ABSTRACT
Vaccine responsiveness is often reduced in older adults. Yet, our lack of understanding of low vaccine responsiveness hampers the development of effective vaccination strategies to reduce the impact of infectious diseases in the ageing population. Young-adult (25-49 y), middle-aged (50-64 y) and older-adult ( ≥ 65 y) participants of the VITAL clinical trials (n = 315, age-range: 28-98 y), were vaccinated with an annual (2019-2020) quadrivalent influenza (QIV) booster vaccine, followed by a primary 13-valent pneumococcal-conjugate (PCV13) vaccine (summer/autumn 2020) and a primary series of two SARS-CoV-2 mRNA-1273 vaccines (spring 2021). This unique setup allowed investigation of humoral responsiveness towards multiple vaccines within the same individuals over the adult age-range. Booster QIV vaccination induced comparable H3N2 hemagglutination inhibition (HI) titers in all age groups, whereas primary PCV13 and mRNA-1273 vaccination induced lower antibody concentrations in older as compared to younger adults (primary endpoint). The persistence of humoral responses, towards the 6 months timepoint, was shorter in older adults for all vaccines (secondary endpoint). Interestingly, highly variable vaccine responder profiles overarching multiple vaccines were observed. Yet, approximately 10% of participants, mainly comprising of older male adults, were classified as low responders to multiple vaccines. This study aids the identification of risk groups for low vaccine responsiveness and hence supports targeted vaccination strategies. Trial number: NL69701.041.19, EudraCT: 2019-000836-24.
Subject(s)
2019-nCoV Vaccine mRNA-1273 , Antibodies, Viral , COVID-19 , Immunity, Humoral , Immunization, Secondary , Influenza Vaccines , Influenza, Human , Pneumococcal Vaccines , SARS-CoV-2 , Humans , Middle Aged , Adult , Aged , Male , Female , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Antibodies, Viral/immunology , Antibodies, Viral/blood , Immunity, Humoral/immunology , Pneumococcal Vaccines/immunology , Pneumococcal Vaccines/administration & dosage , COVID-19/prevention & control , COVID-19/immunology , SARS-CoV-2/immunology , Aged, 80 and over , 2019-nCoV Vaccine mRNA-1273/immunology , Influenza, Human/prevention & control , Influenza, Human/immunology , Age Factors , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Influenza A Virus, H3N2 Subtype/immunology , Vaccination , Hemagglutination Inhibition TestsABSTRACT
Antibodies are powerful modulators of ongoing and future B cell responses. While the concept of antibody feedback has been appreciated for over a century, the topic has seen a surge in interest due to the evidence that the broadening of antibody responses to SARS-CoV-2 after a third mRNA vaccination is a consequence of antibody feedback. Moreover, the discovery that slow antigen delivery can lead to more robust humoral immunity has put a spotlight on the capacity for early antibodies to augment B cell responses. Here, we review the mechanisms whereby antibody feedback shapes B cell responses, integrating findings in humans and in mouse models. We consider the major influence of epitope masking and the diverse actions of complement and Fc receptors and provide a framework for conceptualizing the ways antigen-specific antibodies may influence B cell responses to any form of antigen, in conditions as diverse as infectious disease, autoimmunity, and cancer.
