Buchholz UJ, et al. The respiratory syncytial virus vaccine and monoclonal antibody landscape: the road to global access. Lancet Infect Dis. (2024) 24(12):e747–61. doi: 10.1016/s1473-3099(24)00455-9
12. Sommer C, Resch B, Simões EA. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol J. (2011) 5:144–54. doi: 10.2174/1874285801105010144
13. Zhang YX, Shi T, Su QR, Deng JK. Clinical characteristics and related factors of human respiratory syncytial viruses infection in premature infants within 2 years after birth in Shenzhen children’s hospital. Zhonghua Yi Xue Za Zhi. (2021) 101(36):2873–7. doi: 10.3760/cma.j.cn112137-20210226-00505
14. Wang X, Li Y, Shi T, Bont LJ, Chu HY, Zar HJ, et al. Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data. Lancet. (2024) 403(10433):1241–53. doi: 10.1016/s0140-6736(24)00138-7
15. Paschold L, Klee B, Gottschick C, Willscher E, Diexer S, Schultheiß C, et al. Rapid hypermutation B cell trajectory recruits previously primed B cells upon third sars-cov-2 mRNA vaccination. Front Immunol. (2022) 13:876306. doi: 10.3389/fimmu.2022.876306
16. Inoue T, Shinnakasu R, Kurosaki T. Generation of high quality memory B cells. Front Immunol. (2022) 12:825813. doi: 10.3389/fimmu.2021.825813
17. Shlomchik MJ, Weisel F. Germinal center selection and the development of memory B and plasma cells. Immunol Rev. (2012) 247(1):52–63. doi: 10.1111/j.1600-065X.2012.01124.x
18. Baumjohann D, Preite S, Reboldi A, Ronchi F, Ansel KM, Lanzavecchia A, et al. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity. (2013) 38(3):596–605. doi: 10.1016/j.immuni.2012.11.020
19. Syeda MZ, Hong T, Huang C, Huang W, Mu Q. B cell memory: from generation to reactivation: a multipronged defense wall against pathogens. Cell Death Discov. (2024) 10(1):117. doi: 10.1038/s41420-024-01889-5
20. Suryadevara M. Passive immunization strategies to prevent severe respiratory syncytial virus infection among newborns and young infants. J Pediatric Infect Dis Soc. (2024) 13(Supplement_2):S110–4. doi: 10.1093/jpids/piae058
21. Ng LFP, Ochola R, Sande C, Fegan G, Scott PD, Medley GF, et al. The level and duration of rsv-specific maternal igg in infants in Kilifi Kenya. PLoS One. (2009) 4(12):e8088. doi: 10.1371/journal.pone.0008088
22. Koivisto K, Nieminen T, Mejias A, Capella Gonzalez C, Ye F, Mertz S, et al. Respiratory syncytial virus (RSV)–specific antibodies in pregnant women and subsequent risk of RSV hospitalization in young infants. J Infect Dis. (2022) 225(7):1189–96. doi: 10.1093/infdis/jiab315
23. Atwell JE, Lutz CS, Sparrow EG, Feikin DR. Biological factors that may impair transplacental transfer of RSV antibodies: implications for maternal immunization policy and research priorities for low- and middle-income countries. Vaccine. (2022) 40(32):4361–70. doi: 10.1016/j.vaccine.2022.06.034
24. Beeler JA, Eichelberger MC. Influenza and respiratory syncytial virus (RSV) vaccines for infants: safety, immunogenicity, and efficacy. Microb Pathog. (2013) 55:9–15. doi: 10.1016/j.micpath.2012.11.013
25. Rayees S, Malik F, Bukhari SI, Singh G. Linking gata-3 and interleukin-13: implications in asthma. Inflamm Res. (2013) 63(4):255–65. doi: 10.1007/s00011-013-0700-6
