Genome-Wide Association Mapping of the Antibody Response to Diphtheria-Tetanus-acellular Pertussis Vaccine in Mice

Abstract

The objective of the current study was to investigate the genetics of antibody responses to an acellular pertussis vaccine by a genome-wide association study in mice. Female mice of 28 inbred strains received this vaccine at 6, 8, and 12 weeks of age. The antibody titer and avidity of immunoglobulin (Ig) G specific for diphtheria toxin, pertussis toxin, filamentous hemagglutinin and pertactin were measured at 14 and 24 weeks of age. The magnitude, longevity and avidity of IgG differed significantly among mouse strains. There was significant correlation between antigen-specific IgGs for longevity but not for magnitude and avidity. Association mapping and analysis with PolyPhen software identified 6 genetic markers associated with longevity for all 4 antigens, although the expression levels of these genes did not correlate with longevity phenotype. This study provides novel insights into the genetic basis and potential candidate genes for differences in the IgG responses to vaccination.

Genetic Variation in the Magnitude and Longevity of the IgG Subclass Response to a Diphtheria-Tetanus-Acellular Pertussis (DTaP) Vaccine in Mice

“…We reported previously that TLR4-deficient C3H/HeJ mice produced higher IgG titers against the four vaccine antigens than the TLR4-sufficient C3H/HeOuJ mice [26]. Similar results were obtained for IgG1 in the current study when comparing between C3H/HeJ and C3H/HeOuJ.…”

“…This was consistent with the fact that gene association analysis revealed shared genes for IgG2b and IgG3, but not for IgG1. Similar to IgG1, variations in antibody titers for total IgG were also antigen-specific [26] which is not surprising since IgG1 is the dominant subclass produced in response to the DTaP vaccine. The data suggest that antigen-independent factors control the longevity of IgG1, IgG2b, and IgG3 which is consistent with our earlier report for total IgG [26].…”

“…Similar to IgG1, variations in antibody titers for total IgG were also antigen-specific [26] which is not surprising since IgG1 is the dominant subclass produced in response to the DTaP vaccine. The data suggest that antigen-independent factors control the longevity of IgG1, IgG2b, and IgG3 which is consistent with our earlier report for total IgG [26]. It should be noted that different thresholds for significant genetic associations were used in the previous study compared with the current study, and the specific genes cannot be directly compared.…”

“…The experimental protocol was previously described [26]. Briefly, five-week-old female mice (n = 8) of 28 different inbred strains (Jackson Laboratory, Bar Harbor, ME, USA) were vaccinated three times intramuscularly with 50 µL of a diphtheria-tetanus-acellular pertussis vaccine (DTaP) (Infanrix ® , GlaxoSmithKline, Rixensart, Belgium) at 6, 8, and 12 weeks of age in alternating hind legs.…”

“…Serology was performed essentially as described [26]. Briefly, microtiter plates were coated with 2 µg/mL diphtheria toxoid (DT), tetanus toxoid, pertussis toxin (PT), filamentous hemagglutinin (FHA), or pertactin (Prn) (List Biological, Campbell, CA, USA) in 50 mM carbonate buffer (pH 9.6) at 4 • C overnight.…”