Vaccine Non-responders Research Articles

Chronic Viral Infections and Hepatic Oncogenesis

Hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV) are major contrib¬utors to chronic liver disease and hepatocellular carcinoma (HCC) worldwide. Discovered in the 1960s and 1980s, these viruses are associated with significant global health burdens. HBV, a member of the He¬padnaviridae family, is a partially double-stranded DNA virus responsible for chronic liver infections that can lead to HCC. Despite the success of HBV vaccination, challenges such as vaccine escape mutants and non-responders persist. HCV, a member of the Flaviviridae family and a positive-sense single-stranded RNA virus, affects millions globally. While direct-acting antivirals (DAAs) can achieve high rates of viral clearance, vaccine development remains hindered by genetic diversity and immune evasion. HDV, the smallest known human virus, relies on HBV for its propagation. It exacerbates liver disease and increases HCC risk, particularly in co-infected individuals. HDV does not integrate into the host genome, suggesting indirect mechanisms of carcinogenesis, potentially through interactions with HBV. Addressing these chal¬lenges requires enhanced vaccination strategies, improved antiviral therapies, and continued research to understand the complex interplay between these viruses and liver cancer development.

Follow-Up of SARS-CoV-2 Antibody Levels in Belgian Nursing Home Residents and Staff Two, Four and Six Months after Primary Course BNT162b2 Vaccination.

When COVID-19 vaccines were implemented, nursing home residents (NHRs) and staff (NHS) in Belgium were prioritized for vaccination. To characterize the vaccine response over time in this population and to identify poorly responding groups, we assessed antibody concentrations two (T1), four (T2) and six months (T3) after primary course BNT162b2 vaccination in six groups of infection-naive/infection-primed NHRs/NHS, with/without comorbidity (NHRs only). Participant groups (N = 125 per group) were defined within a national serosurveillance study in nursing homes, based on questionnaire data. Dried blood spots were analyzed using ELISA for the quantification of SARS-CoV-2 S1RBD IgG antibodies. Among all groups, antibody concentrations significantly decreased between T1 and T2/T3, all with a ≥70% decrease at T3, except for infection-primed staff (-32%). Antibody concentrations among infection-naive NHRs were 11.96 times lower than those among infection-primed NHR, while the latter were comparable (x1.05) to infection-primed NHS. The largest proportion [13% (95% CI: 11-24%)] of vaccine non-responders was observed in the group of infection-naive NHRs with comorbidities. A longer interval between infection and vaccination (≥3 months) elicited higher antibody responses. Our data retrospectively show the necessity of timely COVID-19 booster vaccination. Infection-naive NHRs require special attention regarding immune monitoring in future epidemics or pandemics.

SARS-CoV-2-Specific Immune Cytokine Profiles to mRNA, Viral Vector and Protein-Based Vaccines in Patients with Multiple Sclerosis: Beyond Interferon Gamma.

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.

Baseline characteristics of SARS-CoV-2 vaccine non-responders in a large population-based sample.

Studies indicate that individuals with chronic conditions and specific baseline characteristics may not mount a robust humoral antibody response to SARS-CoV-2 vaccines. In this paper, we used data from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a longitudinal state-wide seroprevalence program that has enrolled more than 90,000 participants, to evaluate the role of chronic diseases as the potential risk factors of non-response to SARS-CoV-2 vaccines in a large epidemiologic cohort. A participant needed to complete an online survey and a blood draw to test for SARS-CoV-2 circulating plasma antibodies at four-time points spaced at least three months apart. Chronic disease predictors of vaccine non-response are evaluated using logistic regression with non-response as the outcome and each chronic disease + age as the predictors. As of April 24, 2023, 18,240 participants met the inclusion criteria; 0.58% (N = 105) of these are non-responders. Adjusting for age, our results show that participants with self-reported immunocompromised status, kidney disease, cancer, and "other" non-specified comorbidity were 15.43, 5.11, 2.59, and 3.13 times more likely to fail to mount a complete response to a vaccine, respectively. Furthermore, having two or more chronic diseases doubled the prevalence of non-response. Consistent with smaller targeted studies, a large epidemiologic cohort bears the same conclusion and demonstrates immunocompromised, cancer, kidney disease, and the number of diseases are associated with vaccine non-response. This study suggests that those individuals, with chronic diseases with the potential to affect their immune system response, may need increased doses or repeated doses of COVID-19 vaccines to develop a protective antibody level.

