O-Specific Polysaccharide-Specific Memory B Cell Responses in Young Children, Older Children, and Adults Infected with Vibrio cholerae O1 Ogawa in Bangladesh

ABSTRACTCholera caused byVibrio choleraeO1 confers at least 3 to 10 years of protection against subsequent disease regardless of age, despite a relatively rapid fall in antibody levels in peripheral blood, suggesting that memory B cell responses may play an important role in protection. TheV. choleraeO1-specific polysaccharide (OSP) component of lipopolysaccharide (LPS) is responsible for serogroup specificity, and it is unclear if young children are capable of developing memory B cell responses against OSP, a T cell-independent antigen, following cholera. To address this, we assessed OSP-specific memory B cell responses in young children (2 to 5 years,n= 11), older children (6 to 17 years,n= 21), and adults (18 to 55 years,n= 28) with cholera caused byV. choleraeO1 in Dhaka, Bangladesh. We also assessed memory B cell responses against LPS and vibriocidal responses, and plasma antibody responses against OSP, LPS, and cholera toxin B subunit (CtxB; a T cell-dependent antigen) on days 2 and 7, as well as days 30, 90, and 180 after convalescence. In all age cohorts, vibriocidal responses and plasma OSP, LPS, and CtxB-specific responses peaked on day 7 and fell toward baseline over the follow-up period. In comparison, we were able to detect OSP memory B cell responses in all age cohorts of patients with detectable responses over baseline for 90 to 180 days. Our results suggest that OSP-specific memory B cell responses can occur following cholera, even in the youngest children, and may explain in part the age-independent induction of long-term immunity following naturally acquired disease.

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Antigen-Specific Memory B-Cell Responses in Bangladeshi Adults after One- or Two-Dose Oral Killed Cholera Vaccination and Comparison with Responses in Patients with Naturally Acquired Cholera

Clinical and Vaccine Immunology ◽

10.1128/cvi.00562-10 ◽

2011 ◽

Vol 18 (5) ◽

pp. 844-850 ◽

Cited By ~ 52

Author(s):

Mohammad Murshid Alam ◽

M. Asrafuzzaman Riyadh ◽

Kaniz Fatema ◽

Mohammad Arif Rahman ◽

Nayeema Akhtar ◽

...

Keyword(s):

B Cell ◽

Acute Stage ◽

Cholera Toxin B Subunit ◽

Memory B Cell ◽

Content Type ◽

Cell Responses ◽

Specific Memory ◽

Dose Oral ◽

B Cell Responses ◽

Cholera Vaccination

ABSTRACTThe mediators of protective immunity against cholera are currently unknown, but memory B-cell responses may play a central role in facilitating long-term and anamnestic responses againstVibrio cholerae, the cause of cholera. We compared memory B-cell responses in adults with natural cholera in Bangladesh (n= 70) to responses in Bangladeshi adults after one-dose (n= 30) or two-dose (n= 30) administration of an oral killed cholera vaccine, WC-rBS (Dukoral; Crucell), assessing the responses at the acute stage of disease or prevaccination and then on days 3, 30, 90, 180, 270, and 360. Individuals with natural cholera developed prominent vibriocidal and plasma anti-cholera toxin B subunit (CtxB) and lipopolysaccharide (LPS) IgG and IgA responses, but these responses returned to baseline by 1 year of follow-up. Vaccinees developed plasma anti-CtxB and anti-LPS IgG and IgA responses that were generally comparable to those in individuals recovering from natural disease, but vibriocidal responses were lower in vaccinees than in infected patients. Individuals recovering from natural disease developed memory B-cell IgG and IgA anti-CtxB and anti-LPS responses by day 30, and these responses were detectable through at least days 180 to 360. In contrast, we detected no IgA or IgG memory B-cell responses to LPS in vaccinees; anti-CtxB IgA responses were only detectable on day 30, and anti-CtxB IgG responses were detectable until days 90 to 180, compared to days 270 to 360 in patients. These findings may explain in part the relatively short-term protection afforded by oral cholera vaccination compared to natural disease.

