Evaluation of attenuation, immunogenicity and efficacy of a bovine parainfluenza virus type 3 (PIV-3) vaccine and a recombinant chimeric bovine/human PIV-3 vaccine vector in rhesus monkeys

Abstract

Restricted replication in the respiratory tract of rhesus monkeys is an intrinsic property of bovine parainfluenza virus type 3 (bPIV-3) strains. This host range phenotype of bPIV-3 has been utilized as a marker to evaluate the attenuation of bPIV-3 vaccines for human use. Two safety, immunogenicity and efficacy studies in primates evaluated and compared three human parainfluenza virus type 3 (hPIV-3) vaccine candidates: biologically derived bPIV-3, a plasmid-derived bPIV-3 (r-bPIV-3) and a chimeric bovine/human PIV-3 (b/hPIV-3). These studies also examined the feasibility of substituting Vero cells, cultured in the presence or absence of foetal bovine serum, for foetal rhesus lung-2 (FRhL-2) cells as the tissue culture substrate for the production of bPIV-3 vaccine. The results demonstrated that (i) Vero cell-produced bPIV-3 was as attenuated, immunogenic and efficacious as bPIV-3 vaccine grown in FRhL-2 cells, (ii) plasmid-derived bPIV-3 was as attenuated, immunogenic and efficacious as the biologically derived bPIV-3 and (iii) the b/hPIV-3 chimera displayed an intermediate attenuation phenotype and protected animals completely from hPIV-3 challenge. These results support the use of bPIV-3 vaccines propagated in Vero cells in human clinical trials and the use of b/hPIV-3 as a virus vaccine vector to express foreign viral antigens. The bPIV-3 vaccine strain (bPIV-3/Kansas/15626/84) used here was isolated in 1984 from a calf with pneumonia in Kansas and was shown to be immunogenic in hamsters (Haller et al., 2000) and in Old World and New World non-human primates (van Wyke Coelingh et al., 1988). Compared to hPIV-3, bPIV-3 was approximately 100-to 1000-fold restricted for replication in the lower (LRT) and S. Pennathur and A. A. Haller contributed equally to this work.

Parainfluenza Virus Type 3 Expressing the Native or Soluble Fusion (F) Protein of Respiratory Syncytial Virus (RSV) Confers Protection from RSV Infection in African Green Monkeys

“…The levels of hPIV3 HAI and neutralizing antibodies observed for the primate sera obtained from animals immunized with both kinds of b/h PIV3/RSV F vaccines were similar to the titers displayed by rhesus monkeys vaccinated with b/h PIV3 (30). Rhesus monkeys immunized with b/h PIV3 were effectively protected from challenge with wild-type hPIV3.…”

A host-range restricted parainfluenza virus type 3 (PIV3) expressing the human metapneumovirus (hMPV) fusion protein elicits protective immunity in African green monkeys

“…However, the restricted replication of bPIV3 compared to hPIV3 was previously demonstrated in the respiratory tract of chimpanzees and rhesus monkeys and this attenuation phenotype was shown to correlate with the safety profile of bPIV3 in human infants [29][30][31][32]. We have previously shown that rbPIV3, the virus vector was restricted in replication in the upper and lower respiratory tract of rhesus monkeys compared to hPIV3, and that replacement of the bovine PIV3 F and HN gene with human PIV3 F and HN resulted in an intermediate level of attenuation [33]. Here, we compared the replication of the chimeric b/h PIV3/hMPV F2 virus with wt hPIV3, recombinant bPIV3 (rbPIV3) and a bovine parainfluenza virus expressing the human PIV3 F and HN genes (b/h PIV3) in the respiratory tract of rhesus monkeys.…”

“…However, the titers between b/h PIV3/hMPV F2 and b/h PIV3 or rbPIV3 in the URT and LRT were not significantly different (P > 0.05). Therefore, b/h PIV3/hMPV F2 replicated to the same level as rbPIV3, a virus that was attenuated and safe in human infants [31][32][33].…”

Complete Genome Sequence and Pathogenicity of Two Swine Parainfluenzavirus 3 Isolates from Pigs in the United States

“…Further, there is rapid virus clearance and limited virus replication, which are ideal qualities for a vaccine vector. A construct with bPIV3/hPIV3 chimeric virus (2, 71) as a vector backbone with the F and HN glycoproteins from hPIV3 has been evaluated as a vaccine against hPIV3 (26,54). A construct consisting of bPIV3 as a backbone with F and HN proteins from hPIV3 and F protein from RSV was also generated.…”