Systems and Computational Screening identifies SRC and NKIRAS2 as Baseline Correlates of Risk (CoR) for Live Attenuated Oral Typhoid Vaccine (TY21a) associated Protection

AimWe investigated the molecular underpinnings of variation in immune responses to the live attenuated typhoid vaccine (Ty21a) by analyzing the baseline immunological profile. We utilized gene expression datasets obtained from the Gene Expression Omnibus (GEO) database (accession number: GSE100665) before and after immunization. We then employed two distinct computational approaches to identify potential baseline biomarkers associated with responsiveness to the Ty21a vaccine. Main methodsThe first pipeline (knowledge-based) involved the retrieval of differentially expressed genes (DEGs), functional enrichment analysis, protein-protein interaction network construction, and topological network analysis of post-immunization datasets before gauging their pre-vaccination expression levels. The second pipeline utilized an unsupervised machine learning algorithm for data-driven feature selection on pre-immunization datasets. Supervised machine-learning classifiers were employed to computationally validate the identified biomarkers. Key findingsBaseline activation of NKIRAS2 (a negative regulator of NF-kB signalling) and SRC (an adaptor for immune receptor activation) was negatively associated with Ty21a vaccine responsiveness, whereas LOC100134365 exhibited a positive association. The Stochastic Gradient Descent (SGD) algorithm accurately distinguished vaccine responders and non-responders, with 88.8%, 70.3%, and 85.1% accuracy for the three identified genes, respectively. SignificanceThis dual-pronged novel analytical approach provides a comprehensive comparison between knowledge-based and data-driven methods for the prediction of baseline biomarkers associated with Ty21a vaccine responsiveness. The identified genes shed light on the intricate molecular mechanisms that influence vaccine efficacy from the host perspective while pushing the needle further towards the need for development of precise enteric vaccines and on the importance of pre-immunization screening.

Clinical and immunological outcomes of SARS-CoV-2-infected vaccine responders, vaccine non-responders, and unvaccinated patients evaluated for neutralizing monoclonal antibody treatment at a single German tertiary care center: a retrospective cohort study with prospective follow-up

PurposeThis study assessed the clinical and immunological outcomes of SARS-CoV-2-infected patients with risk factors for severe disease depending on their immunological status.MethodsIn this retrospective study with single follow-up visit, clinical outcome and humoral immunity was monitored in SARS-CoV-2 infected patients at risk. The results were compared based on the patients’ initial immunological status: unvaccinated (UV), patients who did not develop neutralizing antibodies after vaccination (vaccine non-responders, VNR), and patients who expressed neutralizing antibodies after vaccination (vaccine responders, VR). Patients who lacked neutralizing antibodies (VNR and UV) were treated with nMABs.ResultsIn total, 113 patients at risk of severe COVID-19 consented to participate in the study. VR and UV were not admitted to the hospital. During the observation period, UVs had the highest rate of SARS-CoV-2 re-infections. Three of 41 VNRs (7.3%) were hospitalized due to severe COVID-19, with two of them having undergone iatrogenic B-cell depletion. The humoral immune response after infection was significantly lower in the VNR group than in the VR group in terms of anti-N, anti-receptor-binding domain (RBD), anti-S antibody titers, and anti-S antibody avidity. In a sub-analysis of VNR, B cell-deficient non-responders had significantly lower levels of anti-N antibodies and anti-S avidity after infection than other VNRs.ConclusionVNR, particularly B-cell-depleted VNR, remained at risk of hospitalization due to COVID-19. In the VR group, however, no clinical complications or severe disease were observed, despite not receiving nMAbs. Tailoring the administration of nMABs according to patient vaccination and immunological status may be advisable.

Clinical Course, Immunogenicity, and Efficacy of BNT162b2 mRNA Vaccination Against SARS-CoV-2 Infection in Liver Transplant Recipients.

Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P < 0.001). Among LT recipients, older age and higher tacrolimus trough levels were associated with poorer immune response to 2-dose SARS-CoV-2 vaccination. Further studies are needed to assess variables associated with breakthrough infections and, hence, who should be prioritized for booster vaccination.

