Cold-passaged human parainfluenza type 3 viruses contain ts and non-ts mutations leading to attenuation in rhesus monkeys

1992 ◽  
Vol 22 (3) ◽  
pp. 173-184 ◽  
Author(s):  
Susan L. Hall ◽  
Anne Stokes ◽  
Eveline L. Tierney ◽  
William T. London ◽  
Robert B. Belshe ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Type 3 ◽  
Ts Mutations

scholarly journals Determinants of the Host Range Restriction of Replication of Bovine Parainfluenza Virus Type 3 in Rhesus Monkeys Are Polygenic

2003 ◽  
Vol 77 (2) ◽  
pp. 1141-1148 ◽  
Author(s):  
Mario H. Skiadopoulos ◽  
Alexander C. Schmidt ◽  
Jeffrey M. Riggs ◽  
Sonja R. Surman ◽  
William R. Elkins ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Host Range ◽  
Rhesus Monkeys ◽  
Single Unit ◽  
Parainfluenza Virus ◽  
Wild Type ◽  
Range Restriction ◽  
Type 3 ◽  
Bovine Parainfluenza Virus ◽  
Host Range Restriction

ABSTRACT The Kansas strain of bovine parainfluenza virus type 3 (BPIV3) is 100- to 1,000-fold restricted in replication in the respiratory tracts of nonhuman primates compared to human PIV3 (HPIV3), an important pathogen of infants and young children. BPIV3 is also restricted in replication in human infants and children, yet it is immunogenic and is currently being evaluated in clinical trials as a vaccine candidate to protect against illness caused by HPIV3. We have examined the genetic basis for the host range attenuation phenotype of BPIV3 by exchanging each open reading frame (ORF) of a recombinant wild-type HPIV3 with the analogous ORF from BPIV3, with the caveats that the multiple ORFs of the P gene were exchanged as a single unit and that the HN and F genes were exchanged as a single unit. Recombinant chimeric bovine-human PIV3s were recovered from cDNA, and the levels of viral replication in vitro and in the respiratory tract of rhesus monkeys were determined. Recombinant chimeric HPIV3s bearing the BPIV3 N or P ORF were highly attenuated in the upper and lower respiratory tracts of monkeys, whereas those bearing the BPIV3 M or L ORF or the F and HN genes were only moderately attenuated. This indicates that the genetic determinants of the host range restriction of replication of BPIV3 for primates are polygenic, with the major determinants being the N and P ORFs. Monkeys immunized with these bovine-human chimeric viruses, including the more highly attenuated ones, developed higher levels of HPIV3 hemagglutination-inhibiting serum antibodies than did monkeys immunized with BPIV3 and were protected from challenge with wild-type HPIV3. Furthermore, host range determinants could be combined with attenuating point mutations to achieve an increased level of attenuation. Thus, chimeric recombinant bovine-human PIV3 viruses that manifest different levels of attenuation in rhesus monkeys are available for evaluation as vaccine candidates to protect infants from the severe lower respiratory tract disease caused by HPIV3.

scholarly journals Packaging and Prefusion Stabilization Separately and Additively Increase the Quantity and Quality of Respiratory Syncytial Virus (RSV)-Neutralizing Antibodies Induced by an RSV Fusion Protein Expressed by a Parainfluenza Virus Vector

2016 ◽  
Vol 90 (21) ◽  
pp. 10022-10038 ◽  
Author(s):  
Bo Liang ◽  
Joan O. Ngwuta ◽  
Richard Herbert ◽  
Joanna Swerczek ◽  
David W. Dorward ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Rhesus Monkeys ◽  
Neutralizing Antibodies ◽  
Vaccine Candidate ◽  
Parainfluenza Virus ◽  
F Protein ◽  
Syncytial Virus ◽  
Human Parainfluenza Virus ◽  
Type 3

