Effective mucosal immunization against respiratory syncytial virus using purified F protein and a genetically detoxified cholera holotoxin, CT-E29H

We exploited the powerful adjuvant properties of cholera holotoxin (CT) to create a mucosally administered subunit vaccine against respiratory syncytial virus (RSV). A genetically detoxified mutant CT with an E to H substitution at amino acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild ty...

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Veröffentlicht in:Vaccine 2000-06, Vol.18 (24), p.2723-2734
Hauptverfasser: Tebbey, Paul W, Scheuer, Catherine A, Peek, Joel A, Zhu, Duzhang, LaPierre, Natisha A, Green, Bruce A, Phillips, Eric D, Ibraghimov, Alexander R, Eldridge, John H, Hancock, Gerald E
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container_end_page 2734
container_issue 24
container_start_page 2723
container_title Vaccine
container_volume 18
creator Tebbey, Paul W
Scheuer, Catherine A
Peek, Joel A
Zhu, Duzhang
LaPierre, Natisha A
Green, Bruce A
Phillips, Eric D
Ibraghimov, Alexander R
Eldridge, John H
Hancock, Gerald E
description We exploited the powerful adjuvant properties of cholera holotoxin (CT) to create a mucosally administered subunit vaccine against respiratory syncytial virus (RSV). A genetically detoxified mutant CT with an E to H substitution at amino acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild type CT for toxicity and potential use as an intranasal (IN) adjuvant for the natural fusion (F) protein of RSV. When compared to CT the results demonstrated that: (1) CT-E29H binding to GM1 ganglioside was equivalent, (2) ADP-ribosylation of agmatine was 11.7%, and (3) toxicity was attenuated in both Y-1 adrenal (1.2%) and patent mouse gut weight assays. IN vaccination with F protein formulated with CT-E29H induced serum anti-CT and anti-F protein antibodies that were comparable to those obtained after vaccination with equivalent doses of CT. Vaccinations containing CT-E29H at doses of 0.1 μg were statistically equivalent to 1.0 μg in enhancing responses to F protein. Antigen-specific mucosal IgA and anti-RSV neutralizing antibodies were detected in nasal washes and sera, respectively, of mice that had received F protein and 0.1 or 1.0 μg of CT-E29H. Anti-F protein IgA was not detected in the nasal washes from mice IN vaccinated with 0.01 μg CT-E29H or IM with F protein adsorbed to AlOH adjuvant. In addition, the formulation of purified F protein and CT-E29H (0.1 and 1.0 μg) facilitated protection of both mouse lung and nose from live RSV challenge. Collectively, the data have important implications for vaccine strategies that use genetically detoxified mutant cholera holotoxins for the mucosal delivery of highly purified RSV antigens.
doi_str_mv 10.1016/S0264-410X(00)00058-X
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A genetically detoxified mutant CT with an E to H substitution at amino acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild type CT for toxicity and potential use as an intranasal (IN) adjuvant for the natural fusion (F) protein of RSV. When compared to CT the results demonstrated that: (1) CT-E29H binding to GM1 ganglioside was equivalent, (2) ADP-ribosylation of agmatine was 11.7%, and (3) toxicity was attenuated in both Y-1 adrenal (1.2%) and patent mouse gut weight assays. IN vaccination with F protein formulated with CT-E29H induced serum anti-CT and anti-F protein antibodies that were comparable to those obtained after vaccination with equivalent doses of CT. Vaccinations containing CT-E29H at doses of 0.1 μg were statistically equivalent to 1.0 μg in enhancing responses to F protein. Antigen-specific mucosal IgA and anti-RSV neutralizing antibodies were detected in nasal washes and sera, respectively, of mice that had received F protein and 0.1 or 1.0 μg of CT-E29H. Anti-F protein IgA was not detected in the nasal washes from mice IN vaccinated with 0.01 μg CT-E29H or IM with F protein adsorbed to AlOH adjuvant. In addition, the formulation of purified F protein and CT-E29H (0.1 and 1.0 μg) facilitated protection of both mouse lung and nose from live RSV challenge. 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A genetically detoxified mutant CT with an E to H substitution at amino acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild type CT for toxicity and potential use as an intranasal (IN) adjuvant for the natural fusion (F) protein of RSV. When compared to CT the results demonstrated that: (1) CT-E29H binding to GM1 ganglioside was equivalent, (2) ADP-ribosylation of agmatine was 11.7%, and (3) toxicity was attenuated in both Y-1 adrenal (1.2%) and patent mouse gut weight assays. IN vaccination with F protein formulated with CT-E29H induced serum anti-CT and anti-F protein antibodies that were comparable to those obtained after vaccination with equivalent doses of CT. Vaccinations containing CT-E29H at doses of 0.1 μg were statistically equivalent to 1.0 μg in enhancing responses to F protein. Antigen-specific mucosal IgA and anti-RSV neutralizing antibodies were detected in nasal washes and sera, respectively, of mice that had received F protein and 0.1 or 1.0 μg of CT-E29H. Anti-F protein IgA was not detected in the nasal washes from mice IN vaccinated with 0.01 μg CT-E29H or IM with F protein adsorbed to AlOH adjuvant. In addition, the formulation of purified F protein and CT-E29H (0.1 and 1.0 μg) facilitated protection of both mouse lung and nose from live RSV challenge. Collectively, the data have important implications for vaccine strategies that use genetically detoxified mutant cholera holotoxins for the mucosal delivery of highly purified RSV antigens.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>10781860</pmid><doi>10.1016/S0264-410X(00)00058-X</doi><tpages>12</tpages></addata></record>
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ispartof Vaccine, 2000-06, Vol.18 (24), p.2723-2734
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subjects AF protein
Animals
Antigens, Viral - immunology
Biological and medical sciences
Bronchoalveolar Lavage
Cholera toxin
Cholera Toxin - immunology
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
F protein
Female
Fundamental and applied biological sciences. Psychology
HN Protein
holotoxin CT-E29H
Immunity, Mucosal
Lung - virology
Mice
Mice, Inbred BALB C
Microbiology
Nasal Mucosa - virology
respiratory syncytial virus
Respiratory Syncytial Viruses - immunology
RSV
Vaccines
Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies
Vibrio cholerae
Viral Envelope Proteins
Viral Proteins - immunology
Viral Vaccines - immunology
Virology
title Effective mucosal immunization against respiratory syncytial virus using purified F protein and a genetically detoxified cholera holotoxin, CT-E29H
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