B-Cell Responses to Intramuscular Administration of a Bivalent Virus-Like Particle Human Norovirus Vaccine

Sasirekha Ramani, Frederick H Neill, Jennifer Ferreira, John J Treanor, Sharon E Frey, David J Topham, Robert R Goodwin, Astrid Borkowski, Frank Baehner, Paul M Mendelman, Mary K Estes, Robert L Atmar, Sasirekha Ramani, Frederick H Neill, Jennifer Ferreira, John J Treanor, Sharon E Frey, David J Topham, Robert R Goodwin, Astrid Borkowski, Frank Baehner, Paul M Mendelman, Mary K Estes, Robert L Atmar

Abstract

Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide. A virus-like particle (VLP) candidate vaccine induces the production of serum histo-blood group antigen (HBGA)-blocking antibodies, the first identified correlate of protection from HuNoV gastroenteritis. Recently, virus-specific IgG memory B cells were identified to be another potential correlate of protection against HuNoV gastroenteritis. We assessed B-cell responses following intramuscular administration of a bivalent (genogroup I, genotype 1 [GI.1]/genogroup II, genotype 4 [GII.4]) VLP vaccine using protocols identical to those used to evaluate cellular immunity following experimental GI.1 HuNoV infection. The kinetics and magnitude of cellular immunity to G1.1 infection were compared to those after VLP vaccination. Intramuscular immunization with the bivalent VLP vaccine induced the production of antibody-secreting cells (ASCs) and memory B cells. ASC responses peaked at day 7 after the first dose of vaccine and returned to nearly baseline levels by day 28. Minimal increases in ASCs were seen after a second vaccine dose at day 28. Antigen-specific IgG memory B cells persisted at day 180 postvaccination for both GI.1 and GII.4 VLPs. The overall trends in B-cell responses to vaccination were similar to the trends in the responses to infection, where there was a greater bias of an ASC response toward IgA and a memory B-cell response to IgG. The magnitude of the ASC and memory B-cell responses to the GI.1 VLP component of the vaccine was also comparable to that of the responses following GI.1 infection. The production of IgG memory B cells and persistence at day 180 is a key finding and underscores the need for future studies to determine if IgG memory B cells are a correlate of protection following vaccination. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168401.).

Keywords: VLP; antibody-secreting cells; immune response; immunity; memory B cells; norovirus; vaccine.

Copyright © 2017 Ramani et al.

Figures

FIG 1
FIG 1
Correlation of IgA and IgG ASC responses obtained using fresh and cryopreserved PBMCs. ASC responses at days 7 and 35 (7 days after each vaccine dose) were compared. A strong correlation between the results obtained using fresh and cryopreserved PBMCs was seen, as indicated by the Spearman correlation coefficient given in each panel. Results for ASC assays using fresh PBMCs were published previously (19).
FIG 2
FIG 2
Comparison of cellular immune responses to infection with GI.1 HuNoV and intramuscular immunization with GI.1 VLPs in a bivalent (GI.1/GII.4) VLP vaccine. (A, B) The geometric mean fold changes in the number of IgA ASCs (A) and IgG ASCs (B) at days 7 and 28 postinfection and postvaccination are shown. (C, D) The fold change in the percentage of virus- or VLP-specific memory B cells at days 28 and 180 postinfection and -vaccination was compared for IgA memory B cells (C) and IgG memory B cells (D). Error bars represent 95% confidence intervals.

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