ABSTRACTHuman respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are major pediatric respiratory pathogens that lack vaccines. A chimeric bovine/human PIV3 (rB/HPIV3) virus expressing the unmodified, wild-type (wt) RSV fusion (F) protein from an added gene was previously evaluated in seronegative children as a bivalent intranasal RSV/HPIV3 vaccine, and it was well tolerated but insufficiently immunogenic for RSV F. We recently showed that rB/HPIV3 expressing a partially stabilized prefusion form (pre-F) of RSV F efficiently induced “high-quality” RSV-neutralizing antibodies, defined as antibodies that neutralize RSVin vitrowithout added complement (B. Liang et al., J Virol 89:9499–9510, 2015, doi:10.1128/JVI.01373-15). In the present study, we modified RSV F by replacing its cytoplasmic tail (CT) domain or its CT and transmembrane (TM) domains (TMCT) with counterparts from BPIV3 F, with or without pre-F stabilization. This resulted in RSV F being packaged in the rB/HPIV3 particle with an efficiency similar to that of RSV particles. Enhanced packaging was substantially attenuating in hamsters (10- to 100-fold) and rhesus monkeys (100- to 1,000-fold). Nonetheless, TMCT-directed packaging substantially increased the titers of high-quality RSV-neutralizing serum antibodies in hamsters. In rhesus monkeys, a strongly additive immunogenic effect of packaging and pre-F stabilization was observed, as demonstrated by 8- and 30-fold increases of RSV-neutralizing serum antibody titers in the presence and absence of added complement, respectively, compared to pre-F stabilization alone. Analysis of vaccine-induced F-specific antibodies by binding assays indicated that packaging conferred substantial stabilization of RSV F in the pre-F conformation. This provides an improved version of this well-tolerated RSV/HPIV3 vaccine candidate, with potently improved immunogenicity, which can be returned to clinical trials.IMPORTANCEHuman respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are major viral agents of acute pediatric bronchiolitis and pneumonia worldwide that lack vaccines. A bivalent intranasal RSV/HPIV3 vaccine candidate consisting of a chimeric bovine/human PIV3 (rB/HPIV3) strain expressing the RSV fusion (F) protein was previously shown to be well tolerated by seronegative children but was insufficiently immunogenic for RSV F. In the present study, the RSV F protein was engineered to be packaged efficiently into vaccine virus particles. This resulted in a significantly enhanced quantity and quality of RSV-neutralizing antibodies in hamsters and nonhuman primates. In nonhuman primates, this effect was strongly additive to the previously described stabilization of the prefusion conformation of the F protein. The improved immunogenicity of RSV F by packaging appeared to involve prefusion stabilization. These findings provide a potently more immunogenic version of this well-tolerated vaccine candidate and should be applicable to other vectored vaccines.

scholarly journals Bovine Parainfluenza Virus Type 3 (BPIV3) Fusion and Hemagglutinin-Neuraminidase Glycoproteins Make an Important Contribution to the Restricted Replication of BPIV3 in Primates

2000 ◽  
Vol 74 (19) ◽  
pp. 8922-8929 ◽  
Author(s):  
Alexander C. Schmidt ◽  
Josephine M. McAuliffe ◽  
Anne Huang ◽  
Sonja R. Surman ◽  
Jane E. Bailly ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Virus Type ◽  
Rhesus Monkeys ◽  
Parainfluenza Virus ◽  
Range Restriction ◽  
Previous Infection ◽  
Previous Demonstration ◽  
Type 3 ◽  
Bovine Parainfluenza Virus ◽  
Host Range Restriction

