Vaccines for the Paramyxoviruses and Pneumoviruses: Successes, Candidates, and Hurdles

Abstract

Human parainfluenza viruses (family Paramyxoviridae), human metapneumovirus, and respiratory syncytial virus (family Pneumoviridae) infect most infants and children within the first few years of life and are the etiologic agents for many serious acute respiratory illnesses. These virus infections are also associated with long-term diseases that impact quality of life, including asthma. Despite over a half-century of vaccine research, development, and clinical trials, no vaccine has been licensed to date for the paramyxoviruses or pneumoviruses for the youngest infants. In this study, we describe the recent reclassification of paramyxoviruses and pneumoviruses into distinct families by the International Committee on the Taxonomy of Viruses. We also discuss some past unsuccessful vaccine trials and some currently preferred vaccine strategies. Finally, we discuss hurdles that must be overcome to support successful respiratory virus vaccine development for the youngest children.

Keywords: Sendai virus; human metapneumovirus; measles virus; parainfluenza virus; respiratory syncytial virus.

FIG. 1.

Phylogenetic relationships between representative members of the Paramyxoviridae, Pneumoviridae, and Filoviridae families. Amino acid sequences of the polymerase (A) and surface glycoprotein (B) genes were used to compare virus families. Taxonomy is shown according to the 2016 release by the International Committee on the Taxonomy of Viruses. The phylogenetic tree was generated with CLC Main Workbench (CLC bio). The scale bar represents branch length as base substitutions per site. Virus names are abbreviated as follows: human metapneumovirus (HMPV), human parainfluenza virus 1 (HPIV1), human parainfluenza virus 2 (HPIV2), human parainfluenza virus 3 (HPIV3), human respiratory syncytial virus (HRSV), and Newcastle disease virus (NDV). L protein sequences are as follows: Ebolavirus Zaire (NP_066251), Marburg virus 1980 (YP_001531159), Hendra virus (NP_047113), HMPV CAN97-83 (YP_012613), HPIV1 Z (CAA272273), HPIV2 Toshiba (P26676), HPIV3 (ZLNZP3), HRSV B1 (NP_056924), measles virus Ichinose-B95a (NP_056924), NDV B1 (NP_071471), and Sendai virus Enders (AAA69579). GP protein sequences are from Ebolavirus Zaire (AAB81004) and Marburg virus Popp (CAA48507). F protein sequences are from Hendra virus (NP_047111.2), HMPV TN/92-4 (ABM67j072), HPIV1 C39 (P12605), HPIV2 (NP_598404), HPIV3 (AAB21447.1), HRSV B 9320 (AAR14266), measles virus Edmonston (AF266288_6), NDV LaSota (AAC28374.1), and Sendai virus Z (AAB06281.1).

FIG. 2.

Prefusion structures of the fusion (F) proteins of PIV5 and HRSV. (A) Ectodomain structure of the F protein. Domains are as follows: domain I (DI, yellow), domain II (DII, green), domain III (DIII, orange), domain III heptad repeat A (DIII HRA, brown), fusion peptide (f.p., magenta), heptad repeat B (HRB, blue), and trimerization domain (t.d.). (B, C) Trimer and monomer structure of the PIV5 F protein in its prefusion form. (D) Monomer structure of the HRSV F protein in its prefusion form. Domains in B–D are color coded as in the domain structure (A). Structures of PIV5 F (96) and HRSV F (54) were rendered with MacPYMOL using coordinates 2B9B and 4JHW, respectively.

FIG. 3.

Schematic diagrams of paramyxovirus and pneumovirus genomes. Genomes shown include Sendai virus (SeV, blue), a generic human parainfluenza virus genome (HPIV, brown), human metapneumovirus (HMPV, green), human respiratory syncytical virus (HRSV green) and an RSV F vaccine vectored by Sendai virus (SeV-RSVF, blue with yellow insert). The additional (termed “addnl” in the figure) proteins expressed from the P genes of HPIV1, HPIV2, and HPIV3 are shown in brown below the generic HPIV genome. Surface glycoproteins of the human viruses are shown in yellow. In each genome, the 3′ leader is on the left terminus and the 5′ trailer is on the right. The intergenic junctions are not shown but contain transcription stop, intergenic, and transcription start sequences. In the HMPV and HRSV genomes, the M2 gene contains two overlapping products, M2-1 and M2-2. The RSV M2 and L genes overlap. Genomes are drawn to scale (bottom), except for the generic HPIV genome.