TY - JOUR
T1 - Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques
AU - Roy, Chad J.
AU - Ehrbar, Dylan
AU - Van Slyke, Greta
AU - Doering, Jennifer
AU - Didier, Peter J.
AU - Doyle-Meyers, Lara
AU - Donini, Oreola
AU - Vitetta, Ellen S.
AU - Mantis, Nicholas J.
N1 - Funding Information:
The work described in this manuscript was supported by grant AI125190 and Contract No. HHSN272201400039C from the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). The work at Tulane National Primate Research Center was also supported in part by grant OD011104 from the Office of Research Infrastructure Programs (ORIP), Office of the Director, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. E.V. was supported in part by the Simmons-Patigian Chair at UT Southwestern. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Kelly Mapes, Ayesha Ahmed, and Steven Ruback for excellent technical support at UTSW. We thank Hayley Novak for technical assistance and Elizabeth Cavosie for administrative assistance at the Wadsworth Center.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain’s (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.
AB - Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain’s (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.
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U2 - 10.1038/s41541-022-00582-x
DO - 10.1038/s41541-022-00582-x
M3 - Article
C2 - 36526642
AN - SCOPUS:85144159970
SN - 2059-0105
VL - 7
JO - npj Vaccines
JF - npj Vaccines
IS - 1
M1 - 164
ER -