The 'specific-solution' paradigm
According to the current paradigm, the immune system is characterized by specificity, i.e. the ability to recognize and respond to a specific pathogen with a specific response. It implies that a vaccine against a pathogen will establish immunity towards that pathogen and nothing else. Micronutrient deficiency may impair the function of the immune system, and micronutrient supplementation works by alleviating deficiency. This understanding shapes the research agenda; few studies have addressed the possibility that a vaccine against one pathogen could affect the response to unrelated pathogens, or that micronutrient supplementation could have fundamental imprinting effects on the immune system. However, there is now increasing evidence that contradicts the paradigm.
The break-down of the 'specific-solution' paradigm
During the last 20 years, the group behind CVIVA, the Bandim Health Project (BHP), has shown that:
- Live vaccines, including measles (MV), tuberculosis (BCG) and smallpox vaccine, have beneficial effects conferring protection against unrelated diseases. In recent randomized controlled trials (RCTs), BCG at birth reduced neonatal mortality among low-birth-weight (LBW) infants by 45%1, BCG revaccination after booster diphtheria-tetanus-pertussis (DTP) vaccine reduced overall mortality by 64%2, and two doses of MV at 4 and 9 months reduced overall mortality by 30%3.
- Inactivated vaccines such as DTP and hepatitis B vaccine are protective against the targeted infections, but they may increase susceptibility to unrelated infections leading to higher mortality among females4,5.
- Vaccines interact and the overall effect on morbidity and mortality depends on the sequence and combination in which they are given2,4,6.
- The overall effect on mortality of live and inactivated vaccines is different for males and females3-5,7.
- Micronutrient supplementation alters the effect of vaccines on mortality8-12; e.g. combining standard MV and vitamin A supplementation (VAS) is particularly beneficial, whereas the combination of DTP and VAS may be harmful for females.
It may be questioned how such effects could go unnoticed. We think that they became evident to us because we
- conduct our studies in a high-mortality area with high infectious disease pressure;
- measure the real-life effects of health interventions on mortality instead of assuming that they work, and
- look for the unexpected observations and try to understand them. Several other groups have reported results which contradict the current paradigm13-16, but only our group has pursued the contradictions.
So far, our results have received little attention, considering the vast perspectives. The main objections have been that our findings are based on post hoc hypotheses; they were made in observational studies with risk of bias; and they are biologically implausible. Indeed, many findings were initially the result of post hoc analyses, since a priori hypotheses were based on the current paradigm. However, all unexpected findings have been tested, lately also in RCTs, and the results have been remarkably consistent. Regarding biological plausibility, there is no evidence that contradicts that vaccines could have other effects than the specific effects. In animal studies, the phenomenon of heterologous immunity is well described, i.e. that one pathogen can affect the response to subsequent challenge with an unrelated pathogen17. This effect can be beneficial, reducing severity of a subsequent infection, or misdirecting, increasing severity. This phenomenon contradicts specificity, and could explain some of our findings.
Towards a 'systemic effect' paradigm
Our findings suggest a new paradigm. They entail that the current concept of the immune system as driven by antigen specificity needs to be broader, including the possibility that an antigen encounter can alter the general reactivity of the immune system across many antigens. This system can be stimulated beneficially or misdirected.
In the proposed paradigm
- Vaccines and micronutrients have marked non-specific effects (NSEs) on the immune system’s ability to handle subsequent challenges;
- NSEs are different for males and females
- Interventions may interact with other interventions producing unexpected but potentially predictable results.
The potential benefit of a paradigm shift may become most obvious when one compares the solutions offered for specific public health situations:
|Situation||Specific-solution paradigm||Systemic-effect paradigm|
|Smallpox eradicated in 1977||Vaccination was stopped||Smallpox vaccine was associated with lower overall mortality and morbidity18-21, unpublished|
|High-titre MV withdrawn in 1992 due to increased female mortality5||Sex-differential effects not examined for other vaccines||Sex-differential effects found for almost all vaccines3,4,5,7,22,23|
|Delays in vaccination schedule||Vaccines can be given in combination and out of sequence||The combination and sequence of vaccines have important implications for overall mortality2,5,6,8,22,23|
|New vaccines introduced||New vaccines can be added to existing vaccines if they do not interfere with antibody development||Vaccines interact with important implications for overall mortality4,6,9|
|Global measles eradication||When measles was eliminated in Latin America, the age of MV was increased to 12 months24||Increasing the age of MV deprives children of the beneficial NSEs and increases mortality3,22|
|VAS to children reduced child mortality in RCTs14||WHO recommends combining VAS with vaccines for logistic reasons25||VAS and vaccine interact. The combination of VAS and DTP is harmful for females8-13|
As will be seen, the new paradigm offers the potential for significant beneficial effects on child survival with available tools without increased costs. Furthermore, adopting the paradigm is likely to lead to a new understanding of the immune system and the immunological mechanisms which alter general susceptibility to disease.
