scholarly journals A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Yaping Liu ◽  
Daniel C. Freed ◽  
Leike Li ◽  
Aimin Tang ◽  
Fengsheng Li ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Clinical Evaluation ◽  
Virus Vaccine ◽  
Hcmv Infection ◽  
Memory B Cells ◽  
High Avidity ◽  
Link Type ◽  
Defective Virus

ABSTRACT Human cytomegalovirus (HCMV) can cause congenital infections, which are a leading cause of childhood disabilities. Since the rate of maternal-fetal transmission is much lower in naturally infected (HCMV-seropositive) women, we hypothesize that a vaccine candidate capable of eliciting immune responses analogous to those of HCMV-seropositive subjects may confer protection against congenital HCMV. We have previously described a replication-defective virus vaccine based on strain AD169 (D. Wang, D. C. Freed, X. He, F. Li, et al., Sci Transl Med 8:362ra145, 2016, https://doi.org/10.1126/scitranslmed.aaf9387). The vaccine, named V160, has been shown to be safe and immunogenic in HCMV-seronegative human subjects, eliciting both humoral and cellular immune responses (S. P. Adler, S. E. Starr, S. A. Plotkin, S. H. Hempfling, et al., J Infect Dis 220:411–419, 2019, https://doi.org/10.1093/infdis/171.1.26). Here, we further showed that sera from V160-immunized HCMV-seronegative subjects have attributes similar in quality to those from seropositive subjects, including high-avidity antibodies to viral antigens, coverage against a panel of genetically distinct clinical isolates, and protection against viral infection in diverse types of human cells in culture. More importantly, vaccination appeared efficient in priming the human immune system, inducing memory B cells in six V160 recipients at frequencies comparable to those of three HCMV-seropositive subjects. Our results demonstrate the ability of V160 to induce robust and durable humoral memory responses to HCMV, justifying further clinical evaluation of the vaccine against congenital HCMV. IMPORTANCE In utero HCMV infection can lead to miscarriage or childhood disabilities, and an effective vaccine is urgently needed. Since children born to women who are seropositive prior to pregnancy are less likely to be affected by congenital HCMV infection, it has been hypothesized that a vaccine capable of inducing an immune response resembling the responses in HCMV-seropositive women may be effective. We previously described a replication-defective virus vaccine that has been demonstrated safe and immunogenic in HCMV-seronegative subjects. Here, we conducted additional analyses to show that the vaccine can induce antibodies with functional attributes similar to those from HCMV-seropositive subjects. Importantly, vaccination can induce long-lived memory B cells at frequencies comparable to those seen in HCMV-seropositive subjects. We conclude that this vaccine is a promising candidate that warrants further clinical evaluation for prevention of congenital HCMV.

scholarly journals T-independent antigen induces humoral memory through germinal centers

2022 ◽  
Vol 219 (3) ◽  
Author(s):  
Xin Liu ◽  
Yongshan Zhao ◽  
Hai Qi
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Plasma Cells ◽  
Underlying Mechanism ◽  
Memory B Cells ◽  
Antigen B ◽  
Per Se ◽  
Humoral Responses ◽  
Human And Mouse

T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-independent humoral memory is not clear. While T-independent antigen can induce GCs, they are transient and thought to be nonproductive. Unexpectedly, by genetic fate-mapping, we find that these GCs actually output memory B cells and PCs. Using a conditional BCL6 deletion approach, we show memory B cells and PCs fail to last when T-independent GCs are precluded, suggesting that the GC experience per se is important for programming longevity of T-independent memory B cells and PCs. Consistent with the fact that infants cannot mount long-lived humoral memory to T-independent antigen, B cells from young animals intrinsically fail to form T-independent GCs. Our results suggest that T-independent GCs support humoral memory, and GC induction may be key to effective vaccines with T-independent antigen.

scholarly journals Memory B cells: Effectors of long-lived immune responses

2009 ◽  
Vol 39 (8) ◽  
pp. 2065-2075 ◽  
Author(s):  
Stuart G. Tangye ◽  
David M. Tarlinton
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Memory B Cells

scholarly journals Preexisting Immunity, More Than Aging, Influences Influenza Vaccine Responses

