Research Article: Immunological Memory Transferred with CD4 T Cells Specific for Tuberculosis Antigens Ag85B-TB10.4: Persisting Antigen Enhances Protection

Date Published: December 14, 2009

Publisher: Public Library of Science

Author(s): Darragh Duffy, Amina Dawoodji, Else Marie Agger, Peter Andersen, Jürgen Westermann, Eric B. Bell, Derya Unutmaz.

Abstract: High levels of death and morbidity worldwide caused by tuberculosis has stimulated efforts to develop a new vaccine to replace BCG. A number of Mycobacterium tuberculosis (Mtb)-specific antigens have been synthesised as recombinant subunit vaccines for clinical evaluation. Recently a fusion protein of TB antigen Ag85B combined with a second immunodominant TB antigen TB10.4 was emulsified with a novel non-phospholipid-based liposomal adjuvant to produce a new subunit vaccine, investigated here. Currently, there is no consensus as to whether or not long-term T cell memory depends on a source of persisting antigen. To explore this and questions regarding lifespan, phenotype and cytokine patterns of CD4 memory T cells, we developed an animal model in which vaccine-induced CD4 memory T cells could transfer immunity to irradiated recipients.

Partial Text: Tuberculosis remains one of the world’s leading causes of mortality and morbidity [1] despite the widespread use of the BCG vaccine (Mycobacterium bovis, bacille Calmette-Guérin). The BCG vaccine confers protection during childhood [2] and in some populations was found to have an efficacy of about 50% for up to 60 years[3]. Despite the beneficial effects, BCG vaccination does not prevent substantial problems with pulmonary disease in the adult population, especially in many developing countries [1]. There is an urgent need for a new vaccine. As a result of technological advances, increases in funding and heightened interest within the scientific community, there are a number of candidate vaccines in various stages of clinical trials [4]. The current candidate vaccines are broadly divided into live mycobacterium-based preparations, viral vectors or synthetic subunit vaccines. One strategy for developing new live vaccines is to introduce highly immunogenic, but non-pathogenic, epitopes from Mycobacterium tuberculosis (Mtb) into the BCG genome or alternatively to use a mutated Mtb in which at least two virulence genes have been altered so as to render the microorganism harmless [5]. Another option is to express Mtb antigens in the modified vaccinia virus Ankara (MVA) as a vaccine to boost subjects previously immunised with BCG [6]. The third approach aims to develop vaccines comprised of highly immunogenic Mtb antigens that can be combined with novel adjuvant systems. The present study is concerned with the latter type of vaccine.

The development of a new vaccine to supplement or replace BCG is an international priority. To make the investigation of vaccine-induced immunological memory to TB more accessible, we wanted to establish an animal model suitable for laboratories without class III (P3) containment facilities. Hence, we opted to challenge recipients with live BCG rather than Mtb. Aside from the clear difference in virulence, Mtb and BCG are very similar – both are intracellular pathogens controlled predominantly by CD4 T cells. In the more advanced stages of infection, Mtb appears to induce a subset of CD8 T cells not seen after BCG vaccination [21], but the role of these CD8 T cells in protection has never been formally demonstrated. In the first stages of infection (the focus of the present study), it is clear that both BCG and Mtb are controlled by CD4 T cells. Furthermore, the new recombinant vaccine Ag85B-TB10.4 used in the present investigation expresses two immunodominant antigens common to both BCG and Mtb. This vaccine has been shown to induce protective immunity in mice infected with Mtb[11]. Hence, BCG should serve at this stage as a reliable surrogate for Mtb challenge.



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