Summary
The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Access any 5 articles from the Lancet Family of journals
Subscribe:
Subscribe to The Lancet Infectious Diseases
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 1.
The contribution of vaccination to global health: past, present and future.Philos Trans R Soc Lond B Biol Sci. 2014; 36920130433
- 2.
Taking advantage of the positive side-effects of smallpox vaccination.J Vet Med B Infect Dis Vet Public Health. 2004; 51: 199-201
- 3.
Preventive vaccination against tuberculosis with BCG.Proc R Soc Med. 1931; 24: 1481-1490
- 4.
EU Vaccination glossary.https://ec.europa.eu/health/sites/health/files/vaccination/docs/glossary_en.pdfDate: 2018Date accessed: November 5, 2019
- 5.
WHO recommendations for routine immunization - summary tables: interrupted and delayed vaccination.https://www.who.int/immunization/policy/Immunization_routine_table3.pdfDate: 2019Date accessed: November 5, 2019
- 6.
The structure of scientific revolutions.University of Chicago Press, Chicago1962
- 7.
The optimal age of measles immunisation in low-income countries: a secondary analysis of the assumptions underlying the current policy.BMJ Open. 2012; 2e000761
- 8.
Influence of measles vaccination on survival pattern of 7–35-month-old children in Kasongo, Zaire.Lancet. 1981; 317: 764-767
- 9.
Impact of measles vaccination on childhood mortality in rural Bangladesh.Bull World Health Organ. 1990; 68: 441-447
- 10.
Childhood survival in Haiti: protective effect of measles vaccination.Pediatrics. 1990; 85: 188-194
- 11.
Measles vaccination and child mortality.Lancet. 1981; 2: 93
- 12.
Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study.Pediatr Infect Dis J. 2003; 22: 798-805
- 13.
Non-specific effects of standard measles vaccine at 4·5 and 9 months of age on childhood mortality: randomised controlled trial.BMJ. 2010; 341c6495
- 14.
Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality.Science. 2015; 348: 694-699
- 15.
How to evaluate potential non-specific effects of vaccines: the quest for randomized trials or time for triangulation?.Expert Rev Vaccines. 2018; 17: 411-420
- 16.
Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections.JAMA. 2014; 311: 826-835
- 17.
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
- 18.
Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands.BMJ. 2017; 358j3862
- 19.
Risk of nontargeted infectious disease hospitalizations among US children following inactivated and live vaccines, 2005–2014.Clin Infect Dis. 2017; 65: 729-737
- 20.
Beneficial non-specific reduction in hospital admissions for respiratory infections following MMR and MenC vaccinations in the Netherlands.BMJ. 2017; 358j3862
- 21.
Trial of high-dose Edmonston-Zagreb measles vaccine in Guinea-Bissau: protective efficacy.Lancet. 1988; 2: 809-811
- 22.
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
- 23.
Differential mortality by measles vaccine titer and sex.J Infect Dis. 1993; 168: 1087-1096
- 24.
Consultation on studies involving high titre of measles vaccines.Wkly Epidemiol Rec. 1992; 67: 357-361
- 25.
Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa.BMJ. 2000; 321: 1435-1438
- 26.
Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial.Clin Infect Dis. 2017; 65: 1183-1190
- 27.
Two randomized trials of the effect of the Russian strain of bacillus Calmette-Guérin alone or with oral polio vaccine on neonatal mortality in infants weighing <2000 g in India.Pediatr Infect Dis J. 2019; 38: 198-202
- 28.
Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau.BMJ. 2010; 340: c671
- 29.
The effect of oral polio vaccine at birth on infant mortality: a randomized trial.Clin Infect Dis. 2015; 61: 1504-1511
- 30.
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
- 31.
A two-center randomized trial of an additional early dose of measles vaccine: effects on mortality and measles antibody levels.Clin Infect Dis. 2018; 66: 1573-1580
- 32.
BCG vaccination at birth and rate of hospitalization for infection until 15 months of age in danish children: a randomized clinical multicenter trial.J Pediatric Infect Dis Soc. 2019; 8: 213-220
- 33.
