TB is an infection that is common in Kenya, with approximately 132,000 new cases per year. TB can spread from one person to another and is a common cause of death. There are many medicines that can treat and cure TB. These medicines are expensive and must be taken for a long time. TB medicines cause bad effects in some people even when their TB is getting better. Only one vaccine is approved that helps prevent getting TB but it does not always work. This TB vaccine is called BCG and is given to most babies in Kenya. BCG is made from a TB germ in cows and is weakened so it does not usually make people sick. This research study is being done to help find a better TB vaccine. The investigational TB vaccine in this study is called AERAS-402 and is made from an adenovirus. Normal adenoviruses cause colds and pneumonia when breathed in, but AERAS-402 adenovirus has been weakened. It will be given as an injection in your baby’s leg muscle. It is possible that AERAS-402 will help BCG work, so people who get AERAS-402 after BCG will be better able to resist TB infections. This has been shown in animals. Adults in Kenya, South Africa and the United States have received the AERAS-402 vaccine. Some of these adults were infected with HIV or tuberculosis when they received the vaccine and to-date, the vaccine has been generally well-tolerated. This vaccine has been given to babies in South Africa, but this study will be the first time the AERAS-402 vaccine is given to babies in Kenya. The main purpose of this study is to see if the AERAS-402 vaccine is safe in babies. Other purposes are to find the best dose of AERAS-402 and to test if it helps prevent TB. There is a chance that your baby could still get TB. There are two phases in this study. The first includes Study Groups 1-3 and is the dose-finding phase. These study groups will receive TWO dose of either AERAS402 OR placebo, approximately four weeks apart. The placebo contains all the same ingredients of the vaccine EXCEPT the active medicine and will have no prevention effect. After the dose is decided, the second phase of the study includes Study Groups 4-7. These study groups will also receive TWO vaccinations of either AERAS-402 OR placebo, 4 weeks apart. KEMRI/CDC Phase IIB AERAS-402 Trial Protocol Add

TITLE: A Phase II, Double-blind, Randomized, Placebo-controlled, Multicenter, Proof-of-concept Study to Evaluate the Safety and Efficacy of AERAS-402 in BCG-vaccinated, HIV-uninfected Infants Without Evidence of Tuberculosis

RATIONALE:The only currently available tuberculosis vaccine, bacillus Calmette-Guérin (BCG), is estimated to reduce the risk of tuberculosis (TB) in children by up to 70-80%, but protection is incomplete. Efforts to increase TB protection in children include new vaccines for primary immunizations as well as combinations of vaccines given as primary and boosting vaccinations. AERAS-402 presents Mycobacterium tuberculosis (Mtb) antigens in the setting of a new, live, replication-deficient adenovirus vaccine that may increase T cell-mediated immunity and thus protection from tuberculosis. AERAS-402 appears safe and immunogenic in adults. Since BCG-vaccinated infants are the population for which AERAS-402 might be indicated, the first dose of AERAS-402 will be administered to infants of at least 16 weeks of age who have already been vaccinated with BCG. A second dose will be administered on Study Day 28, i.e., 28 days after the first dose, and, in the expanded safety and efficacy phase of the study, a third dose will be administered 280 days after the first dose. The rationale for dose selection for the expanded safety and efficacy phase will be based on safety experience and immunogenicity data from a prior Phase I infant trial and from the dose-finding phase in this study. Safety and immunogenicity data from the second and third doses in the expanded safety cohort will be reviewed before moving into the expanded efficacy cohorts. This is the first Phase II study of AERAS-402 in infants.

In the dose-finding phase of this study, the immune responder rate measured by multifunctional CD8+ T cell intracellular cytokine staining (ICS) on Study Day 56 (28 days after the second dose) was 30-50% in recipients of the selected high dose. Further, additional assays using potentially more sensitive ELISPOT and ELISA methods (the latter for antibodies to TB antigens in the vaccine) will be conducted on samples from recipients who received the high dose from Study Groups 3-5 in this study in an effort to identify responders not identified by ICS, and to increase the body of data on immunogenicity of AERAS-402. A responder rate of at least 70% after the second or after the third dose of AERAS-402, based on analysis of all high dose recipients in the study and on documented pre-defined assay positivity criteria to be developed prior to evaluating the total body of immunogenicity data, is considered critical to support proceeding to the expanded efficacy phase of this study.

In addition, the C-029-402 Collaboration Oversight Group (COG, composed of Aeras, Crucell, NIAID [DAIDS], HVTN, and IMPAACT members responsible for overseeing Aeras C-029-402 collaboration activities and for making decisions on specific issues) recommends all infants in Groups 5 through 8 receive a third dose of AERAS-402 on Study Day 280 (at approximate age 13-15 months). A third vaccine dose is part of the standard immunizing regimen for many vaccines, and may potentially improve both the magnitude and durability of the immune response and possibly result in greater protection. In a separate small (N=3) pilot study of AERAS-402 in adults, a three dose series of the AERAS-402 at 1 x 1011 vp (N=2) or 3 x 1010 vp (N=1) was determined to be safe and to produce a strong anamnestic response that was greater than that achieved with two doses. CD8+ cytokine (IFN-γ, IL-2, or TNF-α) immune responses to antigens Ag85A and Ag85B were boosted after the third dose of AERAS-402 in these subjects, with greater responses observed at the higher dose level of 1 x 1011 vp compared to 3 x 1010 vp.

Aeras is developing low volume formulations of AERAS-402 for use in infants, and it is expected that different volumes of vaccine for varying doses will be administered in clinical trials. Licensed vaccines, which are fixed in volume, may therefore not be suitable controls for AERAS-402 in blinded studies. As a result, use of a placebo control is indicated.