Intranasal HBsAg/HBcAg-Containing Vaccine Induces Neutralizing Anti-HBs Production in Hepatitis B Vaccine Non-Responders.

Hepatitis B vaccine induces the production of antibodies against hepatitis B surface antigen (anti-HBs) and prevents hepatitis B virus (HBV) infection. However, 5-10% of individuals cannot develop anti-HBs even after multiple vaccinations (HB vaccine non-responders). We developed an intranasal vaccine containing both HBs antigen (HBsAg) and HB core antigen (HBcAg) and mixed it with a viscosity enhancer, carboxyl vinyl polymer (CVP-NASVAC). Here, we investigated the prophylactic capacity of CVP-NASVAC in HB vaccine non-responders. Thirty-four HB vaccine non-responders were administered three doses of intranasal CVP-NASVAC. The prophylactic capacity of CVP-NASVAC was assessed by evaluating the induction of anti-HBs and anti-HBc (IgA and IgG) production, HBV-neutralization activity of sera, and induction of HBs- and HBc-specific cytotoxic T lymphocytes (CTLs). After CVP-NASVAC administration, anti-HBs and anti-HBc production were induced in 31/34 and 27/34 patients, respectively. IgA anti-HBs and anti-HBc titers significantly increased after CVP-NASVAC vaccination. HBV-neutralizing activity in vitro was confirmed in the sera of 26/29 CVP-NASVAC-administered participants. HBs- and HBc-specific CTL counts substantially increased after the CVP-NASVAC administration. Mild adverse events were observed in 9/34 participants; no serious adverse events were reported. Thus, CVP-NASVAC could be a beneficial vaccine for HB vaccine non-responders.

Single-cell RNA sequencing reveals the transcriptomic characteristics of peripheral blood mononuclear cells in hepatitis B vaccine non-responders.

The emergence of a vaccine against hepatitis B has proven to be an important milestone in the prevention of this disease; however, 5%-10% of vaccinated individuals do not generate an immune response to the vaccine, and its molecular mechanism has not been clarified. In this study, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from three volunteers with a high immune response (HR) and three with no immune response (NR) to the hepatitis B vaccine. We found that the antigen-presenting activity scores of various antigen-presenting cells, the mitogen-activated protein kinase (MAPK) pathway activity scores of naive B cells, and the cell activity scores of three types of effector T cells were significantly decreased, whereas the cytotoxicity scores of CD3highCD16lowKLRG1high natural killer T (NKT) cells were significantly increased in the NR group compared with those in the HR group. Additionally, the expression levels of some classical molecules associated with distinct signaling pathways-including HLA-B, HLA-DRB5, BLNK, BLK, IL4R, SCIMP, JUN, CEBPB, NDFIP1, and TXNIP-were significantly reduced in corresponding subsets of PBMCs from the NR group relative to those of the HR group. Furthermore, the expression of several cytotoxicity-related effector molecules, such as GNLY, NKG7, GZMB, GZMM, KLRC1, KLRD1, PRF1, CST7, and CTSW, was significantly higher in CD3highCD16lowKLRG1high NKT cells derived from non-responders. Our study provides a molecular basis for the lack of response to the hepatitis B vaccine, including defective antigen presentation, decreased T cell activity, and reduced IL-4 secretion, as well as novel insight into the role of NKT cells in the immune response to the hepatitis B vaccine.

Revaccination for Hepatitis B in Previous Nonresponders Following Hepatitis C Eradication.

Patients with chronic hepatitis C virus (HCV) do not respond to hepatitis B virus (HBV) vaccination as efficiently as the general population. We assessed if revaccination after HCV treatment resulted in improved response. Previous HBV vaccine nonresponders were prospectively recruited for revaccination after HCV eradication. Hepatitis B surface antibody (HBsAb) testing was performed 1 month after series completion. Follow-up HBsAb testing was performed in 31 of 34 enrolled patients with 21 (67.7%) reactive results. There were no significant differences in HBsAb reactivity based on age, sex, race, or advanced fibrosis presence. HBV vaccine nonresponders should be considered for revaccination following HCV cure.

