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Experiences with BCG vaccination in the UK and Malawi Hazel M Dockrell London School of Hygiene & Tropical Medicine

Experiences with BCG vaccination in the UK and Malawi Hazel M Dockrell London School of Hygiene & Tropical Medicine. We need correlates of protection to use in trials of new TB vaccines in man

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Experiences with BCG vaccination in the UK and Malawi Hazel M Dockrell London School of Hygiene & Tropical Medicine

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  1. Experiences with BCG vaccination in the UK and MalawiHazel M DockrellLondon School of Hygiene & Tropical Medicine

  2. We need correlates of protection to use in trials of new TB vaccines in man • Can we exploit the observations that BCG vaccination can induce protection against pulmonary TB when given to adolescents in the UK, but not when given to young adults in Malawi?

  3. BCG protection in Malawi and the UK • In Malawi, a single BCG vaccination gives 50% or more protection against leprosy but no protection against pulmonary tuberculosis* • In the UK, vaccination of schoolchildren with BCG provides 77% protection against tuberculosis *Lancet, 348,: 17 (1996)

  4. Immunity to Tuberculosis • Cell mediated immunity is important • Interaction between activated m, CD4+, CD8+,  T cells • Type 1 cytokines such as IFN/IL-12 play a role in protection; also role for TNFa • Could whole blood assays measuring such cytokines be used as a correlate of protection?

  5. Diluted whole blood assays to measure antigen-specific interferon-g responses • Heparinised blood just diluted in tissue culture medium and antigens added • Cytokines measured in culture supernatants • Assay proved easy, reliable and reproducible for field use when used with M.leprae antigens in Nepal • It has now been used in studies in Malawi, Pakistan, The Philippines, South Africa, Uganda, China…. Weir et al J Immunol Meth 176: 93 (1994)

  6. Interferon-g responses measured in diluted whole blood cultures Black et al, Int J Tuberc Lung Dis 5: 664 (2001)

  7. Use of positive control supernatants to control for assay variation

  8. Field work in Malawi633 recruited (age 10-28) (HIV-ve, BCG-ve) 562 eligible (Mantoux <10mm) 2/3 BCG vaccinated 80% follow-up at 1 year

  9. and in Essex, UK…. • 435 recruited (age 12-15, BCG scar -ve), • Heaf test grade >2 excluded • 2/3 given BCG vaccination • 80% followed up at 1 year Rosemary Weir

  10. Does IFNg production increase in both UK and Malawian vaccinees? • IFNg responses to M.tuberculosis PPD tested pre vaccination and 1 year post vaccination

  11. Pre- and post- BCG vaccination IFNg responses to PPD in UK Increase in % responders Controls 19% to 21% Vaccinees 23% to 83% Black, Weir et al, Lancet 139: 1393 (2002)

  12. Pre- and post- BCG vaccination IFNg responses to PPD in Malawi Increase in % responders Placebo 60% to 76% Vaccinees 61% to 78% Black, Weir et al, Lancet 139: 1393 (2002)

  13. Increase 1.4 vs 2.4 1.05 vs 8.3

  14. IFNg responses detected in 6 day whole blood assays are more variable in a tropical setting such as Malawi, than in the UK IFNg responses to PPD: % changes over 1 year in placebo/control groups decrease no change increase Malawi 38 7 55 UK 25 43 32

  15. Distribution of IFNg responses to MTb PPD 1 year after BCG vaccination in Malawi &UK • The increase in IFNg is associated with protection in the UK • There are conflicting views about whether exposure to • mycobacteria confers protection or blocks its induction

  16. Controlling for effective vaccination:Comparison of BCG scar size of vaccinees in Malawi and UK Malawi: 98.5% scar +ve UK: 96.7% scar +ve

  17. Choice of time point: maximal responses will be different in naive and sensitised subjects • A small group of subjects were tested 10-12 weeks after BCG vaccination in Malawi • Results did indicate that BCG vaccination boosted the IFNg response, but this increase was transient • In our current study we are testing at both 3 and 12 months….

  18. Pre-vaccination, placebo (n=27) Pre-vaccination, vaccine (n=34) 1 1 .9 .9 proportion .8 .8 .7 .7 .6 .6 .5 .5 .4 .4 .3 .3 .2 .2 .1 .1 0 0 Post-vaccination, placebo (n=27) Post-vaccination, vaccine (n=34) 1 1 .9 .9 .8 .8 .7 .7 .6 .6 proportion .5 .5 .4 .4 .3 .3 .2 .2 .1 .1 0 0 0 31 62 125 250 500 1000 2000 4000 0 31 62 125 250 500 1000 2000 4000 response (pg/ml) response (pg/ml) Frequency distributions of IFNγ responses to M tuberculosis PPD among 13-year olds in the UK, prior to and 3 months after receiving BCG vaccine or placebo Change: 1.3x vs 16.9x