Campaigns with oral polio vaccine may lower mortality and create unexpected results.Vaccine. 2017; 35: 1113-1116
- 34.
National immunization campaigns with oral polio vaccine reduce all-cause mortality: a natural experiment within seven randomized trials.Front Public Health. 2018; 6: 13
- 35.
No effect of an additional early dose of measles vaccine on hospitalization or mortality in children: A randomized controlled trial.Vaccine. 2018; 36: 1965-1971
- 36.
Fewer out-of-sequence vaccinations and reduction of child mortality in Northern Ghana.Vaccine. 2017; 35: 2496-2503
- 37.
Oral polio vaccination and hospital admissions with non-polio infections in Denmark: nationwide retrospective cohort study.Open Forum Infect Dis. 2015; 3ofv204
- 38.
Nonspecific effects of oral polio vaccine on diarrheal burden and etiology among bangladeshi infants.Clin Infect Dis. 2017; 65: 414-419
- 39.
Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media.Vaccine. 2011; 29: 8615-8618
- 40.
Immunization, Vaccines and Biologicals.https://www.who.int/immunization/diseases/poliomyelitis/endgame_objective2/en/Date: 2013Date accessed: February 10, 2020
- 41.
Vaccinia scars associated with better survival for adults. An observational study from Guinea-Bissau.Vaccine. 2006; 24: 5718-5725
- 42.
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
- 43.
Expanded programme on immunization. The optimal age for measles immunization.Wkly Epidemiol Rec. 1982; 57: 89-91
- 44.
Meeting of the immunization Strategic Advisory Group of Experts, November 2006—conclusions and recommendations.Wkly Epidemiol Rec. 2007; 82: 1-16
- 45.
Is early measles vaccination better than later measles vaccination?.Trans R Soc Trop Med Hyg. 2015; 109: 16-28
- 46.
Measles vaccination in presence of measles antibody may enhance child survival.FrontPediatr. 2020; (published online Feb 7.)
- 47.
Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival.Clin Infect Dis. 2014; 59: 484-492
- 48.
Reduced all-cause child mortality after general measles vaccination campaign in rural Guinea-Bissau.Pediatr Infect Dis J. 2015; 34: 1369-1376
- 49.
Revaccination with live attenuated vaccines confer additional beneficial nonspecific effects on overall survival: a review.EBioMedicine. 2016; 10: 312-317
- 50.
A general measles vaccination campaign in urban Guinea-Bissau: comparing child mortality among participants and non-participants.Vaccine. 2017; 35: 33-39
- 51.
Measles vaccination supports millennium development goal 4: increasing coverage and increasing child survival in northern Ghana, 1996–2012.Front Public Health. 2018; 6: 28
- 52.
Premunition antituberculose par le BCG. Campagne poursuive depuis 1935 sur 21,244 nouveau-nes vaccines et 20,063 non vaccines: premiere note.Arch Inst Pasteur Alger. 1954; 32: 1-8
- 53.
Revaccination with measles-mumps-rubella vaccine and infectious disease morbidity: a Danish register-based cohort study.Clin Infect Dis. 2019; 68: 282-290
- 54.
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
- 55.
Evidence of increase in mortality after the introduction of diphtheria-tetanus-pertussis vaccine to children aged 6–35 months in Guinea-Bissau: a time for reflection?.Front Public Health. 2018; 6: 79
- 56.
The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study.Int J Epidemiol. 2004; 33: 374-380
- 57.
The WHO review of the possible nonspecific effects of diphtheria-tetanus-pertussis vaccine.Pediatr Infect Dis J. 2016; 35: 1247-1257
- 58.
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
- 59.
Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial.Lancet. 2015; 386: 31-45
- 60.
RTS,S/AS01 malaria vaccine and child mortality.Lancet. 2015; 386: 1735-1736
- 61.
RTS,S Malaria Vaccine and Increased Mortality in Girls.MBio. 2016; 7: e00514-e00516
- 62.
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
- 63.
