Differential antibody dynamics to SARS-CoV-2 infection and vaccination

ABSTRACTOptimal immune responses furnish long-lasting (durable) antibodies protective across dynamically mutating viral variants (broad). To assess robustness of mRNA vaccine-induced immunity, we compared antibody durability and breadth after SARS-CoV-2 infection and vaccination. While vaccination delivered robust initial virus-specific antibodies with some cross-variant coverage, pre-variant SARS-CoV-2 infection-induced antibodies, while modest in magnitude, showed highly stable long-term antibody dynamics. Vaccination after infection induced maximal antibody magnitudes with enhanced longitudinal stability while infection-naïve vaccinee antibodies fell with time to post-infection-alone levels. The composition of antibody neutralizing activity to variant relative to original virus also differed between groups, with infection-induced antibodies demonstrating greater relative breadth. Differential antibody durability trajectories favored COVID-19-recovered subjects with dual memory B cell features of greater early antibody somatic mutation and cross-coronavirus reactivity. By illuminating an infection-mediated antibody breadth advantage and an anti-SARS-CoV-2 antibody durability-enhancing function conferred by recalled immunity, these findings may serve as guides for ongoing vaccine strategy improvement.

Download Full-text

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

Clinical and Vaccine Immunology ◽

10.1128/cvi.00270-13 ◽

2013 ◽

Vol 20 (9) ◽

pp. 1388-1395 ◽

Cited By ~ 39

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.

Download Full-text

Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma

Blood ◽

10.1182/blood-2012-05-432393 ◽

2013 ◽

Vol 121 (2) ◽

pp. 251-259 ◽

Cited By ~ 92

Author(s):

Simon J. Dovedi ◽

Monique H. M. Melis ◽

Robert W. Wilkinson ◽

Amy L. Adlard ◽

Ian J. Stratford ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Systemic Delivery ◽

Tlr7 Agonist ◽

Specific Memory ◽

T Cell Malignancies ◽

Memory Immune Response

Abstract Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B-cell malignancies, although many still relapse and little progress has been made with T-cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhance antitumor immune responses using novel immunomodulatory agents in combination with standard of care treatments. Here we report that intravenous administration of the Toll-like receptor 7 (TLR7) agonist, R848 in combination with radiation therapy (RT), leads to the longstanding clearance of tumor in T- and B-cell lymphoma bearing mice. In combination, TLR7/RT therapy leads to the expansion of tumor antigen-specific CD8+ T cells and improved survival. Furthermore, those mice that achieve long-term clearance of tumor after TLR7/RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response. Our findings demonstrate the potential for enhancing the efficacy of conventional cytotoxic anticancer therapy through combination with a systemically administered TLR7 agonist to improve antitumor immune responses and provide durable remissions.

Download Full-text

Targeting Long-Lived Plasma Cells Is Essential For Treating Hemophilia A Inhibitors

Blood ◽

10.1182/blood.v122.21.927.927 ◽

2013 ◽

Vol 122 (21) ◽

pp. 927-927

Author(s):

Chao Lien Liu ◽

Meghan Lyle ◽

Simon Shin ◽

Carol H. Miao

Keyword(s):

