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The non-specific and sex-differential effects of vaccines


The textbook view of vaccination is that it functions to induce immune memory of the specific pathogen components of the vaccine, leading to a quantitatively and qualitatively better response if the host is exposed to infection with the same pathogen. However, evidence accumulated over the past few decades increasingly suggests that vaccines can also have non-specific effects on unrelated infections and diseases, with important implications for childhood mortality particularly in low-income settings. Furthermore, many of these non-specific effects, as well as the pathogen-specific effects, of vaccines show differences between the sexes. Here, members of the Optimmunize consortium discuss the evidence for and potential mechanisms of non-specific and sex-differential effects of vaccines, as well as their potential policy implications. Given that the non-specific effects of some vaccines are now being tested for their ability to protect against COVID-19, the authors also comment on the broader implications of these trials.

The contributors

Peter Aaby was trained as an anthropologist but has built a large health surveillance system in Guinea-Bissau since 1978, focusing on the high levels of child mortality there. Crowding and intensive exposure to measles were key determinants of child mortality. This led to vaccine research and the discovery of the non-specific effects of measles vaccine.

Christine Stabell Benn is a professor in global health at the University of Southern Denmark. She conducts epidemiological and immunological studies of vaccines and vitamin A, with a focus on their real-life effects on overall health in Africa and Denmark. She formulated the hypothesis that these health interventions with immunomodulatory effects interact, often in a sex-differential manner.

Katie L. Flanagan is Director of Infectious Diseases for north/north-west Tasmania, an adjunct professor at the University of Tasmania and RMIT University and an adjunct associate professor at Monash University. She is Honorary Secretary of the Australasian Society for Infectious Diseases (ASID), Chair of the ASID Vaccination Special Interest Group and a member of the Australian Technical Advisory Group on Immunisation. Her current research focuses on using systems vaccinology to study the sex-differential and non-targeted effects of vaccines.

Sabra L. Klein is a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, USA. She is an expert on sex and gender differences in immune responses and susceptibility to infection. She is the immediate past president of the Organization for the Study of Sex Differences, a principal investigator of the Johns Hopkins Specialized Center for Research Excellence in sex and age differences in immunity to influenza and a co-director of the Johns Hopkins Center for Women’s Health, Sex, and Gender Research.

Tobias R. Kollmann is a paediatric infectious disease clinician and systems vaccinologist at Telethon Kids Institute and Perth Children’s Hospital in Perth, Australia. His expertise centres on newborn infectious diseases, immune ontogeny and early-life vaccine responses, using cutting-edge technology and analytics to extract the most information out of the typically small biological samples obtainable in early life.

David J. Lynn is Director of the Computational and Systems Biology Program and an EMBL Australia group leader at the South Australian Health and Medical Research Institute. He is also a professor at the Flinders University College of Medicine and Public Health. He leads a research programme in systems immunology, investigating how pathogenic and commensal microorganisms modulate the immune system in different contexts, including vaccination.

Frank Shann worked as a paediatrician in Papua New Guinea and then for 20 years was Director of Intensive Care at the Royal Children’s Hospital in Melbourne, Australia. He is a professorial fellow in the Department of Paediatrics, University of Melbourne, engaged in research on the non-specific effects of vaccines.


  1. 1.

    Higgins, J. P. et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 355, i5170 (2016).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Shann, F. Nonspecific effects of vaccines and the reduction of mortality in children. Clin. Ther. 35, 109–114 (2013).

    PubMed  Google Scholar 

  3. 3.

    Aaby, P., Kollmann, T. R. & Benn, C. S. Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges. Nat. Immunol. 15, 895–899 (2014).

    CAS  PubMed  Google Scholar 

  4. 4.

    Benn, C. S., Fisker, A. B., Rieckmann, A., Sørup, S. & Aaby, P. Vaccinology: time to change paradigm? Lancet Infect. Dis. (in the press).

  5. 5.

    Aaby, P., Ravn, H. & Benn, C. S. The WHO review of the possible non-specific effects of diphtheria-tetanus-pertussis vaccine. Pediatr. Infect. Dis. J. 35, 1247–1257 (2016).

    PubMed  Google Scholar 

  6. 6.

    Klein, S. L., Shann, F., Moss, W. J., Benn, C. S. & Aaby, P. RTS,S malaria vaccine and increased mortality in girls. mBio 7, e00514-16 (2016).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Aaby, P. et al. 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 2, e000707 (2012).

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Shann, F. A live-vaccine-last schedule: saving an extra million lives a year? Clin. Infect. Dis. (2020).

