The landscape of respiratory syncytial virus (hRSV) prevention is rapidly evolving, with recent FDA approvals of vaccines and monoclonal antibodies marking significant progress. These developments address the substantial disease burden hRSV places on vulnerable populations, including infants, older adults, and immunocompromised individuals. The global incidence of hRSV-related acute lower respiratory infections (ALRI) reached 33 million cases in 2019, resulting in 3.6 million hospitalizations and 26,300 deaths, with the majority of cases occurring in low- and middle-income countries. This underscores the urgent need for effective preventive measures.
Targeting the Fusion Protein
The fusion glycoprotein (F protein) is a primary target for neutralizing antibodies (nAbs) and has become a focal point in vaccine research. The F protein exists in two distinct conformations: the metastable prefusion form (PreF) and the stable postfusion form (PostF). Recent research indicates that PreF elicits a broader-spectrum nAb response compared to PostF, making it a preferred immunogen for new vaccine candidates. Site Ø, located on top of PreF, is particularly crucial for inducing nAb production, and maintaining its stability is vital for vaccine development.
Vaccine Development Approaches
Currently, over 20 hRSV vaccine candidates are in clinical development worldwide, utilizing five main mechanisms:
- Live-Attenuated Vaccines (LAVs): LAVs mimic natural infections, activating local mucosal immunity and systemic humoral and cellular immunity. Examples include SP0125, which has shown high genetic stability and immunogenicity in infants, and MV-012-968, which demonstrated favorable tolerability and strong mucosal IgA responses.
- Recombinant Vector Vaccines: These vaccines use attenuated viruses to express hRSV target protein antigens. BLB-201, using an attenuated strain of parainfluenza virus 5 (PIV5), has shown promising IgA responses and nAb surges in healthy adults.
- Subunit Vaccines: Subunit vaccines, primarily targeting PreF, require adjuvants or multiple doses to elicit a sustained immune response. Arexvy and Abrysvo, both FDA-approved, have demonstrated high efficacy in older adults and infants through maternal vaccination, respectively.
- Particle-Based Vaccines: These vaccines enhance immunogenicity through particle assembly and adjuvant addition. IVX-A12, a bivalent vaccine consisting of hMPV vaccine candidates IVX-121 and IVX-241, has shown robust immune responses and favorable tolerability.
- Nucleic Acid Vaccines: mRNA vaccines, like Moderna's mRNA-1345 (mRESVIA), have shown high efficacy and tolerability in older adults, inducing both nAb and T-cell responses. mRNA-1345 demonstrated 83.7% vaccine efficacy when two or more hRSV-LRTD symptoms were present.
Monoclonal Antibody Treatments
Monoclonal antibodies (mAbs) are crucial for controlling hRSV infection, particularly in infants. Nirsevimab, a recombinant human IgG1 mAb, targets the site Ø epitope unique to PreF and neutralizes multiple hRSV A/B subtypes. A single injection of Nirsevimab can provide protection against hRSV infection for up to five months, with a 74.5% efficacy against medically attended LRTD in infants.
Challenges and Future Directions
Despite significant progress, challenges remain in hRSV vaccine development. These include safety concerns, insufficient validity, and differences in immune populations. An ideal hRSV vaccine should induce highly efficient cellular immune responses based on nAbs and type 1 T helper cells, providing protection across all age groups. Combination vaccines and mRNA modalities are being explored to broaden protection and improve vaccine delivery. Moderna plans to integrate mRNA-1345 with human metapneumovirus/parainfluenza virus 3 mRNA-1653 to create a single formulation for childhood vaccination against three pathogens. However, mRNA vaccine development requires further optimization, such as in vitro stability, delivery system optimization, protein translation efficiency, and nucleic acid impurity removal, during the production process.
