A randomized trial of an early measles vaccine at 4½ months of age in Guinea-Bissau: sex-differential immunological effects.
BACKGROUND
After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females.


OBJECTIVE
We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality.


METHODS
Within a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A.


RESULTS
Overall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction.


CONCLUSIONS
In this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects.


BACKGROUND
clinicaltrials.gov number NCT 00168545.
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; Department of Cardiovascular and Renal Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.
Kristoffer Jarlov
KJ
Jensen
Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.
Mia
M
Søndergaard
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark.
Andreas
A
Andersen
Leiden University Medical Center, Leiden, The Netherlands.
Erliyani
E
Sartono
Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.
Cesario
C
Martins
Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.
May-Lill
ML
Garly
Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
Jesper
J
Eugen-Olsen
Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark.
Henrik
H
Ullum
Leiden University Medical Center, Leiden, The Netherlands.
Maria
M
Yazdanbakhsh
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.
Peter
P
Aaby
Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
Christine Stabell
CS
Benn
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
Christian
C
Erikstrup
D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005260:Female; D006169:Guinea-Bissau; D006801:Humans; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008457:Measles / Q000276:immunology* / Q000401:mortality* / Q000517:prevention & control*; D008458:Measles Vaccine / Q000494:pharmacology*; D012044:Regression Analysis; D012737:Sex Factors; D014801:Vitamin A / Q000378:metabolism
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8; D008458:Measles Vaccine; D014801:Vitamin A