First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002).
BACKGROUND
We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA.


METHODS
Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed.


RESULTS
Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5.


CONCLUSIONS
Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.
Division of Infectious Diseases, Brigham and Women's Hospital Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, Massachusetts.
Lindsey R
LR
Baden
Division of Infectious Diseases, Brigham and Women's Hospital Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, Massachusetts.
Stephen R
SR
Walsh
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, Massachusetts.
Michael S
MS
Seaman
Division of Infectious Diseases, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts.
Jennifer A
JA
Johnson
Division of Infectious Diseases, Brigham and Women's Hospital.
Robert P
RP
Tucker
Division of Infectious Diseases, Brigham and Women's Hospital.
Jane A
JA
Kleinjan
Division of Infectious Diseases, Brigham and Women's Hospital.
Jon A
JA
Gothing
Division of Infectious Diseases, Brigham and Women's Hospital.
Brian A
BA
Engelson
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center.
Brittany R
BR
Carey
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center.
Avinash
A
Oza
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center.
Shringkhala
S
Bajimaya
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center.
Lauren
L
Peter
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center.
Chelsea
C
Bleckwehl
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center.
Peter
P
Abbink
Crucell Holland BV, Leiden, the Netherlands.
Maria G
MG
Pau
Crucell Holland BV, Leiden, the Netherlands.
Mo
M
Weijtens
EMMES Corporation, Rockville.
Meghan
M
Kunchai
Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Edith M
EM
Swann
EMMES Corporation, Rockville.
Mark
M
Wolff
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, Massachusetts.
Raphael
R
Dolin
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, Massachusetts.
Dan H
DH
Barouch
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D000260:Adenoviruses, Human / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D036022:Capsid Proteins / Q000235:genetics*; D004311:Double-Blind Method; D004337:Drug Carriers; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000097:blood; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D055815:Young Adult; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; D004337:Drug Carriers; D015483:HIV Antibodies; D010919:Placebos; D014614:Vaccines, Synthetic; D054299:env Gene Products, Human Immunodeficiency Virus; C018315:hexon capsid protein, Adenovirus
HIV vaccine; adenovirus 5 HVR48; dose escalation; immunogenicity; safety