2015 ◽  
Vol 2 (2) ◽  
Author(s):  
Adrian J. Reber ◽  
Jin Hyang Kim ◽  
Renata Biber ◽  
H. Keipp Talbot ◽  
Laura A. Coleman ◽  
...  
Keyword(s):  
Older Adults ◽  
B Cells ◽  
Immune Responses ◽  
Influenza Vaccine ◽  
Hemagglutination Inhibition ◽  
Negative Impact ◽  
Memory B Cells ◽  
Vaccine Response ◽  
Vaccine Responses ◽  
Antibody Levels

Abstract Background.  Influenza disproportionately impacts older adults while current vaccines have reduced effectiveness in the older population. Methods.  We conducted a comprehensive evaluation of cellular and humoral immune responses of adults aged 50 years and older to the 2008–2009 seasonal trivalent inactivated influenza vaccine and assessed factors influencing vaccine response. Results.  Vaccination increased hemagglutination inhibition and neutralizing antibody; however, 66.3% of subjects did not reach hemagglutination inhibition titers ≥ 40 for H1N1, compared with 22.5% for H3N2. Increasing age had a minor negative impact on antibody responses, whereas prevaccination titers were the best predictors of postvaccination antibody levels. Preexisting memory B cells declined with age, especially for H3N2. However, older adults still demonstrated a significant increase in antigen-specific IgG+ and IgA+ memory B cells postvaccination. Despite reduced frequency of preexisting memory B cells associated with advanced age, fold-rise in memory B cell frequency in subjects 60+ was comparable to subjects age 50–59. Conclusions.  Older adults mounted statistically significant humoral and cell-mediated immune responses, but many failed to reach hemagglutination inhibition titers ≥40, especially for H1N1. Although age had a modest negative effect on vaccine responses, prevaccination titers were the best predictor of postvaccination antibody levels, irrespective of age.

scholarly journals Differential T- and B-Cell Responses to Pertussis in Acellular Vaccine-Primed versus Whole-Cell Vaccine-Primed Children 2 Years after Preschool Acellular Booster Vaccination

2013 ◽  
Vol 20 (9) ◽  
pp. 1388-1395 ◽  
Author(s):  
Rose-Minke Schure ◽  
Lotte H. Hendrikx ◽  
Lia G. H. de Rond ◽  
Kemal Öztürk ◽  
Elisabeth A. M. Sanders ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Booster Vaccination ◽  
Memory B Cells ◽  
Vaccine Antigen ◽  
Whole Cell ◽  
Cell Responses

ABSTRACTThis study investigated long-term cellular and humoral immunity against pertussis after booster vaccination of 4-year-old children who had been vaccinated at 2, 3, 4, and 11 months of age with either whole-cell pertussis (wP) or acellular pertussis (aP) vaccine. Immune responses were evaluated until 2 years after the preschool booster aP vaccination. In a cross-sectional study (registered trial no. ISRCTN65428640), blood samples were taken from wP- and aP-primed children prebooster and 1 month and 2 years postbooster. Pertussis vaccine antigen-specific IgG levels, antibody avidities, and IgG subclasses, as well as T-cell cytokine levels, were measured by fluorescent bead-based multiplex immunoassays. The numbers of pertussis-specific memory B cells and gamma interferon (IFN-γ)-producing T cells were quantified by enzyme-linked immunosorbent spot assays. Even 2 years after booster vaccination, memory B cells were still present and higher levels of pertussis-specific antibodies than prebooster were found in aP-primed children and, to a lesser degree, also in wP-primed children. The antibodies consisted mainly of the IgG1 subclass but also showed an increased IgG4 portion, primarily in the aP-primed children. The antibody avidity indices for pertussis toxin and pertactin in aP-primed children were already high prebooster and remained stable at 2 years, whereas those in wP-primed children increased. All measured prebooster T-cell responses in aP-primed children were already high and remained at similar levels or even decreased during the 2 years after booster vaccination, whereas those in wP-primed children increased. Since the Dutch wP vaccine has been replaced by aP vaccines, the induction of B-cell and T-cell memory immune responses has been enhanced, but antibody levels still wane after five aP vaccinations. Based on these long-term immune responses, the Dutch pertussis vaccination schedule can be optimized, and we discuss here several options.

