The current perception of health, development of health policies and development of interventions is based the assumption that for each specific disease or deficiency there is one solution; for example, measles vaccine against measles infection, rotavaccine against rotavirus infection and vitanmin A supplementation against vitamin A deficiency. However, this perception disregard the fact that these solutions are mediated through the immune system and the immune system may learn more general strategies from an intervention but may also be deregulated by an intervention leading to increased morbidity and mortality. These nonspecific effects are far more important than has previously been appreciated.

There are an increasing number of observational and randomised studies from particularly INDEPTH sites which document that  the non-specific effects are often more important than the specific effects. Several preliminary generalisations have emerged from these studies:

  • Live vaccines (measles vaccine, BCG, OPV, vaccinia) have usually major beneficial non-specific effects, i.e. effects not explained by prevention of the vaccine-targeted infection (1,2).
  • Inactivated vaccines (DTP, HBV, IPV) may be associated with negative effects for female morbidity and mortality (3).
  • The non-specific effects are often sex-differential (3), e.g. live vaccines have a stronger beneficial effect for girls than for boys.
  • Interventions interact. Since interventions act through the immune system they may interact, enhancing or reducing the effect of other interventions. For example, vitamin A supplementation appears to enhance the non-specific effects of vaccines (4).
  • Though this has been an underresearched area, an increasing number of immunological studies show that one infection/antigen may modulate the immune system non-specifically enhancing or reducing resistance to other infections (5,6).
The existence of non-specific effects has major implications for health that INDEPTH HDSS centres are in unique position to examine. Most health policy is based on assumptions (2) or studies which are only examining what the researchers expect to see (3). We may therefore not see negative effects of an intervention.  HDSS centres have the possibility of seeing what the researchers had not planned because they follow the total population for a number of key variables like morbidity or mortality. For example, it was HDSS centres in Guinea-Bissau and Senegal which observed that high-titre measles vaccine was associated with increased female mortality (1,3).  Another important implication of non-specific effects is that if we eradicate an infection (e.g. measles or polio) which is controlled by a vaccine with beneficial non-specific effects, we may do harm by reducing/stopping vaccinations once the infection is eradicated.


1. Aaby P, Whittle HC, Benn CS. Vaccine programmes must consider their effect on general resistance. BMJ. 2012;344:e3769. doi: 10.1136/bmj.e3769.

2. Aaby P, Martins CL, Garly ML, Rodrigues A, Benn CS, Whittle HC. The optimal age of measles immunization in low-income countries: A secondary analysis of the assumptions underlying the current policy. BMJ Open 2012:2:e000761

3. Aaby P, Benn CS, 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.

4. Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. 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

5. Flanagan KL, Klein SL, Skakkebæk NE, Marriott I, Marchant A, Selin L, Fish EN, Prentice A, Whittle H, Benn CS, Aaby P. Sex differences in the vaccine-specific and non-targeted effects of vaccines. Vaccine 2011;13:2349-54

6. Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell host & microbe 2011;9:355-61.

Last revised 11 February 2013