A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.
BACKGROUND
Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design.


METHODS
In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years.


RESULTS
We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses.


CONCLUSIONS
AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa. Electronic address: michele.tameris@uct.ac.za.
M
M
Tameris
Aeras, Rockville, MD, USA.
D A
DA
Hokey
KEMRI/CDC, Kisumu, Kenya.
V
V
Nduba
Centro de Investigação em Saúde de Manhiça (CISM), Manhiça, Mozambique; Faculty of Medicine, Universidade Eduardo Mondlane, Maputo, Mozambique.
J
J
Sacarlal
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
F
F
Laher
KEMRI/CDC, Kisumu, Kenya.
G
G
Kiringa
Centro de Investigação em Saúde de Manhiça (CISM), Manhiça, Mozambique.
K
K
Gondo
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
E M
EM
Lazarus
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
G E
GE
Gray
State University of New York at Stony Brook, Stony Brook, NY, USA.
S
S
Nachman
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
H
H
Mahomed
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
K
K
Downing
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
B
B
Abel
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
T J
TJ
Scriba
Aeras, Rockville, MD, USA.
J B
JB
McClain
Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands.
M G
MG
Pau
Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands.
J
J
Hendriks
Aeras, Rockville, MD, USA.
V
V
Dheenadhayalan
Aeras, Rockville, MD, USA.
S
S
Ishmukhamedov
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
A K K
AK
Luabeya
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
H
H
Geldenhuys
Aeras, Rockville, MD, USA.
B
B
Shepherd
Aeras, Rockville, MD, USA.
G
G
Blatner
Aeras, Rockville, MD, USA.
V
V
Cardenas
Aeras, Rockville, MD, USA.
R
R
Walker
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
W A
WA
Hanekom
Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands.
J
J
Sadoff
Crucell Holland BV, Archimedesweg 4-6, 2333 CN Leiden, The Netherlands.
M
M
Douoguih
Aeras, Rockville, MD, USA.
L
L
Barker
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
M
M
Hatherill
D000217:Acyltransferases / Q000276:immunology; D000328:Adult; D017954:Africa South of the Sahara; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D056724:Immunity, Humoral; D007223:Infant; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D014376:Tuberculosis / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA
C000592463:AERAS-402; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001500:BCG Vaccine; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis
Adenovirus vectored; Infant; Novel TB vaccine trial; Tuberculosis vaccine