Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations

Deeva Uthayakumar, Simon Paris, Ludivine Chapat, Ludovic Freyburger, Hervé Poulet, Karelle De Luca, Deeva Uthayakumar, Simon Paris, Ludivine Chapat, Ludovic Freyburger, Hervé Poulet, Karelle De Luca

Abstract

Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with in vitro models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.

Keywords: BCG; epidemiology; epigenetics; non-specific effects; trained immunity; vaccines.

Figures

Figure 1
Figure 1
Summary of the potential mechanisms of vaccine NSEs. (A) The top half illustrates adaptive mechanisms. Cross-reactive TCRs and antibodies. Lymphocyte antigen receptors recognize similar epitopes from different antigens. Bystander effect. Bystander activation of pre-existing effector or memory cells occurs via changes in the cytokine environment. Classical cell-mediated immunity. Adaptive immune cells potentiate the non-specific activity of innate cells in classical cell-mediated immunity. (B) The bottom half illustrates pathways of trained immunity. Primary stimulus of BCG. PRR signaling leads to TF activation, which then recruits chromatin modifiers to genes of interest. This stimulus also activate the autophagy and NOD2 signaling pathway. Upregulation of the Akt/mTOR pathway alters metabolite levels that regulate chromatin-modifying enzymes. Heterologous secondary stimulus. Epigenetic changes within innate cells after training act as de novo enhancers to boost the immune response against a secondary challenge.
Figure 2
Figure 2
Approaches to investigate BCG NSEs. After designing a model to study trained innate immunity in vitro, -omics studies help to identify the global cellular pathways involved. The variations in gene expression are assessed both at the transcriptomic level and at the epigenetic level and then confirmed at the protein level. The modifications of cell metabolism and effector functions are also various angles by which to grant NSEs biological plausibility. The last step consists in narrowing down these modifications in order to find protective biomarkers which can be applied in vivo in clinical settings.

