How to evaluate potential non-specific effects of vaccines: the quest for randomized trials or time for triangulation?

References

• Benn CS, Netea MG, Selin LK, et al. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34:431–439.
   PubMed Web of Science ®Google Scholar
• Higgins JP, Soares-Weiser K, Lopez-Lopez JA, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. Bmj. 2016;355:i5170.
   PubMed Web of Science ®Google Scholar
• JPT, Soares-Weiser K, Reingold A Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines. Available from: http://www.who.int/immunization/sage/meetings/2014/april/3_NSE_Epidemiology_review_Report_to_SAGE_14_Mar_FINAL.pdfUpdated 6 May 2018.
   Google Scholar
• Kleinnijenhuis J, Quintin J, Preijers F, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012;109:17537–17542.
   PubMed Web of Science ®Google Scholar
• Kleinnijenhuis J, Quintin J, Preijers F, et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun. 2014;6:152–158.
   PubMed Web of Science ®Google Scholar
• Aaby P, Benn CS. Saving lives by training innate immunity with Bacille Calmette-Guerin vaccine. Proc Natl Acad Sci U S A. 2012;109:17317–17318.
   PubMed Web of Science ®Google Scholar
• Arts RJW, Moorlag S, Novakovic B, et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe. 2018;23:89–100 e5.
   PubMed Web of Science ®Google Scholar
• WHO. Meeting of the strategic advisory group of experts on immunization, april 2014 – conclusions and recommendations. Wkly Epidemiol Rec. 2014;89:233–235.
   Google Scholar
• Pollard AJ, Finn A, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child. 2017;102:1077–1081.
   PubMed Web of Science ®Google Scholar
• Munafo MR, Davey Smith G. Robust research needs many lines of evidence. Nature. 2018;553:399–401.
   PubMed Web of Science ®Google Scholar
• Rothman KJ. Six persistent research misconceptions. J Gen Intern Med. 2014;29:1060–1064.
   PubMed Web of Science ®Google Scholar
• Hernan MA, Hernandez-Diaz S, Robins JM. Randomized trials analyzed as observational studies. Ann Intern Med. 2013;159:560–562.
   PubMed Web of Science ®Google Scholar
• Krauss A. Why all randomised controlled trials produce biased results. Ann Med. 2018;1–11.
   PubMed Web of Science ®Google Scholar
• Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95(Suppl 1):S144–50.
   PubMed Web of Science ®Google Scholar
• Aaby P, Ravn H, Benn CS, et al. Randomized trials comparing inactivated vaccine after medium- or high-titer measles vaccine with standard titer measles vaccine after inactivated vaccine: a meta-analysis. Pediatr Infect Dis J. 2016;35:1232–1241.
   PubMed Web of Science ®Google Scholar
• Klein SL, Shann F, Moss WJ, et al. RTS,S malaria vaccine and increased mortality in girls. MBio. 2016;7.
   Web of Science ®Google Scholar
• Aaby P, Jensen H, Samb B, 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. 2003;361:2183–2188.
   PubMed Web of Science ®Google Scholar
• Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol. 2016;45:1866–1886.
   PubMed Web of Science ®Google Scholar
• Hartfield J, Morley D. Efficacy of measles vaccine. J Hyg (Lond). 1963;61:143–147.
   PubMedGoogle Scholar
• Benn CS, Bale C, Sommerfelt H, et al. Hypothesis: vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines? Int J Epidemiol. 2003;32:822–828.
   PubMed Web of Science ®Google Scholar
• Aaby P, Garly ML, Nielsen J, 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. 2007;26:247–252.
   PubMed Web of Science ®Google Scholar
• Aaby P, Martins CL, Garly ML, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. Bmj. 2010;341:c6495.
   PubMed Web of Science ®Google Scholar
• Aaby P, Martins CL, Garly ML, et al. The optimal age of measles immunisation in low-income countries: a secondary analysis of the assumptions underlying the current policy. BMJ Open. 2012 Jul 19;2(4). pii: e000761. doi: 10.1136/bmjopen-2011-000761.
   Web of Science ®Google Scholar
• Aaby P, Martins CL, Garly ML, et al. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin Infect Dis. 2014;59:484–492.
   PubMed Web of Science ®Google Scholar
• Fisker AB, Nebie E, Schoeps A, et al. A two-center randomized trial of an additional early dose of measles vaccine: effects on mortality and measles antibody levels. Clin Inf Dis. 2017.
   PubMed Web of Science ®Google Scholar
• Martins C, Garly ML, Bale C, et al. Measles antibody levels after vaccination with Edmonston-Zagreb and Schwarz measles vaccine at 9 months or at 9 and 18 months of age: a serological study within a randomised trial of different measles vaccines. Vaccine. 2013;31:5766–5771.
