Lipopolysaccharide-specific memory B cell responses to an attenuated live cholera vaccine are associated with protection against Vibrio cholerae infection

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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Parenteral Vaccination with a Cholera Conjugate Vaccine Boosts Vibriocidal and Anti-OSP Responses in Mice Previously Immunized with an Oral Cholera Vaccine

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1511 ◽

2021 ◽

Author(s):

Aklima Akter ◽

Meagan Kelly ◽

Richelle C. Charles ◽

Jason B. Harris ◽

Stephen B. Calderwood ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

Conjugate Vaccine ◽

Oral Vaccine ◽

Cholera Vaccine ◽

Memory B Cell ◽

Cell Responses ◽

Oral Cholera Vaccine ◽

B Cell Responses ◽

Cholera Vaccination

Oral cholera vaccination protects against cholera; however, responses in young children are low and of short duration. The best current correlates of protection against cholera target Vibrio cholerae O-specific polysaccharide (anti-OSP), including vibriocidal responses. A cholera conjugate vaccine has been developed that induces anti-OSP immune responses, including memory B-cell responses. To address whether cholera conjugate vaccine would boost immune responses following oral cholera vaccination, we immunized mice with oral cholera vaccine Inaba CVD 103-HgR or buffer only (placebo) on day 0, followed by parenteral boosting immunizations on days 14, 42, and 70 with cholera conjugate vaccine Inaba OSP: recombinant tetanus toxoid heavy chain fragment or PBS/placebo. Compared with responses in mice immunized with oral vaccine alone or intramuscular cholera conjugate vaccine alone, mice receiving combination vaccination developed significantly higher vibriocidal, IgM OSP-specific serum responses and OSP-specific IgM memory B-cell responses. A combined vaccination approach, which includes oral cholera vaccination followed by parenteral cholera conjugate vaccine boosting, results in increased immune responses that have been associated with protection against cholera. These results suggest that such an approach should be evaluated in humans.

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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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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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Memory T-Cell Responses to Vibrio cholerae O1 Infection

Infection and Immunity ◽

10.1128/iai.00793-09 ◽

2009 ◽

Vol 77 (11) ◽

pp. 5090-5096 ◽

Cited By ~ 34

Author(s):

Ana A. Weil ◽

Mohammad Arifuzzaman ◽

Taufiqur R. Bhuiyan ◽

Regina C. LaRocque ◽

Aaron M. Harris ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

B Cell ◽

Vibrio Cholerae ◽

Protective Immunity ◽

T Cell Responses ◽

Memory B Cell ◽

Memory T Cell ◽

Cell Responses ◽

B Cell Responses

ABSTRACTVibrio choleraeO1 can cause diarrheal disease that may be life-threatening without treatment. Natural infection results in long-lasting protective immunity, but the role of T cells in this immune response has not been well characterized. In contrast, robust B-cell responses toV. choleraeinfection have been observed. In particular, memory B-cell responses to T-cell-dependent antigens persist for at least 1 year, whereas responses to lipopolysaccharide, a T-cell-independent antigen, wane more rapidly after infection. We hypothesize that protective immunity is mediated by anamnestic responses of memory B cells in the gut-associated lymphoid tissue, and T-cell responses may be required to generate and maintain durable memory B-cell responses. In this study, we examined B- and T-cell responses in patients with severeV. choleraeinfection. Using the flow cytometric assay of the specific cell-mediated immune response in activated whole blood, we measured antigen-specific T-cell responses usingV. choleraeantigens, including the toxin-coregulated pilus (TcpA), aV. choleraemembrane preparation, and theV. choleraecytolysin/hemolysin (VCC) protein. Our results show that memory T-cell responses develop by day 7 after infection, a time prior to and concurrent with the development of B-cell responses. This suggests that T-cell responses toV. choleraeantigens may be important for the generation and stability of memory B-cell responses. The T-cell proliferative response to VCC was of a higher magnitude than responses observed to otherV. choleraeantigens.

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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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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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