  19. Vaccine group (n=17) Placebo group (n=8) The timing of testing is critical:8-10 weeks after BCG, IFNg responses are boosted in Malawian vaccinees 4000 4000 3000 3000 IFN-g pg/ml IFN-g pg/ml 2000 2000 1000 1000 0 0 Pre Post Pre Post Data: Gill Black

  20. IFNg responses to environmental mycobacterial PPDs one year after BCG vaccination in Malawi Exposure to non-tuberculous, environmental mycobacteria appears common in Malawians, and is responsible for sensitisation to MTb PPD

  21. BCG vaccination is given to infants at brith in most low income countries • If exposure to environmental mycobacteria accounts for the differences to response in adolescents to BCG vaccination in Malawi and the UK, would infants in the two settings behave similarly?

  22. Vaccination schedule in Malawi

  23. BCG vaccination is inducing good IFNg responses at 3 months in Malawi in infants

  24. Frequency distributions of IFNγ responses to M tuberculosis PPD in Malawian and UK infants, three months after BCG vaccination • Malawian infants vaccinated at birth give good IFNg responses • 3 months later • Responses seem higher in the UK infants- is this real, is it because • they are older (4 months vs 3 months), or ????

  25. Before and after…... • Before vaccination of adolescents/young adults, only 20% were IFNg responders to PPD in UK, compared to 60% in Malawi • After vaccination, approx 80% of both the UK and Malawi populations responded • Are both populations equally protected? • What else is different?

  26. In Malawi, 55% of the young adults tested were infected with hookworm, 40% with Schistosoma mansoni and 25% with Schistosoma haematobium; filarial infection is also found in the north of the district

  27. Effect of helminth infections on immune responses Odds ratios of having a strong IFNγ response (>250 pg/ml) (a) and a (“positive”) IL-5 response (>62 pg/ml) (b) to M tuberculosis PPD, streptokinase/streptodornase (SK/SD) or phytohaemagglutinin (PHA) by numbers of helminth infections (hookworm, S mansoni, S haematobium, W bancrofti). Baseline is group not infected with any helminths.

  28. IL-5 response to M. tuberculosis PPD post-vaccination, Malawi and UK • BCG vaccination does not induce increased IL-5 production in response to PPD, in Malawi or the UK • IL-5 responders are high, not low, IFNg producers

  29. Differences in innate immunity: Malawians also make more IL-10 and TNFa than UK subjects

  30. Association between IFNg responses and Mantoux skin test response to PPD PPD ESAT-6

  31. Assays for IFNg as an alternative to skin testing • Assays are robust and perform well in field settings • They identify more T cell responders than skin testing- are they more sensitive? • Two responses are associated although there are discordant individuals • Responses are more variable in a tropical setting (Malawi vs UK) • Assays can detect responses to individual recombinant antigens

  32. Overnight and 6 day whole blood assays compared • Overnight assays require more blood, and may need to be put into culture quickly • 6 day assays are similar to traditional PBMC assays, and involve cell proliferation • 6 days assays require access to a tissue culture hood and CO2 incubator • In both assays cytokine can be measured by ELISA (multiplex assay, dipstick)

  33. Conclusions • In adolescents/young adults, the increase in the amount of IFNg produced in cultures stimulated with PPD correlates with the protection BCG vaccination gives against TB in the UK: just measuring absolute amounts of IFNg insufficient • In Malawi, BCG vaccination only induces a temporary boosting in IFNg responses: timing of testing critical • Prior sensitivity to mycobacterial antigens in Malawi seems to result from exposure to environmental mycobacteria: implications for vaccine design and timing • Other infections may influence the status of the immune system in low income countries

  34. Whether IFNg is a correlate of protection depends on whether the Malawians have protective immunity to TB equivalent to that given by BCG vaccination in the UK….. • Does the immunity induced by environmental mycobacteria kill the BCG before it can induce real protection? Test mycobacterial killing… • Does protection need IFNg together with another key cytokine (TNFa, ??) or without another cytokine (IL-4, IL-10, TGFb)? • Does protection need CD8 T cells as well as CD4 T cells?

  35. Some implications and questions .... • Diluted whole blood assays have the potential to be a useful tool for new TB vaccine trials • If a new TB vaccine contains antigens cross-reactive with those in environmental mycobacteria, it may need to be given to infants • There may be differences in the proportion of naïve and memory T cells, and in the maintenance of T cell memory, in tropical and non-tropical settings

  36. BCG vaccination Malawi/UK • Paul Fine • Rosemary Weir, Patricia Gorak-Stolinska (UK) • Gill Black, Anne Ben-Smith (Malawi) • Steven Chaguluka, Huxley Kanyongoloka • Mia Crampin, David Warndorff • Lifted Sichali, Lorren Mwaungulu • Bernadette Nazareth • Sian Floyd, Lyn Bliss, Jacky Saul, Keith Branson Funded by the Wellcome Trust, LEPRA and WHO

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