Subject(s)
B-Lymphocytes , COVID-19 , SARS-CoV-2 , Animals , Humans , B-Lymphocytes/immunology , SARS-CoV-2/immunology , COVID-19/immunology , Mice , Antibodies, Viral/immunology , Immunity, Humoral/immunology , Receptors, Fc/immunology , Receptors, Fc/metabolism , Feedback, Physiological , Antibody Formation/immunologyABSTRACT
Plasmodium vivax serological exposure markers (SEMs) have emerged as promising tools for the actionable surveillance and implementation of targeted interventions to accelerate malaria elimination. To determine the dynamic profiles of SEMs in current and past P. vivax infections, we screened and selected 11 P. vivax proteins from 210 putative proteins using protein arrays, with a set of serum samples obtained from patients with acute P. vivax and documented past P. vivax infections. Then we used a murine protein immune model to initially investigate the humoral and memory B cell response involved in the generation of long-lived antibodies. We show that of the 11 proteins, especially C-terminal 42-kDa region of P. vivax merozoite surface protein 1 (PvMSP1-42) induced longer-lasting long-lived antibodies, as these antibodies were detected in individuals infected with P. vivax in the 1960-1970s who were not re-infected until 2012. In addition, we provide a potential mechanism for the maintenance of long-lived antibodies after the induction of PvMSP1-42. The results indicate that PvMSP1-42 induces more CD73+CD80+ memory B cells (MBCs) compared to P. vivax GPI-anchored micronemal antigen (PvGAMA), allowing IgG anti-PvMSP1-42 antibodies to be maintained for a long time.
Subject(s)
Antibodies, Protozoan , Malaria, Vivax , Memory B Cells , Merozoite Surface Protein 1 , Plasmodium vivax , Plasmodium vivax/immunology , Humans , Malaria, Vivax/immunology , Antibodies, Protozoan/immunology , Animals , Merozoite Surface Protein 1/immunology , Mice , Memory B Cells/immunology , Immunity, Humoral/immunology , Biomarkers/blood , Female , Immunologic Memory/immunology , B-Lymphocytes/immunology , Antigens, Protozoan/immunologyABSTRACT
BACKGROUND: The pathogenesis of migraine remains unclear; however, a large body of evidence supports the hypothesis that immunological mechanisms play a key role. Therefore, we aimed to review current studies on altered immunity in individuals with migraine during and outside attacks. METHODS: We searched the PubMed database to investigate immunological changes in patients with migraine. We then added other relevant articles on altered immunity in migraine to our search. RESULTS: Database screening identified 1,102 articles, of which 41 were selected. We added another 104 relevant articles. We found studies reporting elevated interictal levels of some proinflammatory cytokines, including IL-6 and TNF-α. Anti-inflammatory cytokines showed various findings, such as increased TGF-ß and decreased IL-10. Other changes in humoral immunity included increased levels of chemokines, adhesion molecules, and matrix metalloproteinases; activation of the complement system; and increased IgM and IgA. Changes in cellular immunity included an increase in T helper cells, decreased cytotoxic T cells, decreased regulatory T cells, and an increase in a subset of natural killer cells. A significant comorbidity of autoimmune and allergic diseases with migraine was observed. CONCLUSIONS: Our review summarizes the findings regarding altered humoral and cellular immunological findings in human migraine. We highlight the possible involvement of immunological mechanisms in the pathogenesis of migraine. However, further studies are needed to expand our knowledge of the exact role of immunological mechanisms in migraine pathogenesis.
Subject(s)
Migraine Disorders , Humans , Migraine Disorders/immunology , Cytokines/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunologyABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that gave rise to COVID-19 infection produced a worldwide health crisis. The virus can cause a serious or even fatal disease. Comprehending the complex immunological responses triggered by SARS-CoV-2 infection is essential for identifying pivotal elements that shape the course of the disease and its enduring effects on immunity. The span and potency of antibody responses provide valuable perspicuity into the resilience of post-infection immunity. The analysis of existing literature reveals a diverse controversy, confining varying data about the persistence of particular antibodies as well as the multifaceted factors that impact their development and titer, Within this study we aimed to understand the dynamics of anti-SARS-CoV-2 antibodies against nucleocapsid (anti-SARS-CoV-2 (N)) and spike (anti-SARS-CoV-2 (N)) proteins in long-term immunity in convalescent patients, as well as the factors influencing the production and kinetics of those antibodies. We collected 6115 serum samples from 1611 convalescent patients at different post-infection intervals up to 21 months Study showed that in the fourth month, the anti-SARS-CoV-2 (N) exhibited their peak mean value, demonstrating a 79% increase compared to the initial month. Over the subsequent eight months, the peak value experienced a modest decline, maintaining a relatively elevated level by the end of study. Conversely, anti-SARS-CoV-2 (S) exhibited a consistent increase at each three-month interval over the 15-month period, culminating in a statistically significant peak mean value at the study's conclusion. Our findings demonstrate evidence of sustained seropositivity rates for both anti-SARS-CoV-2 (N) and (S), as well as distinct dynamics in the long-term antibody responses, with anti-SARS-CoV-2 (N) levels displaying remarkable persistence and anti-SARS-CoV-2 (S) antibodies exhibiting a progressive incline.
