Humoral Immune Responses Research Articles

Development and Evaluation of a Newcastle Disease Virus-like Particle Vaccine Expressing SARS-CoV-2 Spike Protein with Protease-Resistant and Stability-Enhanced Modifications

The ongoing global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the continuous development of innovative vaccine strategies, especially in light of emerging viral variants that could undermine the effectiveness of existing vaccines. In this study, we developed a recombinant virus-like particle (VLP) vaccine based on the Newcastle Disease Virus (NDV) platform, displaying a stabilized prefusion form of the SARS-CoV-2 spike (S) protein. This engineered S protein includes two proline substitutions (K986P, V987P) and a mutation at the cleavage site (RRAR to QQAQ), aimed at enhancing both its stability and immunogenicity. Using a prime-boost regimen, we administered NDV-VLP-S-3Q2P intramuscularly at different doses (2, 10, and 20 µg) to BALB/c mice. Robust humoral responses were observed, with high titers of S-protein-specific IgG and neutralizing antibodies against SARS-CoV-2 pseudovirus, reaching titers of 1:2200–1:2560 post-boost. The vaccine also induced balanced Th1/Th2 immune responses, evidenced by significant upregulation of cytokines (IFN-γ, IL-2, and IL-4) and S-protein-specific IgG1 and IgG2a. Furthermore, strong activation of CD4+ and CD8+ T cells in the spleen and lungs confirmed the vaccine’s ability to promote cellular immunity. These findings demonstrate that NDV-S3Q2P-VLP is a potent immunogen capable of eliciting robust humoral and cellular immune responses, highlighting its potential as a promising candidate for further clinical development in combating COVID-19.

Rational Design of an Epidermal Growth Factor Receptor Vaccine: Immunogenicity and Antitumor Research

The epidermal growth factor receptor (EGFR) is frequently overexpressed in a variety of human epithelial tumors, and its aberrant activation plays a pivotal role in promoting tumor growth, invasion, and metastasis. The clinically approved passive EGFR-related therapies have numerous limitations. Seven EGFR-ECD epitope peptides (EG1-7) were selected through bioinformatics epitope prediction tools including NetMHCpan-4.1, NetMHCIIpan-3.2, and IEDB Consensus (v2.18 and v2.22) and fused to the translocation domain of diphtheria toxin (DTT). The A549 tumor model was successfully established in a murine mouse model. The vaccine was formulated by combining the adjuvants Alum and CpG and subsequently assessed for its immunogenicity and anti-tumor efficacy. DTT-EG (3;5;6;7) vaccines elicited specific humoral and cellular immune responses and effectively suppressed tumor growth in both prophylactic and therapeutic mouse tumor models. The selected epitopes EG3 (HGAVRFSNNPALCNV145-159), EG5 (KDSLSINATNIKHFK346-360), EG6 (VKEITGFLLIQAWPE398-412), and EG7 (LCYANTINWKKLFGT469-483) were incorporated into vaccines for active immunization, representing a promising strategy for the treatment of tumors with overexpressed epidermal growth factor receptor (EGFR). The vaccine design and fusion method employed in this study demonstrate a viable approach toward the development of cancer vaccines.

