Skip to main content
PMC home page
Proceedings of the Royal Society B: Biological Sciences logoLink to Proceedings of the Royal Society B: Biological Sciences
. 2004 Mar 22;271(1539):617–623. doi: 10.1098/rspb.2003.2606

The reinfection threshold promotes variability in tuberculosis epidemiology and vaccine efficacy.

M Gabriela M Gomes 1, Ana O Franco 1, Manuel C Gomes 1, Graham F Medley 1
PMCID: PMC1691632  PMID: 15156920

Abstract

Population patterns of infection are determined largely by susceptibility to infection. Infection and vaccination induce an immune response that, typically, reduces susceptibility to subsequent infections. With a general epidemic model, we detect a 'reinfection threshold', above which reinfection is the principal type of transmission and, consequently, infection levels are much higher and vaccination fails. The model is further developed to address human tuberculosis (TB) and the impact of vaccination. The bacille Calmette-Guérin (BCG) is the only vaccine in current use against TB, and there is no consensus about its usefulness. Estimates of protection range from 0 to 80%, and this variability is aggravated by an association between low vaccine efficacy and high prevalence of the disease. We propose an explanation based on three postulates: (i) the potential for transmission varies between populations, owing to differences in socio-economic and environmental factors; (ii) exposure to mycobacteria induces an immune response that is partially protective against reinfection; and (iii) this protection is not significantly improved by BCG vaccination. These postulates combine to reproduce the observed trends, and this is attributed to a reinfection threshold intrinsic to the transmission dynamics. Finally, we demonstrate how reinfection thresholds can be manipulated by vaccination programmes, suggesting that they have a potentially powerful role in global control.