   PubMed Web of Science ®Google Scholar
• Van Lerberghe W. Influence of measles vaccination on survival pattern of 7–35-month-old children in Kasongo, Zaire. The Kasongo Project Team. Lancet. 1981;317: 764–767.
   Google Scholar
• Aaby P, Bhuiya A, Nahar L, et al. The survival benefit of measles immunization may not be explained entirely by the prevention of measles disease: a community study from rural Bangladesh. Int J Epidemiol. 2003;32:106–116.
   PubMed Web of Science ®Google Scholar
• Aaby P, Bukh J, Lisse IM, et al. Measles vaccination and reduction in child mortality: a community study from Guinea-Bissau. J Infect. 1984;8:13–21.
   PubMed Web of Science ®Google Scholar
• Desgrees Du Lou A, Pison G, Aaby P. Role of immunizations in the recent decline in childhood mortality and the changes in the female/male mortality ratio in rural Senegal. Am J Epidemiol. 1995;142:643–652.
   PubMed Web of Science ®Google Scholar
• Aaby P, Samb B, Simondon F, et al. Divergent mortality for male and female recipients of low-titer and high-titer measles vaccines in rural Senegal. Am J Epidemiol. 1993;138:746–755.
   PubMed Web of Science ®Google Scholar
• Kapoor SK, Reddaiah VP. Effectiveness of measles immunization on diarrhea and malnutrition related mortality in 1–4 year olds. Indian J Pediatr. 1991;58:821–823.
   PubMedGoogle Scholar
• Benn CS, Fisker AB, Whittle HC, et al. Revaccination with live attenuated vaccines confer additional beneficial nonspecific effects on overall survival: a review. EBioMedicine. 2016;10:312–317.
   PubMed Web of Science ®Google Scholar
• Aaby P, Ravn H, Fisker AB, et al. Is diphtheria-tetanus-pertussis (DTP) associated with increased female mortality? A meta-analysis testing the hypotheses of sex-differential non-specific effects of DTP vaccine. Trans R Soc Trop Med Hyg. 2016;110:570–581.
   PubMed Web of Science ®Google Scholar
• Martins CL, Benn CS, Andersen A, et al. A randomized trial of a standard dose of Edmonston-Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions. J Infect Dis. 2014;209:1731–1738.
   PubMed Web of Science ®Google Scholar
• Sorup S, Benn CS, Poulsen A, et al. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. Jama. 2014;311:826–835.
   PubMed Web of Science ®Google Scholar
• Bardenheier BH, McNeil MM, Wodi AP, et al. Risk of nontargeted infectious disease hospitalizations among US children following inactivated and live vaccines, 2005–2014. Clin Infect Dis. 2017;65:729–737.
   PubMed Web of Science ®Google Scholar
• La Torre G, Saulle R, Unim B, et al. The effectiveness of measles-mumps-rubella (MMR) vaccination in the prevention of pediatric hospitalizations for targeted and untargeted infections: a retrospective cohort study. Hum Vaccin Immunother. 2017;13:1879–1883.
   PubMed Web of Science ®Google Scholar
• Tielemans S, De Melker HE, Hahne SJM, et al. Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands. Bmj. 2017;358:j3862.
   PubMed Web of Science ®Google Scholar
• Benn CS, Sørup S, Aaby P. Beneficial non-specific reduction in hospital admissions for respiratory infections following MMR and MenC vaccinations in the Netherlands. Rapid response to reference 39, BMJ 2017.
   Google Scholar
• Mina MJ, Metcalf CJ, de Swart RL, et al. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science. 2015;348:694–699.
   PubMed Web of Science ®Google Scholar
• Mina MJ. Measles, immune suppression and vaccination: direct and indirect nonspecific vaccine benefits. J Infect. 2017;74(Suppl 1):S10–S7.
   PubMedGoogle Scholar
• Rieckmann A, Villumsen M, Sorup S, et al. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010. Int J Epidemiol. 2017;46:695–705.
   PubMed Web of Science ®Google Scholar
• Mogensen SW, Aaby P, Smedman L, et al. Introduction of standard measles vaccination in an urban African community in 1979 and overall child survival: a reanalysis of data from a cohort study. BMJ Open. 2016;6:e011317.
   PubMed Web of Science ®Google Scholar
• Aaby P, Lisse IM, Molbak K, et al. No persistent T lymphocyte immunosuppression or increased mortality after measles infection: a community study from Guinea-Bissau. Pediatr Infect Dis J. 1996;15:39–44.