scholarly journals Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection

2021 ◽  
Author(s):  
Eleanor C. Semmes ◽  
Itzayana G. Miller ◽  
Jennifer A. Jenks ◽  
Courtney E. Wimberly ◽  
Stella J. Berendam ◽  
...  
Keyword(s):  
Cord Blood ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Passive Immunization ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
High Avidity ◽  
Igg Binding ◽  
Congenital Hcmv Infection

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital infection has been hindered by limited knowledge of the immune responses that protect against placental HCMV transmission in maternal primary and nonprimary infection. To identify protective antibody responses, we measured anti-HCMV IgG binding and anti-viral functions in maternal and cord blood sera from HCMV transmitting (n=41) and non- transmitting (n=40) mother-infant dyads identified via a large U.S.-based public cord blood bank. In a predefined immune correlate analysis, maternal monocyte-mediated antibody-dependent cellular phagocytosis (ADCP) and high avidity IgG binding to HCMV envelope glycoproteins were associated with decreased risk of congenital HCMV infection. Moreover, HCMV-specific IgG engagement of FcγRI and FcγRIIA, which mediate non-neutralizing antibody responses, was enhanced in non-transmitting mother-infant dyads and strongly correlated with ADCP. These findings suggest that Fc effector functions including ADCP protect against placental HCMV transmission. Taken together, our data indicate that future active and passive immunization strategies to prevent congenital HCMV infection should target Fc-mediated non-neutralizing antibody responses.

scholarly journals Vaccination boosts protective responses and counters SARS-CoV-2-induced pathogenic memory B cells

2021 ◽  
Author(s):  
Pankaj Kumar Mishra ◽  
Natalie Bruiners ◽  
Rahul Ukey ◽  
Pratik Datta ◽  
Alberta Onyuka ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Cell Subset ◽  
Mechanistic Explanation ◽  
Memory B Cells ◽  
Immune Priming ◽  
Neutralizing Activity ◽  
Specific Memory ◽  
Rapid Spread

AbstractGiven the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the recent implementation of SARS-CoV-2 vaccination, we have much to learn about the duration of immune protection and the interface between the immune responses to infection and to vaccination. To address these questions, we monitored immune responses to SARS-CoV-2 infection in convalescent individuals over seven months and following mRNA vaccination. Spike Receptor-Binding-Domain (RBD)-specific circulating antibodies and plasma neutralizing activity generally decreased over time, whereas RBD-specific memory B cells persisted. Additionally, using antibody depletion techniques, we showed that the neutralizing activity of plasma specifically resides in the anti-RBD antibodies. More vigorous antibody and B cell responses to vaccination were observed in previously infected subjects relative to uninfected comparators, presumably due to immune priming by infection. SARS-CoV-2 infection also led to increased numbers of double negative B memory cells, which are described as a dysfunctional B cell subset. This effect was reversed by SARS-CoV-2 vaccination, providing a potential mechanistic explanation for the vaccination-induced reduction in symptoms in patients with “Long-COVID”.

Impact of Autologous Dendritic Cell Immunotherapy (Arcelis™) on B Cell Subsets in HIV-1-Infected Subjects Receiving Antiretroviral Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 80-80
Author(s):  
Mohamed-Rachid Boulassel ◽  
Bader Yassine-Diab ◽  
Don Healey ◽  
Charles Nicolette ◽  
Rafick-Pierre Sékaly ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Memory B Cells ◽  
B Cell Subsets ◽  
Hiv 1

