Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection

Abstract

The RSV Fusion (F) protein is a target for neutralizing antibody responses and is a focus for vaccine discovery; however, the process of RSV entry requires F to adopt a metastable prefusion form and transition to a more stable postfusion form, which displays less potent neutralizing epitopes. mRNA vaccines encode antigens that are translated by host cells following vaccination, which may allow conformational transitions similar to those observed during natural infection to occur. Here we evaluate a panel of chemically modified mRNA vaccines expressing different forms of the RSV F protein, including secreted, membrane associated, prefusionstabilized, and non-stabilized structures, for conformation, immunogenicity, protection, and safety in rodent models. Vaccination with mRNA encoding native RSV F elicited antibody responses to both prefusion-and postfusion-specific epitopes, suggesting that this antigen may adopt both conformations in vivo. Incorporating prefusion stabilizing mutations further shifts the immune response toward prefusion-specific epitopes, but does not impact neutralizing antibody titer. mRNA vaccine candidates expressing either prefusion stabilized or native forms of RSV F protein elicit robust neutralizing antibody responses in both mice and cotton rats, similar to levels observed with a comparable dose of adjuvanted prefusion stabilized RSV F protein. In contrast to the protein subunit vaccine, mRNA-based vaccines elicited robust CD4+ and CD8+ T-cell responses in mice, highlighting a potential advantage of the technology for vaccines requiring a cellular immune response for efficacy.

The Long Road Toward COVID-19 Herd Immunity: Vaccine Platform Technologies and Mass Immunization Strategies

“…mRNA-1273 is a novel LNP-encapsulated, mRNA-based vaccine that encodes the full-length, prefusion-stabilized S protein of SARS-CoV-2. This LNP-based technology platform has previously been shown to induce strong immune responses and protection against a number of different pathogens in preclinical studies ( 204 , 205 ). In addition, the LNP technology was approved in 2018 for siRNA delivery as part of the product Patisiran (Onpattro, Alnylam Pharmaceuticals, Cambridge, MA, USA), which inhibits hepatocyte expression of transthyretin in patients with hereditary transthyretin-mediated amyloidosis ( 206 ).…”

How can nanotechnology help to combat COVID-19? Opportunities and urgent need

“…For this, different materials can be used for the development of nanocarriers, such as lipids, polymers and polysaccharides [180]. For instance, lipidic nanoparticles for the encapsulation of genetic material enhance the immune response to the vaccine, once the nanocarrier system can protect the DNA or RNA against enzymatic degradation and increase cell uptake, releasing the genetic material in target cells [181].…”

Immune Responses Induced by mRNA Vaccination in Mice, Monkeys and Humans

“…This offers the possibility to assess the performance of new mRNA vaccine candidates and benchmark against licensed vaccines if available. A major advantage with mRNA vaccines is that the produced protein (given the sequence encodes for the native form of the pathogenic antigen) will have the accurate and same conformation and glycosylation as the live pathogen and thus favoring the development of correct antibody specificities [ 45 ]. Antibody levels and quality upon vaccination with LNP-formulated mRNA may also be influenced by the size of the LNPs (range up to 200 nm) that enables both cellular and passive transport to the draining lymph nodes which means that B cells at these locations can potentially be directly targeted by the vaccine [ 46 ].…”

“…Vaccination with mRNA encoding native RSV F elicited antibody responses to both prefusion- and postfusion-specific epitopes, suggesting that this antigen may adopt both conformations in vivo. Incorporating prefusion stabilizing mutations further shifted the immune response toward prefusion-specific epitopes, but did not impact neutralizing antibody titer [ 45 ].…”