    Article  PubMed  Google Scholar 

  9. 9.

    Sørup, S. et al. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA 311, 826–835 (2014).

    PubMed  Google Scholar 

  10. 10.

    Bardenheier, B. H., McNeil, M. M., Wodi, A. P., McNicholl, J. M. & DeStefano, F. Risk of nontargeted infectious disease hospitalizations among US children following inactivated and live vaccines, 2005-2014. Clin. Infect. Dis. 65, 729–737 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Freyne, B. & Curtis, N. Does neonatal BCG vaccination prevent allergic disease in later life? Arch. Dis. Child. 99, 182–184 (2014).

    PubMed  Google Scholar 

  12. 12.

    Benitez, M. L. R. et al. Mycobacterium bovis BCG in metastatic melanoma therapy. Appl. Microbiol. Biotechnol. 103, 7903–7916 (2019).

    CAS  PubMed  Google Scholar 

  13. 13.

    Guallar-Garrido, S. & Julian, E. Bacillus Calmette-Guérin (BCG) therapy for bladder cancer: an update. Immunotargets Ther. 9, 1–11 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kühtreiber, W. M. & Faustman, D. L. BCG therapy for type 1 diabetes: restoration of balanced immunity and metabolism. Trends Endocrinol. Metab. 30, 80–92 (2019).

    PubMed  Google Scholar 

  16. 16.

    Yamazaki-Nakashimada, M. A. et al. BCG: a vaccine with multiple faces. Hum. Vaccin. Immunother. (2020).

    Article  PubMed  Google Scholar 

  17. 17.

    Gofrit, O. N. et al. Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer’s disease in bladder cancer patients. PLoS One 14, e0224433 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    de Castro, M. J., Pardo-Seco, J. & Martinon-Torres, F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin. Infect. Dis. 60, 1611–1619 (2015).

    PubMed  Google Scholar 

  19. 19.

    Biering-Sorensen, S. et al. Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial. Clin. Infect. Dis. 65, 1183–1190 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Stensballe, L. G. et al. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch. Dis. Child. 102, 224–231 (2017).

    PubMed  Google Scholar 

  21. 21.

    Arts, R. J. W. et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23, 89–100 e105 (2018).

    CAS  PubMed  Google Scholar 

  22. 22.

    Wardhana, Datau, E. A., Sultana, A., Mandang, V. V. & Jim, E. The efficacy of bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med. Indones. 43, 185–190 (2011).

    CAS  PubMed  Google Scholar 

  23. 23.

    Aaby, P. & Benn, C. S. Developing the concept of beneficial nonspecific effect of live vaccines with epidemiological studies. Clin. Microbiol. Infect. 25, 1459–1467 (2019).

    CAS  PubMed  Google Scholar 

  24. 24.

    Rieckmann, A. et al. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010. Int. J. Epidemiol. 46, 695–705 (2017).

    PubMed  Google Scholar 

  25. 25.

    Klein, S. L., Jedlicka, A. & Pekosz, A. The Xs and Y of immune responses to viral vaccines. Lancet Infect. Dis. 10, 338–349 (2010).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Aaby, P. et al. Long-term survival after Edmonston-Zagreb measles vaccination in Guinea-Bissau: increased female mortality rate. J. Pediatr. 122, 904–908 (1993).

    CAS  PubMed  Google Scholar 

  27. 27.

    Aaby, P. et al. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies. Lancet 361, 2183–2188 (2003).

    PubMed  Google Scholar 

  28. 28.

    Aaby, P. et al. Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanus-pertussis vaccines: observations from vaccination trials in Guinea-Bissau. Pediatr. Infect. Dis. J. 26, 247–252 (2007).

    PubMed  Google Scholar 

  29. 29.

    Flanagan, K. L. et al. Sex differences in the vaccine-specific and non-targeted effects of vaccines. Vaccine 29, 2349–2354 (2011).

    CAS  PubMed  Google Scholar 

  30. 30.

    Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    CAS  PubMed  Google Scholar 

  31. 31.

    Flanagan, K. L., Fink, A. L., Plebanski, M. & Klein, S. L. Sex and gender differences in the outcomes of vaccination over the life course. Annu. Rev. Cell Dev. Biol. 33, 577–599 (2017).

    CAS  PubMed  Google Scholar 

  32. 32.

    Aaby, P. et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 341, c6495 (2010).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Benn, C. S., Netea, M. G., Selin, L. K. & Aaby, P. A small jab – a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 34, 431–439 (2013).