Differential cellular and humoral immune responses in immunocompromised individuals following multiple SARS-CoV-2 vaccinations.

The heterogeneity of the immunocompromised population means some individuals may exhibit variable, weak or reduced vaccine-induced immune responses, leaving them poorly protected from COVID-19 disease despite receiving multiple SARS-CoV-2 vaccinations. There is conflicting data on the immunogenicity elicited by multiple vaccinations in immunocompromised groups. The aim of this study was to measure both humoral and cellular vaccine-induced immunity in several immunocompromised cohorts and to compare them to immunocompetent controls. Cytokine release in peptide-stimulated whole blood, and neutralising antibody and baseline SARS-CoV-2 spike-specific IgG levels in plasma were measured in rheumatology patients (n=29), renal transplant recipients (n=46), people living with HIV (PLWH) (n=27) and immunocompetent participants (n=64) post third or fourth vaccination from just one blood sample. Cytokines were measured by ELISA and multiplex array. Neutralising antibody levels in plasma were determined by a 50% neutralising antibody titre assay and SARS-CoV-2 spike specific IgG levels were quantified by ELISA. In infection negative donors, IFN-γ, IL-2 and neutralising antibody levels were significantly reduced in rheumatology patients (p=0.0014, p=0.0415, p=0.0319, respectively) and renal transplant recipients (p<0.0001, p=0.0005, p<0.0001, respectively) compared to immunocompetent controls, with IgG antibody responses similarly affected. Conversely, cellular and humoral immune responses were not impaired in PLWH, or between individuals from all groups with previous SARS-CoV-2 infections. These results suggest that specific subgroups within immunocompromised cohorts could benefit from distinct, personalised immunisation or treatment strategies. Identification of vaccine non-responders could be critical to protect those most at risk.

Detection of pre-existing neutralizing antibodies against Ad26 in HIV-1-infected individuals not responding to the Ad26.COV2.S vaccine

PurposeThe Ad26.COV2.S vaccine is a replication-incompetent human adenovirus type 26 vector encoding the SARS-CoV-2 spike protein. In a phase 1-2a trial, a single dose of Ad26.COV2.S induced SARS-CoV-2 spike-specific antibodies in ≥ 96% of healthy adults. To investigate vaccine immunogenicity in HIV-1-infection, we measured SARS-CoV-2 spike-specific antibodies in Ad26.COV2.S vaccinated HIV-1-infected patients and analyzed the presence of pre-existing Ad26 neutralizing antibodies.MethodsWe included all Ad26.COV2.S vaccinated HIV-1-infected patients of Erlangen HIV cohort fulfilling all inclusion criteria. The study cohort consisted of 15 HIV-1-infected patients and three HIV-1-uninfected subjects who received the Ad26.COV2.S vaccine between April and November 2021. Pre-vaccination sera were collected between October 2014 and June 2021, post-vaccination sera between June and December 2021. Neutralizing antibodies towards Ad26 were determined by a FACS-based inhibition assay measuring the expression of SARS-CoV-2 spike and adenoviral proteins in HEK293T cells after in-vitro transduction with Ad26.COV2.S or the control ChAdOx1-S.ResultsSix out of 15 HIV-1-infected patients failed to develop SARS-CoV-2-specific antibodies and four patients developed weak antibody responses after vaccination with Ad26.COV2.S. Pre-vaccination sera of four of the six vaccine non-responders showed neutralizing activity towards Ad26.COV2.S but not toward the ChAdOx1-S vaccine at 1:50 dilution. After Ad26.COV2.S vaccination, 17 of the 18 subjects developed strong Ad26-neutralizing activity and only one of the 18 subjects showed neutralizing activity towards the ChAdOx1-S vaccine.ConclusionAd26.COV2.S vaccination showed a high failure rate in HIV-1-infected patients. Pre-existing immunity against Ad26 could be an important contributor to poor vaccine efficacy in a subgroup of patients.

Revaccination of patients with systemic lupus erythematosus or rheumatoid arthritis without an initial COVID-19 vaccine response elicits seroconversion in half of the patients.

To investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with rheumatic diseases (RD) who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion. From a RD cohort vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralising antibodies, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. Forty-seven percent of cases had detectable neutralising antibodies after revaccination. However, antibody levels were significantly lower than in controls and blood donors. Revaccination induced an antibody class switch in cases with a decrease in IgM and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups. Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination. Forty-seven percent of initial non-responders seroconverted after two-dose revaccination but still had lower levels of SARS-CoV-2 antibodies compared with controls and blood donors. RD patients without a detectable serological response after the initial COVID-19 mRNA vaccine had a T-cell response similar to immunocompetent controls and blood donors.

Abstract 6537: Single cell transcriptomics uncovers cellular and molecular differences in PBMCs of responders and non-responders to the MUC1 cancer vaccine given in the preventative setting

Abstract Introduction: A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial (NCT02134925) were conducted in patients with newly diagnosed advanced colonic adenomas to test the safety and immunogenicity of the MUC1 antigen vaccine and its potential to prevent new adenoma formation. These are the first trials of a non-viral cancer vaccine administered in the absence of cancer. In both trials, the vaccine was safe and strongly immunogenic in 43% and 25% of participants (Responders), respectively. The lack of robust response in a significant number of participants suggested, for the first time, that even in a premalignant setting, the immune system may have already been exposed to regulatory influences that, in the case of the vaccine, determine who does and who does not respond. We hypothesized that there could be molecular and cellular differences in the immune competence between vaccine responders and non-responders, and that they could be identified by studying their pre-vaccination peripheral blood mononuclear cells (PBMCs). Methods: The two MUC1 vaccine trials are described in https://doi.org/10.1101/2022.10.05.22280474 and https://doi.org/10.1158%2F1940-6207.CAPR-12-0275. We performed single cell RNA-sequencing (scRNAseq) on banked pre-vaccination PBMCs from 16 Responders and 16 Non-Responders, determined by anti-MUC1 IgG response. Using differential gene expression (DGE), pathway enrichment, and network estimation analyses, we identified specific cell types, genes, and pathways that differ between responders and non-responders. Results: Pre-vaccination PBMCs from Responders contained a significantly higher percentage of CD4+ naive T cells, while Non-Responders showed significantly higher percentage of CD8+ T effector memory (TEM) cells and a higher percentage of CD16+ monocytes. DGE and gene interaction network analysis showed a higher level of expression of T cell activation genes, such as Fos and Jun, in the CD4+ naive T cells in Responders. Further network analysis showed that these genes were directly connected to response. We also found pre-vaccination specific gene ontology (GO) pathways for translational and transcriptional activity enriched in all cell types in Responders compared to Non-Responders. Conclusion: Our analyses identified candidate biomarkers that are predictive of a preventative cancer vaccine response. Thus, our results can be used for patient selection for vaccine administration. Furthermore, we identified cell type differences and transcriptional pathways that provide information of possible mechanisms of vaccine response. Citation Format: Daniel Y. Yuan, Michelle L. McKeague, Matthew T. Dracz, Olivera J. Finn, Panayiotis V. Benos. Single cell transcriptomics uncovers cellular and molecular differences in PBMCs of responders and non-responders to the MUC1 cancer vaccine given in the preventative setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6537.

Hepatitis B virus vaccination post serological testing and antibody levels of vaccinated health care workers in Accra, Ghana