26. Arifuzzaman M, Rashu R, Leung DT, Hosen MI, Bhuiyan TR, Bhuiyan MS, et al. Antigen-specific memory T cell responses after vaccination with an oral killed cholera vaccine in Bangladeshi children and comparison to responses in patients with naturally acquired cholera. Clin Vaccine Immunol. (2012) 19(8):1304–11. doi: 10.1128/cvi.00196-12
27. Nguyen NDNT, Guleed S, Olsen AW, Follmann F, Christensen JP, Dietrich J. Th1/Th17T cell tissue-resident immunity increases protection, but is not required in a vaccine strategy against genital infection with Chlamydia trachomatis. Front Immunol. (2021) 12:790463. doi: 10.3389/fimmu.2021.790463
28. Li C, Sheng A, Jia X, Zeng Z, Zhang X, Zhao W, et al. Th17/treg dysregulation in allergic asthmatic children is associated with elevated notch expression. J Asthma. (2017) 55(1):1–7. doi: 10.1080/02770903.2016.1266494
29. Zheng R, Wang F, Huang Y, Xiang Q, Dai H, Zhang W. Elevated Th17 cell frequencies and Th17/treg ratio are associated with airway hyperresponsiveness in asthmatic children. J Asthma. (2020) 58(6):707–16. doi: 10.1080/02770903.2020.1737710
30. Chen O, Zhu X-b, Ren H, Wang Y-b, Sun R. The imbalance of Th17/treg in Chinese children with Henoch–Schonlein purpura. Int Immunopharmacol. (2013) 16(1):67–71. doi: 10.1016/j.intimp.2013.03.027
31. Bellussi L, Cambi J, Passali D. Functional maturation of nasal mucosa: role of secretory immunoglobulin a (siga). Multidiscip Respir Med. (2013) 8(1):46. doi: 10.1186/2049-6958-8-46
32. Li C, An X, Butt AM, Zhang B, Zhang Z, Wang X, et al. Construction of a chimeric secretory iga and its neutralization activity against avian influenza virus H5n1. J Immunol Res. (2014) 2014:1–10. doi: 10.1155/2014/394127
33. Wang Y, Wang G, Li Y, Zhu Q, Shen H, Gao N, et al. Structural insights into secretory immunoglobulin a and its interaction with a pneumococcal adhesin. Cell Res. (2020) 30(7):602–9. doi: 10.1038/s41422-020-0336-3
34. Paik DH, Farber DL. Influenza infection fortifies local lymph nodes to promote lung-resident heterosubtypic immunity. J Exp Med. (2021) 218(1):e20200218. doi: 10.1084/jem.20200218
35. Anastassopoulou C, Medić S, Ferous S, Boufidou F, Tsakris A. Development, current status, and remaining challenges for respiratory syncytial virus vaccines. Vaccines (Basel). (2025) 13(2):97–109. doi: 10.3390/vaccines13020097
36. Che Y, Gribenko AV, Song X, Handke LD, Efferen KS, Tompkins K, et al. Rational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus vaccine. Sci Transl Med. (2023) 15(693):eade6422. doi: 10.1126/scitranslmed.ade6422
37. Michelle CC, Tracy JR, Man C, Kaitlyn MM, Emily P, Pamela JC, et al. A proof of concept for structure-based vaccine design targeting RSV in humans. Science. (2019) 365(6452):505–9. doi: 10.1126/science.aav9033
38. Didierlaurent AM, Laupèze B, Di Pasquale A, Hergli N, Collignon C, Garçon N. Adjuvant system As01: helping to overcome the challenges of modern vaccines. Expert Rev Vaccines. (2016) 16(1):55–63. doi: 10.1080/14760584.2016.1213632
39. Didierlaurent AM, Collignon C, Bourguignon P, Wouters S, Fierens K, Fochesato M, et al. Enhancement of adaptive immunity by the human vaccine adjuvant As01 Depends on activated dendritic cells. J Immunol. (2014) 193(4):1920–30. doi: 10.4049/jimmunol.1400948
