Broad Blockade Antibody Responses in Human Volunteers after Immunization with a Multivalent Norovirus VLP Candidate Vaccine: Immunological Analyses from a Phase I Clinical Trial

Abstract

BackgroundHuman noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers.Methods and FindingsSera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated.ConclusionsVaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations.Trial RegistrationClinicalTrials.gov NCT01168401

Structural basis for norovirus neutralization by an HBGA blocking human IgA antibody

“…Some of these loop regions have been observed to have sequence and structural changes in other genogroups and within genotypes contributing to variations of HBGA binding specificities (13,15,21). The paratope of Fab 5I2 comprises three of the six CDRs, including CDRL1 (residues [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] and CDRL3 (residues 96-103) in the light chain and CDRH3 (residues 97-113) in the heavy chain (Fig. 3A).…”

“…These studies show that both genogroups have evolved distinct HBGA binding sites localized on the outermost hypervariable P2 subdomain of VP1 (15)(16)(17)(18)(19)(20)(21)(22). Human challenge studies show circulating serum antibodies that block HBGA binding correlate with protection from clinical disease and infection, and these antibodies have been proposed to serve as surrogate neutralizing Abs (NAbs) (4,(23)(24)(25). The presence of HBGA-blocking serum antibodies has also been associated with protection from infection in an i.v.…”

Mapping the Human Memory B Cell and Serum Neutralizing Antibody Responses to Dengue Virus Serotype 4 Infection and Vaccination

“…Assays for blockade of binding were performed as described previously (52,53). Briefly, DENV4 was captured using mouse anti-E MAb 4G2 and was blocked as described above.…”

Norovirus vaccines: Correlates of protection, challenges and limitations

“…81,82 The same group suggested GII.4 virus-specific serum IgA as a possible correlate of protection due to their association with lower frequency of infection and illness. However, previous studies reported the inability of serum-specific IgA levels to protect against GI.1 challenge while prechallenge levels of salivary IgA and NoV-specific memory IgG correlated with protection against NoV. 83 These studies are performed on adults and it is yet to determine whether similar pattern of immune responses would be detected among children.…”

“…This study was taken further and study participants, 18-49 y old, were immunized intramuscularly with 2 doses of GI.I and GII.4C VLPs. 82 Sera samples from vaccinated participants and those receiving placebo were tested for VLP-specific antibodies responses to a variety of HuNoV strains (GI, GII.4 and non-GII.4). Moreover, the potential of cross-protection provided by this vaccine was tested via an antibody blockade assay to test for prevention of HuNoV infection.…”