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Study of Avidity of Antigen-Specific Antibody as a Means of Understanding Development of Long-Term Immunological Memory after Vibrio cholerae O1 Infection

Clinical and Vaccine Immunology ◽

10.1128/cvi.00521-12 ◽

2012 ◽

Vol 20 (1) ◽

pp. 17-23 ◽

Cited By ~ 19

Author(s):

Mohammad Murshid Alam ◽

Mohammad Arifuzzaman ◽

Shaikh Meshbahuddin Ahmad ◽

M. Ismail Hosen ◽

Mohammad Arif Rahman ◽

...

Keyword(s):

B Cell ◽

Vibrio Cholerae ◽

Memory B Cell ◽

Content Type ◽

Cell Responses ◽

Specific Memory ◽

Iga Antibodies ◽

Specific Igg ◽

B Cell Responses

ABSTRACTThe avidity of antibodies to specific antigens and the relationship of avidity to memory B cell responses to these antigens have not been studied in patients with cholera or those receiving oral cholera vaccines. We measured the avidity of antibodies to cholera toxin B subunit (CTB) andVibrio choleraeO1 lipopolysaccharide (LPS) in Bangladeshi adult cholera patients (n= 30), as well as vaccinees (n= 30) after administration of two doses of a killed oral cholera vaccine. We assessed antibody and memory B cell responses at the acute stage in patients or prior to vaccination in vaccinees and then in follow-up over a year. Both patients and vaccinees mounted CTB-specific IgG and IgA antibodies of high avidity. Patients showed longer persistence of these antibodies than vaccinees, with persistence lasting in patients up to day 270 to 360. The avidity of LPS-specific IgG and IgA antibodies in patients remained elevated up to 180 days of follow-up. Vaccinees mounted highly avid LPS-specific antibodies at day 17 (3 days after the second dose of vaccine), but the avidity waned rapidly to baseline by 30 days. We examined the correlation between antigen-specific memory B cell responses and avidity indices for both antigens. We found that numbers of CTB- and LPS-specific memory B cells significantly correlated with the avidity indices of the corresponding antibodies (P< 0.05; Spearman'sρ= 0.28 to 0.45). These findings suggest that antibody avidity after infection and immunization is a good correlate of the development and maintenance of memory B cell responses toVibrio choleraeO1 antigens.

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Agonist for Toll-Like Receptor (TLR) 9 Amplifies as Well as Inhibits the Differentiation of FVIII-Specific Memory B Cells into Antibody-Producing Plasma Cells in Vitro and in Vivo.

Blood ◽

10.1182/blood.v112.11.3382.3382 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3382-3382

Author(s):

Peter Allacher ◽

Christina Hausl ◽

Aniko Ginta Pordes ◽

Rafi Uddin Ahmad ◽

Hartmut J Ehrlich ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Memory B Cells ◽

