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There are many aspects one should scrutinize when new health interventions are implemented in low-income settings; especially since health interventions are usually developed in high-income countries, where circumstances are different. The combination of vitamin A supplementation and immunization, two existing interventions that are usually implemented separately, is in fact a novelty. So far, there are contradictory findings on vaccination and subsequent non-specific morbidity, and whether the simultaneous administration of vaccination and vitamin A could amplify any of these non-specific effects.

Immunization reduces childhood disease by preventing a certain infectious disease. Vaccines stimulate, we may even say trigger, the adaptive immune response to ensure a fierce reaction on a second encounter with a pathogen. Edward Jenner, the pioneer of the small pox vaccine in the late 18th century, discovered that this strategy, back then quite controversial, could save many lives. Vaccination is a powerful early life intervention, especially in countries where the burden of infectious disease is high. But since vaccines are mostly developed in high-income countries, the question arises whether they are equally suitable in low-income countries, in particular since in low-income settings the burden of disease is conditioned by infectious diseases, poverty and malnutrition.

The vaccines widely used in routine vaccination programmes include: Bacillus Calmette-Guérin (BCG; for protection against progression of tuberculosis), measles vaccines (MV), and whole-cell diphtheria-tetanus-pertussis vaccines (DTP). Since the early 90s, several studies have reported so-called non-specific effects (NSEs) associated with these vaccinations among children in high mortality areas.[1-3] The hypothesis on NSEs is that certain vaccines alter the susceptibility to unrelated infectious disease besides protecting against the targeted disease.

NSEs vary for different vaccines. Beneficial NSEs have been reported for live attenuated vaccines such as BCG and MV. ‘Attenuated’ simply means that the harmful (virulent) part of the pathogen is altered or taken away. Children who received these vaccines are reported to have reduced illness from unrelated infectious diseases.[4,5] However, several studies have reported that DTP vaccines may have harmful NSEs.[2,6] DTP is an inactivated vaccine, meaning the pathogen has been killed. The inactivated vaccine is still recognized by the immune system, thereby provoking an adaptive immune response. A recent study has linked DTP vaccination, if administered as the most recent vaccination, to increased susceptibility to other infectious diseases,[2] especially among girls.

Trained and heterologous immunity

The specific mechanisms behind NSEs are not known although there are several theories. It is postulated that vaccines could induce ‘trained immunity’ and ‘heterologous immunity’, thereby increasing resistance or susceptibility to other pathogens.[7,8] Live vaccines are believed to induce trained immunity. This concept roughly means that the innate immune system helps fight against unrelated infectious diseases by a somewhat adaptive characteristic, or ‘epigenetic reprogramming of innate immune cells’.[8] The hypothesis regarding heterologous immunity is that ‘mediated cross-reactivity of T-lymphocytes’ could affect the immune response of an unrelated infection. This can be either beneficial or, as hypothesized with DTP, could impair the desired immune response.

Vitamin A supplementation

Vitamin A deficiency is widespread in low-income countries where NSEs are reported. It can be a severe problem leading to blindness and a deprived immune system. Therefore, vitamin A supplementation is recommended by the World Health Organization in children from six months onwards in areas with high levels of deficiency.[9] It is often provided simultaneously with routine vaccinations. The efficacy of vitamin A supplementation varies depending on the age at which the supplements are given. Since vitamin A is immunomodulatory, which means that it modulates the immune system, it is suggested that supplementation could amplify the child’s ongoing immune response. For live vaccines this would indicate that the aforementioned beneficial NSEs are amplified, while harmful effects would be amplified in the case of inactivated vaccines.[10]

Clarity is needed

Regarding vitamin A supplementation, there is a need to distinguish between the effects on vitamin A status and the effects of its interaction with vaccination on the amplification of NSEs. Currently, we are investigating such interactions by using data sets from several Southeast Asian countries. Preliminary results of our analysis of data from Cambodia indicate divergent directions of the associations between vaccination and morbidity for several vaccines. Children with BCG had less morbidity as compared to children who did not receive the BCG vaccine. On the other hand, girls who received DTP vaccination had a slightly higher prevalence of acute respiratory infections than girls who did not. Among girls who received DTP vaccination, vitamin A supplementation was associated with slightly higher rates of acute respiratory infections compared to non-supplemented girls, although this association was not statistically significant. Recipients of measles vaccines had slightly less morbidity than unvaccinated children, especially when combined with vitamin A supplementation.

Conclusion

Careful scrutiny of the possible combination of vitamin A supplementation and vaccination programmes, which takes into account the beneficial and harmful NSEs of various vaccines, could have a major impact on child survival in low-income countries. More evidence on this topic is emerging, but the exact mechanisms need to be further unravelled.

References

  1. Benn CS. Combining vitamin A and vaccines: convenience or conflict? [Internet]. Vol. 59, Danish medical journal. 2012 [cited 2017 Mar 16]. Available from: http://www.danmedj.dk/portal/pls/portal/!PORTAL.wwpob_page.show?_docname=8550877.PDF
  2. Aaby P, Ravn H, Benn CS. The WHO Review of the Possible Non-Specific Effects of Diphtheria-Tetanus-Pertussis Vaccine. Pediatr Infect Dis J [Internet]. 2016 [cited 2017 Mar 29];35(11). Available from: http://www.ingentaconnect.com/content/wk/inf/2016/00000035/00000011/art00021
  3. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. Bmj [Internet]. 2000 Dec 9 [cited 2017 Mar 9];321(7274):1435-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11110734
  4. Higgins JPT, Soares-Weiser K, López-López JA, Kakourou A, Chaplin K, Christensen H, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ [Internet]. 2016 Oct 13 [cited 2017 Mar 27];15170. Available from: http://www.bmj.com/lookup/doi/10.1136/bmj.i5170
  5. Aaby P, Martins CL, Garly M-L, Balé C, Andersen A, Rodrigues A, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ [Internet]. 2010 [cited 2017 Apr 1];341. Available from: http://www.bmj.com/content/341/bmj.c6495.short
  6. Aaby P, Ravn H, Fisker AB, Rodrigues A, Benn CS. 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 [Internet]. 2016 Dec [cited 2017 Jul 11];110(10):570-81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27856947
  7. Benn CS, Netea MG, Selin LK, Aaby P. A Small Jab – A Big Effect: Nonspecific Immunomodulation By Vaccines [Internet]. Vol. 34, Trends in Immunology. 2013 [cited 2017 Apr 19]. p. 431-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23680130
  8. Jensen KJ, Benn CS, van Crevel R. Unravelling the nature of non-specific effects of vaccines-A challenge for innate immunologists. Semin Immunol [Internet]. 2016 Aug [cited 2018 May 7];28(4):377-83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27354354
  9. WHO. Vitamin A supplementation. WHO [Internet]. 2015 [cited 2017 Mar 28]; Available from: http://www.who.int/immunization/programmes_systems/interventions/vitamin_A/en/
  10. Benn CS, Balé C, Sommerfelt H, Friis H, Aaby P. Hypothesis: Vitamin A supplementation and childhood mortality: Amplification of the non-specific effects of vaccines? Int J Epidemiol [Internet]. 2003 Oct [cited 2017 May 2];32(5):822-8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14559758