ABSTRACT This study examines the contribution of the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein genes of bovine parainfluenza virus type 3 (BPIV3) to its restricted replication in the respiratory tract of nonhuman primates. A chimeric recombinant human parainfluenza type 3 virus (HPIV3) containing BPIV3 F and HN glycoprotein genes in place of its own and the reciprocal recombinant consisting of BPIV3 bearing the HPIV3 F and HN genes (rBPIV3-FHHNH) were generated to assess the effect of glycoprotein substitution on replication of HPIV3 and BPIV3 in the upper and lower respiratory tract of rhesus monkeys. The chimeric viruses were readily recovered and replicated in simian LLC-MK2 cells to a level comparable to that of their parental viruses, suggesting that the heterologous glycoproteins were compatible with the PIV3 internal proteins. HPIV3 bearing the BPIV3 F and HN genes was restricted in replication in rhesus monkeys to a level similar to that of its BPIV3 parent virus, indicating that the glycoprotein genes of BPIV3 are major determinants of its host range restriction of replication in rhesus monkeys. rBPIV3-FHHNH replicated in rhesus monkeys to a level intermediate between that of HPIV3 and BPIV3. This observation indicates that the F and HN genes make a significant contribution to the overall attenuation of BPIV3 for rhesus monkeys. Furthermore, it shows that BPIV3 sequences outside the F and HN region also contribute to the attenuation phenotype in primates, a finding consistent with the previous demonstration that the nucleoprotein coding sequence of BPIV3 is a determinant of its attenuation for primates. Despite its restricted replication in the respiratory tract of rhesus monkeys, rBPIV3-FHHNH conferred a level of protection against challenge with HPIV3 that was indistinguishable from that induced by previous infection with wild-type HPIV3. The usefulness of rBPIV3-FHHNH as a vaccine candidate against HPIV3 and as a vector for other viral antigens is discussed.

POLIOMYELITIS IN CANADIAN ESKIMOS LABORATORY STUDIES. IV. ANTIGENIC TYPING OF VIRUS STRAINS IN MONKEYS AND IN TISSUE CULTURES

1953 ◽  
Vol 31 (3) ◽  
pp. 207-221
Author(s):  
W. Wood ◽  
Eina M. Clark ◽  
F. T. Shimada ◽  
A. J. Rhodes
Keyword(s):  
Rhesus Monkeys ◽  
Direct Method ◽  
Fixed Dose ◽  
Tissue Cultures ◽  
Cytopathogenic Effect ◽  
Type 3 ◽  
A Direct Method ◽  
Virus Strains

Three strains of poliomyelitis virus isolated from Eskimos infected in the outbreak of poliomyelitis occurring at Chesterfield Inlet, N.W.T., in February 1949 have been typed. This typing has been carried out in monkeys and in tissue cultures. Typing was carried out by preparing in rhesus monkeys antiserum to the Eskimo strains and testing these for capacity to neutralize a fixed dose of the Brunhilde (Type 1) and Leon (Type 3) strains on thalamic inoculation of monkeys, and of the Lansing (Type 2) strain on cerebral injection of mice. Antisera prepared against Strains E3-56 and E3-227 completely neutralized Brunhilde virus, as shown on thalamic inoculation of virus-serum mixtures in groups of five monkeys. In contrast, these sera did not neutralize Leon virus. Tests carried out in mice showed that antisera to these Eskimo strains failed to neutralize Lansing virus. It was concluded therefore that Eskimo Strains E3-56 and E3-227 belong to Type 1. The same two sera were tested for their capacity to inhibit the cytopathogenic effect induced in roller-tube cultures of monkey testis by representative strains of the three types (Brunhilde, Y-SK, and Saukett). The two Eskimo sera inhibited the cytopathogenic effect induced by the Brunhilde strain but not the changes induced by the Y-SK and Saukett strains, confirming that the corresponding Eskimo viruses belonged to Type 1. Eskimo Strains E3-79 and E3-227 have also been typed in tissue cultures by a direct method; in this method antisera to the three prototype viruses were tested for capacity to inhibit the cytopathogenic effect induced by the Eskimo strains. Results of this test were in agreement, the Eskimo strains belonging to Type 1. Two strains of virus isolated from the Chesterfield Inlet outbreak have previously been typed by U.S. investigators, by techniques involving the use of monkeys. A total of five strains isolated from this epidemic have therefore been typed, and all have been found to belong to Type 1. This study illustrates that the typing of poliomyelitis strains can be carried out more rapidly and more economically in tissue culture than in monkeys.

