Evaluation of the safety, immunogenicity, and protective efficacy of whole inactivated simian immunodeficiency virus (SIV) vaccines with conformationally and functionally intact envelope glycoproteins.
A novel, general approach to chemical inactivation of retroviruses was used to produce inactivated simian immunodeficiency virus (SIV) particles with functional envelope glycoproteins. Inactivated virions of three different virus isolates (SIVmne E11S, SIVmac239, and SIVmac239 g4,5), prepared by treatment with 2,2'-dithiodipyridine (aldrithol-2, AT-2), were not detectably infectious, in vitro or in vivo. Immunization of pigtailed macaques with inactivated SIVmne E11S particles, without adjuvant, induced both humoral and cellular immune responses. Four of six animals immunized with the inactivated particles did not show measurable SIV RNA in plasma (<100 copy Eq/ml) following intravenous challenge with pathogenic, homologous virus (SIVmne E11S), compared to peak values of > or =10(6) copy Eq/ml in challenged SIV-naive control animals (p = 0.0001). Despite the absence of measurable viral RNA in plasma in these animals, culturable virus and viral DNA were initially detectable in blood and lymph node specimens; in contrast to control animals, SIV DNA could no longer be detected in PBMC by 10 weeks postchallenge in five of six SIV-immunized animals (p = 0.0001). However, vaccines did not resist a sequential rechallenge with the heterologous pathogenic virus SIVsm E660. AT-2-inactivated virus with functional envelope glycoproteins is a novel class of vaccine immunogen and was noninfectious, under conditions of rigorous in vivo challenge, and induced both binding and neutralizing antibody responses, along with cellular immune responses. Results suggest that immunization facilitated effective containment of pathogenic homologous challenge virus. With further optimization, AT-2-inactivated viral particles may be a useful class of immunogen in the development of a vaccine to prevent AIDS.
AIDS Vaccine Program, SAIC Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland 21702, USA. lifson@ncifcrf.gov
Jeffrey D
JD
Lifson
Jeffrey L
JL
Rossio
Michael
M
Piatak
Julian
J
Bess
Elena
E
Chertova
Douglas K
DK
Schneider
Vicky J
VJ
Coalter
Barbara
B
Poore
Rebecca F
RF
Kiser
Robert J
RJ
Imming
Anthony J
AJ
Scarzello
Louis E
LE
Henderson
W Gregory
WG
Alvord
Vanessa M
VM
Hirsch
Raoul E
RE
Benveniste
Larry O
LO
Arthur
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D007111:Immunity, Cellular; D008254:Macaca nemestrina; D009500:Neutralization Tests; D018449:SAIDS Vaccines / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D015164:Vaccines, Inactivated / Q000627:therapeutic use*; D014759:Viral Envelope Proteins / Q000276:immunology / Q000627:therapeutic use*
D018449:SAIDS Vaccines; D015164:Vaccines, Inactivated; D014759:Viral Envelope Proteins