Practical Management of ANCA-associated Vasculitis – A Clinician’s Perspective

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can be a life-threatening condition, characterised by necrotising inflammation of small blood vessels. Major organ involvement, most commonly kidney and lung disease, is associated with significant morbidity and mortality. Intensive early immunosuppressive therapy is the cornerstone of management and has transformed ANCA-associated vasculitis (AAV) into a chronic relapsing condition. Remission induction with tapering glucocorticoids in combination with cyclophosphamide or rituximab is the standard of care for severe disease. Avacopan, an oral C5aR1 antagonist, has been approved for remission induction and helps minimise glucocorticoid exposure. Plasma exchange should be considered for severe kidney or life-threatening disease. Lower dose glucocorticoid induction regimens can be used without compromising remission rates. Remission maintenance therapy is recommended, and rituximab is usually first line over azathioprine. Mycophenolate mofetil (MMF) or methotrexate with low dose glucocorticoids are third line options. Immunosuppression associated infection risk remains a concern; both during acute presentations and in the long term; highlighted by the impact of rituximab on humoral immunity and vaccine response during the COVID-19 pandemic. There remains an ongoing need for therapies which induce rapid remission and optimise kidney recovery whilst minimising infection risk. Clinical trials are evaluating newer therapeutic options. Due to increasing treatment options, management should be individualised, balancing effective immunosuppression against co-morbidities and frailty. Summary: This review focuses on the treatment decision pathways for clinicians and patients in the management of severe AAV (granulomatosis with polyangiitis and microscopic polyangiitis). Key clinical trials, predictors of outcome, novel therapeutics and practical steps to mitigate infection risk are discussed. Key messages: Immunosuppression regimens have been refined due to emerging evidence from clinical trials. Rituximab, avacopan and reduced-dose glucocorticoid schedules have been the focus of recent studies. Infections and immunosuppression-induced immunodeficiency must be considered when determining individualised treatment.

Association between sleep duration and lung function among U.S. adults

BackgroundSleep’s impact on the human immune system and inflammatory responses makes it a potential risk factor for lung function impairment. However, the relationship between sleep duration and lung function impairment in middle-aged and young adults has been rarely investigated.MethodsA total of 9,284 aged 20–64 years were categorized into four groups according to sleep duration (≤ 6 h, 7 h, 8 h, and ≥ 9 h), with 7 h as the reference, by using the U.S. NHANES data, 2007–2012. Forced expiratory volume in the 1 s (FEV1), forced vital capacity (FVC), FEV1 to FVC (FEV1/FVC) ratio, peak expiratory flow (PEF), and forced expiratory flow at 25–75% (FEF25 − 75%) were measured by spirometry. Restrictive impairment was defined as baseline FVC < 80% predicted and obstructive impairment as FEV1/FVC < 0.70. Generalized linear regression and logistic regression were performed to estimate the associations between sleep duration and lung function.ResultsCompared with 7 h of sleep duration, shorter and longer sleep duration were associated with decreases in FEV1 (≤ 6 h: β=-0.010, 95% CI=-0.014 to -0.006; 8 h: β=-0.005, 95% CI=-0.009 to -0.001), FVC (≤ 6 h: β=-0.018, 95% CI=-0.014 to -0.007; 8 h: β=-0.005, 95% CI=-0.009 to -0.002), and PEF (≤ 6 h: β=-0.006, 95% CI=-0.010 to -0.002; 8 h: β=-0.007, 95% CI=-0.011 to -0.002; ≥ 9 h: β=-0.012, 95% CI=-0.020 to -0.004). Similarly, shorter (≤ 6 h: OR = 1.346, 95% CI = 1.065 to 1.700) and longer (≥ 9 h: OR = 1.827, 95% CI = 1.236 to 2.700) sleep duration were associated with increased risks of restrictive impairment. Moreover, the aforementioned associations were more pronounced among male participants.ConclusionsCompared with 7 h of sleep duration, shorter and longer sleep duration were associated with impaired lung function among adults aged 20–64 years, and these associations were stronger among males.

SARS-CoV-2 immune responses in patients with multiple myeloma and lenalidomide maintenance therapy