References

    1. Saadatian-Elahi M, Aaby P, Shann F, Netea MG, Levy O, Louis J, et al. . Heterologous vaccine effects. Vaccine (2016) 34:3923–30. 10.1016/j.vaccine.2016.06.020
    1. Zepp F. Principles of vaccination. vaccine design: methods and protocols. Vaccines Hum Dis. (2016) 1:57–84. 10.1007/978-1-4939-3387-7_3
    1. Mina MJ, Metcalf CJE, De Swart RL, Osterhaus A, Grenfell BT. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science (2015) 348:694–9. 10.1126/science.aaa3662
    1. Aaby P, Hedegaard K, Sodemann M, Nhante E, Veirum JE, Jakobsen M, et al. . Childhood mortality after oral polio immunisation campaign in Guinea-Bissau. Vaccine (2005) 23:1746–51. 10.1016/j.vaccine.2004.02.054
    1. Luca S, Mihaescu T. History of BCG vaccine. Maedica (2013) 8:53–8.
    1. Ferguson R, Sijmes A. BCG vaccination of indian infants in Saskatchewan.(a study carried out with financial assistance from the National Research Council of Canada.). Tubercle (1949) 30:5–11. 10.1016/S0041-3879(49)80055-9
    1. Aronson JD. Protective vaccination against tuberculosis with special reference to BCG vaccination. Am Rev Tuber Pulm Dis. (1948) 58:255–81.
    1. Rosenthal SR, Loewinsohn E, Graham ML, Liveright D, Thorne MG, Johnson V, et al. . BCG vaccination in tuberculous households. Am Rev Res Dis. (1961) 84:690–704.
    1. Velema JP, Alihonou EM, Gandaho T, Hounye FH. Childhood mortality among users and non-users of primary health care in a rural west African community. Int J Epidemiol. (1991) 20:474–9. 10.1093/ije/20.2.474
    1. Roth A, Jensen H, Garly M-L, Djana Q, Martins CL, Sodemann M, et al. . Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: community study from Guinea-Bissau. Pediatr Infect Dis J. (2004) 23:544–50. 10.1097/01.inf.0000129693.81082.a0
    1. Higgins J, Soares-Weiser K, Reingold A. Systematic Review of the Non-Specific Effects of BCG, DTP and Measles Containing Vaccines. WHO: Strategic Advisory Group of Experts on Immunization; (2014).
    1. Hirve S, Bavdekar A, Juvekar S, Benn CS, Nielsen J, Aaby P. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine (2012) 30:7300–8. 10.1016/j.vaccine.2012.09.035
    1. Lehmann D, Vail J, Firth MJ, De Klerk NH, Alpers MP. Benefits of routine immunizations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea. Int J Epidemiol. (2004) 34:138–48. 10.1093/ije/dyh262
    1. Aaby P, Vessari H, Nielsen J, Maleta K, Benn CS, Jensen H, et al. . Sex differential effects of routine immunizations and childhood survival in rural Malawi. Pediatr Infect Dis J. (2006) 25:721–7. 10.1097/
    1. Aaby P, Samb B, Andersen M, Simondon F. No long-term excess mortality after measles infection: a community study from Senegal. Am J Epidemiol. (1996) 143:1035–41.
    1. Aaby P, Jensen H, Whittle H. High-titre measles vaccine and female mortality. Lancet. (2003) 362:1765. 10.1016/S0140-6736(03)14867-2
    1. Moulton LH, Rahmathullah L, Halsey NA, Thulasiraj R, Katz J, Tielsch JM. Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. Trop Med Int Health (2005) 10:947–55. 10.1111/j.1365-3156.2005.01434.x
    1. Biering-Sørensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, et al. . Small randomized trial among low–birth-weight children receiving Bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J. (2012) 31:306–8. 10.1097/INF.0b013e3182458289
    1. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, et al. . Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. (2011) 204:245–52. 10.1093/infdis/jir240
    1. Jensen KJ, Larsen N, Biering-Sørensen S, Andersen A, Eriksen HB, Monteiro I, et al. . Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J Infect Dis. (2014) 211:956–67. 10.1093/infdis/jiu508
    1. O'connor A. Interpretation of odds and risk ratios. J Vet Int Med. (2013) 27:600–603. 10.1111/jvim.12057
    1. Goodridge HS, Ahmed SS, Curtis N, Kollmann TR, Levy O, Netea MG, et al. . Harnessing the beneficial heterologous effects of vaccination. Nat Rev Immunol. (2016) 16:392. 10.1038/nri.2016.43
    1. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. . ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ (2016) 355:i4919. 10.1136/bmj.i4919
    1. Wout J, Poell R, Furth R. The Role of BCG/PPD-Activated macrophages in resistance against systemic candidiasis in mice. Scan J Immunol. (1992) 36:713–20. 10.1111/j.1365-3083.1992.tb03132.x
    1. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, et al. . Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Nat Acad Sci USA. (2012) 109:17537–42. 10.1073/pnas.1202870109
