Live-attenuated respiratory syncytial virus vaccines

Abstract

Live-attenuated respiratory syncytial virus (RSV) vaccines offer several advantages for immunization of infants and young children: (1) they do not cause vaccine-associated enhanced RSV disease; (2) they broadly stimulate innate, humoral, and cellular immunity, both systemically and locally in the respiratory tract; (3) they are delivered intranasally; and (4) they replicate in the upper respiratory tract of young infants despite the presence of passively acquired maternally derived RSV neutralizing antibody. This chapter describes early efforts to develop vaccines through the classic methods of serial cold-passage and chemical mutagenesis, and recent efforts using reverse genetics to derive attenuated derivatives of wild-type (WT) RSV and to develop parainfluenza vaccine vectors that express RSV surface glycoproteins.

Fig. 1

Two types of live RSV candidate vaccines made by reverse genetics that have been evaluated clinically. The rA2cp248/404/1030ΔSH virus (upper panel) represents the strategy of developing an attenuated derivative of WT RSV. This mutant contains five cold-passaged (cp) mutations in the N, F, and L proteins, two amino acid substitutions (248 and 1030) in L, and one nucleotide substitution in the M2 GS signal (404) that independently confer temperature-sensitivity, and deletion of the SH gene. This virus was previously shown to be well-tolerated and immunogenic in infants and young children (Karron et al. 2005). MEDI-559 is another version of this virus that differs by a number of silent mutations and is phenotypically indistinguishable from rA2cp248/404/1030ΔSH. As noted in the text, MEDI-559 is currently being evaluated in a phase I-II clinical trial. The MEDI-534 virus (lower panel) represents the strategy of using a parainfluenza virus vector to express RSV antigen, in this case the RSV F protein, to provide a bivalent vaccine against RSV and HPIV3. MEDI-534 is a chimeric virus in which the F and HN genes from BPIV3 have been replaced by their counterparts from HPIV3 and the coding sequence for the RSV F gene was placed under the control of HPIV3 transcription signals and inserted as an added gene between the N and P genes. This virus also has been evaluated in clinical studies (Bernstein et al. 2012; Gomez et al. 2009; Tang RS 2012; Tang et al. 2008)