Abstract
ABSTRACT More effective rotavirus vaccines are essential for preventing extensive diarrheal morbidity and mortality in children under five years of age in low-resource regions. Nonreplicating rotavirus vaccines (NRRV) administered parenterally provide an alternate vaccination method to the current licensed oral vaccine. Live attenuated vaccines and may generate increased efficacy in low-resource settings because the parenteral administration route bypasses some of the challenges associated with oral administration, including differences in intestinal environments. Work described here supports development of a trivalent NRRV vaccine for parenteral administration to avoid complications of the gastrointestinal route. Recombinant VP8* subunit proteins representing some of the most prevalent strains of rotavirus infecting humans – DS-1 (P[4]), 1076 (P[6]), and Wa (P[8]) – were combined with an aluminum adjuvant and the P2 epitope of tetanus toxoid to enhance the immune response to this NRRV antigen. Vaccine formulation development included selection of aluminum hydroxide (Alhydrogel®) as an appropriate adjuvant as well as an optimal buffer to maintain antigen stability and optimize antigen binding to the adjuvant. Characterization assays were used to select the lead vaccine formulation and monitor formulation stability. The NRRV liquid formulation was stable for one year at 2°C to 8°C and four weeks at 37°C. Immunogenicity of the NRRV formulation was evaluated using a guinea pig model, where we demonstrated that the adjuvant provided a 20-fold increase in neutralization titer against a homologous antigen and that the P2-fusion also enhanced the serum neutralizing antibody responses. This vaccine candidate is currently being evaluated in human clinical trials.
Highlights
Rotavirus is a leading cause of severe diarrheal disease worldwide in children under five years of age, with infections resulting in 146,000 to 215,000 deaths annually, mostly in low- and lower-middle-income countries.1,2 To address the significant morbidity and mortality caused by rotavirus, multiple vaccines have been or are being developed and licensed for use.3 All of the licensed rotavirus vaccines are oral, live attenuated formulations, and two – Rotarix® (GlaxoSmithKline) and RotaTeq® (Merck) – have support from Gavi, the Vaccine Alliance for use in low-income countries
Immunogenicity of the nonreplicating rotavirus vaccine (NRRV) formulation was evaluated using a guinea pig model, where we demonstrated that the adjuvant provided a 20-fold increase in neutralization titer against a homologous antigen and that the P2-fusion enhanced the serum neutralizing antibody responses
Several factors have been identified as contributing to the rotavirus disease burden in low-income countries, including reduced vaccine efficacy (~50%) compared with that in middle- and high-income countries. (>90%).6,9-11. The cause of this dramatic difference in efficacy is unknown; several potential causes have been identified, including higher rotavirus transmission rates; differences in intestinal environments; and host mucosal factors.9,10,12. Alternative approaches such as nonreplicating rotavirus vaccine (NRRV) candidates administered via the parenteral route may provide higher efficacy compared with oral rotavirus vaccination in these settings by eliminating the complications of the gastrointestinal route
Summary
The cause of this dramatic difference in efficacy is unknown; several potential causes have been identified, including higher rotavirus transmission rates; differences in intestinal environments (e.g., microbiome, coinfection); and host mucosal factors (e.g., presence of breast milk constituents at the time of immunization, histo-blood group antigens, and Lewis secretor antigens).. The cause of this dramatic difference in efficacy is unknown; several potential causes have been identified, including higher rotavirus transmission rates; differences in intestinal environments (e.g., microbiome, coinfection); and host mucosal factors (e.g., presence of breast milk constituents at the time of immunization, histo-blood group antigens, and Lewis secretor antigens).9,10,12 Alternative approaches such as nonreplicating rotavirus vaccine (NRRV) candidates administered via the parenteral route may provide higher efficacy compared with oral rotavirus vaccination in these settings by eliminating the complications of the gastrointestinal route.. Despite introduction of several vaccines, rotavirus is still a major cause of gastroenteritis and diarrhea worldwide. Several factors have been identified as contributing to the rotavirus disease burden in low-income countries, including reduced vaccine efficacy (~50%) compared with that in middle- and high-income countries. (>90%). The cause of this dramatic difference in efficacy is unknown; several potential causes have been identified, including higher rotavirus transmission rates; differences in intestinal environments (e.g., microbiome, coinfection); and host mucosal factors (e.g., presence of breast milk constituents at the time of immunization, histo-blood group antigens, and Lewis secretor antigens). Alternative approaches such as nonreplicating rotavirus vaccine (NRRV) candidates administered via the parenteral route may provide higher efficacy compared with oral rotavirus vaccination in these settings by eliminating the complications of the gastrointestinal route. Parenteral vaccines may be manufactured at lower cost and could be delivered along with routine Expanded Program on Immunization vaccines via established networks, further reducing costs.
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