TY - JOUR
T1 - Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates
AU - Ault, Alida
AU - Tennant, Sharon M.
AU - Gorres, J. Patrick
AU - Eckhaus, Michael
AU - Sandler, Netanya G.
AU - Roque, Annelys
AU - Livio, Sofie
AU - Bao, Saran
AU - Foulds, Kathryn E.
AU - Kao, Shing Fen
AU - Roederer, Mario
AU - Schmidlein, Patrick
AU - Boyd, Mary Adetinuke
AU - Pasetti, Marcela F.
AU - Douek, Daniel C.
AU - Estes, Jacob D.
AU - Nabel, Gary J.
AU - Levine, Myron M.
AU - Rao, Srinivas S.
N1 - Funding Information:
This research was supported by the Intramural Research Program of the NIH Vaccine Research Center and the Middle Atlantic RCE Program NIAID/NIH 2 U54 AI057168 grant. To fully disclose any potential conflicts of interest, the authors Myron M. Levine and Sharon Tennant are listed on a patent application entitled “Broad spectrum vaccine against non-typhoidal Salmonella” , US 2011/0274714 A1. The authors would like to thank Mr. Sunil Sen and Mr. Paul Kamate for identification of Salmonella . We would also like to thank Dr. Raphael Simon for providing purified LPS and flagella for use in ELISAs, Judy Stein for assistance in coordinating material transfers and managing regulatory issues, Alan Dodson and John-Paul Todd for supporting monkey studies, Hana Bao and Wanxin Liu for their assistance in CD68+ quantification, Mythreyi Shastri and Brenda Hartman for assistance in manuscript preparation, and Linda Bessacque for administrative support.
PY - 2013/12/2
Y1 - 2013/12/2
N2 - Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques.
AB - Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques.
KW - Human immunodeficiency virus
KW - Live oral vaccine
KW - Nonhuman primates
KW - Nontyphoidal Salmonella
KW - Simian immunodeficiency virus
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UR - http://www.scopus.com/inward/citedby.url?scp=84887614270&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2013.09.041
DO - 10.1016/j.vaccine.2013.09.041
M3 - Article
C2 - 24099872
AN - SCOPUS:84887614270
SN - 0264-410X
VL - 31
SP - 5879
EP - 5888
JO - Vaccine
JF - Vaccine
IS - 49
ER -