title: Protein-energy malnutrition alters IgA responses to rotavirus vaccination and infection but does not impair vaccine efficacy in mice.
abstract: BACKGROUND
  Conflicting evidence links malnutrition to the reduced efficacy of rotavirus vaccines in developing countries, where diarrhea and undernutrition remain leading causes of child deaths. Here, we adapted mouse models of rotavirus vaccination (rhesus rotavirus, RRV), rotavirus infection (EDIM), and protein-energy malnutrition (PEM) to test the hypothesis that undernutrition reduces rotavirus vaccine immunogenicity and efficacy.
  
  
  METHODS
  We randomized wild type Balb/C dams with 3-day-old pups to a control diet (CD) or an isocaloric, multideficient regional basic diet (RBD) that produces PEM. At 3 weeks of age, we weaned CD and RBD pups to their dams' diet and subrandomized weanlings to receive a single dose of either live oral rotavirus vaccine (RRV) or PBS. At 6 weeks of age, we orally challenged all groups with murine rotavirus (EDIM). Serum and stool specimens were collected before and after RRV and EDIM administration to measure viral shedding and antibody responses by ELISA.
  
  
  RESULTS
  RBD pups and weanlings exhibited significant failure to thrive compared to age-matched CD mice (P<.0001). RRV vaccination induced higher levels of serum anti-RV IgA responses in RBD vs. CD mice (P<.0001). Vaccination protected CD and RBD mice equally against EDIM infection, as measured by viral shedding. In unvaccinated RBD mice, EDIM shedding peaked 1 day earlier (P<.05), however we detected no effects of undernutrition on viral clearance nor of infection on bodyweight. EDIM infection provoked higher anti-RV serum IgA levels in RBD vs. CD mice, regardless of vaccination (P<.0001). Last, RRV vaccination mitigated stool IgA responses to EDIM more in CD vs. RBD mice (P<.0001).
  
  
  CONCLUSIONS
  Despite modulated IgA responses to vaccination and infection, undernutrition does not impair rotavirus vaccine efficacy nor exacerbate infection in this mouse model of protein-energy malnutrition. Alternative models are needed to elucidate host-pathogen factors undermining rotavirus vaccine effectiveness in high-risk global settings.
authors.affiliation: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maier
authors.affiliation: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA.
authors.forename: Kristina J
authors.initials: KJ
authors.lastname: Weage
authors.affiliation: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA.
authors.forename: Marjorie M
authors.initials: MM
authors.lastname: Guedes
authors.affiliation: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.affiliation: Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: McNeal
authors.affiliation: Infectious Diseases, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.affiliation: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA; Center for Global Child Health, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH, USA. Electronic address: sean.moore@cchmc.org.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Moore
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D004032:Diet; D004195:Disease Models, Animal; D007114:Immunization; D007070:Immunoglobulin A / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D051379:Mice; D011502:Protein-Energy Malnutrition / Q000276:immunology*; D012401:Rotavirus / Q000276:immunology*; D012400:Rotavirus Infections / Q000276:immunology* / Q000517:prevention & control*; D022243:Rotavirus Vaccines / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022243:Rotavirus Vaccines
keywords: EDIM; Environmental enteropathy; Epizootic diarrhea of infant mice; Malnutrition; RRV; RV; Rhesus rotavirus; Rotavirus; Tropical barrier; epizootic diarrhea of infant mice; rhesus rotavirus vaccine; rotavirus, ELISA