Combined Live Oral Priming and Intramuscular Boosting Regimen with Rotarix® and a Nanoparticle-Based Trivalent Rotavirus Vaccine Evaluated in Gnotobiotic Pig Models of G4P[6] and G1P[8] Human Rotavirus Infection

Abstract

Human rotavirus (HRV) is the causative agent of severe dehydrating diarrhea in children under the age of five, resulting in up to 215,000 deaths each year. These deaths almost exclusively occur in low- and middle-income countries where vaccine efficacy is the lowest due to chronic malnutrition, gut dysbiosis, and concurrent enteric viral infection. Parenteral vaccines for HRV are particularly attractive as they avoid many of the concerns associated with currently used live oral vaccines. In this study, a two-dose intramuscular (IM) regimen of the trivalent, nanoparticle-based, nonreplicating HRV vaccine (trivalent S60-VP8*), utilizing the shell (S) domain of the capsid of norovirus as an HRV VP8* antigen display platform, was evaluated for immunogenicity and protective efficacy against P[6] and P[8] HRV using gnotobiotic pig models. A prime–boost strategy using one dose of the oral Rotarix® vaccine, followed by one dose of the IM trivalent nanoparticle vaccine was also evaluated. Both regimens were highly immunogenic in inducing serum virus neutralizing, IgG, and IgA antibodies. The two vaccine regimens failed to confer significant protection against diarrhea; however, the prime–boost regimen significantly shortened the duration of virus shedding in pigs challenged orally with the virulent Wa (G1P[8]) HRV and significantly shortened the mean duration of virus shedding, mean peak titer, and area under the curve of virus shedding after challenge with Arg (G4P[6]) HRV. Prime–boost-vaccinated pigs challenged with P[8] HRV had significantly higher P[8]-specific IgG antibody-secreting cells (ASCs) in the spleen post-challenge. Prime–boost-vaccinated pigs challenged with P[6] HRV had significantly higher numbers of P[6]- and P[8]-specific IgG ASCs in the ileum, as well as significantly higher numbers of P[8]-specific IgA ASCs in the spleen post-challenge. These results suggest the promise of and warrant further investigation into the oral priming and parenteral boosting strategy for future HRV vaccines.

A Viral Protein 4-Based Trivalent Nanoparticle Vaccine Elicited High and Broad Immune Responses and Protective Immunity against the Predominant Rotaviruses

“…To address this limitation, we plan to conduct a follow-up study with help from our collaborators using the gnotobiotic (Gn) pig model 59,60 with live human RV vaccines as comparators. 61 The outcomes from the Gn pig model will provide further solid data to prove the efficacy of our S-VP4e PVNP vaccine, supporting future clinical trials. As explained above, the current live RV vaccines reveal reduced efficacy generally between 40% and 60% 7,8 in LMICs, likely due to several intestine-associated factors, 15,16 including malnutrition, 19 dysbiosis, 20 gut HBGAs, 21 and infections with enteric pathogens.…”

“…Live attenuated oral RV vaccines were not included as comparators because these live human vaccines do not efficiently infect mice and, therefore, would not elicit comparable immune responses for meaningful comparisons. To address this limitation, we plan to conduct a follow-up study with help from our collaborators using the gnotobiotic (Gn) pig model , with live human RV vaccines as comparators . The outcomes from the Gn pig model will provide further solid data to prove the efficacy of our S-VP4e PVNP vaccine, supporting future clinical trials.…”