Progress in the development of human parainfluenza virus vaccines

Abstract

In children under 5 years of age, human parainfluenza viruses (HPIVs) as a group are the second most common etiology of acute respiratory illness leading to hospitalization, surpassed only by respiratory syncytial virus but ahead of influenza viruses. Using reverse genetics systems for HPIV serotypes 1, 2 and 3 (HPIV1, 2 and 3), several live-attenuated HPIVs have been generated and evaluated as intranasal vaccines in adults and in children. Two vaccines against HPIV3 were found to be well tolerated, infectious and immunogenic in Phase I trials in HPIV3-seronegative infants and children and should progress to proof-of-concept trials. Vaccines against HPIV1 and HPIV2 are less advanced and have just entered pediatric trials.

Figure 1. Human parainfluenxa virus virion and genome organization

Parainfluenza virus are enveloped viruses in the paramyxovirus family. Their single-strand negative-sense RNA genomes are approximately 15,500 nucleotides in length and encode six common proteins in the invariant order N-P-M-F-HN-L. The N, P and L proteins form the viral nucleocapsid. The M protein is involved in virion morphogenesis whereas the HN and F proteins mediate adhesion to and fusion with the host cell membrane, respectively. Each gene encodes a single major protein with the exception of the P gene, which, in addition to the P protein, encodes one or more accessory proteins, as indicated. F: Fusion; HN: Hemagglutinin–neuraminidase; L: Large; M: Matirx; N: Nucleo; P: Phospho.

Figure 2. Investigational live-attenuated parainfluenza virus vaccines currently in clinical development

Mutations that were introduced into the wild-type virus genome are indicated by asterisks. For HPIV1 and HPIV2, the type and positions of amino acid substitutions are indicated. The T15C mutation is a non coding mutation in the leader sequence of HPIV2. For rHPIV3cp45 (also referred to as MEDI-560) only the position of mutations is indicated. For B/HPIV3 and B/HPIV3-RSV F, BPIV3 genes are in light purple and HPIV3 genes are in light blue. In B/HPIV3-RSV F (also referred to as MEDI-534), the HRSV (subgroup A F protein is expressed from an additional open reading frame inserted between BPIV3 N and P). BPIV3: Bovine parainfluenza viruses; cp: Cold-passaged; HPIV: Human parainfluenza virus; HRSV: human respiratory syncytial virus; MEDI: MedImmune. LLC; N: Nucleo; P: Phospho.