Efficacy of rotavirus-like particle vaccines and pathogenesis of human rotavirus evaluated in a gnotobiotic pig model
Year: 2005
Type: article
Abstract: Rotaviruses are the most important cause of gastrointestinal disease in infants and young children in developed and developing countries, causing about 600,000 deaths annually worldwide.Since the discovery of rotavirus in humans in the early 70's, and despite great efforts devoted to understanding the pathogenicity of and protective immunity to rotavirus infection and the development of rotavirus vaccines, a definite correlate of protective immunity after vaccination has not been identified.There is a lack of knowledge about the extraintestinal spread of the virus.The immune responses to rotavirus infection and vaccination have been evaluated mostly based on antibody responses.The cytokine responses after rotavirus infection or vaccination have not been delineated.The main goals of this dissertation were: 1) to identify correlates of protective immunity after vaccination with virus-like particle (VLP) vaccines; 2) to examine the extent of extraintestinal spread of rotavirus and its potential implication for rotavirus protective immunity; and 3) to delineate comprehensively the cytokine profiles induced by virulent (Vir) and attenuated (Att) rotaviruses and the potential role of cytokines in rotavirus pathogenicity or immunity.We evaluated the magnitude of iii serum and intestinal isotype-specific and virus-neutralizing antibody responses induced by oral priming with AttHRV Wa strain and intranasal boosting with 2/6VLP+mutant E. coli heat labile toxin (mLT) and the correlation of these antibody responses with protection.The serum IgM, IgA and IgG antibody titers and neutralizing antibody titers were all correlated with protection.However, only IgA antibody titers in serum were highly correlated with the corresponding IgA antibody titers in the intestines, indicating that serum IgA antibody titer is a reliable indicator of intestinal antibody responses and protection.Respiratory symptoms with rotavirus shedding in nasopharyngeal secretions have been reported in children with or without gastrointestinal symptoms.We investigated if AttHRV and VirHRV strains cause upper respiratory tract infections or viremia in gnotobiotic (Gn) pigs.Pigs inoculated orally or intranasally with AttHRV shed virus mainly nasally (79-95%) and to a lesser extent, rectally (5-17%).In contrast, 100% of pigs inoculated with VirHRV (oral, IN or gavage) developed diarrhea, shed virus nasally and rectally and had viremia.The infectivity of sera from the viremic VirHRV-inoculated pigs was confirmed by inoculating Gn pigs orally with pooled HRV-positive serum.Serum-inoculated pigs developed diarrhea, fecal and nasal virus shedding and seroconverted with serum and intestinal HRV antibodies.This study provided new evidence that VirHRV causes transient viremia and upper respiratory tract infection in addition to gastrointestinal infection in Gn pigs.The importance of cytokine responses in protection against rotavirus infection or pathogenesis of rotavirus disease has not been clearly defined.After VirHRV infection, a significantly higher percentage of pigs had IFN-γ and IL-10 responses in serum than iv after AttHRV infection or in controls.Low and transient IFN-γ responses occurred in serum and intestinal contents of the AttHRV-infected pigs, compared to significantly higher and prolonged IFN-γ responses in the VirHRV-infected pigs.This observation coincides with the diarrhea and viremia induced by the VirHRV, but not the AttHRV.These data further indicate a balanced Th1/Th2 response during rotavirus infection, but generally with higher cytokine levels early after infection with VirHRV compared to AttHRV.These findings have improved our understanding of rotavirus pathogenesis, immunogenicity and correlates of protection.This knowledge will facilitate the design of rotavirus vaccines, which are essential for protection against rotavirus diarrhea in human infants and young animals worldwide.v I dedicate this dissertation to my husband Walton, daughters Ana Clara, Marcela and Milena and son-in-law Severin, from whom, love and devotion motivated my days throughout this ultimate endeavor, in special to my husband, who sacrificed his dreams to fulfill mine.
Author: Marli S.P. Azevedo
Institution: The Ohio State University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2603182120