Hepatitis B vaccination associated with higher female than male mortality in Guinea-Bissau: an observational study.Pediatr Infect Dis J. 2004; 23: 1086-1092
- 64.
Contrasting female-male mortality ratios after routine vaccinations with pentavalent vaccine versus measles and yellow fever vaccine. A cohort study from urban Guinea-Bissau.Vaccine. 2016; 34: 4551-4557
- 65.
Non-specific effects of vaccines and sex-differential child mortality in rural Bangladesh.(PhD thesis) University of Southern Denmark, 2018
- 66.
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; 2e000707
- 67.
Vaccination coverage and factors associated with adherence to the vaccination schedule in young children of a rural area in Burkina Faso.Glob Health Action. 2017; 101399749
- 68.
Effects of the introduction of new vaccines in Guinea-Bissau on vaccine coverage, vaccine timeliness, and child survival: an observational study.Lancet Glob Health. 2014; 2: e478-e487
- 69.
Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.BMJ. 2016; 355i5170
- 70.
Non-live pentavalent vaccines after live measles vaccine may increase mortality.Vaccine. 2018; 36: 6039-6042
- 71.
Non-specific and sex-differential effects of vaccinations on child survival in rural western India.Vaccine. 2012; 30: 7300-7308
- 72.
Sex-differential effects on mortality of BCG and diphtheria-tetanus-pertussis vaccines in a rural area with high vaccination coverage: observational study from Senegal.Trans R Soc Trop Med Hyg. 2016; 110: 527-533
- 73.
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
- 74.
Simultaneous vaccination with MMR and DTaP-IPV-Hib and rate of hospital admissions with any infections: A nationwide register based cohort study.Vaccine. 2016; 34: 6172-6180
- 75.
Vitamin A and childhood mortality.Lancet. 1993; 342: 861
- 76.
Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial.Am J Clin Nutr. 2009; 90: 629-639
- 77.
The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea-Bissau.Int J Epidemiol. 2009; 38: 304-311
- 78.
The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination.Vaccine. 2009; 27: 2891-2898
- 79.
Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau.BMJ Open. 2012; 2e000448
- 80.
Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau.Vaccine. 2014; 32: 5468-5474
- 81.
Hypothesis: vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines?.Int J Epidemiol. 2003; 32: 822-828
- 82.
An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality.Int J Epidemiol. 2015; 44: 906-918
- 83.
High-dose vitamin A with vaccination after 6 months of age: a randomized trial.Pediatrics. 2014; 134: e739-e748
- 84.
On being a scientist. Committee on the Conduct of Science, National Academy of Sciences of the United States of America.Proc Natl Acad Sci USA. 1989; 86: 9053-9074
- 85.
Measles-mumps-rubella vaccination and respiratory syncytial virus-associated hospital contact.Vaccine. 2015; 33: 237-245
- 86.
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; 6e013335
- 87.
Evolution and strain variation in BCG.Adv Exp Med Biol. 2017; 1019: 155-169
- 88.
BCG vaccination and all-cause neonatal mortality.Pediatr Infect Dis J. 2019; 38: 195-197
- 89.
Changing oral vaccine to inactivated polio vaccine might increase mortality.Lancet. 2016; 387: 1054-1055
- 90.
Stopping live vaccines after disease eradication may increase mortality.Vaccine. 2020; 38: 10-14
- 91.
Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.Proc Natl Acad Sci USA. 2012; 109: 17537-17542
- 92.
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
- 93.
Outcomes of controlled human malaria infection after BCG vaccination.Nat Commun. 2019; 10: 874
- 94.
Non-specific effects of vaccines illustrated through the BCG example: from observations to demonstrations.Front Immunol. 2018; 92869
- 95.
BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study.J Infect Dis. 2015; 212: 1930-1938
- 96.
Opposite effects of vaccinia and modified vaccinia Ankara on trained immunity.Eur J Clin Microbiol Infect Dis. 2019; 38: 449-456
- 97.
Interacting non-specific immunological effects of BCG and TDAPF vaccinations: an explorative randomized trial.Clin Infect Dis. 2019; 70: 455-463
- 98.
