Researchers are exploring the development of mRNA vaccines against respiratory syncytial virus

In a recently published study in Cytokine and Growth Factor Reviewsresearchers discussed the development of messenger ribonucleic acid (mRNA) vaccines against respiratory syncytial virus (RSV).

The single-stranded (ss) RNA virus, RSV, is the primary pathogen causing pneumonia and bronchitis in infants and the elderly. Although no vaccines against RSV have been approved, advances in the structural resolution and characterization of the viral surface fusion glycoprotein (G) have been critical to vaccine development.

Monoclonal antibodies (mAbs) and various vaccine technologies have been explored for prophylactic RSV therapeutics. Several RSV vaccines and mAbs are currently being evaluated in clinical trials and preliminary results in infants and older adults are encouraging. The success of mRNA vaccine technology for Coronavirus disease 2019 (COVID-19) has led to the advancement of mRNA vaccines against various pathogens.

Moderna has received Food and Drug Administration (FDA) approval for an investigational single-dose RSV vaccine (mRNA-1345) for older adults. Therefore, mRNA vaccines could be a more viable and successful measure against RSV. In the present review, researchers discussed RSV properties with a focus on vaccine development.

Pathology of RSV infection

RSV is an enveloped filamentous virus with a negative-sense ssRNA genome. Its 15.2kb genome is made up of 10 genes that code for 11 proteins. Viral replication and resulting immune responses lead to airway damage in RSV infection. Histopathological examination of autopsy specimens suggests that RSV replication contributes to lung injury. Studies have revealed neutrophil-intensive inflammatory responses during RSV infection in infants. In addition, the neutrophilic inflammatory response to RSV infection has been associated with asthma exacerbation.

RSV fusion protein

Existing RSV vaccine candidates target the fusion protein (F). The conserved sequence of the F protein could explain the existence of only one serotype. Infected individuals have significantly higher titers of F-specific neutralizing antibodies (nAbs) than G-specific nAbs. During infection, the F protein undergoes conformational changes from an unstable prefusion protein (pre-F) to a stable trimer (post-F).

Antibodies against pre-F protein determine the extent of RSV neutralization. As such, the pre-F protein could be a promising target for RSV vaccine development. Structural characterization has revealed six and four antigenic epitopes, respectively, in pre- and post-F protein conformations. Of these, the stable φ site has been proposed for vaccine development.

RSV vaccine development

Vector-based, subunit, particle-based, live attenuated and mRNA vaccines against RSV are currently under development. Live attenuated vaccines activate local mucosal antibodies and cellular responses and are generally considered safe because they do not cause enhanced respiratory disease (ERD). Due to ERD concerns with protein-based vaccines, subunit vaccines have only been studied for use in pregnant and elderly populations.

DS-Cav1 is a subunit vaccine based on the stabilized pre-F protein that elicits a robust nAb response. In addition, strong F-specific antibodies and neutralization with DS-Cav1 persisted at least 44 weeks above baseline in a phase I clinical study. DPX-RSV is another protein subunit vaccine based on the small hydrophobic (SH) protein of RSV. It is unique because it does not induce nAbs and is designed to eliminate infected cells.

The safety and immunogenicity of DPX-RSV were evaluated in healthy subjects aged 50 to 64 years. Robust SH-specific immune responses were evident and the vaccine was generally safe, with somnolence, myalgia, and mild pain as common adverse events. In addition, five vector-based vaccine candidates are being tested at various stages of development.

The ChAd155 RSV vaccine was developed in 2020 for pediatric use. It uses a chimpanzee-derived adenovirus as a vector and encodes F, core, and matrix proteins. A clinical study concluded that the vaccine elicited RSV-specific cellular and humoral responses and had an acceptable safety profile. The remarkable success of COVID-19 mRNA vaccines underscores the potential of mRNA vaccine technology for other infectious diseases, including influenza and RSV.

Current mRNA vaccine candidates for RSV are based on the conserved F protein. Moderna has developed three vaccine candidates that encode the pre-F protein — mRNA-1172, mRNA-1777, and mRNA-1345. A Phase I study for mRNA-1777 was conducted in 72 young and older adults. The study found that the vaccine was well tolerated with no reports of serious side effects.

Humoral and cellular responses to vaccine antigens were observed in a dose-dependent manner. The mRNA-1345 vaccine is currently in Phase III clinical trials. Like mRNA-1777, it had a good safety profile. A single dose (50, 100, or 200 mcg) was well tolerated in older adults. In addition, mRNA-1345 elicited eight-fold higher nAbs than mRNA-1777 one month after administration.

Final remarks

In summary, decades of research into nucleic acid design and delivery and the discovery of new antigen targets have made mRNA vaccines excellent tools for combating infectious diseases and emerging pandemics. mRNA vaccines are generally considered safe because they lack pathogenic viral components. Thus, mRNA vaccines represent a new, safer, and more effective means of preventing RSV.