IntroductionMultiple myeloma (MM) is an uncontrolled plasma cell proliferation in the bone marrow, leading to immune dysregulation with impaired humoral immune responses. Conversely, cellular-based responses play a vital role in MM patients. However, the extent and duration of cellular-induced protection remain unclear to date. Here, immunomodulatory drugs (IMiDs) like Lenalidomide (Lena) become interesting, as they may have stimulatory effects on T-cell functioning.MethodsIn this study we investigated immune responses elicited by COVID-19 vaccine or infection comparing 43 healthy volunteers (avg. 35y, 72.1% female, 81.4% previously COVID-19 infected), with 41 MM patients under Lena maintenance therapy (avg. 63.8y, 51.2% female, 61% previously COVID-19 infected). Humoral responses to SARS-CoV-2 spike (S), spike-RBD, and nucleocapsid (N) were measured via ELISA in subjects’ plasma. Freshly isolated PBMCs, incubated with SARS-CoV-2 peptides (N, S), activation induced marker (AIM) assays and flow cytometry, allowed us to assess cellular responses (CD8+ T, T(F)H: CD4+ T (follicular) helper).ResultsWhereas healthy controls showed significant better humoral responses (N IgA p&amp;lt;0.001), T cell responses were robust in the MM group (higher S-act. TH, p&amp;lt;0.001). Stratified by COVID-19 status, the MM group showed higher N-act. TH (p=0.03). These results were unchanged comparing a Lena intake with Lena break around vaccination.DiscussionTaken together, MM patients under Lena therapy exhibit weakened antibody production but present a robust T cell response following SARS-COV-2 infection or vaccination. Our results highlight the importance of vaccination in this subgroup and moreover, argue against a Lena intake break around the time of vaccination.

Construction and immunological evaluation of recombinant adenovirus vaccines of new novel NADC34-PRRSV strains in pigs

IntroductionPorcine reproductive and respiratory syndrome virus (PRRSV) causes reproductive and respiratory diseases in sow herds and piglets. The emergence of ORF5 RFLP 1–7-4-like (NADC34-like) PRRSV strain in China has brought a new round of challenges to PRRSV prevention.MethodsIn addition, recombinant adenovirus vaccine candidates against the newly emerged NADC34-like strain were constructed in the study; the immunogenicity of the vaccine was investigated in piglets. After inoculation with PRRSV recombinant adenovirus, specific antibodies, neutralizing antibodies, and levels of IFN-γ and IL-4 cytokines were detected in serum.ResultsThirty-five days after immunization, the levels of IFN-γ and IL-4 cytokines in the pac-Ad5-34-GP3, pac-Ad5-34-GP5, and pac-Ad5-34-GP35 experimental groups were significantly higher (p &amp;lt; 0.05) than those of the PBS and the adenovirus group. All vaccines can cause corresponding Th1 and Th2 immune responses based on animal experimental results. After the challenge, no obvious clinical symptoms were observed in the immune groups compared with the control group, vaccinated animals could reduce the occurrence of viremia, and the occurrence of viremia was alleviated, with no obvious pathological changes in the lungs, indicating that recombinant adenovirus vaccine could provide a good protective immunity and produce a good humoral and cellular immune response at the same time.DiscussionIt shows that the recombinant adenovirus vaccine group has better protection against the virus. Provide vaccine reserve and theoretical support for the emergence of new PRRSV subtypes in China.

Immune Response and Histopathological Changes of Serratia rubidaea in Mice

Serratia rubidaea is a zoonotic opportunistic pathogen that causes respiratory tract infection, septicemia, and encephalitis in humans and animals. The current study aimed to estimate the immunological response (IgG, IL-6by ELISA test and Delayed Type Hypersensitivity (DTH)-Skin Test and histopathological lesions (intestine, liver, kidney, and spleen) by using twenty-four Swiss mice divided into three equal groups (8/each).The first group(G1) as control negative given PBS (pH 7.2) 0.1ml S/C, the second group(G2) immunized by killed whole cell antigen Serratia rubidaea (KWCA SR) (1.2 ×109CFU ml) S/C and the third group(G3) immunized by sonicated whole cell antigen Serratia rubidaea (SWCASR) (1000 μg/ml) S/C. A booster dose was given after 14 days of immunization to the G2 and G3 the same as the immunizing dose. At 21 and 28 days of immunization, IgG and IL-6 concentrations were increased significantly (P≤0.05) in the groups G2 and G3 compared to the negative control group. DTH-Skin Tests of G2 and G3 groups showed increased induration diameter after 24 and 48 hours. and a decrease at 72 hours. Histopathological lesions showed mild to moderate changes in immunized groups compared with the positive control group in all organs. In conclusion, it was found that KWCASR and SWCASR induce humoral (IgG) and cellular immune responses(IL-6,DTH), which reduce the pathological lesions in the immunized mice.

