The Xs and Y of immune responses to viral vaccines

Abstract

The biological differences associated with the sex of an individual are a major source of variation, affecting immune responses to vaccination. Compelling clinical data illustrate that men and women differ in their innate, humoral, and cell-mediated responses to viral vaccines. Sex affects the frequency and severity of adverse effects of vaccination, including fever, pain, and inflammation. Pregnancy can also substantially alter immune responses to vaccines. Data from clinical trials and animal models of vaccine efficacy lay the groundwork for future studies aimed at identifying the biological mechanisms that underlie sex-specific responses to vaccines, including genetic and hormonal factors. An understanding and appreciation of the effect of sex and pregnancy on immune responses might change the strategies used by public health officials to start efficient vaccination programmes (optimising the timing and dose of the vaccine so that the maximum number of people are immunised), ensure sufficient levels of immune responses, minimise adverse effects, and allow for more efficient protection of populations that are high priority (eg, pregnant women and individuals with comorbid conditions).

Conflict of interest statement

Conflicts of Interest: None

Copyright 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. YFV-17D vaccination induced TLR/IFN signaling is significantly higher in women than men.

(A) Separate lists of genes for females and males are visualized with a Venn diagram illustrating unique and common genes expressed in women (pink) and men (blue) 3–10 days after YFV-17D vaccination. Ingenuity Pathways Analysis of innate immunity genes identified as being important predictors of adaptive responses to YFV-17D vaccination (adapted from Figure 3 and Supplemental document 2 from Gaucher et al. 2008) and the changes in expression specific to female (B) and male (C) study participants (2-way ANOVA with FDR p < 0.05). In the pathway analysis, node colors indicate fold change of gene expression (red = 2 to 18 fold upregulation; green = −1.2 to −2.3 downregulation; white = n.s. change from baseline) between Day 0 and 7 in women (n = 11) and men (n = 5). Illumina microarray data (GSE13699) were imported into Partek Genomics Suite and a 2-way ANOVA was conducted using time post-vaccination (i.e., Days 0, 3, 7, and 10) and sex (male and female) as the independent variables. Contrast analyses were conducted as described in the original paper (Gaucher et al. 2008) to compare gene expression values at 3, 7, and 10 days post-vaccination to Day 0 (i.e., pre-vaccination) values for females and males separately. Lists of genes were generated after establishing the False Discovery Rate p < 0.05 and using a fold-change cut off of ≥2. Analyses were conducted on the Montreal dataset; one woman was omitted because the overall gene expression Principle Component Analysis (PCA) revealed she was an outlier (YF019) and one man from Lausanne (YF10) was included in our analyses because the PCA analysis revealed that expression levels of genes from this man were similar to those from the 4 Montreal men.

Figure 2:. Hormonal changes during pregnancy affect T cell responses.

The upper panel illustrates the shift in the T helper 1 (Th1) versus T helper 2 (Th2) balance toward a Th2 -bias by the third trimester of pregnancy and the corresponding changes in regulatory T (Treg) cell activity. The bottom panel illustrates the variations in estradiol, progesterone, and human chorionic gonadotropin (hCG) during the trimesters of pregnancy. Variations in sex hormone levels can lead to significant alterations in T cell activity during pregnancy.

Figure 3:. Sex –based differences in innate and adaptive immune responses following vaccination.

Following vaccination, the activity of innate immune cells, including dendritic cells (DCs) and macrophages (MΦ), and the production of inflammatory cytokines (e.g., interferon [IFN] α/β/γ, interleukin [IL]-6, IL-12, IL-15, and tumor necrosis factor [TNF]-α) and chemokines (e.g., CC-chemokine ligand 2 [CCL2, also called MCP-1], CX-chemokine ligand [CXCL8, also called IL-8], and CXCL10 [also called IP-10]) is elevated in females compared with males. The increased number and activity of innate immune cells in females drives heightened expansion and activity of B cells and T cells during the early adaptive immune response. Elevated T helper 2 (Th2) responses, including the production of IL-4, IL-5, IL-10, and IL-13 further expands B cell responses and drives the elevated humoral immune response in females during the late adaptive phase of the immune response. Several modifying variables including sex steroid hormones (e.g., estradiol, progesterone, and testosterone), sex chromosomal genes (e.g., Il2rγ, Irak, Tlr7, Tlr8, Foxp3, and Ikkγ), and immune gene polymorphisms are hypothesized to mediate dimorphic innate and adaptive immune responses to viral vaccines.