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. 2012 May;19(5):704-10.
doi: 10.1128/CVI.05652-11. Epub 2012 Feb 22.

CD46 measles virus receptor polymorphisms influence receptor protein expression and primary measles vaccine responses in naive Australian children

Holly D Clifford  1 , Catherine M Hayden, Siew-Kim Khoo, Guicheng Zhang, Peter N Le Souëf, Peter Richmond
Affiliations

CD46 measles virus receptor polymorphisms influence receptor protein expression and primary measles vaccine responses in naive Australian children

Holly D Clifford et al. Clin Vaccine Immunol. 2012 May.

Abstract

Despite the availability of measles vaccines, infants continue to die from measles. Measles vaccine responses vary between individuals, and poor immunogenicity is likely to preclude protection against measles. CD46 is a ubiquitously expressed specific receptor for vaccine strains of measles virus. CD46 polymorphisms have not been functionally investigated but may affect CD46 protein expression, which in turn may mediate primary measles antibody responses in infants. In a cohort of children aged 12 to 14 months from Perth, Australia (n = 137), after their first dose of measles-mumps-rubella (MMR) vaccine, CD46 polymorphisms were genotyped, and postvaccination measles IgG and CD46 protein expression before and after measles lysate stimulation of cells were measured. Three CD46 variants (rs7144, rs11118580, and rs2724384) were significantly associated with measles virus-specific IgG levels (P = 0.008, P = 0.026, and P = 0.018, respectively). There were significant differences between CD46 rs7144 genotypes and CD46 protein expression on T cells, as well as the downregulation of CD46 and T-cell frequency after measles lysate stimulation. We show that CD46 polymorphisms were associated with primary measles antibody responses in naive infants. We also report the first association of a measles virus receptor polymorphism with functional effects on the receptor, suggesting a possible mechanism through which antibody responses are altered. Elucidating all of the interconnecting genetic factors that alter primary measles vaccine responses may be important for identifying children at risk of poor immunogenicity or vaccine failure and for the future design of vaccine strategies to help these children.

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Figures

Fig 1
Fig 1
Associations between CD46 polymorphisms and measles IgG antibody levels in the Perth cohort. The data are presented as median values and interquartile ranges. P values were obtained by using Kruskal-Wallis tests.
Fig 2
Fig 2
CD46 polymorphisms and mumps and rubella IgG levels. (A and B) Mumps (A)- and rubella (B)-specific IgG levels. The data are presented as median values and interquartile ranges. P values are all >0.05 (obtained by using Kruskal-Wallis tests).
Fig 3
Fig 3
Cell surface protein expression of CD46 before and after measles lysate and PHA stimulation in all cell types. CD46 expression (i.e., the mean fluorescence intensity [MFI]) after stimulation with ML or PHA compared to at 0 h in T cells (A) and APCs (B) is depicted. Horizontal lines represent median values.
Fig 4
Fig 4
Proportion of cells before and after ML stimulation in each cell type. The proportions of cells (% of total cells) at 0 h (□) and after ML stimulation (■) are shown. Monocytes and DCs have a smaller y axis compared to other cell types. **, P < 0.0001; *, P = 0.0009.
Fig 5
Fig 5
Associations between CD46 rs7144 genotypes and CD46 receptor protein expression at baseline and CD46 downregulation after ML stimulation in T cells and APCs. CD46 expression (i.e., the mean fluorescence intensity [MFI]) at 0 h (left) and the percent CD46 downregulation after ML stimulation (right) in T cells (A) and APCs (B) is depicted. The data are presented as median values and interquartile ranges. The CD46 rs7144 genotypes included TT (circles), CT (diamonds), and TT (squares). The percent CD46 downregulation after ML stimulation was calculated according to the method by Sakurai et al. (26).
Fig 6
Fig 6
Proportions of cells (percent frequency) before and after ML stimulation between the genotypes of CD46 rs7144 polymorphism. The cell frequencies (percentage of total cells) in T cells (A) and APCs (B) at 0 h and after ML stimulation are given. Horizontal lines represent means.
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