IntroductionHepatitis B Virus (HBV) infection is an important occupational hazard to Health Care Workers (HCWs) all over the world. International health organizations have strongly recommended the use of the HBV vaccine, especially among individuals at risk of HBV infection. A laboratory test aimed at measuring Anti-HBs concentration (titer) 1–2 months following a 3-dose vaccination schedule is the most reliable approach for diagnosing seroprotection against HBV. This study sought to assess post-vaccination serological testing, seroprotection against HBV, and associated factors among vaccinated HCWs in Ghana. MethodsA hospital-based analytical cross-sectional study involving 207 HCWs. Pretested questionnaires were used to collect data. 5mls of venous blood were collected from consenting HCWs under strict aseptic conditions and quantitatively analyzed for Anti-HBs using ELISA procedures. SPSS Version 23 was used to analyze data with the level of significance set at 0.05. ResultsMedian age; 33, IQR of 29–39. The post-vaccination serological testing rate was 21.3 %. HCWs with high-risk perception and working at the regional hospital had lower odds of adherence to post-vaccination serological testing (aOR = 0.2; 95 % CI = 0.1–0.7) and (aOR = 0.1; 95 % CI = 0.1–0.6) p < 0.05. The seroprotection rate was 91.3 % (95 % CI = 87 %-95 %). Minority, 18 (8.7 %) of the 207 vaccinated HCWs had antibody titers below 10mIU/mL and were not seroprotected against HBV. Geometric Mean Titers (GMTs) were higher in those who received three doses, took a booster, and were less than 25 kg/m2. ConclusionThe post-vaccination serological testing practice was sub-optimal. The seroprotection rate was higher with higher GMTs in those who adhered to the 3-dose vaccination regimen, took a booster dose, and had BMI < 25 kg/m2. It may be inferred that those with Anti-HBs below 10 IU/ml had their antibodies diminishing or waning off with time or they are true vaccine non-responders. This observation calls for strict adherence to post-vaccination serological testing, especially for HCWs who are at high risk of percutaneous and mucocutaneous exposures that could result in HBV infection.

IP10 is a predictor of successful vaccine protection against paratuberculosis infection in sheep.

The cell mediated immune response and ability of immune cells to migrate to the site of infection are both key aspects of protection against many pathogens. Mycobacterium avium subsp. paratuberculosis (MAP) is an intracellular pathogen and the causative agent of paratuberculosis, a chronic wasting disease of ruminants. Current commercial vaccines for paratuberculosis reduce the occurrence of clinical disease but not all animals are protected from infection. Therefore, there is a need to understand the immune responses triggered by these vaccines at the site of infection, in circulating immune cells and their relationships to vaccine-mediated protection. The magnitude and location of gene expression related to the cell mediated immune response and cellular migration were studied in the ileum of sheep. In addition, longitudinal IP10 (also known as IP10) secretion by circulating immune cells was examined in the same sheep. Animals were grouped based on vaccination status (vaccinated vs non-vaccinated) and MAP exposure (experimentally exposed vs unexposed). Vaccination of unexposed sheep increased the expression of IP10, CCL5 and COR1c. Sheep that were successfully protected by vaccination (uninfected following experimental exposure) had significantly reduced expression of IP10 in the ileum at 12months post exposure compared to vaccine non-responders (those that became infected) and non-vaccinated infected sheep. Successfully protected sheep also had significantly increased secretion of IP10 in in vitro stimulated immune cells from whole blood compared to vaccine non responders at 4months post exposure. Therefore, the IP10 recall response has the potential to be used as marker for infection status in vaccinated sheep and could be a biomarker for a DIVA test in sheep.

Rituximab-treated rheumatic patients: B cells predict seroconversion after COVID-19 boost or revaccination in initial vaccine non-responders.

To investigate the effect of either a booster vaccine (one dose) or revaccination (two doses 3 weeks apart) on the antibody response to the COVID-19 mRNA vaccines in patients with rheumatic disease (RD) treated with rituximab (RTX) who had not produced vaccine-reactive antibodies after the initial two vaccine doses. Further, to examine if B cell levels in peripheral blood predicted seroconversion. We included 91 RTX-treated RD patients previously vaccinated against COVID-19. Patients were offered revaccination or a single booster vaccination with an mRNA vaccine. Serum total antibodies against SARS-CoV-2 spike protein were measured before and 6 weeks after the last vaccine dose. B cells (CD19+CD45+) were measured by flow cytometry at inclusion. Of RD patients with undetectable SARS-CoV-2 antibody levels before inclusion, seroconversion was seen in 38% 6 weeks after the booster dose and 32% after revaccination. Patients receiving revaccination had significantly higher antibody levels than patients receiving a booster dose (P < 0.001). In both univariate and multivariate logistic regression analysis, only B cells higher than 10/µl before boost or revaccination were associated with seroconversion (P = 0.009 and P = 0.01, respectively). Seroconversion was independent of age, gender, diagnosis, cumulative RTX dose, RTX treatment time and time since last RTX treatment. Continuously impaired humoral response to mRNA vaccines was found in most RTX-treated patients after a booster dose or revaccination. Seroconversion was observed in approximately one-third of the patients. Measurable B cells before boosting or revaccination was the strongest predictor of antibody response after boost or revaccination.