Subject(s)
Antibodies, Viral , COVID-19 , Immunity, Humoral , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , COVID-19/immunology , Humans , Antibodies, Viral/immunology , Antibodies, Viral/blood , SARS-CoV-2/immunology , Immunity, Humoral/immunology , Spike Glycoprotein, Coronavirus/immunology , Female , Male , Adult , Middle Aged , Coronavirus Nucleocapsid Proteins/immunology , Phosphoproteins/immunology , Aged , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/bloodABSTRACT
Vaccines are an effective intervention for preventing infectious diseases. Currently many vaccine strategies are designed to improve vaccine efficacy by controlling antigen release, typically involving various approaches at the injection site. Yet, strategies for intracellular slow-release of antigens in vaccines are still unexplored. Our study showed that controlling the degradation of antigens in dendritic cells and slowing their transport from early endosomes to lysosomes markedly enhances both antigen-specific T-cell immune responses and germinal center B cell responses. This leads to the establishment of sustained humoral and cellular immunity in vivo imaging and flow cytometry indicated this method not only prolongs antigen retention at the injection site but also enhances antigen concentration in lymph nodes, surpassing traditional Aluminium (Alum) adjuvants. Additionally, we demonstrated that the slow antigen degradation induces stronger follicular helper T cell responses and increases proportions of long-lived plasma cells and memory B cells. Overall, these findings propose that controlling the speed of antigens transport in dendritic cells can significantly boost vaccine efficacy, offering an innovative avenue for developing highly immunogenic next-generation vaccines.
Subject(s)
Antigens , Dendritic Cells , Immunity, Cellular , Immunity, Humoral , Vaccines , Dendritic Cells/immunology , Dendritic Cells/metabolism , Animals , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Vaccines/immunology , Antigens/immunology , Immunity, Cellular/drug effects , Mice, Inbred C57BL , Mice , Female , B-Lymphocytes/immunologyABSTRACT
Immune responses from prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination mitigate disease severity, but they do not fully prevent subsequent infections, especially from genetically divergent strains. We examined the incidence of and immune differences against human endemic coronaviruses (eCoVs) as a proxy for response against future genetically heterologous coronaviruses (CoVs). We assessed differences in symptomatic eCoV and non-CoV respiratory disease incidence among those with known prior SARS-CoV-2 infection or previous COVID-19 vaccination but no documented SARS-CoV-2 infection or neither exposure. Retrospective cohort analyses suggest that prior SARS-CoV-2 infection, but not previous COVID-19 vaccination alone, associates with a lower incidence of subsequent symptomatic eCoV infection. There was no difference in non-CoV incidence, implying that the observed difference was eCoV specific. In a second cohort where both cellular and humoral immunity were measured, those with prior SARS-CoV-2 spike protein exposure had lower eCoV-directed neutralizing antibodies, suggesting that neutralization is not responsible for the observed decreased eCoV disease. The three groups had similar cellular responses against the eCoV spike protein and nucleocapsid antigens. However, CD8+ T cell responses to the nonstructural eCoV proteins nsp12 and nsp13 were higher in individuals with previous SARS-CoV-2 infection as compared with the other groups. This association between prior SARS-CoV-2 infection and decreased incidence of eCoV disease may therefore be due to a boost in CD8+ T cell responses against eCoV nsp12 and nsp13, suggesting that incorporation of nonstructural viral antigens in a future pan-CoV vaccine may improve vaccine efficacy.
Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Humans , COVID-19/immunology , COVID-19/prevention & control , COVID-19/epidemiology , COVID-19/virology , COVID-19 Vaccines/immunology , Incidence , SARS-CoV-2/immunology , Male , Female , Middle Aged , Retrospective Studies , Vaccination , Antibodies, Viral/immunology , Antibodies, Viral/blood , Adult , Spike Glycoprotein, Coronavirus/immunology , Immunity, Humoral/immunology , Aged , Antibodies, Neutralizing/immunologyABSTRACT
Despite advancements in vaccinology, there is currently no effective anti-HIV vaccine. One strategy under investigation is based on the identification of epitopes recognized by broadly neutralizing antibodies to include in vaccine preparation. Taking into account the benefits of anti-idiotype molecules and the diverse biological attributes of different antibody formats, our aim was to identify the most immunogenic antibody format. This format could serve as a foundational element for the development of an oligo-polyclonal anti-idiotype vaccine against HIV-1. For our investigation, we anchored our study on an established b12 anti-idiotype, referred to as P1, and proposed four distinct formats: two single chains and two minibodies, both in two different orientations. For a deeper characterization of these molecules, we used immunoinformatic tools and tested them on rabbits. Our studies have revealed that a particular minibody conformation, MbVHVL, emerges as the most promising candidate. It demonstrates a significant binding affinity with b12 and elicits a humoral anti-HIV-1 response in rabbits similar to the Fab format. This study marks the first instance where the minibody format has been shown to provoke a humoral response against a pathogen. Furthermore, this format presents biological advantages over the Fab format, including bivalency and being encoded by a monocistronic gene, making it better suited for the development of RNA-based vaccines.
Subject(s)
AIDS Vaccines , Antibodies, Anti-Idiotypic , HIV Antibodies , HIV-1 , Immunity, Humoral , Animals , Rabbits , HIV Antibodies/immunology , HIV-1/immunology , Immunity, Humoral/immunology , Antibodies, Anti-Idiotypic/immunology , AIDS Vaccines/immunology , HIV Infections/immunology , HIV Infections/virology , Humans , Antibodies, Neutralizing/immunology , Computer Simulation , Epitopes/immunologyABSTRACT
Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution.
Subject(s)
Antibodies, Viral , Cross Reactions , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Humans , Respiratory Syncytial Virus Infections/immunology , Infant , Antibodies, Viral/immunology , Cross Reactions/immunology , Respiratory Syncytial Virus, Human/immunology , Female , Immunity, Humoral/immunology , Viral Fusion Proteins/immunology , Longitudinal Studies , Male , Immunoglobulin G/immunology , Immunoglobulin G/blood , Infant, Newborn , Immunity, Maternally-AcquiredABSTRACT
Seasonal influenza remains a serious global health problem, leading to high mortality rates among the elderly and individuals with comorbidities. Vaccination is generally accepted as the most effective strategy for influenza prevention. While current influenza vaccines are effective, they still have limitations, including narrow specificity for certain serological variants, which may result in a mismatch between vaccine antigens and circulating strains. Additionally, the rapid variability of the virus poses challenges in providing extended protection beyond a single season. Therefore, mRNA technology is particularly promising for influenza prevention, as it enables the rapid development of multivalent vaccines and allows for quick updates of their antigenic composition. mRNA vaccines have already proven successful in preventing COVID-19 by eliciting rapid cellular and humoral immune responses. In this study, we present the development of a trivalent mRNA vaccine candidate, evaluate its immunogenicity using the hemagglutination inhibition assay, ELISA, and assess its efficacy in animals. We demonstrate the higher immunogenicity of the mRNA vaccine candidate compared to the inactivated split influenza vaccine and its enhanced ability to generate a cross-specific humoral immune response. These findings highlight the potential mRNA technology in overcoming current limitations of influenza vaccines and hold promise for ensuring greater efficacy in preventing seasonal influenza outbreaks.