Sex-differential non-vaccine-specific immunological effects of diphtheria-tetanus-pertussis and measles vaccination.Clin Infect Dis. 2016; 63: 1213-1226
- 99.
Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau.Vaccine. 2004; 22: 3014-3017
- 100.
Nonspecific effect of BCG vaccination at birth on early childhood infections: a randomized, clinical multicenter trial.Pediatr Res. 2016; 80: 681-685
- 101.
Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial.Allergy. 2018; 73: 498-504
- 102.
Maternal priming: bacillus Calmette-Guérin (BCG) vaccine scarring in mothers enhances the survival of their child with a BCG vaccine scar.J Pediatric Infect Dis Soc. 2020; 9: 166-172
- 103.
Maternal BCG scar is associated with increased infant proinflammatory immune responses.Vaccine. 2017; 35: 273-282
- 104.
Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes.J Leukoc Biol. 2015; 98: 129-136
- 105.
Vitamin A, infection, and immune function.Annu Rev Nutr. 2001; 21: 167-192
- 106.
Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes.Clin Microbiol Rev. 2005; 18: 446-464
- 107.
Neonatal vitamin A: time to move on?.Lancet. 2015; 386: 132-133
- 108.
Nonspecific effects of vaccines and the reduction of mortality in children.Clin Ther. 2013; 35: 109-114
- 109.
Meeting of the Strategic Advisory Group of Experts on immunization, April 2014—conclusions and recommendations.Wkly Epidemiol Rec. 2014; 89: 221-236
- 110.
Triangulation in aetiological epidemiology.Int J Epidemiol. 2016; 45: 1866-1886
- 111.
Editorial commentary: different STRAINS of bacillus Calmette-Guérin vaccine have very different effects on tuberculosis and on unrelated infections.Clin Infect Dis. 2015; 61: 960-962
- 112.
Efficacy of bacillus Calmette-Guérin Strains for treatment of nonmuscle invasive bladder cancer: a systematic review and network meta-analysis.J Urol. 2017; 198: 503-510
- 113.
Development of BCG scar and subsequent morbidity and mortality in rural Guinea-Bissau.Clin Infect Dis. 2015; 61: 950-959
- 114.
BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis.Cell. 2018; 172: 176-190
- 115.
Could the RTS,S/AS01 meningitis safety signal really be a protective effect of rabies vaccine?.Vaccine. 2017; 35: 716-721
- 116.
Rabies vaccine is associated with decreased all-cause mortality in dogs.Vaccine. 2017; 35: 3844-3849
- 117.
Rabies vaccination of 6-week-old puppies born to immunized mothers: a randomized controlled trial in a high-mortality population of owned, free-roaming dogs.Trop Med Infect Dis. 2020; 5: 45
- 118.
A small jab—a big effect: nonspecific immunomodulation by vaccines.Trends Immunol. 2013; 34: 431-439
- 119.
Heterologous vaccine effects.Vaccine. 2016; 34: 3923-3930
- 120.
Non-specific effects of live attenuated pertussis vaccine against heterologous infectious and inflammatory diseases.Front Immunol. 2018; 92872
- 121.
Nonspecific effects of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a.Sci Adv. 2019; 5eaau6849-eaau
- 122.
Trained immunity-based vaccines: a new paradigm for the development of broad-spectrum anti-infectious formulations.Front Immunol. 2018; 92936
- 123.
WHO's rollout of malaria vaccine in Africa: can safety questions be answered after only 24 months?.BMJ. 2020; (published online Jan 24.)
- 124.
Meeting of the Strategic Advisory Group of Experts on immunization, April 2016—conclusions and recommendations.Wkly Epidemiol Rec. 2016; 91: 266-284
- 125.
The importance of randomised vs non-randomised trials.Lancet. 2019; 394: 634
- 126.
Re: Non-specific effects of childhood vaccines. Rapid response.BMJ. 2016; 355i5434
Article info
Publication history
Published: July 06, 2020
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.