The effect of sleep and shift work on the primary immune response to messenger RNA-based COVID-19 vaccination.

Shift work can cause circadian misalignment, which often results in sleeping problems and has been associated with immune dysfunction. To better understand the impact of shift work on a primary immune response to vaccination, we compared severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific humoral and cellular immune responses after one injection of the messenger RNA (mRNA)-1273 vaccine between day workers (n = 24) and night shift workers (n = 21). In addition, duration and quality of sleep were assessed for a period of 7 days around the time of vaccination using actigraphy and daily sleep diaries, and their relationship with immunogenicity of mRNA-1273 vaccination was studied. We found that median total sleep time on the 2 days immediately after vaccination, which coincided with the days that night shift workers worked night shifts, was significantly lower in night shift workers (342 and 318 min) than day workers (431 and 415 min) (both p < 0.001). There was no difference in sleep quality between day workers and night shift workers. Furthermore, no difference in the antibody response between the two groups was observed, yet night shift workers had a significantly higher virus-specific T-cell response than day workers 28 days after immunisation (p = 0.013). Multivariate regression analysis showed no association between sleep duration, sleep quality and SARS-CoV-2-specific humoral or cellular immune responses. Collectively, these findings indicate that shift work-induced sleep loss and night shift work have little to no effect on the primary immune response to mRNA-based COVID-19 vaccination.

IFN-I promotes T cell-independent immunity and RBC autoantibodies via modulation of B-1 cell subsets in murine SCD.

The pathophysiology of sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusion, although its impact on the adaptive immune responses remains incompletely understood. To comprehensibly profile the humoral immune responses, we immunized SCD mice with T cell-independent (TI) and T cell-dependent (TD) antigens. Our study showed that SCD mice have significantly enhanced type 2 TI (TI-2) immune responses in a manner dependent on the level of type I IFN (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of antigen administration. Consistent with the enhanced TI-2 immune responses in SCD mice, the frequencies of B-1b cells (B-1 cells in humans), a major cell type responding to TI-2 antigens, were significantly increased in both the peritoneal cavity and spleens of SCD mice and in blood of patients with SCD. In support of expanded B-1 cells, elevated levels of anti-red blood cell (RBC) autoantibodies were detected in both SCD mice and patients. Both the levels of TI-2 immune responses and anti-RBC autoantibodies were significantly reduced following IFNAR antibody blockades and in IFNAR-1 deficient SCD mice. Moreover, the alteration of B-1 cell subsets were reversed in IFNAR-1 deficient SCD mice, uncovering a critical role for IFN-I in the enhanced TI-2 immune responses and the increased production of anti-RBC autoantibodies by modulating the innate B-1 cell subsets in SCD. Overall, our study provides experimental evidence that the modulation of B-1 cells and IFN-I can regulate TI immune responses and the levels of anti-RBC autoantibodies in SCD.

Immunomodulatory Effects of Andrographis paniculata Leaf Extract in Cyclophosphamide-induced Immunosuppressed Mice

Background Cyclophosphamide is one of the most extensively used chemotherapeutic drugs and is employed to treat several malignancies. Cyclophosphamide often comes with several unpleasant side effects. The primary negative consequence of cyclophosphamide in clinical chemotherapy is immunosuppression, which can lead to life-threatening complications. Objectives: The present work was dedicated to exploring the therapeutic effects of Andrographis paniculata against cyclophosphamide-induced immunosuppression in mice. Materials and Methods The BALB/c mice were treated with 80 mg/kg of cyclophosphamide to achieve immunosuppression and treated with 250 and 500 mg/kg of A. paniculata extract. 10 mg/kg of levamisole was used as a standard drug. After the completion of the treatments, the body weights of the experimental animals were measured. The immune organs (spleen and thymus) were determined by standard methods. The levels of blood components were studied using an automated hematological analyzer. The macrophage phagocytic index, humoral response, and delayed immune response were studied by standard methods. The histopathological analysis was done on the heart, spleen, and thymus. Results The treatment with 250 and 500 mg/kg of A. paniculata extract substantially increased the body weight and elevated the immune organ index in the immunosuppressed mice. The changes in the levels of hematological parameters were successfully modulated by A. paniculata. The levels of macrophage phagocytic index and delayed and humoral immune responses were boosted by the A. paniculata extract treatment in the immunosuppressed mice. The outcomes of histopathological analysis exhibited that the A. paniculata extract attenuated the cyclophosphamide-induced damage to the heart, thymus, and spleen tissues. Conclusion The findings of the current work validate the immunomodulatory properties of A. paniculata extract in cyclophosphamide-induced immunosuppressed mice. Hence, it was clear that A. paniculata can be a talented immunomodulatory agent to treat immunological complications.

