Alphavirus replicon particles as candidate HIV vaccines.
Replicon particles based on Venezuelan equine encephalitis virus (VEE) contain a self-replicating RNA encoding the VEE replicase proteins and expressing a gene of interest in place of the viral structural protein genes. Structural proteins for packaging of replicon RNA into VEE replicon particles (VRPs) are expressed from separate helper RNAs. Aspects of the biology of VEE that are exploited in VRP vaccines include 1) expression of very high levels of immunogen, 2) expression of immunizing proteins in cells in the draining lymph node, and 3) the ability to induce mucosal immunity from a parental inoculation. Results of experiments with VRPs expressing green fluorescent protein or influenza virus hemagglutinin (HA) demonstrated that specific mutations in the VRP envelope glycoproteins affect both targeting in the draining lymph node and efficiency of the immune response in mice. VRPs expressing either the matrix-capsid portion of Gag, the full-length envelope gp160, or the secreted gp140 of cloned SIVsm H-4i were mixed in a cocktail and used to immunize macaques at 0, 1, and 4 months. Neutralizing antibodies against SIVsm H-4 were induced in 6 of 6 vaccinates and CTL in 4 of 6. An intrarectal challenge with the highly pathogenic SIVsm E660 was given at 5 months. A vaccine effect was seen in reduced peak virus loads, reduced virus loads both at set point and at 41 weeks postchallenge, and preserved or increased CD4 counts compared to controls. A candidate VRP HIV vaccine expressing Clade C Gag contains a sequence that is very close to the South African Clade C consensus and was selected from a recent seroconverter in the Durban cohort to represent currently circulating genotypes in South Africa. A GMP lot of this vaccine has been manufactured and tested for a phase I trial in the first months of 2002.
Davis
Nancy L
NL
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599, USA. joiner@med.unc.edu
West
Ande
A
Reap
Elizabeth
E
MacDonald
Gene
G
Collier
Martha
M
Dryga
Sergey
S
Maughan
Maureen
M
Connell
Mary
M
Walker
Chris
C
McGrath
Kathryn
K
Cecil
Chad
C
Ping
Li-Hua
LH
Frelinger
Jeff
J
Olmsted
Robert
R
Keith
Paula
P
Swanstrom
Ronald
R
Williamson
Carolyn
C
Johnson
Philip
P
Montefiori
David
D
Johnston
Robert E
RE
D016915:AIDS Vaccines / Q000235:genetics*; D000818:Animals; D002986:Clinical Trials as Topic; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D015683:Gene Products, gag / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins; D019302:HIV Envelope Protein gp160 / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control*; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D013019:South Africa; D013997:Time Factors
D016915:AIDS Vaccines; C033904:GP 140; D015683:Gene Products, gag; D006023:Glycoproteins; D019302:HIV Envelope Protein gp160; D006388:Hemagglutinins; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins