Phase 1 safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1 B'/C candidate vaccine.
BACKGROUND
We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B'/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.


RESULTS
ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1x10(7) (low), 5x10(7) (mid), or 2.5x10(8) pfu (high)] volunteers were randomized in a 3:1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA. ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNgamma ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.


CONCLUSIONS
ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.


BACKGROUND
Clinicaltrials.gov NCT00252148.
Vasan
Sandhya
S
Aaron Diamond AIDS Research Center, New York, New York, United States of America. svasan@adarc.org
Schlesinger
Sarah J
SJ
Chen
Zhiwei
Z
Hurley
Arlene
A
Lombardo
Angela
A
Than
Soe
S
Adesanya
Phumla
P
Bunce
Catherine
C
Boaz
Mark
M
Boyle
Rosanne
R
Sayeed
Eddy
E
Clark
Lorna
L
Dugin
Daniel
D
Boente-Carrera
Mar
M
Schmidt
Claudia
C
Fang
Qing
Q
LeiBa
Huang
Yaoxing
Y
Zaharatos
Gerasimos J
GJ
Gardiner
David F
DF
Caskey
Marina
M
Seamons
Laura
L
Ho
Martin
M
Dally
Len
L
Smith
Carol
C
Cox
Josephine
J
Gill
Dilbinder
D
Gilmour
Jill
J
Keefer
Michael C
MC
Fast
Patricia
P
Ho
David D
DD
D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D000293:Adolescent; D000328:Adult; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D009500:Neutralization Tests; D010919:Placebos; D014616:Vaccinia virus / Q000235:genetics*; D055815:Young Adult
D016915:AIDS Vaccines; D010919:Placebos