Serum IgG antibodies to<i>Shigella</i>lipopolysaccharide antigens – a correlate of protection against shigellosis

Cohen, Dani; Meron-Sudai, Shiri; Bialik, Anya; Asato, Valeria; Goren, Sophy; Ariel-Cohen, Ortal; Reizis, Arava; Hochberg, Amit; Ashkenazi, Shai

doi:10.1080/21645515.2019.1606971

Cited by 73 publications

(82 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antecedent shigellosis reduces the risk of subsequent infection in a serotypespecific manner, indicating a role for LPS-specific immune responses in protection (31)(32)(33)40). LPS-specific serum IgG has been indicated as an immune correlate of protection responsible for this observed serotype-specific protection (41,42); however, several of these studies have investigated serum IgG levels after parenteral immunization with conjugate vaccines, which would be expected to induce large amounts of LPS-specific serum IgG (41,(43)(44)(45)(46). Furthermore, immunological analyses in many previous studies has been limited with incomplete analysis of other immune parameters outside serum IgG.…”

Section: Discussionmentioning

confidence: 99%

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

Clarkson

Frenck

Dickey

et al. 2020

mSphere

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Clarkson

Frenck

Dickey

et al. 2020

mSphere

View full text Add to dashboard Cite

show abstract

“…Our studies on other bacterial pathogens, namely Shigella spp., that target the colon and cause dysentery also show the importance of circulating IgG antibodies in the prevention of shigellosis [ 31 ]. The pre-existing serum IgG antibody level against Shigella lipopolysaccharides (LPSs) was shown to be protective against natural infection caused by Shigella sonnei [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials with conjugate S. sonnei vaccines (based on the LPS linked with carrier protein) administered intramuscularly resulted in significant protection against the disease in young adults [ 33 ]. The vaccine also resulted in increases in serum IgG level against S. sonnei LPS [ 33 ] and it has been proposed as the correlate of protection [ 31 ]. Similarly, serum IgG antibodies against C. difficile toxins might serve as a correlate of protection in clinical trials with active vaccines targeting C. difficile .…”

Section: Discussionmentioning

confidence: 99%

Enhanced Humoral Immune Responses against Toxin A and B of Clostridium difficile is Associated with a Milder Disease Manifestation

Na’amnih

Carmeli

Asato

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

The role of the humoral immune response to Clostridium difficile in modulating the severity of C. difficile infection (CDI) is unclear. We compared the levels of serum immunoglobulin G (IgG) and immunoglobulin A (IgA) against toxin A (TcdA) and toxin B (TcdB) of C. difficile between CDI and control patients and according to disease severity. The levels of IgG and IgA antibodies against TcdA and TcdB were measured in sera from patients with CDI (n = 50; 19 had severe CDI) and control patients (n = 52), using ELISA. Patients with CDI had higher levels of IgG antibodies against TcdA and TcdB than controls (p = 0.001 and p = 0.04, respectively). Higher IgG levels against TcdA and TcdB were found in patients with mild vs. severe CDI 7–14 days after the diagnosis (p = 0.004 and 0.036, respectively). A factor analysis included both IgA and IgG levels against both toxins into one composite variable, which was of higher values in patients with mild vs. severe CDI (p = 0.026). In conclusion, the systemic humoral immune responses against TcdA and TcdB might modulate the severity of CDI. These preliminary findings provide a basis for future large-scale studies and support the development and evaluation of active and passive immunotherapies for CDI management.

show abstract

“…The predominant readout for Shigella vaccine immunogenicity has been traditionally considered the serum IgG antibody level against LPS (28), that can be assessed through LPS-specific ELISA. Several assays can be considered as immunological functional readouts to determine effectiveness of antibodies raised upon vaccination, like opsonophagocytosis or serum bactericidal assay, to determine cell-mediated and cell-independent bactericidal activity of antibodies respectively (20).…”

Section: Discussionmentioning

confidence: 99%

Intralaboratory evaluation of luminescence based high-throughput Serum Bactericidal Assay (L-SBA) to determine bactericidal activity of human sera againstShigella

Rossi

Molesti

Saul

et al. 2020

Preprint

View full text Add to dashboard Cite

17Despite the huge decrease in deaths caused by Shigella worldwide in the last decades, shigellosis is 18 still causing over 200,000 deaths every year. No vaccine is currently available, and the morbidity of 19 disease coupled with the rise of antimicrobial resistance renders the introduction of an effective 20 vaccine extremely urgent. Although a clear immune correlate of protection against shigellosis has not 21 been established yet, the demonstration of bactericidal activity of antibodies induced upon 22 vaccination may provide one means of functionality of antibodies induced on protecting against 23 Shigella. The method of choice to evaluate the complement-mediated functional activity of vaccine-24 induced antibodies is the Serum Bactericidal Assay (SBA). 25Here we present the development and intra-laboratory characterisation of a high-throughput 26 luminescence-based SBA (L-SBA) method, based on the detection of ATP as a proxy of surviving 27 bacteria, to evaluate the complement-mediated killing of human sera. We demonstrated the high 28 specificity of the assay against homologous strain without any heterologous aspecificity detected 29 against species-related and not species-related strains. We assessed linearity, repeatability and 30 reproducibility of L-SBA on human sera. 31This work will guide the bactericidal activity assessment of clinical sera raised against S. sonnei. The 32 method has the potential of being applicable with similar performances to determine bactericidal 33 activity of any non-clinical and clinical sera that rely on complement mediated killing. 34 35 IMPORTANCE 36Shigella is an important cause of diarrhoea worldwide and antimicrobial resistance is on rise, thus 37 efforts by several groups are ongoing to produce a safe and effective vaccine against shigellosis. 38Although a clear immune correlate of protection has not been established, demonstration of 39 bactericidal capacity of sera from patients immunised with Shigella vaccines may provide one means 40 characterisation L-SBA on human sera of protecting against shigellosis. We have developed and fully characterised a novel high-throughput 41 L-SBA method for evaluation of functionality of antibodies raised against S. sonnei in human sera. 42This work will allow the clinical testing of human sera raised against GMMA-based and potentially 43 all vaccines producing antibodies than can work via complement mediated manner. 44 45 46 47 48 Diarrheal diseases, such as shigelloses and salmonelloses, are the second leading cause of death 49 worldwide, resulting in millions of deaths per year, mostly in developing countries (1). Shigella is 50 major cause of sustained endemic bacterial diarrhoea, especially in low and middle-income countries 51 where accessibility to clean water is restricted. Although the improvement of hygienic conditions in 52 the last decade has dramatically reduced the burden of the disease, Shigella is still responsible for 53 more than 200,000 deaths, with a third of them being in young children (1). On top of deaths...

show abstract

Serum IgG antibodies toShigellalipopolysaccharide antigens – a correlate of protection against shigellosis

Cited by 73 publications

References 76 publications

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

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

Enhanced Humoral Immune Responses against Toxin A and B of Clostridium difficile is Associated with a Milder Disease Manifestation

Intralaboratory evaluation of luminescence based high-throughput Serum Bactericidal Assay (L-SBA) to determine bactericidal activity of human sera againstShigella

Contact Info

Product

Resources

About