Subject(s)
Immunity, Humoral , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Orthomyxoviridae Infections , mRNA Vaccines , Animals , Female , Humans , Mice , Cross Reactions/immunology , Enzyme-Linked Immunosorbent Assay , HEK293 Cells , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Immunity, Humoral/immunology , Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza Vaccines/immunology , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , Mice, Inbred BALB C , mRNA Vaccines/administration & dosage , mRNA Vaccines/chemistry , mRNA Vaccines/genetics , mRNA Vaccines/immunology , Seasons , Time Factors , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/virologyABSTRACT
Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.
Subject(s)
Antigens, CD19 , Bone Marrow , Interleukins , Plasma Cells , Humans , Plasma Cells/immunology , Interleukins/immunology , Interleukins/metabolism , Bone Marrow/immunology , Antigens, CD19/immunology , Antigens, CD19/metabolism , Immunity, Humoral/immunology , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/immunology , Bone Marrow Cells/immunology , Bone Marrow Cells/cytology , Single-Cell Analysis , Adult , B-Lymphocytes/immunology , Antibody-Producing Cells/immunology , Female , Male , Vaccination , Middle Aged , Diphtheria-Tetanus-Pertussis Vaccine/immunologyABSTRACT
This paper aims to compare the cellular immune response to the SARS-CoV-2 BNT162b2 vaccine of pediatric patients with autoimmune inflammatory rheumatic disease (pAIIRD) and healthy controls. A prospective longitudinal study was conducted between April 2021 and December 2022 at the Tel Aviv Medical Center. Children <18 years, with pediatric-onset AIIRD and healthy controls, who have received at least two doses of the BNT162b2 vaccine, were included. Humoral response was evaluated by serum levels of anti-SARS-CoV-2 receptor-binding domain antibodies. Cellular response was evaluated by flow cytometry, measuring IFNγ and TNFα production by CD4+ T cells following stimulation with SARS-CoV-2 Spike peptide mix. The study included 20 pAIIRD patients and 11 controls. The mean age of participants was 12.6â ±â 2.94 years, with 58.1% females. The cellular response to the BNT162b2 vaccine was statistically similar in both groups. However, the humoral response was statistically lower in pAIIRD compared with the healthy control group. There was no statistically significant correlation between the humoral response and cellular response. During the study period, 43.75% of AIIRD children and 72.7% of controls had a breakthrough COVID-19 infection (Pâ =â 0.48). Bivariate models examining the effect of the cellular response and presence of an AIIRD on breakthrough infections found no effect. Compared with healthy controls, pAIIRD demonstrated similar cellular responses. Patients showed reduced humoral response compared with healthy adolescents, but similar breakthrough infection rates. These findings may support the importance of the cellular response in protecting against COVID-19 infections.
