Dose-Response of a Norovirus GII.2 Controlled Human Challenge Model Inoculum

Abstract

Background: Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge.

Methods: Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain virus (SMV) GII.2 norovirus inoculum (1.2 × 104 to 1.2 × 107 genome equivalent copies [GEC]; n = 38) or placebo (n = 6). Illness was defined as diarrhea and/or vomiting postchallenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV immunoglobulin G [IgG] seroconversion).

Results: The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between prechallenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary immunoglobulin A and infection. The median infectious dose (ID50) was 5.1 × 105 GEC.

Conclusions: High rates of infection and illness were observed in both secretor-positive and secretor-negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics.

Clinical trials registration: NCT02473224.

Keywords: ID50; Snow Mountain virus; human challenge; infectious dose; norovirus; viral gastroenteritis.

Conflict of interest statement

Potential conflicts of interest. N. R. has research support from Merck, Sanofi Pasteur, Lilly, Quidel, Pfizer and do not pose a conflict of interest for this paper. M. J. M. has research support from Lilly, Pfizer, Sanofi; personal fees from Pfizer and Meissa Vaccines and do not pose a conflict of interest for this paper. L. C. L. and R. S. B. have ongoing collaborations with Hillvax, VaxArt and Takeda that are unrelated and do not pose conflicts of interest with this report. C.L.M has collaborations with Takeda that are unrelated and do not pose conflicts of interest with this report. V. R. has research support from Sanofi Pasteur, unrelated, no conflict of interest with this report. E. J. A. has consulted for Pfizer, Sanofi Pasteur, Janssen, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc. and Sanofi Pasteur. No conflict of interest with this report. C. P., J. E. K., A. E. K., A. B., P. L., M. S. N., L. L., V. P., J. W., M. H. C., T. G., A. A., N. B., V. K., J. A. R., Y. W., and S. B. have no competing interests to declare. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) flow diagram. The following laboratory tests were performed at screening: white blood cells, hemoglobin, platelets, absolute neutrophil count, creatinine, alanine aminotransferase, total bilirubin, potassium, sodium, hemoglobin A1c, serologies for human immunodeficiency virus, hepatitis B, hepatitis C, urine protein, stool culture, norovirus stool by reverse-transcription quantitative polymerase chain reaction, and microscopic examination of the stool for ova and parasites. Abbreviations: BP, blood pressure; GEC, genome equivalent copies; mITT, modified intention-to-treat; PCR, polymerase chain reaction; PP, per protocol.

Figure 2.

Duration of RNA positivity and symptoms in subjects with GII.2 Snow Mountain virus infection following challenge in the modified intention-to-treat population. 1.2 × 104 genome equivalent copies (GEC) and 1.2 × 106 GEC were only administered to secretor-positive subjects. Abbreviations: GEC, genome equivalent copies; S-Neg, secretor-negative; S-Pos, secretor-positive.

Figure 3.

Serum Snow Mountain virus immunoglobulin G geometric mean fold rise and 4-fold rise by time point and treatment group. 1.2 × 104 genome equivalent copies (GEC) and 1.2 × 106 GEC were only administered to secretor-positive subjects. Abbreviations: CI, confidence interval; GEC, genome equivalent copies; GMFR, geometric mean fold rise; S-Neg, secretor-negative; S-Pos, secretor-positive.

Figure 4.

Geometric mean titer of Snow Mountain virus (SMV)–specific carbohydrate blockade serum antibody over time by treatment group. Cohort challenged with 1.2 × 104 genome equivalent copies (GEC) was not tested for SMV-specific carbohydrate blockade serum as no subject developed illness. Error bars represent standard error. Abbreviations: GEC, genome equivalent copies; S-Neg, secretor-negative; S-Pos, secretor-positive.