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01
What is Respiratory Syncytial Virus (RSV)
The disease spectrum ranges from mild rhinitis to severe upper and lower respiratory tract illnesses, such as bronchiolitis and pneumonia. Although the virus can directly cause cytopathology in respiratory epithelium, in immunocompetent individuals, the immune response plays a more significant role in the pathogenesis. Once the virus enters the host via transmission routes, it rapidly spreads to the respiratory tract, replicating in the apical ciliated epithelial cells.
RSV’s attachment glycoprotein (G) and fusion protein (F) are key to inducing protective neutralizing antibody responses. A strong and timely immune response against the F protein can prevent severe infection. Additionally, the F protein is highly conserved across strains, making it an excellent target for potential vaccines and monoclonal antibodies (mAb). The F protein exists in two conformations: prefusion (pre-F) and postfusion (post-F). Infectious RSV displays both forms on its surface, but after the virus infects a cell, the pre-F conformation changes to the post-F conformation, so vaccines are being developed to target the stable pre-F structure.
02
Susceptible Populations
RSV is a significant cause of lower respiratory tract infections in infants under one year of age. Other high-risk groups include individuals with compromised immune systems, lung or heart conditions, and the elderly. RSV infection can lead to upper respiratory tract infections and bronchiolitis, rarely progressing to pneumonia, respiratory failure, apnea, or death. The seven major at-risk groups include:
1
Infants under 6 months
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Infants exposed to secondhand smoke
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Asthma patients
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Patients with cardiopulmonary disease
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Elderly patients with chronic obstructive pulmonary disease (COPD)
03
Global Research Progress on RSV-mRNA Vaccines
Moderna’s mRNA-1345 is a candidate vaccine developed to prevent RSV infections. It encodes a protein called prefusion F glycoprotein, triggering an effective neutralizing antibody response. This experimental vaccine consists of a single mRNA sequence encoding the stabilized pre-fusion F glycoprotein.
The vaccine uses lipid nanoparticles (LNPs), similar to those in Moderna’s COVID-19 vaccine. The F glycoprotein, located on the surface of the virus, facilitates its entry into host cells and exists in two states: pre-fusion and post-fusion. The pre-fusion conformation is a crucial target for potent neutralizing antibodies and is highly conserved in both RSV-A and RSV-B subtypes.
Recent results from Moderna's ongoing Phase 1 study have shown that mRNA-1345 is well tolerated across all dose levels, demonstrating positive immune responses. A Phase 2/3 trial (NCT05127434) is currently evaluating the safety, tolerability, and efficacy of mRNA-1345 in adults aged 60 and older. This study aims to assess the vaccine's effectiveness in preventing the first occurrence of RSV-related lower respiratory tract disease (RSV-LRTD) within 14 days to 12 months post-injection, compared to a placebo.
This research, which began in November 2021, is expected to be completed by November 2024.
04
Advantages of mRNA Vaccines
mRNA vaccines typically refer to mRNA COVID-19 vaccines, used to prevent infections caused by the novel coronavirus. Other types of vaccines include inactivated vaccines, live attenuated vaccines, and DNA vaccines. Compared to these, mRNA vaccines offer advantages such as safety, high efficacy, and ease of production, but they also have drawbacks like strong immune responses and stringent storage requirements.
mRNA vaccines have high immunogenicity and do not require adjuvants, minimizing potential side effects.
Disadvantages
05
mRNA Drug Delivery Methods
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Researchers have found that apolipoprotein E (ApoE) adsorption plays a key role in mediating liver targeting by lipid nanoparticles (LNPs). The current LNP delivery systems used for mRNA vaccines are liver-targeted. However, by altering the composition of the four lipids in the LNP formulation or adding auxiliary lipids, it’s possible to modulate the "protein corona" components, enabling LNP delivery to the lungs, spleen, and liver.
Active targeting delivery strategies involve adding peptides, antibodies, antibody fragments, or nucleic acid aptamers to the LNP surface. This enhances the specific recognition and binding of LNPs to receptors on target tissues or cells, improving mRNA delivery efficiency and reducing toxicity.
The End
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Akinc A, Maier MA, Manoharan M, Fitzgerald K, Jayaraman M, Barros S, Ansell S, Du X, Hope MJ, Madden TD, Mui BL, Semple SC, Tam YK, Ciufolini M, Witzigmann D, Kulkarni JA, van der Meel R, Cullis PR. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat Nanotechnol. 2019 Dec;14(12):1084-1087. doi: 10.1038/s41565-019-0591-y. PMID: 31802031.
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