40. Van Maele L, Fougeron D, Cayet D, Chalon A, Piccioli D, Collignon C, et al. Toll-like receptor 4 signaling in hematopoietic-lineage cells contributes to the enhanced activity of the human vaccine adjuvant As01. Eur J Immunol. (2019) 49(12):2134–45. doi: 10.1002/eji.201948234
41. Bechtold V, Smolen KK, Burny W, de Angelis SP, Delandre S, Essaghir A, et al. Functional and epigenetic changes in monocytes from adults immunized with an As01-adjuvanted vaccine. Sci Transl Med. (2024) 16(758):eadl3381. doi: 10.1126/scitranslmed.adl3381
42. Okiro EA, White LJ, Ngama M, Cane PA, Medley GF, Nokes DJ. Duration of shedding of respiratory syncytial virus in a community study of Kenyan children. BMC Infect Dis. (2010) 10:15. doi: 10.1186/1471-2334-10-15
43. Ibuka Y, Ohkusa Y, Sugawara T, Chapman GB, Yamin D, Atkins KE, et al. Social contacts, vaccination decisions and influenza in Japan. J Epidemiol Community Health. (2016) 70(2):162–7. doi: 10.1136/jech-2015-205777
44. Ujiie M, Tsuzuki S, Nakamoto T, Iwamoto N. Resurgence of respiratory syncytial virus infections during COVID-19 pandemic, Tokyo, Japan. Emerg Infect Dis. (2021) 27(11):2969–70. doi: 10.3201/eid2711.211565
45. DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, et al. Viral load drives disease in humans experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med. (2010) 182(10):1305–14. doi: 10.1164/rccm.201002-0221OC
46. Mossong J, Hens N, Jit M, Beutels P, Auranen K, Mikolajczyk R, et al. Social contacts and mixing patterns relevant to the spread of infectious diseases. PLoS Med. (2008) 5(3):e74. doi: 10.1371/journal.pmed.0050074
47. Munywoki PK, Koech DC, Agoti CN, Lewa C, Cane PA, Medley GF, et al. The source of respiratory syncytial virus infection in infants: a household cohort study in rural Kenya. J Infect Dis. (2014) 209(11):1685–92. doi: 10.1093/infdis/jit828
48. Korsten K, Adriaenssens N, Coenen S, Butler CC, Pirçon JY, Verheij TJM, et al. Contact with young children increases the risk of respiratory infection in older adults in Europe—the Resceu study. J Infect Dis. (2022) 226(Supplement_1):S79–86. doi: 10.1093/infdis/jiab519
49. Jacoby P, Glass K, Moore HC. Characterizing the risk of respiratory syncytial virus in infants with older siblings: a population-based birth cohort study. Epidemiol Infect. (2016) 145(2):266–71. doi: 10.1017/s0950268816002545
50. Jordan E, Kabir G, Schultz S, Silbernagl G, Schmidt D, Jenkins VA, et al. Reduced respiratory syncytial virus load, symptoms, and infections: a human challenge trial of MVA-BN-RSv vaccine. J Infect Dis. (2023) 228(8):999–1011. doi: 10.1093/infdis/jiad108
51. Jones HG, Battles MB, Lin CC, Bianchi S, Corti D, McLellan JS. Alternative conformations of a major antigenic site on rsv F. PLoS Pathog. (2019) 15(7):e1007944. doi: 10.1371/journal.ppat.1007944
52. Holland LA, Holland SC, Smith MF, Leonard VR, Murugan V, Nordstrom L, et al. Genomic sequencing surveillance to identify respiratory syncytial virus mutations, Arizona, USA. Emerg Infect Dis. (2023) 29(11):2380–2. doi: 10.3201/eid2911.230836
53. Miyamoto S, Nishiyama T, Ueno A, Park H, Kanno T, Nakamura N, et al. Infectious virus shedding duration reflects secretory iga antibody response latency after sars-cov-2 infection. Proc Natl Acad Sci U S A. (2023) 120(52):e2314808120. doi: 10.1073/pnas.2314808120
