Neurovirulence and immunogenicity of attenuated recombinant vesicular stomatitis viruses in nonhuman primates.
In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation.


OBJECTIVE
The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans.
Profectus Biosciences, Tarrytown, New York, USA DClarke@profectusbiosciences.net.
David K
DK
Clarke
University of Texas Medical Branch, Galveston, Texas, USA.
Farooq
F
Nasar
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Siew
S
Chong
Pfizer Pharmaceuticals, Pearl River, New York, USA.
J Erik
JE
Johnson
The International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn, New York, USA.
John W
JW
Coleman
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Margaret
M
Lee
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Susan E
SE
Witko
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Cheryl S
CS
Kotash
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Rashed
R
Abdullah
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Shakuntala
S
Megati
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Amara
A
Luckay
Profectus Biosciences, Tarrytown, New York, USA.
Becky
B
Nowak
Tulane National Primate Research Center, Tulane University, New Orleans, Louisiana, USA.
Andrew
A
Lackner
Veterinary Pathology Services, Houston, Texas, USA.
Roger E
RE
Price
EPL Inc., Research Triangle Park, North Carolina, USA.
Peter
P
Little
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Narender
N
Kalyan
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Valerie
V
Randolf
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Ali
A
Javadian
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Timothy J
TJ
Zamb
The International AIDS Vaccine Initiative, AIDS Vaccine Design and Development Laboratory, Brooklyn, New York, USA.
Christopher L
CL
Parks
Profectus Biosciences, Tarrytown, New York, USA.
Michael A
MA
Egan
Profectus Biosciences, Tarrytown, New York, USA.
John
J
Eldridge
Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Michael
M
Hendry
Pfizer Pharmaceuticals, Pearl River, New York, USA.
Stephen A
SA
Udem
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology / Q000821:virology*; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008252:Macaca fascicularis / Q000235:genetics / Q000276:immunology / Q000821:virology; D008297:Male; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D016915:AIDS Vaccines; D000914:Antibodies, Viral; D014613:Vaccines, Attenuated; D054301:gag Gene Products, Human Immunodeficiency Virus