   PubMed Web of Science ®Google Scholar
• Aaby P, Samb B, Andersen M, et al. No long-term excess mortality after measles infection: a community study from Senegal. Am J Epidemiol. 1996;143:1035–1041.
   PubMed Web of Science ®Google Scholar
• Aaby P, Simondon F, Samb B, et al. Low mortality after mild measles infection compared to uninfected children in rural West Africa. Vaccine. 2002;21:120–126.
   PubMed Web of Science ®Google Scholar
• Lund N, Andersen A, Hansen AS, et al. the effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin Infect Dis. 2015;61:1504–1511.
   PubMed Web of Science ®Google Scholar
• Benn CS, Jacobsen LH, Fisker AB, et al. Campaigns with oral polio vaccine may lower mortality and create unexpected results. Vaccine. 2017;35:1113–1116.
   PubMed Web of Science ®Google Scholar
• Andersen A, Fisker AB, Rodrigues A, et al. National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials. Front Public Health. 2018 Feb 2;6:13. doi:10.3389/fpubh.2018.00013
   PubMed Web of Science ®Google Scholar
• Welaga P, Oduro A, Debpuur C, et al. Fewer out-of-sequence vaccinations and reduction of child mortality in Northern Ghana. Vaccine. 2017;35:2496–2503.
   PubMed Web of Science ®Google Scholar
• Aaby P, Andersen A, Martins CL, et al. Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine. BMJ Open. 2016;6:e013335.
   PubMedGoogle Scholar
• Aaby P, Rodrigues A, Biai S, et al. Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2004;22:3014–3017.
   PubMed Web of Science ®Google Scholar
• Mogensen SW, Andersen A, Rodrigues A, et al. The introduction of diphtheria-tetanus-pertussis and oral polio vaccine among young infants in an urban African community: a natural experiment. EBioMedicine. 2017;17:192–198.
   PubMed Web of Science ®Google Scholar
• Aaby P, Jensen H, Gomes J, et al. The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study. Int J Epidemiol. 2004;33:374–380.
   PubMed Web of Science ®Google Scholar
• Sorup S, Stensballe LG, Krause TG, et al. oral polio vaccination and hospital admissions with non-polio infections in Denmark: nationwide retrospective cohort study. Open Forum Infect Dis. 2016;3:ofv204.
   PubMed Web of Science ®Google Scholar
• Upfill-Brown A, Taniuchi M, Platts-Mills JA, et al. nonspecific effects of oral polio vaccine on diarrheal burden and etiology among Bangladeshi infants. Clin Infect Dis. 2017;65:414–419.
   PubMed Web of Science ®Google Scholar
• Seppala E, Viskari H, Hoppu S, et al. Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media. Vaccine. 2011;29:8615–8618.
   PubMed Web of Science ®Google Scholar
• Biering-Sørensen S, Aaby P, Lund N, et al. Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial. Clin Inf Dis. 2017;65:1183–1190.
   PubMed Web of Science ®Google Scholar
• Vandenbroucke JP, Broadbent A, Pearce N. Causality and causal inference in epidemiology: the need for a pluralistic approach. Int J Epidemiol. 2016;45:1776–1786.
   PubMedGoogle Scholar
• Knudsen KM, Aaby P, Whittle H, et al. Child mortality following standard, medium or high titre measles immunization in West Africa. Int J Epidemiol. 1996;25:665–673.
   PubMed Web of Science ®Google Scholar
• Krieger N, Davey Smith G. The tale wagged by the DAG: broadening the scope of causal inference and explanation for epidemiology. Int J Epidemiol. 2016.
   Web of Science ®Google Scholar
• Cornfield J. Principles of research. Am J Ment Defic. 1959;64:240–252.
   PubMedGoogle Scholar
• Aaby P, Ravn H, Benn CS. The WHO Review of the Possible Nonspecific Effects of Diphtheria-Tetanus-Pertussis Vaccine. Pediatr Infect Dis J. 2016 Nov;35(11):1247–1257.
   Web of Science ®Google Scholar
• Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ. 2000 Dec 9;321(7274):1435–1438.
   PubMedGoogle Scholar
• Aaby P, Ravn H, Roth A, et al. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child. 2012;97:685–691.
   PubMed Web of Science ®Google Scholar
• Aaby P, Jensen H, Rodrigues A, et al. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. Int J Epidemiol. 2004;33:367–373.
   PubMed Web of Science ®Google Scholar
• Aaby P, Andersen A, Ravn H, et al. Co-administration of BCG and diphtheria-tetanus-pertussis (dtp) vaccinations may reduce infant mortality more than the WHO-schedule of BCG first and then DTP. A re-analysis of demographic surveillance data from rural Bangladesh. EBioMedicine. 2017;22:173–180.
   PubMed Web of Science ®Google Scholar