Adenovirally-Induced Polyfunctional T Cells Do Not Necessarily Recognize the Infected Target: Lessons from a Phase I Trial of the AERAS-402 Vaccine.

The development of a vaccine for Mycobacterium tuberculosis (Mtb) has been impeded by the absence of correlates of protective immunity. One correlate would be the ability of cells induced by vaccination to recognize the Mtb-infected cell. AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA expressing a fusion protein of Mtb antigens 85A, 85B and TB10.4. We undertook a phase I double-blind, randomized placebo controlled trial of vaccination with AERAS-402 following BCG. Analysis of the vaccine-induced immune response revealed strong antigen-specific polyfunctional CD4+ and CD8+ T cell responses. However, analysis of the vaccine-induced CD8+ T cells revealed that in many instances these cells did not recognize the Mtb-infected cell. Our findings highlight the measurement of vaccine-induced, polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying the Mtb-infected cell and correspondingly, the value of detailed experimental medicine studies early in vaccine development.

Preclinical evidence for implementing a prime-boost vaccine strategy for tuberculosis.

In this review, published peer-reviewed preclinical studies using prime-boost tuberculosis (TB) vaccine regimens in animal challenge models for tuberculosis have been evaluated. These studies have been divided into groups that describe prime-boost vaccine combinations that performed better than, equivalent to, or worse than the currently used BCG vaccine. Review of the data has revealed interesting findings, including that more than half of the published studies using BCG as a prime combined with a novel boost vaccine give better efficacy than BCG alone and that the greatest reduction in Mycobacterium tuberculosis (M.tb.) colonization of animal tissues is provided by viral vectored vaccines delivered intranasally. Careful evaluation of these data should assist in defining the value of prime-boost regimens for advancement into human TB vaccine trials and stimulate the development of criteria for choosing which vaccine candidates should be studied further.

The challenges of developing new tuberculosis vaccines.

The World Health Organization estimates that tuberculosis is causing nearly two million deaths annually, mostly in developing countries. Widespread administration of the current tuberculosis vaccine to newborns is not a reliable route for preventing the disease in adults, the population that drives the epidemic. Several new vaccine candidates are in development, and a few have entered clinical trials. However, the field faces formidable scientific and policy challenges. A collaborative approach to solving scientific, policy, and resource obstacles--as well as new partnerships among emerging economies and vaccine development organizations--will be critical to developing a new tuberculosis vaccine that could achieve its public health potential to save lives and reduce the burden of disease.

Tuberculosis vaccine research: the impact of immunology.

A safe and effective vaccine to prevent tuberculosis is necessary to combat this ancient disease that kills millions worldwide. Recent advances in our understanding of the host immune response to Mycobacterium tuberculosis (Mtb) are facilitating the development of several novel vaccine approaches. New tools for measuring and characterizing cell-mediated immune responses to Mtb have furthered the assessment of these new vaccines in animal models and in human clinical studies including efficacy trials. Measurements of the relative contribution of CD4+ and CD8+ T cells, central and effector memory T cells, and regulatory T cells are being completed in these studies, as well as broad screening efforts utilizing bead array cytokine determination and microarray technology in an effort to determine the immunologic markers that predict vaccine-induced efficacy for different stages of TB infection and disease.

Advancing TB vaccines to Phase I clinical trials in the US: regulatory/manufacturing/licensing issues.

This article discusses the steps required to file an investigational new drug (IND) application to the United States Food and Drug Administration (FDA) and begin a Phase I trial of a new tuberculosis vaccine in the US. Many different groups play a role in bringing a new vaccine to market. But it is the researcher who begins the process by converting an idea into a new vaccine construct. Awareness of certain chemistry, manufacturing, and control (CMC) issues on the part of the researcher who develops the investigational vaccine can prevent later problems that might cause the vaccine to be unapprovable or fail to meet regulatory requirements for eventual licensure. CMC information included in an IND is described.