Kristoffer Jarlov Jensen

Jensen, Kristoffer Jarlov. 2014. Sex-differential Non-specific Immunological Effects of Childhood Vaccines. Bandim Health Project, Research Center for Vitamins and Vaccines, Statens Serum Institut, Department of Cardiovascular and Renal Research Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmarkl. 111 p. 

Vaccines may have non-specific effects (NSE), i.e. immune-modulating effects on host defence to other diseases than the targeted pathogen. These effects may be beneficial or detrimental depending on the vaccine in question and the context in which the vaccine is given. Bacillus Calmette-Guérin (BCG) vaccine, measles vaccine (MV) and oral polio vaccine (OPV) are some of the most widely used childhood vaccines in low-income countries. Observational studies and randomised-controlled trials (RCT) have consistently found that BCG and MV have beneficial non-specific effects in children. Data is still sparse and not unequivocal in respect to the NSE of OPV. Several studies also indicate that the effects are sex-differential, the NSE generally being more pronounced in females.

The mechanisms behind these NSE are not fully elucidated; several distinct biological mechanisms may be involved. The present PhD project aimed to explore the immunological effects of BCG, MV and OPV. We hypothesised that the vaccines affect cellular responses to heterologous antigens and mitogens, and that the effects are different in males and females.

The investigation took advantage of three RCTs of BCG, MV and OPV, respectively, conducted by the Bandim Health Project in Guinea-Bissau, West Africa. Nested within each of these trials we conducted immunological sub-group studies of the effects of the vaccines on in vitro cytokine production, in vivo cytokine levels, blood cell distribution and other biomarkers of immune status.

In RCT 1, we investigated the immunological effects of early BCG vaccination versus the usual delayed BCG in low-birth weight infants. Four weeks after randomisation, BCG was associated with increased responses to heterologous stimulation, demonstrating a T-helper cell type-1 (Th1) polarisation, and a potentiation of monocyte-derived pro-inflammatory cytokine responses. The immunological effects of BCG tended to be more pronounced in females than males and in the dry than the rainy season.

In RCT 2, we investigated the immunological effects of early MV given at 4.5 months of age versus no early MV. Six weeks after randomisation, we found that MV was associated with higher plasma levels of MCP-1, IL-1Ra and IL-8 in females. Some of the enrolled infants had previously been included in a trial of vitamin A supplementation at birth. Post hoc analyses found that the MV effects were strongest in neonatal vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction.

In RCT 3, we investigated the immunological effects of receiving OPV plus BCG versus BCG alone at birth in normal birth weight infants. At 2-6 weeks after randomisation, co-administration of OPV with BCG reduced the IFN-γ response to PPD, confirming a previous finding. In addition, the IL-5 response to PPD was impaired. Other heterologous immune responses or activation markers were not affected, and there were no differences in the effects between males and females.

In summary, from the immunological studies on NSE of childhood vaccines we made five principal observations:

 1) The hypothesis that childhood vaccines have NSE on cellular immunity was supported; cytokine production to heterologous stimulation was affected by BCG and OPV; plasma levels of inflammatory biomarkers were affected by MV.
 2) The OPV study indicated that vaccines may interact, as OPV attenuated the immunological effects of BCG vaccination.
 3) These immunological NSE may depend to some extent on the sex of the recipient; for BCG and MV the effects were strongest in females. No sex differences were seen for OPV.
 4) The studies also indicate that vaccine effects may depend on immune-modulating co-factors; the effect of MV was modified by neonatal vitamin A supplementation, even though the vitamin A and MV were administered more than 4 months apart.
 5) The non-specific effects of vaccines may also be observed as a shift in the qualitative profile in the cytokine responses; for BCG, the increased responsiveness was primarily polarized towards a Th1-type and pro-inflammatory response.