Bone Marrow ◽

B Cells ◽

Immune Responses ◽

B Cell ◽

Plasma Cells ◽

Hemophilia A ◽

Combined Treatment ◽

Therapeutic Effects ◽

Anti Cd20

Abstract The most critical and challenging problem for therapeutic treatment in hemophilia A patients is due to the formation of Inhibitory antibodies. It is hypothesized that long-lived plasma cells (LLPCs) play an important role in the persistent production of anti-FVIII antibodies in hemophilia A (HemA) inhibitor patients. The migration of plasma cells to the BM, where they become the LLPCs, is largely controlled by an interaction between the C-X-C type chemokine ligand 12 (CXCL12) produced by bone marrow (BM) stromal cells and its receptor CXC receptor4 (CXCR4; CD184) on plasma cells surface. Our previous data showed that administration of anti-murine CD20 (IgG2a) alone can deplete B cells significantly and reduce anti-FVIII inhibitor titers transiently in FVIII plasmid-treated HemA mice with pre-existing inhibitors, however, complete tolerance to FVIII was not achieved probably due to the persistence of LLPCs. We sought novel therapeutic strategies that target CXCL12/CXCR4 pathway to reduce/eliminate LLPCs and achieve the goal for long-term tolerance to FVIII in the HemA inhibitor mice. AMD3100, the CXCR4 antagonist, plus G-CSF inhibit the interaction of CXCL12 and CXCR4, thus facilitating the mobilization of stem cells and blocking the homing and retention of LLPCs. The combined treatment strategy used anti-CD20, G-CSF and AMD3100 to target B cells plus with the specific IL-2/IL-2mAb (JES6-1) complexes to target T cells for preventing both T and B cell-dependent anti-FVIII immune responses. Two groups of FVIII-primed inhibitor mice were treated with different combined immunomodulation regimens: (1) IL-2 complexes+AMD3100+G-CSF+anti-CD20, (2) AMD3100+G-CSF+anti-CD20. Control mouse groups were treated with each of the single regimens and FVIII only, or untreated as the naive control. All the treatments were administered one cycle per two weeks for 6 weeks and the therapeutic effects (FVIII activities) as well as immune responses (anti-FVIII inhibitors) were evaluated at different time points after treatment. Significant expansion of Treg cells reaching a 5∼7-fold increase on the peak days (day 3-7 after treatment) was observed in the IL-2/IL-2mAb complexes treated groups, whereas ∼95% of B cell populations were depleted in the anti-CD20 treated groups. In addition, administration of AMD3100 plus G-CSF significantly reduced circulating and bone marrow CXCR4+ plasma cells by flow cytometry analysis as well as decreased FVIII-specific plasma cells in bone marrow by ELISPOT assay. Except for the control groups, the two mouse groups treated with combined immunosuppressive regimens showed a significant reduction of inhibitory titers following the treatment. Long-term responses are being followed and second challenge with FVIII plasmid will be used to evaluate the induction of long term tolerance to FVIII. These combination regimens are highly promising in modulating/eliminating pre-existing anti-FVIII antibodies and inducing long-term tolerance in FVIII primed subjects. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling

Blood ◽

10.1182/blood-2012-11-465039 ◽

2013 ◽

Vol 122 (2) ◽

pp. 227-238 ◽

Cited By ~ 51

Author(s):

Hugues de Lavallade ◽

Ahmad Khoder ◽

Melanie Hart ◽

Anushruti Sarvaria ◽

Takuya Sekine ◽

...

Keyword(s):

Immune Responses ◽

Cell Signaling ◽

B Cell ◽

Kinase Inhibitors ◽

Cell Function ◽

Close Monitoring ◽

B Cell Signaling ◽

Key Points ◽

Long Term Impact

Key Points TKIs impair B-cell immune responses in CML through off-target inhibition of kinases important for B-cell signaling. Our results call for close monitoring of patients on TKI to assess the long-term impact of impaired B-cell function.

Download Full-text

The way of SARS-CoV-2 vaccine development: success and challenges

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00796-w ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yetian Dong ◽

Tong Dai ◽

Bin Wang ◽

Lei Zhang ◽

Ling-hui Zeng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Immune Responses ◽

Vaccine Development ◽

Natural Infection ◽

Wild Type ◽

Mutational Hotspots ◽

Long Term Changes ◽

Induced Immunity ◽

Shed Light

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). To halt the pandemic, multiple SARS-CoV-2 vaccines have been developed and several have been allowed for emergency use and rollout worldwide. With novel SARS-CoV-2 variants emerging and circulating widely, whether the original vaccines that were designed based on the wild-type SARS-CoV-2 were effective against these variants has been a contentious discussion. Moreover, some studies revealed the long-term changes of immune responses post SARS-CoV-2 infection or vaccination and the factors that might impact the vaccine-induced immunity. Thus, in this review, we have summarized the influence of mutational hotspots on the vaccine efficacy and characteristics of variants of interest and concern. We have also discussed the reasons that might result in discrepancies in the efficacy of different vaccines estimated in different trials. Furthermore, we provided an overview of the duration of immune responses after natural infection or vaccination and shed light on the factors that may affect the immunity induced by the vaccines, such as special disease conditions, sex, and pre-existing immunity, with the aim of aiding in combating COVID-19 and distributing SARS-CoV-2 vaccines under the prevalence of diverse SARS-CoV-2 variants.

Download Full-text