Non-specific effect of vaccines
[1] Non-specific effects of non-live vaccination may be detrimental, increasing overall mortality at least 30% by some estimates, despite providing protection against the target disease.
Rather, non-specific effects represent a form of general immunomodulation, with important consequences for the immune system's ability to handle subsequent challenges.
It is estimated that millions of child deaths in low income countries could be prevented every year if the non-specific effects of vaccines were taken into consideration in immunization programs.
[1] The hypothesis that vaccines have non-specific effects was formulated in the early 1990s by Peter Aaby at the Bandim Health Project in West Africa.
[8] It was later discovered that it was not the HTMV, but rather a subsequent inactivated vaccine (DTP or IPV for different children), that caused the increase in female mortality.
Numerous observational studies and randomised trials (RCTs) have found that the impact on mortality of live and inactivated vaccines differ markedly.
[10] The live attenuated BCG vaccine developed against tuberculosis has been shown to have strong beneficial effects on the ability to combat non-tuberculosis infections.
[12] These observations encouraged randomised controlled trials to examine BCG vaccination's beneficial non-specific effects on overall health.
In the first two randomised controlled trials receipt of BCG+OPV at birth vs. OPV only ('delayed BCG') was associated with strong reductions in neonatal mortality; these effects were seen as early as 3 days after vaccination.
[15][19][20] In a recent WHO-commissioned review based on five clinical trials and nine observational studies, it was concluded that "the results indicated a beneficial effect of BCG on overall mortality in the first 6–12 months of life.
[17] Relevant follow-up in some of the trials was short, and all of the observational studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria and "There was a suggestion that BCG vaccination may be more beneficial the earlier it is given".
[2] Based on the evidence, the WHO's Strategic Group of Experts on Immunization (SAGE) concluded that "the non-specific effects on all-cause mortality warrant further research".
[26] Immunization with OPV was found to reduce all-cause childhood mortality [27][28] even in the absence of wild poliovirus circulation, hospital admission rate,[29] incidence of bacterial diarrhea,[30] and otitis media.
[2] Based on the evidence, the Strategic Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research".
These results are consistent with hypotheses that DTP vaccine may have detrimental effects on mortality, although a majority of the evidence was generated by a group centred in Guinea-Bissau who have often written in defence of such a hypothesis.
There are accumulating data illustrating that males and females may respond differently to vaccination, both in terms of the quality and quantity of the immune response.
The non-specific effects were primarily observed in low-income countries with high infectious disease burdens, but they may not be limited to these areas.
Recent Danish register-based studies have shown that the live attenuated measles-mumps-rubella vaccine (MMR) protects against hospital admissions with infectious diseases and specifically getting ill by respiratory syncytial virus.
It is not known how vaccination induces rapid beneficial or harmful changes in the general susceptibility to infectious diseases, but the following mechanisms are likely to be involved.
The concept that not only plants and insects, but also humans have innate immune memory may provide new clues to why vaccines have non-specific effects.
[62] However, Aaby and colleagues subsequently pointed out that the studies which failed to show any mortality increase associated with DTP vaccination used methods of analysis that can introduce a bias against finding such an effect.
This method opens up a potential bias, insofar as the updating of person time at risk from unvaccinated to vaccinated is only possible for children who survive to the second follow-up.
[66] In 2013, WHO established a working group tasked with reviewing the evidence for the non-specific effects of BCG, measles and DTP vaccines.
The published literature does not provide confidence in the quality, quantity, or kinetics of impact of any non-specific immunological effects in young children after vaccination.
[...] SAGE considered that additional observational studies with substantial risk of bias would be unlikely to contribute to policy decision making and therefore should not be encouraged.