54. Michalets S, Saha A, Jimenez A, Uddbäck I, Williams ME, Mattingly C, et al. Tissue resident memory Cd8T cells limit respiratory virus transmission by ifn-Γ production and activation of nasal cavity epithelial cells. J Immunol. (2024) 212(1_Supplement):0918_4685-0918_4685. doi: 10.4049/jimmunol.212.supp.0918.4685
55. Boyce TG, Gruber WC, Coleman-Dockery SD, Sannella EC, Reed GW, Wolff M, et al. Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children. Vaccine. (1999) 18(1-2):82–8. doi: 10.1016/s0264-410x(99)00183-8
56. Cattin M, Jonnalagedda S, Makoliso S, Schönenberger K. The Status of refrigeration techniques for vaccine storage and transportation in low-income settings. Acad Eng. (2023) 1:1–14. doi: 10.31224/osf.io/gx8fn
57. Kahn A-L, Kristensen D, Rao R. Extending supply chains and improving immunization coverage and equity through controlled temperature chain use of vaccines. Vaccine. (2017) 35(17):2214–6. doi: 10.1016/j.vaccine.2016.10.091
58. Adhikari BB, Goodson JL, Chu SY, Rota PA, Meltzer MI. Assessing the potential cost-effectiveness of microneedle patches in childhood measles vaccination programs: the case for further research and development. Drugs R D. (2016) 16(4):327–38. doi: 10.1007/s40268-016-0144-x
59. Kolluru C, Gomaa Y, Prausnitz MR. Development of a thermostable microneedle patch for polio vaccination. Drug Deliv Transl Res. (2018) 9(1):192–203. doi: 10.1007/s13346-018-00608-9
60. O’Shea J, Prausnitz MR, Rouphael N. Dissolvable microneedle patches to enable increased access to vaccines against sars-cov-2 and future pandemic outbreaks. Vaccines (Basel). (2021) 9(4):320–5. doi: 10.3390/vaccines9040320
61. Iroh Tam P-Y, Obaro SK, Storch G. Challenges in the etiology and diagnosis of acute febrile illness in children in low- and middle-income countries. J Pediatric Infect Dis Soc. (2016) 5(2):190–205. doi: 10.1093/jpids/piw016
62. Nyawanda BO, Opere VA, Nyiro JU, Vodicka E, Fleming JA, Baral R, et al. Respiratory syncytial virus (RSV) disease and prevention products: knowledge, attitudes, and preferences of Kenyan healthcare workers in two counties in 2021. Vaccines (Basel). (2023) 11(6):1055–64. doi: 10.3390/vaccines11061055
63. Gavi. African Vaccine Manufacturing Accelerator (2024). Available online at: https://www.gavi.org/programmes-impact/types-support/regional-manufacturing-strategy/avma#what (Accessed March 2025)
64. Sun S, Xie Z, Yu K, Jiang B, Zheng S, Pan X. COVID-19 and healthcare system in China: challenges and progression for a sustainable future. Global Health. (2021) 17(1):14–20. doi: 10.1186/s12992-021-00665-9
65. Bryce E, Ong S. COVID-19 and mRNA technology are helping Africa fix its vaccine problems. Br Med J. (2022) 377:o1196. doi: 10.1136/bmj.o1196
66. Sideri K. Mrna vaccine politics: responsible governance coordination for vaccine innovation in times of urgency. J Responsible Innov. (2024) 11(1):2425121. doi: 10.1080/23299460.2024.2425121
67. Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med. (2001) 344(12):889–96. doi: 10.1056/nejm200103223441204
68. Loeb M, Russell ML, Moss L, Fonseca K, Fox J, Earn DJ, et al. Effect of influenza vaccination of children on infection rates in Hutterite communities: a randomized trial. JAMA. (2010) 303(10):943–50. doi: 10.1001/jama.2010.250