Memory B Cell ◽

Cpg Dna ◽

Cell Responses ◽

Specific Memory ◽

B Cell Responses

Abstract Memory B cells are essential for maintaining long-term antibody responses. They can persist for years even in the absence of antigen and are rapidly re-stimulated to differentiate into antibody-producing plasma cells when they encounter their specific antigen. Previously we demonstrated that ligands for TLR 7 and 9 amplify the differentiation of FVIII-specific memory B cells into anti-FVIII antibody-producing plasma cells at low concentrations of FVIII and prevent the inhibition of memory-B-cell differentiation at high concentrations of FVIII. The modulation of FVIII-specific memory-B-cell responses by agonists for TLR is highly relevant for the design of new immunotherapeutic approaches in patients with FVIII inhibitors because TLR are activated by a range of different viral and bacterial components. Specifically, TLR 7 is triggered by single-stranded RNA derived from viruses and TLR 9 is triggered by bacterial DNA containing unmethylated CpG motifs. We further explored the modulation of FVIII-specific memory-B-cell responses by agonists for TLRs by studying a broad range of concentrations of CpG DNA, a ligand for TLR 9, both in vitro and in vivo using the murine E17 model of hemophilia A. We used CpG-DNA in concentrations ranging from 0.1 to 10,000 ng/ml to study the modulation of FVIII-specific memory-B-cell responses in vitro and verified the specificity of the effects observed by including a blocking agent for TLR 9 and GpC-DNA, a non-stimulating negative control for CpG DNA. Furthermore, we used doses of CpG DNA ranging from 10 to 50,000 ng per dose to study the modulation of FVIII-specific memory-B-cell responses in vivo. E17 hemophilic mice were treated with a single intravenous dose of 200 ng FVIII to stimulate the generation of FVIII-specific memory B cells and were subsequently treated with another dose of FVIII that was given together with CpG DNA. We analyzed titers of anti-FVIII antibodies in the circulation of these mice one week after the second dose of FVIII. Previously we had shown that a single dose of 200 ng FVIII, given intravenously to E17 hemophilic mice, stimulates the formation of FVIII-specific memory B cells but is not sufficient to induce anti-FVIII antibodies that would be detectable in the circulation. Our results demonstrate a biphasic effect of CpG DNA on the re-stimulation of FVIII-specific memory B cells and their differentiation into antibody-producing plasma cells. Both in vitro and in vivo studies show that CpG DNA at high doses inhibits the re-stimulation and differentiation of FVIII-specific memory B cells. However, CpG DNA at low doses amplifies these processes. Amplification and inhibition of memory-B-cell responses are due to specific interactions of CpG DNA with TLR 9. Both effects are blocked by addition of a blocking agent for TLR 9 in vitro. We conclude that triggering of TLR 9 by bacterial DNA has a substantial influence on FVIII-specific memory-B-cell responses. The consequence of TLR 9 triggering can be inhibitory or stimulatory, depending on the actual concentration of the bacterial DNA. Our findings demonstrate the potential modulatory effects of bacterial infections on the regulation of FVIII inhibitor development.

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Towards detection of HLA class II specific memory B cell responses in sensitized patients

Transplant Immunology ◽

10.1016/j.trim.2014.11.173 ◽

2014 ◽

Vol 31 (4) ◽

pp. 243

Author(s):

G.E. Karahan ◽

Y.J.H. de Vaal ◽

R. Buchli ◽

F.H.J. Claas ◽

S. Heidt

Keyword(s):

B Cell ◽

Class Ii ◽

Hla Class Ii ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

B Cell Responses

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Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV

Journal of Hepatology ◽

10.1016/j.jhep.2020.01.024 ◽

2020 ◽

Vol 73 (1) ◽

pp. 52-61

Author(s):

Thomas Vanwolleghem ◽

Zwier M.A. Groothuismink ◽

Kim Kreefft ◽

Magdeleine Hung ◽

Nikolai Novikov ◽

...

Keyword(s):

Hepatitis B ◽

B Cell ◽

Clinical Parameters ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

Chronic Hbv ◽

B Cell Responses

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Hepatitis C virus (HCV)-specific memory B-cell responses in transiently and chronically infected HIV positive individuals

Journal of Clinical Virology ◽

10.1016/j.jcv.2014.01.023 ◽

2014 ◽

Vol 59 (4) ◽

pp. 218-222 ◽

Cited By ~ 5

Author(s):

Sven Reiche ◽

Claudia Nestler ◽

Michael Sieg ◽

Katharina Schulz ◽

Christiane Cordes ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Hiv Positive ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

B Cell Responses

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Vibrio cholerae Sialidase-Specific Immune Responses Are Associated with Protection against Cholera

mSphere ◽

10.1128/msphere.01232-20 ◽

2021 ◽

Vol 6 (2) ◽

Author(s):

