There is no vaccine currently approved for paramyxovirus-induced respiratory diseases in humans, despite their major clinical importance. We review the development and evaluation of new vaccine strategies based on live-attenuated chimeric and recombinant vaccines against human respiratory syncytial virus, human metapneumovirus and human parainfluenza viruses types 1 to 3, which are significant causes of upper and lower tract respiratory diseases. Most promising strategies are based on virus attenuation through (i) mutations in key genes involved in replication; (ii) deletion of accessory genes; or (iii) the use of a corresponding animal viral vector, such as bovine parainfluenza type 3 and Sendai virus, as a background for the expression of a viral glycoprotein. Indeed, the fusion (F), or attachment (HN/H/G) glycoproteins are the most immunogenic antigens in paramyxoviruses. For each strategy, we will review the immunogenicity (increase in neutralising antibody titres) and the protection conferred by the most promising recombinant vectored vaccines and list ongoing clinical trials. We will conclude by discussing the most important challenges regarding the introduction of such vaccines into immunisation programmes.

Human parainfluenza viruses (hPIV) are pathogens responsible for upper and lower respiratory tract infections. We previously described clinical variant strains of hPIV-2 that display unusual large syncytial cytopathic effects. Their molecular characterization revealed a recurrent conserved specific amino acid substitution: A96T in the F2 subunit of the fusion glycoprotein F. The objective of this study was to investigate the contribution of this A96T substitution to the specific hyperfusogenic properties of the hPIV-2 variant strains. Based on a transient expression strategy, quantification of cell-cell fusion assays, and flow cytometry, we have shown that the A96T mutation strongly alters the fusogenic properties of F hPIV-2, highlighting this key residue in the F2 subunit and its possible role in fusion regulation. This work highlights the benefits of monitoring genetic and phenotypic changes of circulating strains to complete our understanding of Paramyxovirus fusion and related pathogenesis.