Development and application of an uncapped mRNA platform

Background A novel uncapped mRNA platform was developed. Methods Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), SδT-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gDED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gDFR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1–400). Results Quantifiable target protein expression was achieved in vitro and in vivo with eGFP- and Fluc-mRNA-LNP. SδT-mRNA-LNP, gDED-mRNA-LNP and gDFR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, SδT-mRNA-LNP elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gDED-mRNA-LNP and gDFR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1mψTP) in the induction of antibodies via SδT-mRNA-LNP. Conclusions Our uncapped, process-simplified and economical mRNA platform may have broad utility in vaccines and protein replacement drugs. KEY MESSAGES The mRNA platform described in our paper uses internal ribosome entry site (IRES) (Rapid, Amplified, Capless and Economical, RACE; Register as BH-RACE platform) instead of caps and uridine triphosphate (UTP) instead of N1-methylpseudouridine triphosphate (N1mψTP) to synthesize mRNA. Through the self-developed packaging instrument and lipid nanoparticle (LNP) delivery system, mRNA can be expressed in cells more efficiently, quickly and economically. Particularly exciting is that potent neutralizing antibodies against Delta and Omicron real viruses were induced with the new coronavirus S protein mRNA vaccine from the BH-RACE platform.

Health Promoting Properties of Vitamins C and D Against HIV Disease Progression, a Narrative Review

Human immunodeficiency virus (HIV) has troubled humankind for many years. The rate of new HIV cases is decreasing steadily, mostly because of safer sexual practices and scientific advances in medicine. However, the number of HIV-related trials has significantly increased, as the search for a definite cure for HIV is still fruitless. Our current treatment options involve antiretroviral therapy (ART) with various drug combinations that lower the patients’ viral load in order for the immune system to reconstitute itself. This way, adherent patients achieve a life expectancy similar to the general population. Besides the established treatment protocols, the focus has currently shifted towards secondary pharmaceutical regimen programs that enhance a patient’s immune system and response to opportunistic infections. Vitamins C and D are easily obtainable even in the developing world and are known to improve an individual’s daily life, with vitamin D enhancing the human immune response and vitamin C having an assisting role in both the immune response and as an important antioxidant. Recently, many studies assessing the effect of these vitamins on the progression of HIV have been performed. We aimed to collect and review these studies in order to determine the necessity of the supplementation of these vitamins in HIV-infected patients, which might complement the existing ART. To this day, the scientific community is conflicted, and more studies must be conducted before a definite conclusion about these vitamins’ effects on HIV patients can be reached.

Assessment of the immunity gap of two vaccination programs against Gumboro disease in Luong Phuong chicken

