The virion of RSV

The RSV genome is 15.2 kb and contains 10 genes encoding 11 proteins (Fig. 1). The M2 gene has two overlapping ORFs, generating both M2-1 (a transcription processivity factor) and M2-2 (a protein that governs the switch from transcription to genome replication). The first two transcribed genes are the nonstructural proteins NS1 and NS2, which together inhibit apoptosis and interferon responses^[1].

The RSV virion contains a lipid bilayer displaying the fusion (F), attachment (G) and small hydrophobic (SH) proteins (Fig. 1). The F and G proteins are in greater abundance than the SH protein, which is a pentameric ion channel thought to be involved in delaying apoptosis in infected cells. The viral envelope is supported by a layer of matrix (M) and M2-1 proteins. The M protein is a non-glycosylated structural protein lining the inner leaflet of the viral envelope, and it associates with the cytoplasmic domain of the F protein. M2-1 mediates the association between M and the enclosed ribonucleoprotein complexes (RNPs) comprising viral genomic RNA tightly associated with nucleoprotein (N). Also associated with the RNP is the RNA-dependent RNA polymerase complex (RdRp) composed of the large polymerase subunit (L), a phosphoprotein polymerase cofactor (P) and N^[2].

Fig. 1 Respiratory syncytial virus virion

G and F are the major glycoproteins on the surface of the virion and have important roles in entry. The G glycoprotein functions primarily as an attachment protein that binds virions to target cells by interacting with one or more host cell surface molecules. The F glycoprotein can also facilitate attachment, although to a lesser extent than G, but its primary function is to mediate fusion of the viral and host cell membranes^{[2, 3]}.

The life cycle of respiratory syncytial virus

The infectious cycle of respiratory syncytial virus (RSV) begins upon attachment of the virion to the apical surface of polarized, ciliated airway epithelial cells (Fig 3). (1) The virion initially binds to the host cell through its G protein and membrane fusion is mediated by the F protein, which anchors into the membrane of the target cell and then folds on itself to bring the viral and host membranes into contact, resulting in membrane fusion. (2) The genome of the virus is used for protein synthesis, with large amounts of NS1/2 and sG protein produced shortly after infection. These proteins protect the replicating virus from the host immune defences. (3) The viral genome is replicated and structural proteins are produced. Transcription and replication occur in the cytoplasm in viral inclusion bodies that serve to concentrate viral products. The viral RNA-dependent RNA polymerase (RdRp) complex is responsible for transcribing viral mRNA and synthesizing positive-sense anti-genome intermediates needed for replication of new negative-sense genomes for packaging into virions. In addition to performing non-proofreading polymerase functions, the RdRp caps and polyadenylates viral mRNAs. (4) The surface glycoproteins are synthesised in the Golgi body and deposited in the host membrane. (5) Assembly of the new virion takes place in the cytoplasm, before budding through the host cell membrane, picking up its surface glycoproteins as part of this process. sG protein is also released. Assembly of RSV virions occurs at or near the plasma membrane. Initial models posited that F proteins associate with lipid rafts and, through the F cytoplasmic tail, recruit and concentrate matrix (M) proteins; this process initiates filament budding through actin-dependent outward membrane deformation^[2].

Fig 3 Binding and entry of RSV into the host cell.

Development Process of RSV Vaccine Product

AREXVY was approved by the US Food and Drug Administration (FDA) on May 3rd, 2023, for the prevention of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus (RSV) in adults aged 60 and older. AREXVY, contains recombinant respiratory syncytial virus glycoprotein F stabilized in the prefusion conformation (RSVPreF3). In clinical trials, the vaccine was generally well tolerated. The most frequently observed solicited adverse events were injection site pain, fatigue, myalgia, headache, and arthralgia. These were generally mild to moderate and transient. The main clinical study of Arexvy was designed to assess the safety and effectiveness of a single dose administered to individuals 60 years of age and older^[8].

ABRYSVO is a respiratory syncytial virus (RSV) prefusion F (RSVpreF) vaccine, to help protect both infants through maternal immunization and older adults. ABRYSVO is indicated for: 1) Passive protection against lower respiratory tract disease (LRTD) caused by RSV in infants from birth through six months of age following maternal immunization during pregnancy. 2) Active immunization of individuals 60 years of age and older for the prevention of LRTD caused by RSV. Two additional clinical trials evaluating ABRYSVO has been initiated . One trial is being conducted in children at higher risk for RSV disease ages two to less than 18 years. A second trial is evaluating adults ages 18 to 60 years at higher risk for RSV due to underlying medical conditions such as asthma, diabetes and COPD, and adults ages 18 and older who are immunocompromised and at high-risk for RSV to further describe the safety of the vaccine^[9].

References

1. Cameron Griffiths, Steven J. Drews, David J. Marchant (2017). "Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment." Clinical Microbiology Reviews. Jan; 30(1): 277-319.
2. Michael B. Battles and Jason S. McLellan (2019). "Respiratory syncytial virus entry and how to block it." Nature. 17(4): 233-245.
3. Rixon, H. W. et al (2014). The small hydrophobic (SH) protein accumulates within lipid-raft structures of the Golgi complex during respiratory syncytial virus infection. Journal of General Virology. 85, 1153–1165.
4. Krusat T, Streckert HJ (1997). "Heparin-dependent attachment of respiratory syncytial virus (RSV) to host cells." Arch Virol. 142:1247–1254.
5. Johnson SM, McNally BA, Ioannidis I, et al (2015). "Respiratory syncytial virus uses CX3CR1 as a receptor on primary human airway epithelial cultures." PLoS Pathog. 11:e1005318.
6. Tayyari F, Marchant D, Moraes TJ, et al (2011). "Identification of nucleolin as a cellular receptor for human respiratory syncytial virus." Nature Medicine. 17:1132–1135.
7. Yoshihiko Murata, MD PhD (2009). "Respiratory Syncytial Virus Vaccine Development." Clinics in Laboratory Medicine. 29(4): 725-739.
8. US FDA news release. Issued 3 May 2023. Available at: fda.gov/news-events/press-announcements/fda-approves-first-respiratory-syncytial-virus-rsv-vaccine
9. Pfizer Inc., Letter on File, August 24, 2023