References to the relevant literature
To limit the length only first authors have been listed.
- Aaby P. Randomized trial of BCG vaccination at birth to low-birth-weight children: Beneficial non-specific effects in the neonatal period? J Infect Dis 2011 (in press)
- Roth A. A randomized trial of the effect of revaccination with BCG in early childhood and mortality BMJ 2010;340:c809
- Aaby P. 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
- Aaby P. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: a re-analysis of the West African studies. Lancet 2003;361:2183-8
- Garly ML. Hepatitis B vaccination associated with higher female than male mortality in Guinea-Bissau: an observational study. Ped Inf Dis J 2004;23:1086-92
- Aaby P. Assessment of childhood immunisation coverage? Lancet 2009;373:1428
- Aaby P. Routine vaccinations and child survival in war situation with high mortality: effect of gender. Vaccine 2002;21:15-20
- Benn CS. Vitamin A supplementation and childhood mortality: Amplification of the non-specific effects of vaccines? Int J Epidemiol 2003:32: 822-8
- Benn CS. Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial. Am J Clin Nutr 2009;90:629-39
- Benn CS. Randomized trial of the effect on mortality of 50,000 IU vitamin A given with BCG vaccine to infants in Guinea-Bissau, West-Africa. BMJ 2008;336:1416-20
- Benn CS. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomized controlled trial. BMJ 2010;340:c1101
- Benn CS. Sex-differential effects of neonatal vitamin A supplementation on mortality? J Infect Dis 2006;194:721
- Sazawal S. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transition setting: community-based, randomised, placebo-controlled trial. Lancet 2006;367:133–43
- Beaton GH. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries − Nutrition policy discussion paper No. 13. United Nations Administrative Committee on Coordination/Subcommittee on Nutrition 1993
- Humphrey JH. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis 2006;193:860-71
- Moulton LH. 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
- Welsh RM. No one is naive: the significance of heterologous T-cell immunity. Nature reviews 2002; 2: 417-426
- Bager P. Smallpox vaccination and risk of atopy and asthma. J Allergy Clin Immunol 2003;111:1227-31
- Sorup S. Smallpox Vaccination Reduces the Risk of Infectious Disease Hospitalisation. Int J Epidemiol (in press)
- Aaby P. Vaccinia scars associated with better survival for adults. An observational study from Guinea-Bissau. Vaccine 2006;24:5718-25
- Jensen ML. Vaccinia Scars Associated with Improved Survival among Adults in Rural Guinea-Bissau. PLoS One 2006;1:e101
- Aaby P. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: An unplanned study. Ped Inf Dis J 2003;22:798-803
- Aaby P. Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanus-pertussis vaccines: Observations from vaccination trials in Guinea-Bissau. Ped Inf Dis J 2007;26:247-52
- De Quadros CA. Measles eradication in the Americas: Progress to date. J Infect Dis 2004 ;189 (Suppl 1) : S227
- Aaby P&Benn CS. Measles vaccination in presence of maternal measles antibodies confers non-specific beneficial effects on child survival. Oral presentation 128. 14th Annual Conference on Vaccine Research, Baltimore, May 18, 2011
- Aaby P. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries.BMJ 1995;311:481-485
- Aaby P. Reduced childhood mortality after standard measles vaccination at 4-8 months compared with 9-11 months of age. BMJ 1993;307:1308-1311
- Jensen H. Survival bias in observational studies of the impact of routine immunisations on childhood survival. Trop Med Int Health 2007;12:5-14
- Jensen H. DTP in low-income countries: improved child survival or survival bias? BMJ 2005;330:845-6
- Flanagan KL. Sex differences in the vaccine-specific and non-targeted effects of vaccines. Vaccine 2011;epub
- Jørgensen M. The effect of vitamin A supplementation and DTP vaccination on parasitemia in an experimental murine malaria model. Scand J Inf Dis 2010;epub