Maternal-derived antibody (MDA) is the priority protection against environmental Infectious Bursal Disease Virus (IBDV) in the first weeks. The passive immunity decreases, but the active immunity is not enough to protect chicks, so shortening the high-risk period is crucial to IBD control. The objective of this study was to evaluate the immunity gap between 2 vaccination programs against infectious bursal disease (IBD) in Luong Phuong chickens. A total of 34,600 chicks were administered by subcutaneous injection of IBD vaccine at 0.1 mL/dose at the hatchery. At 12 days old, 18,000 chicks were vaccinated with the M.B strain vaccine and 16,600 chicks were vaccinated with the 228E strain vaccine by drinking water. The IBD and Newcastle disease (ND) antibody evaluations were based on the Enzyme-linked immunosorbent assay (ELISA) technique. Parameters were recorded until slaughter including body weight, average daily gain, feed conversion rate, and mortality. The IBD MDA at 1 day old was medium and uniform (3809 and 45.3%), which could protect against IBD virus from 1 to 2 weeks old. At 28 days old, the IBD antibody titer of the MB vaccine was higher than that of the 228E vaccine, various proportions of samples in the M.B group exceeding 1,000 titers (40% vs. 0%), and it was a statistically significant difference (1,133 vs. 161) (P &lt; 0.01). Besides, the M.B vaccine created a faster and stronger immune response than the 228E vaccine, shortening the immune gap and protecting chicks earlier. The humoral immune response to the ND vaccine was good, with no difference between 2 groups, which proved that the M.B virus did not cause immunosuppression. The production parameters of chickens between the 2 groups were the same. In summary, the M.B vaccine made a short immune gap and did not cause immunodeficiency in chickens.

The Impact of HIV on B Cell Compartment and Its Implications for COVID-19 Vaccinations in People with HIV

HIV causes intense polyclonal activation of B cells, resulting in increased numbers of spontaneously antibody-secreting cells in the circulation and hypergammaglobulinemia. It is accompanied by significant perturbations in various B cell subsets, such as increased frequencies of immature/transitional B cells, activated memory B cells, atypical memory B cells, short-lived plasmablasts and regulatory B cells, as well as by decreased frequencies of resting memory and resting naïve B cells. Furthermore, both memory and antigen-inexperienced naïve B cells show exhausted and immune-senescent phenotypes. HIV also drives the expansion and functional impairment of CD4+ T follicular helper cells, which provide help to B cells, crucial for the generation of germinal center reactions and production of long-lived plasma and memory B cells. By suppressing viral replication, anti-retroviral therapy reverses the virus-induced perturbations and functional defects, albeit inadequately. Due to HIV’s lingering impact on B cells, immune senescence and residual chronic inflammation, people with HIV (PWH), especially immune non-responders, are immunocompromised and mount suboptimal antibody responses to vaccination for SARS-CoV-2. Here, we review how functionally and phenotypically distinct B cell subsets are induced in response to a vaccine and an infection and how HIV infection and anti-retroviral therapy (ART) impact them. We also review the role played by HIV-induced defects and perturbations in B cells in the induction of humoral immune responses to currently used anti-SARS-CoV-2 vaccines in PWH on ART. We also outline different strategies that could potentially enhance the vaccine-induced antibody responses in PWH. The review will provide guidance and impetus for further research to improve the immunogenicity of these vaccines in this human population.

Maintenance of Long-Term Effective Humoral Immune Response in Patients with COVID-19 with Homologous or Heterologous Booster Vaccines: A Retrospective Study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first identified in Wuhan, China, in December 2019, has led to global efforts in vaccination to mitigate rising morbidity and mortality, with vaccines proving crucial in controlling the pandemic. This study evaluated the humoral responses to the inactivated virus vaccine Sinopharm or Koxing Kerlafor, the protein subunit vaccine ZF001, and the adenoviral vector vaccine Convidecia after 18 months of inactivated virus vaccination by heterologous and homologous booster vaccination in patients with previous SARS-CoV-2 infection and healthy individuals. We discovered that patients who had recovered from the infection and then received a third vaccine dose (booster) exhibited durable immunity. Furthermore, the heterologous booster vaccine induced higher neutralizing antibody responses compared with the homologous booster. These findings offer valuable insights into the efficacy of different COVID-19 vaccine strategies following booster immunization.

Characterizing the SARS-CoV-2 antibody response and associations with patient factors: Serological profiling of participants enrolled in the GENCOV study.

