A randomized trial of an early measles vaccine at 4½ months of age in Guinea-Bissau: sex-differential immunological effects

PLoS One. 2014 May 16;9(5):e97536. doi: 10.1371/journal.pone.0097536. eCollection 2014.

Abstract

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.

Trial registration: clinicaltrials.gov number NCT 00168545.

Trial registration: ClinicalTrials.gov NCT00168545.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemokine CCL2 / metabolism
  • Cytokines / blood
  • Female
  • Guinea-Bissau
  • Humans
  • Infant
  • Interleukin 1 Receptor Antagonist Protein / blood
  • Interleukin-8 / blood
  • Male
  • Measles / immunology*
  • Measles / mortality*
  • Measles / prevention & control*
  • Measles Vaccine / pharmacology*
  • Regression Analysis
  • Sex Factors
  • Vitamin A / metabolism

Substances

  • CCL2 protein, human
  • Chemokine CCL2
  • Cytokines
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-8
  • Measles Vaccine
  • Vitamin A

Associated data

  • ClinicalTrials.gov/NCT00168545

Grant support

The present study received support from Novo Nordisk Foundation, Fonden til Lægevidenskabens Fremme, Danish Medical Research Council, Augustinus Fonden, Beckett fonden, Dagmar Marshalls fond and the Aase og Ejnar Danielsens fond. PA holds a research professorship grant from the Novo Nordisk Foundation. CSB is funded by an ERC Starting Grant (ERC-2009-StG-243149). KJJ was supported by a grant from University of Southern Denmark and by a Female Research Leader grant (no.09-066317) from the Danish Council of Independent Research to CSB. CVIVA is funded by the Danish National Research Foundation (DNRF108). The Bandim Health Project received support from DANIDA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.