scholarly journals A Chimeric Human-Bovine Parainfluenza Virus Type 3 Expressing Measles Virus Hemagglutinin Is Attenuated for Replication but Is Still Immunogenic in Rhesus Monkeys

2001 ◽  
Vol 75 (21) ◽  
pp. 10498-10504 ◽  
Author(s):  
Mario H. Skiadopoulos ◽  
Sonja R. Surman ◽  
Jeffrey M. Riggs ◽  
Peter L. Collins ◽  
Brian R. Murphy
Keyword(s):  
Immune Response ◽  
Virus Type ◽  
Rhesus Monkeys ◽  
Measles Virus ◽  
Protective Antigen ◽  
Serum Antibody ◽  
Parainfluenza Virus ◽  
Syncytial Virus ◽  
Type 3

ABSTRACT The chimeric recombinant virus rHPIV3-NB, a version of human parainfluenza virus type 3 (HPIV3) that is attenuated due to the presence of the bovine PIV3 nucleocapsid (N) protein open reading frame (ORF) in place of the HPIV3 ORF, was modified to encode the measles virus hemagglutinin (HA) inserted as an additional, supernumerary gene between the HPIV3 P and M genes. This recombinant, designated rHPIV3-NBHA, replicated like its attenuated rHPIV3-NB parent virus in vitro and in the upper and lower respiratory tracts of rhesus monkeys, indicating that the insertion of the measles virus HA did not further attenuate rHPIV3-NB in vitro or in vivo. Monkeys immunized with rHPIV3-NBHA developed a vigorous immune response to both measles virus and HPIV3, with serum antibody titers to both measles virus (neutralizing antibody) and HPIV3 (hemagglutination inhibiting antibody) of over 1:500. An attenuated HPIV3 expressing a major protective antigen of measles virus provides a method for immunization against measles by the intranasal route, a route that has been shown with HPIV3 and respiratory syncytial virus vaccines to be relatively refractory to the neutralizing and immunosuppressive effects of maternally derived virus-specific serum antibodies. It should now be possible to induce a protective immune response against measles virus in 6-month-old infants, an age group that in developing areas of the world is not responsive to the current measles virus vaccine.

scholarly journals Shigellosis in rhesus monkeys in quarantine

1973 ◽  
Vol 7 (2) ◽  
pp. 101-109 ◽  
Author(s):  
S. C. Arya ◽  
A. Verghese ◽  
D. S. Agarwal ◽  
S. C. Pal
Keyword(s):  
Rhesus Monkeys ◽  
Shigella Flexneri ◽  
Clinical Results ◽  
Therapeutic Action ◽  
Enteric Disease ◽  
In Vitro Sensitivity ◽  
Type 3

Shigellae and salmonellae were isolated both from rhesus monkeys that displayed and from others that were free from signs of enteric disease. There was some resistance in vitro among the shigellae to chloramphenicol and to streptomycin, but none to furazolidone. Generally in-vitro sensitivity corresponded to clinical results, and mortality could be reduced by prompt and appropriate therapeutic action. The only symptomless excretor of Shigella flexneri type 3 ceased to excrete it only after extensive treatment.

scholarly journals 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

2003 ◽  
Vol 84 (12) ◽  
pp. 3253-3261 ◽  
Author(s):  
Sridhar Pennathur ◽  
Aurelia A. Haller ◽  
Mia MacPhail ◽  
Tom Rizzi ◽  
Sepideh Kaderi ◽  
...  
Keyword(s):  
Virus Type ◽  
Rhesus Monkeys ◽  
Intrinsic Property ◽  
Vero Cells ◽  
Vaccine Vector ◽  
Parainfluenza Virus ◽  
Human Parainfluenza Virus ◽  
Type 3 ◽  
Bovine Parainfluenza Virus ◽  
Foetal Bovine Serum

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.

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