Safety and Immunogenicity of the Recombinant BCG Vaccine AERAS-422 in Healthy BCG-naïve Adults: A Randomized, Active-controlled, First-in-human Phase 1 Trial.
BACKGROUND
We report a first-in-human trial evaluating safety and immunogenicity of a recombinant BCG, AERAS-422, over-expressing TB antigens Ag85A, Ag85B, and Rv3407 and expressing mutant perfringolysin.


METHODS
This was a randomized, double-blind, dose-escalation trial in HIV-negative, healthy adult, BCG-naïve volunteers, negative for prior exposure to Mtb, at one US clinical site. Volunteers were randomized 2:1 at each dose level to receive a single intradermal dose of AERAS-422 (>10(5)-<10(6)CFU=low dose, ≥10(6)-<10(7)CFU=high dose) or non-recombinant Tice BCG (1-8×10(5)CFU). Randomization used an independently prepared randomly generated sequence of treatment assignments. The primary and secondary outcomes were safety and immunogenicity, respectively, assessed in all participants through 182days post-vaccination. ClinicalTrials.gov registration number: NCT01340820.


RESULTS
Between Nov 2010 and Aug 2011, 24 volunteers were enrolled (AERAS-422 high dose, n=8; AERAS-422 low dose, n=8; Tice BCG, n=8); all were included in the safety and immunogenicity analyses. All 24 subjects had at least one adverse event, primarily expected local reactions. High dose AERAS-422 vaccination induced Ag85A- and Ag85B-specific lymphoproliferative responses and marked anti-mycobacterial activity in a whole blood bactericidal activity culture assay (WBA), but was associated with varicella zoster virus (VZV) reactivation in two vaccinees. These volunteers displayed high BCG-specific IFN-γ responses pre- and post-vaccination possibly predisposing them to autocrine/paracrine negative regulation of immune control of latent VZV. A systems biology transcriptomal approach identified positive correlations between post-vaccination T cell expression modules and WBA, and negative correlations between post-vaccination monocyte expression modules and WBA. The expression of one key macrophage marker (F4/80) was constitutively elevated in the two volunteers with zoster.


CONCLUSIONS
The unexpected development of VZV in two of eight healthy adult vaccine recipients resulted in discontinuation of AERAS-422 vaccine development. Immunological and transcriptomal data identified correlations with the development of TB immunity and VZV that require further investigation.


BACKGROUND
Aeras, FDA, Bill and Melinda Gates Foundation.
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States. Electronic address: hoftdf@slu.edu.
Daniel F
DF
Hoft
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
Azra
A
Blazevic
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
Asmir
A
Selimovic
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
Aldin
A
Turan
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
Jan
J
Tennant
Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States.
Getahun
G
Abate
Aeras, United States.
John
J
Fulkerson
Seattle BioMed, United States.
Daniel E
DE
Zak
Aeras, United States.
Robert
R
Walker
Aeras, United States.
Bruce
B
McClain
Aeras, United States.
Jerry
J
Sadoff
Aeras, United States.
Judy
J
Scott
Aeras, United States.
Barbara
B
Shepherd
Aeras, United States.
Jasur
J
Ishmukhamedov
Aeras, United States.
David A
DA
Hokey
Aeras, United States.
Veerabadran
V
Dheenadhayalan
Seattle BioMed, United States.
Smitha
S
Shankar
Seattle BioMed, United States.
Lynn
L
Amon
Seattle BioMed, United States.
Garnet
G
Navarro
Seattle BioMed, United States.
Rebecca
R
Podyminogin
Seattle BioMed, United States.
Alan
A
Aderem
Aeras, United States.
Lew
L
Barker
Aeras, United States.
Michael
M
Brennan
Aurum Institute, South Africa.
Robert S
RS
Wallis
Division of Pediatric Infectious Diseases, Columbia University, United States.
Anne A
AA
Gershon
Division of Pediatric Infectious Diseases, Columbia University, United States.
Michael D
MD
Gershon
Division of Pediatric Infectious Diseases, Columbia University, United States.
Sharon
S
Steinberg
D000217:Acyltransferases / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006460:Hemolysin Proteins / Q000276:immunology / Q000378:metabolism; D014645:Herpesvirus 3, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D014614:Vaccines, Synthetic / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D014775:Virus Activation; D055815:Young Adult
D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D014614:Vaccines, Synthetic; C020452:Clostridium perfringens theta-toxin; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; C121433:antigen 85B, Mycobacterium tuberculosis
Functional T cell assays; Herpes zoster;; Recombinant BCG;; Transcriptomes;; Tuberculosis;