The GENCOV study sought to evaluate serological differences between individuals with differing COVID-19 severity and outcomes. We assessed the SARS-CoV-2 antibody response of GENCOV participants cross-sectionally 1-, 6-, and 12-months following COVID-19 diagnosis to identify patient factors associated with more robust and durable humoral immune responses. COVID-19 patients and a control cohort of vaccinated infection-naïve participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada. Commercially available and laboratory-developed serological assays were used to characterize features of participants' antibody responses, including both binding and neutralizing antibodies. Regression analyses were performed to identify associations between participant characteristics and features of the SARS-CoV-2 antibody response. Samples were obtained from participants 1- (n = 938), 6- (n = 842), and 12-months (n = 662) post-infection or vaccination. At all time points, vaccinees, and to a greater extent those who were both infected and vaccinated, had significantly elevated anti-spike antibody levels compared to unvaccinated participants. Increasing age and/or illness severity were associated with significantly higher antibody levels among unvaccinated participants. Among vaccines, those who were vaccinated after infection (i.e., hybrid immunity) had consistently higher antibody levels compared to participants who were infection-naïve or vaccinated before their infection (i.e., breakthrough infections). Additionally, receiving more vaccine doses and having a more recent vaccination were strongly associated with higher antibody levels across all time points. Our findings highlight various patient factors, including vaccination, which contribute to robust, durable SARS-CoV-2 antibody responses. Overall, the findings presented here may inform future vaccine development and rollout plans.

The capicua-ataxin-1-like complex regulates Notch-driven marginal zone B cell development and sepsis progression

Follicular B (FOB) and marginal zone B (MZB) cells are pivotal in humoral immune responses against pathogenic infections. MZB cells can exacerbate endotoxic shock via interleukin-6 secretion. Here we show that the transcriptional repressor capicua (CIC) and its binding partner, ataxin-1-like (ATXN1L), play important roles in FOB and MZB cell development. CIC deficiency reduces the size of both FOB and MZB cell populations, whereas ATXN1L deficiency specifically affects MZB cells. B cell receptor signaling is impaired only in Cic-deficient FOB cells, whereas Notch signaling is disrupted in both Cic-deficient and Atxn1l-deficient MZB cells. Mechanistically, ETV4 de-repression leads to inhibition of Notch1 and Notch2 transcription, thereby inhibiting MZB cell development in B cell-specific Cic-deficient (Cicf/f;Cd19-Cre) and Atxn1l-deficient (Atxn1lf/f;Cd19-Cre) mice. In Cicf/f;Cd19-Cre and Atxn1lf/f; Cd19-Cre mice, humoral immune responses and lipopolysaccharide-induced sepsis progression are attenuated but are restored upon Etv4-deletion. These findings highlight the importance of the CIC-ATXN1L complex in MZB cell development and may provide proof of principle for therapeutic targeting in sepsis.

Immunogenicity and Safety According to Immunosuppressive Drugs and Different COVID-19 Vaccine Platforms in Immune-Mediated Disease: Data from SAFER Cohort

Background/Objectives: The effectiveness of COVID-19 vaccine in patients with immune-mediated inflammatory diseases (IMID) depends on the underlying disease, immunosuppression degree and the vaccine regimens. We evaluate the safety and immunogenicity of different COVID-19 vaccine schedules. Methods: The SAFER study: “Safety and effectiveness of the COVID-19 Vaccine in Rheumatic Disease”, is a Brazilian multicentric prospective observational phase IV study in the real-life. Data were analyzed after 2 or 3 doses of COVID-19 vaccines: adenoviral vectored vaccine (ChAdOx1 nCoV-19, Astrazeneca), mRNA vaccine (BNT162b2, Pfizer–BioNTech) or inactivated SARS-COV-2 vaccine (CoronaVac, Sinovac Biotech). IgG antibody against SARS-CoV-2 spike (IgG-S) receptor-binding domain level were quantified at baseline (T1) and 28 days after the first (T2), 2nd (T3) and 3rd (T4) doses by chemiluminescence (SARS-CoV-2-IgG-II Quant-assay, Abbott-Laboratories). Results: 721 patients with IMID were included in the analysis. The median titers of IgG-S (BAU/mL) increased progressively over the times: at baseline was 6.26 (5.41–7.24), T2: 73.01 (61.53–86.62), T3: 200.0 (174.36–229.41) and T4: 904.92 (800.49–1022.97). The multivariate linear regression showed that greater IgG-S titers were associated with pre-exposure to COVID-19 (p &lt; 0.001) and BNT162b2 booster vaccine (p &lt; 0.001). Rituximab and immunosuppressant drugs were independent factors for low titers (p = 0.002, p &lt; 0.001, respectively). No serious adverse event was reported. Conclusions: All platforms were safe and induced an increase in IgG-S antibodies. COVID-19 pre-exposure and BNT162b2 booster regimens were predictors of higher humoral immune responses, which is relevant in immunosuppressed populations. Immunosuppressants (mainly rituximab) predicted the lowest antibodies.

