Abstract
BackgroundConflicting 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. MethodsWe 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. ResultsRBD 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). ConclusionsDespite 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.
Highlights
Rotavirus is the most common cause of severe diarrhea in children under 5 years of age and the leading cause of diarrheal deaths worldwide. [1,2,3,4,5]
All pups of regional basic diet (RBD) dams showed reduced weight (Figure 2A) by day of life (DOL) 9 compared to pups of control diet (CD) dams and remained underweight at the time of both rhesus rotavirus (RRV) inoculation and EDIM challenge (Figure 2B; P
To determine the effects of undernutrition on mouse responses to rotavirus vaccination, 22day-old RBD and CD weanlings were immunized with either RRV (1.0×107 ffu/ml, N=47) or PBS (N= 39) by oral gavage
Summary
Rotavirus is the most common cause of severe diarrhea in children under 5 years of age and the leading cause of diarrheal deaths worldwide. [1,2,3,4,5]. Over 90% of global child deaths from rotavirus occur in low-income countries, predominantly in Asia and Africa [4, 6]. The two currently available rotavirus vaccines (RotarixTM and RotaTeqTM) produce high rates of seroconversion (85–98%) and protection against severe gastroenteritis (85–89%) in the United States and Europe [10]; they do not provide an equal measure of protection in the developing world [11, 12]. Subsequent reports by Zaman et al and Armah et al of rotavirus vaccine trials in Asia and sub-Saharan Africa found efficacy against severe diarrhea to be only 48.3% and 39.3%, respectively [15, 16]. Conflicting evidence links malnutrition to the reduced efficacy of rotavirus vaccines in developing countries, where diarrhea and undernutrition remain leading causes of child deaths. 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
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