Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates.
Bottom Line: Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species.However, only IN administration could prevent infection in the upper respiratory tract.In addition, animals primed in the nose developed mucosal IgA against the F protein.
Affiliation: ReiThera Srl , Rome, Italy (former Okairos Srl).
Respiratory Syncytial Virus (RSV) is a leading cause of severe respiratory disease in infants and the elderly. No vaccine is presently available to address this major unmet medical need. We generated a new genetic vaccine based on chimpanzee Adenovirus (PanAd3-RSV) and Modified Vaccinia Ankara RSV (MVA-RSV) encoding the F, N, and M2-1 proteins of RSV, for the induction of neutralizing antibodies and broad cellular immunity. Because RSV infection is restricted to the respiratory tract, we compared intranasal (IN) and intramuscular (M) administration for safety, immunogenicity, and efficacy in different species. A single IN or IM vaccination completely protected BALB/c mice and cotton rats against RSV replication in the lungs. However, only IN administration could prevent infection in the upper respiratory tract. IM vaccination with MVA-RSV also protected cotton rats from lower respiratory tract infection in the absence of detectable neutralizing antibodies. Heterologous prime boost with PanAd3-RSV and MVA-RSV elicited high neutralizing antibody titers and broad T-cell responses in nonhuman primates. In addition, animals primed in the nose developed mucosal IgA against the F protein. In conclusion, we have shown that our vectored RSV vaccine induces potent cellular and humoral responses in a primate model, providing strong support for clinical testing.
No MeSH data available.
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Mentions: We designed a synthetic HRSV antigen composed of three viral proteins: F, N, and M2-1 (F0ΔTM–N–M2-1), which were encoded by a single open reading frame with a self-cleaving Foot and Mouth Disease virus 2A sequence21 between F and N sequences. A short sequence encoding a flexible linker was inserted between the N and the M2-1 sequences to facilitate folding (Figure 1a). The transmembrane and cytoplasmic regions of the F protein were deleted for efficient secretion of a soluble form of the F protein. The synthetic gene was codon-optimized for expression in human cells. Mature N–M2-1 fusion protein was detected by Western blot (WB) in cell lysates of DNA transfected HeLa cells (Figure 1b). The high molecular weight precursor F–N–M2-1 was barely detectable indicating efficient 2A-driven self-processing. Consistent with this observation, the soluble F protein was found in the medium of transfected cells with an apparent molecular weight of ~170 kDa on a nonreducing SDS–PAGE gel, compatible with F protein trimers, and was recognized by the conformation sensitive neutralizing antibody mAb 13 (ref. 22) (Figure 1c). When the soluble F protein was run on a reducing SDS–PAGE, two fragments were revealed consistent with the size of F1 and F2, indicating that the protein was correctly processed at the furin-cleavage sites (see Supplementary Figure S1).
No MeSH data available.