    CAS  PubMed  Google Scholar 

  34. 34.

    Brook, B. et al. BCG-vaccination induced emergency granulopoiesis provides rapid protection from neonatal sepsis. Sci. Transl Med. (2020).

  35. 35.

    Aaby, P. et al. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin. Infect. Dis. 59, 484–492 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Benn, C. S., Fisker, A. B., Whittle, H. C. & Aaby, P. Revaccination with live attenuated vaccines confer additional beneficial nonspecific effects on overall survival: a review. EBioMed. 10, 312–317 (2016).

    Google Scholar 

  37. 37.

    Kollmann, T. R., Marchant, A. & Way, S. S. Vaccination strategies to enhance immunity in neonates. Science 368, 612–615 (2020).

    CAS  PubMed  Google Scholar 

  38. 38.

    Noho-Konteh, F. et al. Sex-differential non-vaccine-specific immunological effects of diphtheria-tetanus-pertussis and measles vaccination. Clin. Infect. Dis. 63, 1213–1226 (2016).

    CAS  PubMed  Google Scholar 

  39. 39.

    Zivkovic, I. et al. Sexual diergism in antibody response to whole virus trivalent inactivated influenza vaccine in outbred mice. Vaccine 33, 5546–5552 (2015).

    CAS  PubMed  Google Scholar 

  40. 40.

    Zivkovic, I. et al. Sex bias in mouse humoral immune response to influenza vaccine depends on the vaccine type. Biologicals 52, 18–24 (2018).

    CAS  PubMed  Google Scholar 

  41. 41.

    Fink, A. L., Engle, K., Ursin, R. L., Tang, W. Y. & Klein, S. L. Biological sex affects vaccine efficacy and protection against influenza in mice. Proc. Natl Acad. Sci. USA 115, 12477–12482 (2018).

    CAS  PubMed  Google Scholar 

  42. 42.

    Potluri, T. et al. Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females. NPJ Vaccines 4, 29 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Andersen, A. et al. National immunization campaigns with oral polio vaccine reduce all-cause mortality: a natural experiment within seven randomized trials. Front. Public Health 6, 13 (2018).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Uthayakumar, D. et al. Non-specific effects of vaccines illustrated through the BCG example: from observations to demonstrations. Front. Immunol. 9, 2869 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Miller, A. et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. Preprint at medRxiv (2020).

  46. 46.

    Shet, A. et al. Differential COVID-19-attributable mortality and BCG vaccine use in countries. Preprint at medRxiv (2020).

  47. 47.

    Sala, G. & Miyakawa, T. Association of BCG vaccination policy with prevalence and mortality of COVID-19. Preprint at medRxiv (2020).

  48. 48.

    Floc’h, F. & Werner, G. H. Increased resistance to virus infections of mice inoculated with BCG (bacillus Calmette-Guérin). Ann. Immunol. 127, 173–186 (1976).

    Google Scholar 

  49. 49.

    Curtis, N., Sparrow, A., Ghebreyesus, T. A. & Neteta, M. G. Considering BCG vaccination to reduce the impact of COVID-19. Lancet (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Wenham, C., Smith, J. & Morgan, R. COVID-19: the gendered impacts of the outbreak. Lancet 395, 846–848 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zeng, F. et al. A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: a possible reason underlying different outcome between sex. J. Med. Virol. (2020).

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T.R.K. is supported by the NIH National Institute of Allergy and Infectious Diseases (U19AI118608-02) and Telethon Kids and Perth Children’s Hospital Foundation. D.J.L.’s work on the non-specific effects of vaccines is supported by the Flinders Foundation and the Australian National Health and Medical Research Council. The BRACE trial is supported by the Bill & Melinda Gates Foundation, Sarah and Lachlan Murdoch, the Royal Children’s Hospital Foundation, the Minderoo Foundation, the South Australian government, the NAB Foundation, the Calvert-Jones Foundation and individual donors.

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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Peter Aaby or Christine Stabell Benn or Katie L. Flanagan or Sabra L. Klein or Tobias R. Kollmann or David J. Lynn or Frank Shann.

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Competing interests

K.L.F. has received consultation and lecture fees from Sanofi Pasteur, Seqirus and Pfizer in the past 5 years and is a member of the Australian Technical Advisory Group on Immunisation. The other authors declare no competing interests.

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Aaby, P., Benn, C.S., Flanagan, K.L. et al. The non-specific and sex-differential effects of vaccines. Nat Rev Immunol 20, 464–470 (2020).

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