M. Hasanul Kaisar ◽

Mohammed Saruar Bhuiyan ◽

Aklima Akter ◽

Danial Saleem ◽

Anita S. Iyer ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

Vibrio Cholerae ◽

Natural Infection ◽

Intestinal Epithelial ◽

Older Children ◽

Memory B Cell ◽

Content Type ◽

Cell Responses ◽

Age Related

ABSTRACT Cholera remains a major public health problem in resource-limited countries. Vaccination is an important strategy to prevent cholera, but currently available vaccines provide only 3 to 5 years of protection. Understanding immune responses to cholera antigens in naturally infected individuals may elucidate which of these are key to longer-term protection seen following infection. We recently identified Vibrio cholerae O1 sialidase, a neuraminidase that facilitates binding of cholera toxin to intestinal epithelial cells, as immunogenic following infection in two recent high-throughput screens. Here, we present systemic, mucosal, and memory immune responses to sialidase in cholera index cases and evaluated whether systemic responses to sialidase correlated with protection using a cohort of household contacts. Overall, we found age-related differences in antisialidase immune response following cholera. Adults developed significant plasma anti-sialidase IgA, IgG, and IgM responses following infection, whereas older children (≥5 years) developed both IgG and IgM responses, and younger children only developed IgM responses. Neither older children nor younger children had a rise in IgA responses over the convalescent phase of infection (day 7/day 30). On evaluation of mucosal responses and memory B-cell responses to sialidase, we found adults developed IgA antibody-secreting cell (ASC) and memory B-cell responses. Finally, in household contacts, the presence of serum anti-sialidase IgA, IgG, and IgM antibodies at enrollment was associated with a decrease in the risk of subsequent infection. These data show cholera patients develop age-related immune responses against sialidase and suggest that immune responses that target sialidase may contribute to protective immunity against cholera. IMPORTANCE Cholera infection can result in severe dehydration that may lead to death within a short period of time if not treated immediately. Vaccination is an important strategy to prevent the disease. Oral cholera vaccines provide 3 to 5 years of protection, with 60% protective efficacy, while natural infection provides longer-term protection than vaccination. Understanding the immune responses after natural infection is important to better understand immune responses to antigens that mediate longer-term protection. Sialidase is a neuraminidase that facilitates binding of cholera toxin to intestinal epithelial cells. We show here that patients with cholera develop systemic, mucosal, and memory B-cell immune responses to the sialidase antigen of Vibrio cholerae O1 and that plasma responses targeting this antigen correlate with protection.

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Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination

Science Immunology ◽

10.1126/sciimmunol.abi6950 ◽

2021 ◽

Vol 6 (58) ◽

pp. eabi6950 ◽

Cited By ~ 1

Author(s):

Rishi R. Goel ◽

Sokratis A. Apostolidis ◽

Mark M. Painter ◽

Divij Mathew ◽

Ajinkya Pattekar ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Vaccine Dose ◽

Memory B Cells ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

Resource Limited ◽

B Cell Responses ◽

Vaccine Distribution

Novel mRNA vaccines for SARS-CoV-2 have been authorized for emergency use. Despite their efficacy in clinical trials, data on mRNA vaccine-induced immune responses are mostly limited to serological analyses. Here, we interrogated antibody and antigen-specific memory B cells over time in 33 SARS-CoV-2 naïve and 11 SARS-CoV-2 recovered subjects. SARS-CoV-2 naïve individuals required both vaccine doses for optimal increases in antibodies, particularly for neutralizing titers against the B.1.351 variant. Memory B cells specific for full-length spike protein and the spike receptor binding domain (RBD) were also efficiently primed by mRNA vaccination and detectable in all SARS-CoV-2 naive subjects after the second vaccine dose, though the memory B cell response declined slightly with age. In SARS-CoV-2 recovered individuals, antibody and memory B cell responses were significantly boosted after the first vaccine dose; however, there was no increase in circulating antibodies, neutralizing titers, or antigen-specific memory B cells after the second dose. This robust boosting after the first vaccine dose strongly correlated with levels of pre-existing memory B cells in recovered individuals, identifying a key role for memory B cells in mounting recall responses to SARS-CoV-2 antigens. Together, our data demonstrated robust serological and cellular priming by mRNA vaccines and revealed distinct responses based on prior SARS-CoV-2 exposure, whereby COVID-19 recovered subjects may only require a single vaccine dose to achieve peak antibody and memory B cell responses. These findings also highlight the utility of defining cellular responses in addition to serologies and may inform SARS-CoV-2 vaccine distribution in a resource-limited setting.

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