EDCTP Alumni Network

Title

The BCG-induced immune correlates of protection against tuberculosis

Objectives

To identify BCG immune correlates of protection against TB in children whose understanding is critical for TB vaccine development. 1. To determine whether the post-vaccination number, function and/or antigenic repertoire of specific conventional CD4+ and CD8+ T cells correlate with protection against TB 2. To determine whether the post-vaccination number and/or function of specific regulatory CD4+ T cells correlate with protection against TB 3. To determine whether the post-vaccination gene expression and cytokine secretion profiles of whole blood, and of PBMC, correlate with protection against TB.

Host Organisation

Institution	Country
University of Cape Town (UCT)	South Africa

Participants

Name	Institution	Country
Adrian Hill	University of Oxford	United Kingdom
Gregory Hussey	University of Cape Town (UCT)	United Kingdom
Gilla Kaplan	New Jersey Medical School	United Kingdom

Study Design

Prospective cohort analyses

Sites

South African Tuberculosis Vaccine Initiative (SATVI, South Africa)

Results & Outcomes

There were no differences in plasma levels of interferon-gamma, a cytokine commonly used to measure vaccination outcome, or any other cytokine, between the TB protected and TB non-protected children. However, when combinations of cytokines were evaluated, a model that included fractalkine, interleukin 12p40 and epidermal growth factor, correct discrimination in 82% of “protected” and “unprotected” infants was possible. Combinations of cytokines from plasma from blood incubated for 7 hours without antigen also allowed correct discrimination between the 2 groups. The studies on correlates of protective immunity from BCG have strengthened laboratories at SATVI which has since been awarded several EDCTP grants for TB vaccine studies and trials. This fellowship supported the return of Willem Hanekom to the country to re-establish his research career in South Africa.

Publications

Hatherill M, Hawkridge T, Whitelaw A, Tameris M, Mahomed H, Moyo S, Hanekom W, Hussey G. Isolation of Non-Tuberculous Mycobacteria in Children Investigated for Pulmonary Tuberculosis. PLoS ONE. 2006 Dec;1:e21

Hanekom WA. The immune response to BCG vaccination of newborns. Ann N Y Acad Sci. 2005 Dec;1062:69-78

Murray RA, Mansoor N, Harbacheuski R, Soler J, Davids V, Soares A, Hawkridge A, Hussey GD, Maecker H, Kaplan G, Hanekom WA. Bacillus Calmette Guerin vaccination of human newborns induces a specific, functional CD8+ T cell response. J Immunol. 2006 Oct 15;177(8):5647-51

Hanekom WA, Abel B, Scriba TJ. Immunological protection against tuberculosis. S Afr Med J. 2007 Oct;97(10 Pt 2):973-7

Hussey G, Hawkridge T, Hanekom W. Childhood tuberculosis: old and new vaccines. Paediatr Respir Rev. 2007 Jun;8(2):148-54

Scriba TJ, Kalsdorf B, Abrahams D-A, Isaacs F, Hofmeister J, Black G, Hassan HY, Wilkinson RJ, Walzl G, Gelderbloem SG, Mahomed H, Hussey GD, Hanekom WA. Distinct, specific IL-17 and IL-22- producing CD4+ T cell subsets contribute to the human antimycobacterial immune response. J Immunol. 2008; 180:1962- 1970

Beveridge NER, Fletcher HA, Hughes J, Pathan AA, Scriba TJ, Minassian A, Sander CR, Whelan KT, Dockrell HM, Hill A, Hanekom WA, McShane H. A comparison of IFNy detection methods used in tuberculosis vaccine trials. Tuberculos. November 2008;88(6):631-640.

Hatherill M, Hawkridge T, Zar HJ, Whitelaw A, Tameris M, Workman L, Geiter L, Hanekom WA, Hussey G. Induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis? Arch. Dis. Child. 2009;94;195-201; originally published online 1 Oct 2008.

Soares AP, Scriba TJ, Joseph S, Harbacheuski R, Murray RA, Gelderbloem SJ, Hawkridge A, Hussey GD, Maecker H, Kaplan G, Hanekom WA. Bacille Calmette Guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles. J Immunol. 2008 Mar 1;180(5):3569-77

Fletcher HA, Filali-Mouhim A, Nemes E, et al. Human newborn bacille Calmette–Guérin vaccination and risk of tuberculosis disease: a case-control study. BMC Medicine. 2016;14:76. doi:10.1186/s12916-016-0617-3.