Current worldwide circulation and burden of RSV
Respiratory syncytial virus (RSV) is a highly contagious, seasonal pathogen and a leading global cause of acute lower respiratory infections (ALRIs). Globally, RSV is responsible for an immense health and economic burden, causing an estimated 33 million new ALRI cases and over three million hospitalisations each year in children under the age of five1. Furthermore, it accounts for approximately 118,000 annual pediatric deaths, with the vast majority (>99%) occurring in low- and middle-income countries (LMICs)2.
Beyond the pediatric population, RSV is now widely recognised as a major cause of severe respiratory disease and mortality in older adults and immunocompromised individuals. At the epidemiological level, current global circulation is largely defined by specific viral lineages: for the RSVA subtype, the A.D.3 lineage has been steadily increasing in prevalence since 2022, while the B.D.E.1 lineage has been dominating RSVB circulation since 2023 (Figure 1). This widespread transmission, evolving strain dynamics, and high disease burden underscore the urgent need for effective preventive strategies, driving heavy global investment into RSV vaccine and monoclonal antibody research.
Clinical research status of RSV vaccines
The clinical landscape for RSV prevention has advanced rapidly in recent years, largely driven by breakthroughs in the structural biology of the RSV fusion (F) glycoprotein—specifically the stabilisation of the prefusion (preF) conformation. Currently, the global RSV pipeline includes dozens of active vaccine candidates and monoclonal antibodies (mAbs) in clinical trials. Vaccine development is heavily segmented into three primary target populations: pediatric (via mAbs or live-attenuated vaccines), maternal (to induce protective antibodies for newborns), and older adults (relying on adjuvanted subunit, mRNA, and vector-based platforms).
With several first-generation RSV vaccines recently receiving regulatory approval, clinical research has shifted toward optimising immunogenicity, evaluating the durability of revaccination, and developing combination respiratory vaccines.
Examples of current vaccines under clinical trials
The clinical pipeline for next-generation RSV vaccines is highly active, showcasing a variety of advanced platforms and combination strategies:
- Clover Biopharmaceuticals (SCB-1019 & combination vaccines): Clover is advancing a recombinant RSV preF subunit vaccine (SCB-1019). Recent Phase 1 data demonstrated its potential as a highly effective revaccination booster for older adults who previously received other approved RSV vaccines3. Expanding on this, Clover initiated a Phase 2 trial evaluating multivalent respiratory combination candidates—SCB-1022 (RSV + hMPV) and SCB-1033 (RSV + hMPV + PIV3)—utilising their protein-based trimer platform4.
- Moderna (mRNA-1365): After launching its RSV mRNA vaccine (mRESVIA), Moderna began phase 1 clinical trials for mRNA-1365, a combination vaccine utilising mRNA technology to target both RSV and human metapneumovirus (hMPV) in a single dose5.
- The PIPELINE-RSV trial: This massive international adaptive platform trial is evaluating a combined prevention approach. The trial randomly assigns pregnant women and their infants to receive a maternal RSV vaccine, an infant monoclonal antibody, or both simultaneously to determine if dual administration provides superior infant protection6.
Real-world effectiveness of RSV vaccines in vulnerable populations
While phase three clinical trials have consistently demonstrated moderate to high efficacy for RSV preF vaccines, assessing their impact in real-world settings is crucial. Clinical trials often underrepresent the populations at the highest risk for severe RSV disease, such as individuals over 80 years old, those with extensive cardiopulmonary comorbidities and immunocompromised patients. Recent observational studies are bridging this gap. A multi-centre, test-negative case–control study by Symes and colleagues evaluated the bivalent RSV preF vaccine across 14 hospitals in England. Focusing on adults admitted with acute respiratory illness (ARI), the study reported highly encouraging real-world protection rates7:
- 72.8% estimated vaccine effectiveness among those with immunosuppression.
- 82.3% effectiveness against hospital admission for RSV-associated ARI.
- 86.7% effectiveness against severe RSV disease requiring oxygen use, intensive care unit admission, or mechanical ventilation.
- 78.8% protection against hospital admission for exacerbations of chronic lung disease, heart disease, and/or frailty.
Research applications
Recombinant respiratory syncytial virus (RSV) fusion (F) proteins, especially prefusion-stabilised pre-F antigens, are now important tools in RSV vaccine research. They are used as vaccine antigens. They are also used as design tools for new vaccines and as assay reagents for antigen testing and immune-response analysis.
Recent studies show that recombinant pre-F proteins support RSV vaccine development from clinical vaccines to nanoparticle and mRNA vaccine studies. In a phase three trial, Papi et al. demonstrated that an AS01E-adjuvanted subunit vaccine using recombinant prefusion RSV F protein (RSVPreF3 OA) provided older adults with strong protection against RSV-related lower respiratory tract disease and acute infection (Figure 2). This confirms that recombinant pre-F functions successfully as a highly effective clinical vaccine antigen8.
Marcandalli et al. utilised recombinant prefusion-stabilised RSV F trimers (DS-Cav1) as the scaffold for a self-assembling nanoparticle vaccine (Figure 3). Displaying multiple copies of recombinant preF on nanoparticles yielded significantly stronger neutralising antibody responses than soluble trimers alone, highlighting its value in structure-guided vaccine design9.
In developing an AAV5-based RSV vaccine, Ma et al. leveraged recombinant RSV proteins for crucial testing and immune response analysis. They utilised RSV-F antibodies (11049-R302, Sino Biological) for Western blot expression confirmation, alongside recombinant RSV-F (11049-V08B, Sino Biological) and RSV-G (40041-V08H, Sino Biological) proteins as ELISA coating antigens to track post-vaccination serum antibody responses (Figure 4)10.
In a 2025 study, Sun et al. developed a Pre-F-EABR eVLP mRNA vaccine, utilising the pre-F construct as the immunogen scaffold (Figure 5). To precisely analyse immune responses, they used Sino Biological recombinant RSV Pre-F (11049-VNAS, Sino Biological) and Post-F (11049-V08H5, Sino Biological) as ELISA coating antigens to successfully differentiate and confirm robust, pre-F-specific protective antibodies11.
References
1. Li, X. et al. Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries. BMC Med. 18, 82 (2020).
2. Mazur, N. I. et al. Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape. Lancet Infect. Dis. 23, e2–e21 (2023).
3. https://www.cloverbiopharma.com/media/191.html
4. https://www.cloverbiopharma.com/media/189.html
5. https://www.modernatx.com/en-US/research/product-pipeline
6. https://clinicaltrials.gov/study/NCT07041190
7. Symes R. et al. Vaccine effectiveness of a bivalent respiratory syncytial virus (RSV) pre-F vaccine against RSV-associated hospitalisation among adults aged 75-79 years in England: a multicentre, test-negative, case–control study. The Lancet Infectious Diseases. 26, 229-238 (2025).
8. Papi, A. et al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. New England Journal of Medicine 388, 595–608 (2023).
9. Marcandalli, J. et al. Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus. Cell 176, 1420-1431.e17 (2019).
10. Ma, G. et al. Induction of neutralizing antibody responses by AAV5-based vaccine for respiratory syncytial virus in mice. Front. Immunol. 15, (2024).
11. Sun, L. et al. Developing an eVLP mRNA vaccine for respiratory syncytial virus with enhanced pre-fusion targeting humoral responses. J. Virol. 99, (2025).