Abstract We demonstrated the enhancement of CD8-specific responses following the administration of an immune-based therapy consisting of dendritic cells (DC) electroporated with autologous amplified HIV-1 RNA and CD40 ligand (CD40 L) RNA manufactured by the Arcelis™ process in HIV patients receiving antiretroviral therapy (ART). We conducted a sub study on circulating B cell populations to further assess changes induced by this autologous DC therapy as CD40L is a major B cell co-stimulatory factor. To this end, we assessed B cell subset changes in relation to the proliferative capacity of CD4+ and CD8+ T cells response to DC targets containing the 4 HIV-1 antigens (Gag, Vpr, Rev, Nef). The co-expression of CD19, CD38, IgD, CD10, CD23, CD27, CD5, and CD138 were analyzed by multi-parametric flow cytometry to assess circulating B cell subsets such as naïve resting B-cells (Bm1), activated naïve B cells (Bm2), GC founder cells (Bm2’), centroblasts and centrocytes (Bm3 and Bm4), early memory B cells (eBm5), memory B cells (Bm5), IgD memory cells, plasma cells, and B-1 cells. Changes in B cells subsets were analyzed before and after the four intradermal injections of this immunotherapeutic product containing 1.2 × 107 DC. Ten ART treated subjects with undetectable viral load (< 50 copies/ml), median CD4+ count of 440 cells/μl (range: 316–1102), and with a CD4+ nadir > 200 cells/μl were studied. Throughout the study, no significant changes in CD4+ cell count, CD4/CD8 ratio, and no viral blips were noticed. The percentage of total B cells, Bm1, Bm2, Bm2′, eBm5, IgD memory, plasma cells, and B-1 cell subsets did not significantly change. However, a decrease in the percentage of Bm3 and Bm4 cells was found (0.36 [0.06–0.86] versus 0.11 [0.04–0.36]; P=0.05). Conversely, an important increase in the Bm5 cell subset was evidenced (10.4 [1.6–24.2] versus 18.1 [5.1–27.5]; P=0.005) suggesting a proliferation of B memory cells induced by DC immunization. In addition, the multifunctional and polyvalent CD8+ T cell proliferative responses to the 4 HIV genes used in this immunotherapy were noticed in 8 out of 9 subjects available for analysis and characterized by an effector memory phenotype. No CD4+ T cell immune responses were detected, consistent with the endogenous HLA class I loading of the antigens. Collectively, these results indicate that this immunotherapy induces an increase in the B memory cell population in the absence of inducing any clinically apparent autoimmunity along with strong HIV specific multifunctional CD8+ T cell specific immune responses.

scholarly journals Primary Human Cytomegalovirus Infection Induces the Expansion of Virus-Specific Activated and Atypical Memory B Cells

2014 ◽  
Vol 210 (8) ◽  
pp. 1275-1285 ◽  
Author(s):  
Nicolas Dauby ◽  
Caroline Kummert ◽  
Sandra Lecomte ◽  
Corinne Liesnard ◽  
Marie-Luce Delforge ◽  
...  
Keyword(s):  
B Cells ◽  
Human Cytomegalovirus ◽  
Cytomegalovirus Infection ◽  
Memory B Cells ◽  
Human Cytomegalovirus Infection

Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3965-3971 ◽  
Author(s):  
Gwendolin Muehlinghaus ◽  
Luisa Cigliano ◽  
Stephan Huehn ◽  
Anette Peddinghaus ◽  
Heike Leyendeckers ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Plasma Cell ◽  
Chemokine Receptor ◽  
Plasma Cells ◽  
Cxcr4 Expression ◽  
Memory B Cells ◽  
Interleukin 4 ◽  
Limiting Factor ◽  
Ifn Γ

Abstract C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4 expressed on immunoglobulin G (IgG)–plasma-cell precursors formed in memory immune responses are crucial modulators of the homing of these cells. Here, we studied the regulation of the expression of these chemokine receptors during the differentiation of human memory B cells into plasma cells. We show that CXCR3 is absent on CD27- naive B cells but is expressed on a fraction of memory B cells, preferentially on those coexpressing IgG1. On differentiation into plasma-cell precursors, CXCR3+ memory B cells maintain the expression of this chemokine receptor. CXCR3- memory B cells up-regulate CXCR3 and migrate toward concentration gradients of its ligands only when costimulated with interferon γ (IFN-γ), but not interleukin 4 (IL-4), IL-1β, IL-6, IFN-α, IFN-β, or tumor necrosis factor α (TNF-α). In contrast, the differentiation of CXCR4- B cells into plasma cells is generally accompanied by the induction of CXCR4 expression. These results show that lack of CXCR4 expression on plasma-cell precursors is not a limiting factor for plasma-cell homing and that the expression of CXCR3 on memory B cells and plasma-cell precursors is induced by IFN-γ, provided in human T helper type 1 (Th1)–biased immune responses. Once induced in memory B cells, CXCR3 expression remains part of the individual cellular memory.

Sign in / Sign up

Export Citation Format

Share Document