    1. Tribouley J, Tribouley-Duret J, Appriou M. Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C R Seances Soc Biol Fil. (1978) 172:902–4.
    1. Freyne B, Marchant A, Curtis N. BCG-associated heterologous immunity, a historical perspective: experimental models and immunological mechanisms. Trans R Soc Trop Med Hyg. (2015) 109:46–51. 10.1093/trstmh/trv021
    1. De Groot AS, Ardito M, Mcclaine EM, Moise L, Martin WD. Immunoinformatic comparison of T-cell epitopes contained in novel swine-origin influenza A (H1N1) virus with epitopes in 2008–2009 conventional influenza vaccine. Vaccine (2009) 27:5740–7. 10.1016/j.vaccine.2009.07.040
    1. Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LA, Jacobs C, et al. . Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun. (2014) 6:152–8. 10.1159/000355628
    1. Smith SG, Kleinnijenhuis J, Netea MG, Dockrell HM. Whole blood profiling of bacillus Calmette–Guérin-induced trained innate immunity in infants identifies epidermal growth factor, IL-6, platelet-derived growth factor-AB/BB, and natural killer cell activation. Front Immunol. (2017) 8:644. 10.3389/fimmu.2017.00644
    1. Ugolini M, Gerhard J, Burkert S, Jensen KJ, Georg P, Ebner F, et al. Recognition of microbial viability via TLR8 drives T FH cell differentiation and vaccine responses. Nat Immunol. (2018) 19:386 10.1038/s41590-018-0068-4
    1. Knobel DL, Arega S, Reininghaus B, Simpson GJ, Gessner BD, Stryhn H, et al. . Rabies vaccine is associated with decreased all-cause mortality in dogs. Vaccine (2017) 35:3844–9. 10.1016/j.vaccine.2017.05.095
    1. Thome JJ, Bickham KL, Ohmura Y, Kubota M, Matsuoka N, Gordon C, et al. . Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat Med. (2016) 22:72. 10.1038/nm.4008
    1. Ritz N, Mui M, Balloch A, Curtis N. Non-specific effect of Bacille Calmette-Guerin vaccine on the immune response to routine immunisations. Vaccine (2013) 31:3098–103. 10.1016/j.vaccine.2013.03.059
    1. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. . Trained immunity: a program of innate immune memory in health and disease. Science (2016) 352:aaf1098. 10.1126/science.aaf1098
    1. Martinez-Gonzalez I, Mathä L, Steer CA, Takei F. Immunological memory of group 2 innate lymphoid cells. Trends Immunol. (2017) 38:423–31. 10.1016/j.it.2017.03.005
    1. Bekkering S, Blok BA, Joosten LA, Riksen NP, Van Crevel R, Netea MG. In vitro experimental model of trained innate immunity in human primary monocytes. Clin Vaccine Immunol. (2016) 23:926–33. 10.1128/CVI.00349-16
    1. Freyne B, Donath S, Germano S, Gardiner K, Casalaz D, Robins-Browne R, et al. . Neonatal BCG vaccination influences cytokine responses to Toll-like receptor ligands and heterologous antigens. J Infect Dis. (2018) 217:1798–808. 10.1093/infdis/jiy069
    1. Arts R.J, Moorlag S. J., Novakovic B., Li Y., Wang S.-Y., Oosting M., et al. . (2018). BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23:e105. 10.1016/j.chom.2017.12.010
    1. Cheng S-C, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. . mTOR-and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science (2014) 345:1250684. 10.1126/science.1250684
    1. Arts RJ, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R, et al. . Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. (2016) 17:2562–71. 10.1016/j.celrep.2016.11.011
    1. Bekkering S, Arts R. J., Novakovic B., Kourtzelis I., Van Der Heijden C. D., Li Y., et al. . (2018). Metabolic induction of trained immunity through the mevalonate pathway. Cell 172:e139. 10.1016/j.cell.2017.11.025
    1. Arts RJW, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. . Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. (2016) 24:807–19. 10.1016/j.cmet.2016.10.008
    1. Gruenbacher G, Thurnher M. Mevalonate metabolism in cancer stemness and trained immunity. Front Oncol. (2018) 8:394 10.3389/fonc.2018.00394
    1. Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt MS, Arts RJW, et al. . The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metabol. (2018). 10.1016/j.cmet.2018.09.003. [Epub ahead of print].
    1. Blok BA, Arts RJ, Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukocyte Biol. (2015) 98:347–56. 10.1189/jlb.5RI0315-096R
    1. Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, et al. . Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. (2014) 10:e1004485. 10.1371/journal.ppat.1004485