A Self‐Adjuvanting Large Pore 2D Covalent Organic Framework as a Vaccine Platform

Vaccines are one of the greatest human achievements in public health, as they help prevent the spread of diseases, reduce illness and death rates, saving thousands of lives with few side effects. Traditional vaccine development is centered around using live attenuated or inactivated pathogens, which is expensive and has resulted in vaccine‐associated illnesses. Advancements have led to the development of safer subunit vaccines, which contain recombinant proteins isolated from pathogens. Their short half‐life and small size make most subunit vaccines less immunogenic. Here, we introduce a large pore 2D covalent organic framework (COF), PyCOFamide, as a promising solution for an effective subunit platform. Our study demonstrates that simple adsorption of a model antigen, ovalbumin (OVA), onto PyCOFamide (OVA@COF) significantly enhances humoral and cell‐mediated immune response compared to free OVA. OVA@COF exhibited heightened immune cell activation and acts as an antigen reservoir, facilitating antigen‐presenting cell trafficking to the draining lymph nodes, amplifying the humoral immune response. Additionally, the breakdown of the COF releases monomers that adjuvant the activation of immune cells vital to creating strong immunity. This platform offers a potential avenue for safer, more effective subunit vaccines.

Spatial transcriptomics and in situ immune cell profiling of the host ectocervical landscape of HIV infected Kenyan sex working women

IntroductionChronic immune activation is a hallmark of human immunodeficiency virus (HIV) infection that significantly impacts disease pathogenesis. However, in-depth studies characterizing the immunological landscape of the ectocervix during chronic HIV infection remain scarce despite the importance of this tissue site for HIV transmission.MethodsEctocervical tissue samples were obtained from antiretroviral-naïve HIV-seropositive and -seronegative Kenyan female sex workers. These samples were assessed by spatial transcriptomics and Gene Set Enrichment Analysis. We further performed multi-epitope ligand cartography (MELC) using an in situ staining panel that included 17 markers of primarily T cell–mediated immune responses.ResultsSpatial transcriptomics revealed tissue-wide immune activation encompassing immune responses associated with chronic HIV infection. First, both the epithelial and submucosal compartments showed diverse but significant upregulation of humoral immune responses, as indicated by the expression of several antibody-related genes. Second, an antiviral state–associated cellular immunity was also observed in the HIV-seropositive group, characterized by upregulation of genes involved in interferon signaling across the mucosal tissue and a more spatially restricted mucosal expression of genes related to T cell activity and effector functions relative to the HIV-seronegative group. Additionally, HIV associated structural alterations were evident within both compartments. Downregulated genes across the epithelium were mainly linked to epithelial integrity, with the outer layer involved in terminal differentiation and the inner layer associated with epithelial structure. MELC analysis further revealed a significantly increased ectocervical leukocyte population in HIV-seropositive participants, primarily driven by an increase in CD8+ T cells while the CD4+ T cell population remained stable. Consistent with our spatial transcriptomics data, T cells from HIV-seropositive participants showed an increased effector phenotype, defined by elevated expression of various granzymes.ConclusionBy combining spatial transcriptomics and MELC, we identified significant HIV-associated cervical immune activity driven by induction of both T and B cell activity, together with a general antiviral state characterized by sustained interferon induction. These findings underscore that chronic HIV infection is associated with an altered ectocervical mucosal immune landscape years after primary infection. This sheds light on HIV pathogenesis at distant local sites and complements current knowledge on HIV-associated systemic immune activation.