Subject(s)
Antibodies, Viral , BNT162 Vaccine , COVID-19 , Immunity, Cellular , Rheumatic Diseases , SARS-CoV-2 , Humans , Female , BNT162 Vaccine/immunology , Male , Child , COVID-19/immunology , COVID-19/prevention & control , Adolescent , SARS-CoV-2/immunology , Rheumatic Diseases/immunology , Prospective Studies , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoimmune Diseases/immunology , Longitudinal Studies , COVID-19 Vaccines/immunology , Spike Glycoprotein, Coronavirus/immunology , Immunity, Humoral/immunology , CD4-Positive T-Lymphocytes/immunology , Interferon-gamma/immunologyABSTRACT
Following infection and vaccination against SARS-CoV-2, humoral components of the adaptive immune system play a key role in protecting the host. Specifically, B cells generate high-affinity antibodies against various antigens of the virus. In this review, we discuss the mechanisms of immunity initiation through both natural infection and vaccination, shedding light on the activation of B cell subsets in response to SARS-CoV-2 infection and vaccination. The innate immune system serves as the initial line of primary and nonspecific defence against viruses. However, within several days following infection or a vaccine dose, a virus-specific immune response is initiated, primarily by B cells that produce antibodies. These antibodies contribute to the resolution of the disease. Subsequently, these B cells transition into memory B cells, which play a crucial role in providing long-term immunity against the virus. CD4+ T helper cells initiate a cascade, leading to B cell somatic hypermutation, germinal center memory B cells, and the production of neutralizing antibodies. B-cell dysfunction can worsen disease severity and reduce vaccine efficacy. Notably, individuals with B cell immunodeficiency show lower IL-6 production. Furthermore, this review delves into several aspects of immune responses, such as hybrid immunity, which has shown promise in boosting broad-spectrum protection. Cross-reactive immunity is under scrutiny as well, as pre-existing antibodies can offer protection against the disease. We also decipher breakthrough infection mechanisms, especially with the novel variants of the virus. Finally, we discuss some potential therapeutic solutions regarding B cells including convalescent plasma therapy, B-1 cells, B regulatory cell (Breg) modulation, and the use of neutralizing monoclonal antibodies in combating the infection. Ongoing research is crucial to grasp population immunity trends and assess the potential need for booster doses in maintaining effective immune responses against potential viral threats.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , B-Lymphocytes , COVID-19 Vaccines , COVID-19 , Immunity, Humoral , SARS-CoV-2 , Vaccination , Humans , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Immunity, Humoral/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , Antibodies, Neutralizing/immunology , B-Lymphocytes/immunology , Memory B Cells/immunology , Immunity, Innate/immunologyABSTRACT
Immune responses in early life are characterized by a failure to robustly generate long-lasting protective responses against many common pathogens or upon vaccination. This is associated with a reduced ability to generate T-cell dependent high affinity antibodies. This review highlights the differences in T-cell dependent antibody responses observed between infants and adults, in particular focussing on the alterations in immune cell function that lead to reduced T follicular helper cell-B cell crosstalk within germinal centres in early life. Understanding the distinct functional characteristics of early life humoral immunity, and how these are regulated, will be critical in guiding age-appropriate immunological interventions in the very young.
Subject(s)
Immunity, Humoral , Humans , Immunity, Humoral/immunology , Animals , B-Lymphocytes/immunology , Infant , Germinal Center/immunology , Germinal Center/cytology , AdultABSTRACT
OBJECTIVES: (1) To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to 2 years post-vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity. METHODS: Sixty ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed-effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. RESULTS: The primary vaccination induced an 11- to 208-fold increase in binding and neutralizing antibody levels and a 3- to 4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3- to 5-fold increase in binding antibodies and 4- to 5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity. INTERPRETATION: Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered.
Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 Vaccines , COVID-19 , Multiple Sclerosis , SARS-CoV-2 , Humans , COVID-19/immunology , COVID-19/prevention & control , Male , Female , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/administration & dosage , Adult , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Longitudinal Studies , SARS-CoV-2/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/drug therapy , Antibodies, Viral/blood , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Immunity, Cellular/drug effects , Vaccination , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunologyABSTRACT
INTRODUCTION: With the emergence of newer SARS-CoV-2 variants and their substantial effects on the levels and duration of protection against infection, an understanding of these characteristics of the protection conferred by humoral and cellular immunity can aid in the proper development and implementation of vaccine and safety guidelines. METHODS: We conducted a rapid literature review and searched five electronic databases weekly from 1 November 2021 to 30 September 2022. Studies that assessed the humoral or cellular immunity conferred by infection, vaccination or a hybrid (combination of both) in adults and risk groups (immunocompromised and older populations) were identified. Studies were eligible when they reported data on immunological assays of COVID-19 (related to vaccination and/or infection) or the effectiveness of protection (related to the effectiveness of vaccination and/or infection). RESULTS: We screened 5103 studies and included 205 studies, of which 70 provided data on the duration of protection against SARS-CoV-2 infection. The duration of protection of adaptive immunity was greatly impacted by Omicron and its subvariants: levels of protection were low by 3-6 months from exposure to infection/vaccination. Although more durable, cellular immunity also showed signs of waning by 6 months. First and second mRNA vaccine booster doses increased the levels of protection against infection and severe disease from Omicron and its subvariants but continued to demonstrate a high degree of waning over time. CONCLUSION: All humoral immunities (infection-acquired, vaccine-acquired and hybrid) waned by 3-6 months. Cellular immunity was more durable but showed signs of waning by 6 months. Hybrid immunity had the highest magnitude of protection against SARS-CoV-2 infection. Boosting may be recommended as early as 3-4 months after the last dose, especially in risk groups.
Subject(s)
COVID-19 Vaccines , COVID-19 , Immunity, Cellular , SARS-CoV-2 , Humans , COVID-19/prevention & control , COVID-19/immunology , SARS-CoV-2/immunology , COVID-19 Vaccines/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Immunization, Secondary , VaccinationABSTRACT
OBJECTIVES: In the post-SARS-CoV-2 pandemic era, "breakthrough infections" are still documented, due to variants of concerns (VoCs) emergence and waning humoral immunity. Despite widespread utilization, the definition of the anti-Spike (S) immunoglobulin-G (IgG) threshold to define protection has unveiled several limitations. Here, we explore the advantages of incorporating T-cell response assessment to enhance the definition of immune memory profile. METHODS: SARS-CoV-2 interferon-gamma release assay test (IGRA) was performed on samples collected longitudinally from immunocompetent healthcare workers throughout their immunization by infection and/or vaccination, anti-receptor-binding domain IgG levels were assessed in parallel. The risk of symptomatic infection according to cellular/humoral immune capacities during Omicron BA.1 wave was then estimated. RESULTS: Close to 40% of our samples were exclusively IGRA-positive, largely due to time elapsed since their last immunization. This suggests that individuals have sustained long-lasting cellular immunity, while they would have been classified as lacking protective immunity based solely on IgG threshold. Moreover, the Cox regression model highlighted that Omicron BA.1 circulation raises the risk of symptomatic infection while increased anti-receptor-binding domain IgG and IGRA levels tended to reduce it. CONCLUSION: The discrepancy between humoral and cellular responses highlights the significance of assessing the overall adaptive immune response. This integrated approach allows the identification of vulnerable subjects and can be of interest to guide antiviral prophylaxis at an individual level.
Subject(s)
Antibodies, Viral , COVID-19 , Immunity, Humoral , Immunoglobulin G , Immunologic Memory , Interferon-gamma Release Tests , SARS-CoV-2 , Humans , COVID-19/immunology , SARS-CoV-2/immunology , Immunologic Memory/immunology , Immunity, Humoral/immunology , Antibodies, Viral/immunology , Antibodies, Viral/blood , Immunoglobulin G/immunology , Immunoglobulin G/blood , Male , Female , Adult , Middle Aged , Interferon-gamma Release Tests/methods , Spike Glycoprotein, Coronavirus/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , T-Lymphocytes/immunology , Health Personnel , COVID-19 Vaccines/immunologyABSTRACT
Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.
Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Kidney Transplantation , T-Lymphocytes, Regulatory , Animals , Mice , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Graft Rejection/immunology , Isoantibodies , Kidney Transplantation/adverse effects , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, CXCR5/immunology , Immunity, Humoral/immunologyABSTRACT
Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and cellular immune response to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response in patients with CLL.