Risk Factors and Outcome of COVID-19 Infection in Haematological Patients : A Multicenter Retrospective Analysis in Malaysia

Introduction: Hematological patients as immunocompromised hosts are vulnerable to severe COVID-19 infection. Given the significant risk of heightened morbidity and mortality from COVID-19, there is an urgent and critical need to establish its impact in these population. A better understanding of adverse prognostic factors could assist hematologist to tailor appropriate treatment. With this background, our aims were to analyse the outcome of COVID-19 infection and to identify risk factors associated with severity and mortality. Methods: This is a multicenter retrospective observational study with data collected from 6 Malaysian hematological centers. This cohort included patients age ≧ 15 years with hematological diseases who developed PCR-documented SARS-CoV-2 infection from 1st January 2021 to 31st December 2021. Data were collected locally from the 6 participating centers. Anonymized data were centrally processed by a coordinating team in Penang General Hospital. The variables assessed included baseline characteristics, type of hematological diseases, anti-neoplastic therapies, COVID-19 treatments and outcomes. Analyses were generated using R statistical software version 4.1.2. Prognostic factors were analysed using Cox proportional hazard regression analysis. Results: A total of 300 patients (168 males, 132 females) were evaluated. The median age was 51 years (range: 15-85 years). 52% were 50 years old and above. 44% had at least one comorbidity. There were 153 (51%) lymphoid malignancies, 94 (31%) myeloid malignancies and 53 (18%) benign hematological disorders. Non hodgkin lymphoma (26.6%) was the commonest hematological disease followed by acute myeloid leukaemia (16.3 %), acute lymphoblastic leukaemia (9.0%), autoimmune diseases (8.0%) and multiple myeloma (7.0%). Of the 247 patients with malignancy, 55% patients had refractory disease. 104 (42.1%) patients were receiving intensive chemotherapy, 40 (16.2%) low intensity chemotherapy, 25 (10.1%) hypomethylating agent, 22 (8.9%) molecular targeted therapy, 36 (14.6%) supportive care and the remaining 20 (8.1%) were not on active therapy. 19.0% of patients were treated with B cell depleting monoclonal antibody including Rituximab (15.3%), Daratumomab (2.7%) or Blinatumomab (1.0%). Only 24 (8%) patients had prior hematopoietic stem cell transplantation. 34.7% were fully vaccinated prior to COVID-19 infection. 45% of patients developed severe or critical COVID-19 infection based on WHO criteria. Cytokine release syndrome (37%) and organising pneumonia (33%) were the two commonest complications. The median follow up was 158 days (range: 4 - 345 days). The overall mortality rate was 31.7% with survival rate at 90 days of 68.3% (95% CI: 62.6 to 73.2). Poor prognostic factors identified in the multivariable cox regression included age ≥ 50 (HR 1.66; 95 CI 1.05 - 2.64; p = 0.029), ECOG 2-4 (HR 2.34; 95 CI 1.51 - 3.63; p < 0.001), vaccine naive (HR 3.06; 95 CI 1.85 - 5.06; p < 0.001) and absolute lymphocyte count (ALC) < 0.5 (HR 1.51; 95 CI 0.96 -2.38; p = 0.080). Age ≥ 50 (OR 2.43; 95 CI 1.41- 4.24; P = 0.001), ECOG 2-4 (OR 2.72; 95 CI 1.51 - 4.99; p <0.001), refractory hematological disease (OR 2.15; 95 CI 1.19 - 3.91; p = 0.011) and usage of B cell depleting monoclonal antibody (OR 8.25; 2.80 - 30.74; p <0.001) were significantly associated with severe Covid-19 infection. Conclusion: 45% of hematological patients with COVID-19 had severe or critical infection with mortality rate of 31.7%. Poor survival was correlated with older age (≥ 50 years old), poor performance status, severe lymphopenia and vaccine naive. Vaccination is effective in preventing mortality but not severe infection. Hence, antiviral drugs and anti-SARS COV-2 monoclonal antibodies for early treatment and prophylaxis should also be considered for high risk patients and potential vaccine non-responders. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of COVID-19 Booster Vaccines in Patients with Hematologic Malignancies: Experiences in a Real-World Scenario.

