A Phase I trial to evaluate the safety and immunogenicity of WRSs2 and WRSs3; two live oral candidate vaccines against Shigella sonnei

Frenck, Robert W.; Baqar, Shahida; Alexander, William; Dickey, Michelle; McNeal, Monica; El-Khorazaty, Jill; Baughman, Holly; Hoeper, Amy; Barnoy, Shoshana; Suvarnapunya, Akamol E.; Kaminski, Robert W.; Venkatesan, Malabi M.

doi:10.1016/j.vaccine.2018.06.063

Cited by 32 publications

(40 citation statements)

References 25 publications

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“…Nonnormally distributed data were log 10 transformed in order to meet the assumptions for the parametric tests. If the log transformation did not correct the distribution of the data set, then nonparametric statistical tests were used (Mann-Whitney U test) (51,65). A multivariate logistic regression model was developed to assess the association between various immune parameters at baseline and the odds of progressing either to shigellosis MSD or to no or mild diarrhea.…”

Section: Methodsmentioning

confidence: 99%

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

Clarkson

Frenck

Dickey

et al. 2020

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Shigella is a major cause of moderate to severe diarrhea largely affecting children (<5 years old) living in low- and middle-income countries. Several vaccine candidates are in development, and controlled human infection models (CHIMs) can be useful tools to provide an early assessment of vaccine efficacy and potentially support licensure. A lyophilized strain of S. sonnei 53G was manufactured and evaluated to establish a dose that safely and reproducibly induced a ≥60% attack rate. Samples were collected pre- and postchallenge to assess intestinal inflammatory responses, antigen-specific serum and mucosal antibody responses, functional antibody responses, and memory B cell responses. Infection with S. sonnei 53G induced a robust intestinal inflammatory response as well as antigen-specific antibodies in serum and mucosal secretions and antigen-specific IgA- and IgG-secreting B cells positive for the α4β7 gut-homing marker. There was no association between clinical disease outcomes and systemic or functional antibody responses postchallenge; however, higher lipopolysaccharide (LPS)-specific serum IgA- and IgA-secreting memory B cell responses were associated with a reduced risk of disease postchallenge. This study provides unique insights into the immune responses pre- and postinfection with S. sonnei 53G in a CHIM, which could help guide the rational design of future vaccines to induce protective immune responses more analogous to those triggered by infection. IMPORTANCE Correlate(s) of immunity have yet to be defined for shigellosis. As previous disease protects against subsequent infection in a serotype-specific manner, investigating immune response profiles pre- and postinfection provides an opportunity to identify immune markers potentially associated with the development of protective immunity and/or with a reduced risk of developing shigellosis postchallenge. This study is the first to report such an extensive characterization of the immune response after challenge with S. sonnei 53G. Results demonstrate an association of progression to shigellosis with robust intestinal inflammatory and mucosal gut-homing responses. An important finding in this study was the association of elevated Shigella LPS-specific serum IgA and memory B cell IgA responses at baseline with reduced risk of disease. The increased baseline IgA responses may contribute to the lack of dose response observed in the study and suggests that IgA responses should be further investigated as potential correlates of immunity.

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Section: Methodsmentioning

confidence: 99%

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

Clarkson

Frenck

Dickey

et al. 2020

mSphere

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“…These include the whole cell inactivated S. flexneri 2a Sf2aWC, 28 and the live attenuated S. flexneri 2a CVD 1208S, 29 S. flexneri 2a SC602, 30 and S. sonnei WRSs2 and WRSs3. 31 Orally delivered whole cell organisms generally elicit high levels of LPS-specific serum IgG and IgA as well as fecal IgA, and are potent inducers of LPS-specific IgA ASC. Shigella OPS-protein conjugate vaccines have gained interest and support in recent years due to the record of safety and ability to elicit potent systemic immunity.…”

Section: Vaccine-induced Immunity and The Relevance Of Antibodiesmentioning

confidence: 99%

Functional antibodies as immunological endpoints to evaluate protective immunity againstShigella

Ndungo

Pasetti

2019

Human Vaccines & Immunotherapeutics

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The development, clinical advancement and licensure of vaccines, and monitoring of vaccine effectiveness could be expedited and simplified by the ability to measure immunological endpoints that can predict a favorable clinical outcome. Antigen-specific and functional antibodies have been described in the context of naturally acquired immunity and vaccination against Shigella , and their presence in serum has been associated with reduced risk of disease in human subjects. The relevance of these antibodies as correlates of protective immunity, their mechanistic contribution to protection (e.g. target antigens, interference with pathogenesis, and participation in microbial clearance), and factors that influence their magnitude and makeup (e.g. host age, health condition, and environment) are important considerations that need to be explored. In addition to facilitating vaccine evaluation, immunological correlates of protection could be useful for identifying groups at risk and advancing immune therapies. Herein we discuss the precedent and value of functional antibodies as immunological endpoints to predict vaccine efficacy and the relevance of functional antibody activity to evaluate protective immunity against shigellosis.

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“…Several approaches are currently in development to deliver the O-antigen to the immune system, including whole-cell attenuated bacteria [6], vaccines in which the O-antigens are chemically- [7] or bio-conjugated to carrier proteins [8], synthetic vaccine conjugates [9], and Generalized Modules for Mebrane Antigens (GMMA)-based vaccines [10]. GMMA are outer membrane exosomes released from Gram-negative bacteria, genetically modified to induce hyperblebbing and to reduce the reactogenic potential of lipid A [11,12].…”

Section: Introductionmentioning

confidence: 99%

Intra-Laboratory Evaluation of Luminescence Based High-Throughput Serum Bactericidal Assay (L-SBA) to Determine Bactericidal Activity of Human Sera against Shigella

et al. 2020

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Despite the huge decrease in deaths caused by Shigella worldwide in recent decades, shigellosis still causes over 200,000 deaths every year. No vaccine is currently available, and the morbidity of the disease coupled with the rise of antimicrobial resistance renders the introduction of an effective vaccine extremely urgent. Although a clear immune correlate of protection against shigellosis has not yet been established, the demonstration of the bactericidal activity of antibodies induced upon vaccination may provide one means of the functionality of antibodies induced in protecting against Shigella. The method of choice to evaluate the complement-mediated functional activity of vaccine-induced antibodies is the Serum Bactericidal Assay (SBA). Here we present the development and intra-laboratory characterization of a high-throughput luminescence-based SBA (L-SBA) method, based on the detection of ATP as a proxy of surviving bacteria, to evaluate the complement-mediated killing of human sera. We demonstrated the high specificity of the assay against a homologous strain without any heterologous aspecificity detected against species-related and non-species-related strains. We assessed the linearity, repeatability and reproducibility of L-SBA on human sera. This work will guide the bactericidal activity assessment of clinical sera raised against S. sonnei. The method has the potential of being applicable with similar performances to determine the bactericidal activity of any non-clinical and clinical sera that rely on complement-mediated killing.

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A Phase I trial to evaluate the safety and immunogenicity of WRSs2 and WRSs3; two live oral candidate vaccines against Shigella sonnei

Cited by 32 publications

References 25 publications

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G

Functional antibodies as immunological endpoints to evaluate protective immunity againstShigella

Intra-Laboratory Evaluation of Luminescence Based High-Throughput Serum Bactericidal Assay (L-SBA) to Determine Bactericidal Activity of Human Sera against Shigella

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