- Stensballe LG. Acute lower respiratory tract infections and respiratory syncytial virus in children in Guinea-Bissau: A beneficial effect of BCG vaccination for girls. Vaccine 2005;23:1251-7
- Enemark U. Health services use associated with emergency department closure. J Health Serv Res Policy 2011; epub
- Aaby P. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. Int J Epidemiol 2004;33:367-73
- Aaby P. Age-specific changes in female-male mortality ratio related to the pattern of vaccinations: An observational study from rural Gambia. Vaccine 2006; 24:4701-8
- Aaby P. Non-specific and sex-differential effects of routine immunizations in rural Malawi. Ped Inf Dis J 2006;25:721-7
- Garly ML. Thymus size at 6 months of age and subsequent child mortality. J Pediatr 2008;epub
- Aaby P. Thymus size at birth is associated with infant mortality: a community study from Guinea-Bissau. Acta Paediatr 2002;91:698-703
- Roth A. Tuberculin reaction, BCG scar and lower female mortality. Epidemiology 2006: 17:562-8
- Ota MO. Influence of Mycobacterium bovis bacillus Calmette-Guérin on antibody and cytokine responses to human neonatal vaccination. J Immunol 2002;168:919-25
- Sartono E. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment. PLoS One 2010;5:e10328
- Ennis DP. Whole-cell pertussis vaccine protects against Bordetella pertussis exacerbation of allergic asthma. Immunol Lett 2005;97:91-100
- Hein-Kristensen L. Simultaneous Administration of Vitamin A and DTP Vaccine Modulates the Immune Response in a Murine Cerebral Malaria Model. Scand J Immunol 2010;72:302-8
- Expanded Programme on Immunization. Wkly Epidemiol Rec 1982;57:89-91
- Garenne M. Rougeole e mortalité au Sénégal : étude de l’impact de la vaccination effectuée à Khombole 1965-1968 sur la survie des enfants. Paris : INSERM, 1986 ;145:515-32
- Aaby P. Measles vaccination and reduction in child mortality: a community study from Guinea Bissau. J Infect 1984;8:13 21
- Aaby P. Child mortality related to seroconversion or lack of seroconversion after measles vaccination. Pediatr Infect Dis J 1989;8:197 200
- The Kasongo Project Team. Influence of measles vaccination on survival pattern of 7-35-month-old children in Kasongo, Zaire. Lancet 1981;i:764-7
- Velema JP. Childhood mortality among users and non- users of primary health care in a rural West African community. Int J EpidemioI 1991;20:474-9
- Marchant A. Newborns develop a Th1-type immune response to Mycobacterium Bovis Bacillus Calmette-Guérin vaccination. J Immunol 1999;163(4):2249-55
- Prescott SL. Development of allergen-specific T-cell memory in atopic and normal children. Lancet 1999;353(9148):196-200
- Steenhuis TJ. Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study. Clin Exp Allergy 2008;38:79-85
- Villumsen M. Risk of Lymphoma and Leukaemia after Bacille Calmette-Guérin and Smallpox Vaccination: A Danish Case-Cohort Study. Vaccine 2009;27:6950-8
- Farrington CP. Epidemiological studies of the non-specific effects of vaccines: II--methodological issues in the design and analysis of cohort studies. Trop Med Int Health 2009;14:977-85
- Robins J. Marginal Structural Models and Causal Inference in Epidemiology. Epidemiology 2000;11:550-60
- Martins C. Measles vaccination in Guinea-Bissau – strategies to reduce disease burden and improve child survival. PhD thesis. University of Copenhagen 2011
- 4Prentice AM. Commentary: Challenging public health orthodoxies--prophesy or heresy?Int J Epidemiol 2009;38:591-3
- Prentice AM. Vitamin A supplements and survival in children. BMJ 2010;340:c809
- Shann F. Heterologous immunity and the nonspecific effects of vaccines: a major medical advance? Ped Inf Dis J 2004;23:555-8
- Shann F. The non-specific effects of vaccines. Arch Dis Child 2010;95:662-7
- Shann F. BCG vaccination in developing countries. BMJ 2010;340:c809
- Fine PEM. 'Non-specific effects of vaccines'--an important analytical insight, and call for a workshop. Trop Med Int Health 2007;12:1-4