Background: Two-dose COVID-19 vaccination often results in poor humoral response rates in patients with hematologic malignancies (HMs); yet responses to COVID-19 booster vaccines and the risk of COVID-19 infection post-booster are mostly uncertain. Methods: We included 200 outpatients with HMs and predominantly lymphoid neoplasms (96%, 191/200) in our academic center and reported on the humoral responses, which were assessed by measurement of anti-spike IgG antibodies in peripheral blood as early as 14 days after mRNA-based prime-boost vaccination, as well as factors hampering booster efficacy. Previous basic (double) immunization was applied according to the local recommendations with mRNA- and/or vector-based vaccines. We also report on post-booster COVID-19 breakthrough infections that emerged in the Omicron era and the prophylaxis strategies that were applied to poor and non-responders to booster vaccines. Results: A total of 55% (110/200) of the patients achieved seroconversion (i.e., anti-spike protein IgG antibody titer > 100 AU/mL assessed in median 48 days after prime-boost vaccination) after prime-boost vaccination. Multivariable analyses revealed age, lymphocytopenia, ongoing treatment and prior anti-CD20 B-cell depletion to be independent predictors for booster failure. With each month between anti-CD20-mediated B-cell depletion and booster vaccination, the probability of seroconversion increased by approximately 4% (p < 0.001) and serum−antibody titer (S-AbT) levels increased by 90 AU/mL (p = 0.011). Notably, obinutuzumab treatment was associated with an 85% lower probability for seroconversion after prime-boost vaccination compared to rituximab (p = 0.002). Of poor or non-responders to prime-boost vaccination, 41% (47/114) underwent a second booster and 73% (83/114) underwent passive immunization. COVID-19 breakthrough infections were observed in 15% (29/200) of patients after prime-boost vaccination with predominantly mild courses (93%). Next to seroconversion, passive immunization was associated with a significantly lower risk of COVID-19 breakthrough infections after booster, even in vaccine non-responders (all p < 0.05). In a small proportion of analyzed patients with myeloid neoplasms (9/200), the seroconversion rate was higher compared to those with lymphoid ones (78% vs. 54%, accordingly), while the incidence rate of COVID-19 breakthrough infections was similar (22% vs. 14%, respectively). Following the low frequency of myeloid neoplasms in this study, the results may not be automatically applied to a larger cohort. Conclusions: Patients with HMs are at a high risk of COVID-19 booster vaccine failure; yet COVID-19 breakthrough infections after prime-boost vaccination are predominantly mild. Booster failure can likely be overcome by passive immunization, thereby providing immune protection against COVID-19 and attenuating the severity of COVID-19 courses. Further sophistication of clinical algorithms for preventing post-vaccination COVID-19 breakthrough infections is urgently needed.

Humoral Response to Hepatitis B and COVID-19 Vaccine among Maintenance Hemodialysis Patients.

Maintenance hemodialysis (MHD) patients have impaired immunological responses to pathogens and vaccines. In this study, we compared the humoral response to HBV and COVID-19 vaccines in a cohort of MHD patients. Demographic and clinical characteristics of vaccine responders and non-responders were also compared, and the association between the humoral responses to both vaccines was evaluated. The cohort included 94 MHD patients who were vaccinated at least once for HBV and twice for COVID-19. Among the 94 patients, 28 (29.8%) did not develop protective titers to HBV. Hypertension, coronary heart disease, and heart failure were more common in non-responders. Among MHD patients, 85% had positive IgG anti-spike SARS-CoV-2 levels 6 months after two doses of BNT162b2 (Pfizer/Biotech) vaccine. Age and immunosuppressive therapy were the main predictors of humoral response to COVID-19 vaccine. We did not find any association between non-responders to HBV and non-responders to COVID-19 vaccine. There was no difference in IgG anti-spike titers between HBV responders and non-responders (505 ± 644 vs. 504 ± 781, p = 0.9) Our results suggest that reduced humoral response to hepatitis B is not associated with reduced response to COVID-19 vaccine. Different risk-factors were associated with poor immune response to HBV and to COVID-19 vaccines.