    1. Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, et al. . BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell (2018) 172:e119. 10.1016/j.cell.2017.12.031
    1. Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, et al. . Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell (2018) 172:e112. 10.1016/j.cell.2017.11.034
    1. Rusek P, Wala M, Druszczynska M, Fol M. Infectious agents as stimuli of trained innate immunity. Int J Mol Sci. (2018) 19:456. 10.3390/ijms19020456
    1. Ota MO, Vekemans J, Schlegel-Haueter SE, Fielding K, Sanneh M, Kidd M, et al. . Influence of Mycobacterium bovis bacillus Calmette-Guerin on antibody and cytokine responses to human neonatal vaccination. J Immunol. (2002) 168:919–25. 10.4049/jimmunol.168.2.919
    1. Nissen TN, Birk NM, Smits G, Jeppesen DL, Stensballe LG, Netea MG, et al. . Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial Vaccine (2017) 35:2084–91. 10.1016/j.vaccine.2017.02.048.
    1. Butkeviciute E, Jones CE, Smith SG. Heterologous effects of infant BCG vaccination: potential mechanisms of immunity. Future Microbiol. (2018) 13:1193–208. 10.2217/fmb-2018-0026
    1. Libraty DH, Zhang L, Woda M, Acosta LP, Obcena A, Brion JD, et al. . Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines. Trials Vaccinol. (2014) 3:1–5. 10.1016/j.trivac.2013.11.004
    1. Stensballe LG, Sørup S, Aaby P, Benn CS, Greisen G, Jeppesen DL, et al. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch Dis Child. (2016) 2016:310760 10.1136/archdischild-2016-310760
    1. Nissen T, Birk N, Blok B, Arts R, Andersen A, Kjærgaard J, et al. . Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial. Eur J Clin Microbiol Infect Dis. (2018) 37:29–41. 10.1007/s10096-017-3097-2
    1. Prentice S, Webb EL, Dockrell HM, Kaleebu P, Elliott AM, Cose S. Investigating the non-specific effects of BCG vaccination on the innate immune system in Ugandan neonates: study protocol for a randomised controlled trial. Trials (2015) 16:149. 10.1186/s13063-015-0682-5
    1. Biering-Sørensen S, Aaby P, Lund N, Monteiro I, Jensen KJ, Eriksen HB, et al. . Early BCG-Denmark and neonatal mortality among infants weighing < 2500 g: a randomized controlled trial. Clin Infect Dis. (2017) 65:1183–90. 10.1093/cid/cix525
    1. De Castro MJ, Pardo-Seco J, Martinón-Torres F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin Infect Dis. (2015) 60:1611–9. 10.1093/cid/civ144
    1. Holt EA, Boulos R, Halsey NA, Boulos L-M, Boulos C. Childhood survival in Haiti: protective effect of measles vaccination. Pediatrics (1990) 85:188–94.
    1. De Vries RD, Mcquaid S, Van Amerongen G, Yüksel S, Verburgh RJ, Osterhaus AD, et al. Measles immune suppression: lessons from the macaque model. PLoS Pathog. (2012) 8:e1002885 10.1371/journal.ppat.1002885
    1. Aaby P, Martins CL, Garly M-L, Andersen A, Fisker AB, Claesson MH, et al. . Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin Infect Dis. (2014) 59:484–92. 10.1093/cid/ciu354
    1. Sørup S, Benn CS, Poulsen A, Krause TG, Aaby P, Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. J Am Med Am. (2014) 311:826–35. 10.1001/jama.2014.470
    1. Aaby P, Benn C, Nielsen J, Lisse IM, Rodrigues A, Ravn H. Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open (2012) 2:e000707. 10.1136/bmjopen-2011-000707
    1. Rodrigues A, Fischer TK, Valentiner-Branth P, Nielsen J, Steinsland H, Perch M, et al. . Community cohort study of rotavirus and other enteropathogens: are routine vaccinations associated with sex-differential incidence rates? Vaccine (2006) 24:4737–46. 10.1016/j.vaccine.2006.03.033
    1. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. . Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity (2014) 41:14–20. 10.1016/j.immuni.2014.06.008
    1. Lavan RP, King AIM, Sutton DJ, Tunceli K. Rationale and support for a one health program for canine vaccination as the most cost-effective means of controlling zoonotic rabies in endemic settings. Vaccine (2017) 35:1668–74. 10.1016/j.vaccine.2017.02.014
    1. Moon SH, Lee I, Feng X, Lee HY, Kim J, Ahn DU. Effect of dietary beta-glucan on the performance of broilers and the quality of broiler breast meat. Asian-Australas J Anim Sci. (2016) 29:384. 10.5713/ajas.15.0141
    1. Jacob J, Pescatore AJ. Glucans and the poultry immune system. Am J Immunol. (2017) 13:45 10.3844/ajisp.2017.45.49

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