69. Binagwaho A, Wagner C, Gatera M, Karema C, Nutt C, Ngaboa F. Achieving high coverage in Rwanda’s national human papillomavirus vaccination programme. Bull W H O. (2012) 90(8):623–8. doi: 10.2471/blt.11.097253
70. Torres-Rueda S, Rulisa S, Burchett HED, Mivumbi NV, Mounier-Jack S. HPV vaccine Introduction in Rwanda: impacts on the broader health system. Sex Reprod Healthc. (2016) 7:46–51. doi: 10.1016/j.srhc.2015.11.006
71. U.S. Centers for Disease Control and Prevention (CDC). Vaccinate with Confidence (2024). Available online at: https://www.cdc.gov/vaccines/partners/vaccinate-with-confidence.html (Accessed March 2025)
72. Ridley DB, Sánchez AC. Introduction of European priority review vouchers to encourage development of new medicines for neglected diseases. Lancet. (2010) 376(9744):922–7. doi: 10.1016/s0140-6736(10)60669-1
73. Ridley DB, Lasanta AM, Storer Jones F, Ridley SK. European priority review vouchers for neglected disease product development. BMJ Glob Health. (2024) 9(1):e013686. doi: 10.1136/bmjgh-2023-013686
74. Munro APS, Drysdale SB, Cathie K, Flamein F, Knuf M, Collins AM, et al. 180-day efficacy of nirsevimab against hospitalisation for respiratory syncytial virus lower respiratory tract infections in infants (harmonie): a randomised, controlled, phase 3b trial. Lancet Child Adolesc Health. (2025) 9(6):404–12. doi: 10.1016/s2352-4642(25)00102-6
75. Shirley M. Nirsevimab in the prevention of respiratory syncytial virus lower respiratory tract disease: a profile of its use. Drugs Ther Perspect. (2023) 39(12):413–20. doi: 10.1007/s40267-023-01039-4
76. Fourati S, Reslan A, Bourret J, Casalegno JS, Rahou Y, Chollet L, et al. Genotypic and phenotypic characterisation of respiratory syncytial virus after nirsevimab breakthrough infections: a large, multicentre, observational, real-world study. Lancet Infect Dis. (2025) 25(3):301–11. doi: 10.1016/s1473-3099(24)00570-x
77. Creus-Costa A, Piñana M, Perramon-Malavez A, Andrés C, Rello-Saltor V, Rossich-Verdés R, et al. P-1186. significant reduction in disease burden and a shift in clinical diagnoses in children hospitalized with respiratory syncytial virus (RSV) after nirsevimab implementation in Catalonia (Spain). Open Forum Infect Dis. (2025) 12(Supplement_1):ofae631.1370. doi: 10.1093/ofid/ofae631.1370
Keywords: respiratory syncytial virus (RSV), vaccines, RSV vaccination strategies, global health, epidemiology, monoclonal antibody
Citation: Sheng J, Tao K, Zhang C, Zhang A, Li Y and Ji J (2025) Respiratory syncytial virus vaccines for toddlers and school-aged children: a pressing necessity for global health. Front. Pediatr. 13:1607236. doi: 10.3389/fped.2025.1607236
Received: 20 May 2025; Accepted: 6 August 2025;
Published: 1 September 2025.
Edited by:
Maurizio Aricò, Azienda Sanitaria Locale di Pescara, ItalyReviewed by:
Larry J. Anderson, Emory University, United StatesEnrico Valletta, Azienda Unità Sanitaria Locale (AUSL) della Romagna, Italy
Copyright: © 2025 Sheng, Tao, Zhang, Zhang, Li and Ji. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Aiping Zhang, MTMwMDM2NTI0OEBxcS5jb20=; Yang Li, bGl5YW5nMjAxNjA1QDEyNi5jb20=; Jianjian Ji, amlqakBuanVjbS5lZHUuY24=
†These authors have contributed equally to this work