Full Text

The Full Text of this article is available as a PDF (207.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Black Gillian F., Weir Rosemary E., Floyd Sian, Bliss Lyn, Warndorff David K., Crampin Amelia C., Ngwira Bagrey, Sichali Lifted, Nazareth Bernadette, Blackwell Jenefer M. BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies. Lancet. 2002 Apr 20;359(9315):1393–1401. doi: 10.1016/S0140-6736(02)08353-8. [DOI] [PubMed] [Google Scholar]
  2. Blower S. M., McLean A. R., Porco T. C., Small P. M., Hopewell P. C., Sanchez M. A., Moss A. R. The intrinsic transmission dynamics of tuberculosis epidemics. Nat Med. 1995 Aug;1(8):815–821. doi: 10.1038/nm0895-815. [DOI] [PubMed] [Google Scholar]
  3. Blower S. M., Small P. M., Hopewell P. C. Control strategies for tuberculosis epidemics: new models for old problems. Science. 1996 Jul 26;273(5274):497–500. doi: 10.1126/science.273.5274.497. [DOI] [PubMed] [Google Scholar]
  4. Brandt Lise, Feino Cunha Joana, Weinreich Olsen Anja, Chilima Ben, Hirsch Penny, Appelberg Rui, Andersen Peter. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun. 2002 Feb;70(2):672–678. doi: 10.1128/iai.70.2.672-678.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Britton Warwick J., Palendira Umaimainthan. Improving vaccines against tuberculosis. Immunol Cell Biol. 2003 Feb;81(1):34–45. doi: 10.1046/j.0818-9641.2002.01143.x. [DOI] [PubMed] [Google Scholar]
  6. Chaisson R. E. New developments in the treatment of latent tuberculosis. Int J Tuberc Lung Dis. 2000 Dec;4(12 Suppl 2):S176–S181. [PubMed] [Google Scholar]
  7. Colditz G. A., Brewer T. F., Berkey C. S., Wilson M. E., Burdick E., Fineberg H. V., Mosteller F. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA. 1994 Mar 2;271(9):698–702. [PubMed] [Google Scholar]
  8. Comstock G. W. Field trials of tuberculosis vaccines: how could we have done them better? Control Clin Trials. 1994 Aug;15(4):247–276. doi: 10.1016/0197-2456(94)90042-6. [DOI] [PubMed] [Google Scholar]
  9. Diekmann O., Heesterbeek J. A., Metz J. A. On the definition and the computation of the basic reproduction ratio R0 in models for infectious diseases in heterogeneous populations. J Math Biol. 1990;28(4):365–382. doi: 10.1007/BF00178324. [DOI] [PubMed] [Google Scholar]
  10. Dye C., Garnett G. P., Sleeman K., Williams B. G. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Directly observed short-course therapy. Lancet. 1998 Dec 12;352(9144):1886–1891. doi: 10.1016/s0140-6736(98)03199-7. [DOI] [PubMed] [Google Scholar]
  11. Dye C., Williams B. G. Criteria for the control of drug-resistant tuberculosis. Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8180–8185. doi: 10.1073/pnas.140102797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Edwards M. L., Goodrich J. M., Muller D., Pollack A., Ziegler J. E., Smith D. W. Infection with Mycobacterium avium-intracellulare and the protective effects of Bacille Calmette-Guérin. J Infect Dis. 1982 May;145(5):733–741. doi: 10.1093/infdis/145.2.733. [DOI] [PubMed] [Google Scholar]
  13. Fine P. E., Rodrigues L. C. Modern vaccines. Mycobacterial diseases. Lancet. 1990 Apr 28;335(8696):1016–1020. doi: 10.1016/0140-6736(90)91074-k. [DOI] [PubMed] [Google Scholar]
  14. Fine P. E. Variation in protection by BCG: implications of and for heterologous immunity. Lancet. 1995 Nov 18;346(8986):1339–1345. doi: 10.1016/s0140-6736(95)92348-9. [DOI] [PubMed] [Google Scholar]
  15. Godfrey-Faussett P., Sonnenberg P., Shearer S. C., Bruce M. C., Mee C., Morris L., Murray J. Tuberculosis control and molecular epidemiology in a South African gold-mining community. Lancet. 2000 Sep 23;356(9235):1066–1071. doi: 10.1016/s0140-6736(00)02730-6. [DOI] [PubMed] [Google Scholar]
  16. Gomes M. Gabriela M., Medley Graham F., Nokes D. James. On the determinants of population structure in antigenically diverse pathogens. Proc Biol Sci. 2002 Feb 7;269(1488):227–233. doi: 10.1098/rspb.2001.1869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lienhardt C. From exposure to disease: the role of environmental factors in susceptibility to and development of tuberculosis. Epidemiol Rev. 2001;23(2):288–301. doi: 10.1093/oxfordjournals.epirev.a000807. [DOI] [PubMed] [Google Scholar]
  18. McLean A. R. Vaccination, evolution and changes in the efficacy of vaccines: a theoretical framework. Proc Biol Sci. 1995 Sep 22;261(1362):389–393. doi: 10.1098/rspb.1995.0164. [DOI] [PubMed] [Google Scholar]
  19. Medley G. F., Lindop N. A., Edmunds W. J., Nokes D. J. Hepatitis-B virus endemicity: heterogeneity, catastrophic dynamics and control. Nat Med. 2001 May;7(5):619–624. doi: 10.1038/87953. [DOI] [PubMed] [Google Scholar]
  20. Olsen Anja W., Andersen Peter. A novel TB vaccine; strategies to combat a complex pathogen. Immunol Lett. 2003 Jan 22;85(2):207–211. doi: 10.1016/s0165-2478(02)00232-8. [DOI] [PubMed] [Google Scholar]
  21. Palmer C. E., Long M. W. Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. Am Rev Respir Dis. 1966 Oct;94(4):553–568. doi: 10.1164/arrd.1966.94.4.553. [DOI] [PubMed] [Google Scholar]
  22. Reed S. G., Alderson M. R., Dalemans W., Lobet Y., Skeiky Y. A. W. Prospects for a better vaccine against tuberculosis. Tuberculosis (Edinb) 2003;83(1-3):213–219. doi: 10.1016/s1472-9792(02)00080-x. [DOI] [PubMed] [Google Scholar]
  23. Small P. M., Fujiwara P. I. Management of tuberculosis in the United States. N Engl J Med. 2001 Jul 19;345(3):189–200. doi: 10.1056/NEJM200107193450307. [DOI] [PubMed] [Google Scholar]
  24. Smith D., Wiegeshaus E., Balasubramanian V. An analysis of some hypotheses related to the Chingelput bacille Calmette-Guérin trial. Clin Infect Dis. 2000 Sep;31 (Suppl 3):S77–S80. doi: 10.1086/314073. [DOI] [PubMed] [Google Scholar]
  25. Smith P. G., Rodrigues L. C., Fine P. E. Assessment of the protective efficacy of vaccines against common diseases using case-control and cohort studies. Int J Epidemiol. 1984 Mar;13(1):87–93. doi: 10.1093/ije/13.1.87. [DOI] [PubMed] [Google Scholar]
  26. Sutherland I., Svandová E., Radhakrishna S. The development of clinical tuberculosis following infection with tubercle bacilli. 1. A theoretical model for the development of clinical tuberculosis following infection, linking from data on the risk of tuberculous infection and the incidence of clinical tuberculosis in the Netherlands. Tubercle. 1982 Dec;63(4):255–268. doi: 10.1016/s0041-3879(82)80013-5. [DOI] [PubMed] [Google Scholar]
  27. Vynnycky E., Fine P. E. The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiol Infect. 1997 Oct;119(2):183–201. doi: 10.1017/s0950268897007917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. White L. J., Cox M. J., Medley G. F. Cross immunity and vaccination against multiple microparasite strains. IMA J Math Appl Med Biol. 1998 Sep;15(3):211–233. [PubMed] [Google Scholar]
  29. ten Dam H. G., Pio A. Pathogenesis of tuberculosis and effectiveness of BCG vaccination. Tubercle. 1982 Sep;63(3):225–233. doi: 10.1016/s0041-3879(82)80036-6. [DOI] [PubMed] [Google Scholar]
  30. van Rie A., Warren R., Richardson M., Victor T. C., Gie R. P., Enarson D. A., Beyers N., van Helden P. D. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med. 1999 Oct 14;341(16):1174–1179. doi: 10.1056/NEJM199910143411602. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES