SARS-CoV-2-mRNA Booster Vaccination Reverses Non-Responsiveness and Early Antibody Waning in Immunocompromised Patients - A Phase Four Study Comparing Immune Responses in Patients With Solid Cancers, Multiple Myeloma and Inflammatory Bowel Disease.

Background: Individuals with secondary immunodeficiencies belong to the most vulnerable groups to succumb to COVID-19 and thus are prioritized for SARS-CoV-2 vaccination. However, knowledge about the persistence and anamnestic responses following SARS-CoV-2-mRNA vaccinations is limited in these patients. Methods: In a prospective, open-label, phase four trial we analyzed S1-specific IgG, neutralizing antibodies and cytokine responses in previously non-infected patients with cancer or autoimmune disease during primary mRNA vaccination and up to one month after booster. Results: 263 patients with solid tumors (SOT, n=63), multiple myeloma (MM, n=70), inflammatory bowel diseases (IBD, n=130) and 66 controls were analyzed. One month after the two-dose primary vaccination the highest non-responder rate was associated with lower CD19+ B-cell counts and was found in MM patients (17%). S1-specific IgG levels correlated with IL-2 and IFN-γ responses in controls and IBD patients, but not in cancer patients. Six months after the second dose, 18% of patients with MM, 10% with SOT and 4% with IBD became seronegative; no one from the control group became negative. However, in IBD patients treated with TNF-α inhibitors, antibody levels declined more rapidly than in controls. Overall, vaccination with mRNA-1273 led to higher antibody levels than with BNT162b2. Importantly, booster vaccination increased antibody levels >8-fold in seroresponders and induced anamnestic responses even in those with undetectable pre-booster antibody levels. Nevertheless, in IBD patients with TNF-α inhibitors even after booster vaccination, antibody levels were lower than in untreated IBD patients and controls. Conclusion: Immunomonitoring of vaccine-specific antibody and cellular responses seems advisable to identify vaccination failures and consequently establishing personalized vaccination schedules, including shorter booster intervals, and helps to improve vaccine effectiveness in all patients with secondary immunodeficiencies. Trial registration: EudraCT Number: 2021-000291-11.

Immunogenicity of COVID-19 Vaccinations in Hematological Patients: 6-Month Follow-Up and Evaluation of a 3rd Vaccination.

Here we analyzed SARS-CoV-2-specific antibodies and T-cell responses after two coronavirus disease 2019 vaccinations over a six-month period in patients with hematological malignancies and assessed the effect of a third vaccination in a subgroup. Sixty-six patients and 66 healthy controls were included. After two vaccinations seroconversion was seen in 52% and a T-cell-specific response in 59% of patients compared with 100% in controls (p = 0.001). Risk factors for a poor serological response were age (<65a), history of anti-CD20 therapy within the year preceding vaccination, CD19+ B-cells < 110/µL, and CD4+ T-cells > 310/µL. The magnitude of T-cell response was higher in patients <65a and with CD19+ B-cells < 110/µL. Patients and healthy controls demonstrated a significant decrease in SARS-CoV-2 S antibody levels over the period of six months (p < 0.001). A third vaccination demonstrated a strong serological response in patients who had responded to the previous doses (p < 0.001). The third vaccination yielded seroconversion in three out of 19 patients in those without serological response. We conclude that both humoral and cellular responses after SARS-CoV-2 immunization are impaired in patients with hematological malignancies. A third vaccination enhanced B-cell response in patients who previously responded to the second vaccination but may be of limited benefit in patients without prior seroconversion.

Third dose of SARS-CoV-2 vaccination in hemato-oncological patients and health care workers: immune responses and adverse events - a retrospective cohort study.

BACKGROUND: Due to potentially immune-escaping virus variants and waning immunity, a third SARS-CoV-2 vaccination dose is increasingly recommended. However, data in patients with cancer are limited. PATIENTS AND METHODS: We measured anti-SARS-CoV-2 spike protein antibody levels after the third vaccination dose in 439 patients with cancer and 41 health care workers (HCW) at an academic centre in Austria and a rural community hospital in Italy. Adverse events were retrieved from questionnaires. RESULTS: Overall, 439 patients and 41 HCW were included. SARS-CoV-2 infections were observed in 62/439 (14.1%) patients before vaccination and in 5/439 (1.1%) patients after ≥1 dose. Longitudinal analysis revealed a decrease of antibody levels between 3 and 6 months after second vaccination in patients with solid tumours (p < 0.001) and haematological malignancies without anti-B cell therapies (p < 0.001). After the third dose, anti-S levels increased compared to the first/second dose. Patients receiving B cell-targeted agents had lower antibody levels than patients with haematological malignancies undergoing other treatments (p < 0.001) or patients with solid tumours (p < 0.001). Moreover, anti-S levels correlated with CD19+ (B cell) and CD56+ (NK cell) counts in peripheral blood. The most frequent adverse events after the third dose were local pain (75/160, 46.9%), fatigue (25/160, 15.6%) and fever/chills (16/160, 10.0%). Patients with cancer had lower anti-S levels than HCW (p = 0.015). CONCLUSIONS: This study in patients with cancer shows improved antibody levels after the third vaccination dose at an acceptable side-effect profile. Lower antibody levels than in controls underline the need for further follow-up studies and dedicated trials.

Humoral Immune Response in Hematooncological Patients and Health Care Workers Who Received SARS-CoV-2 Vaccinations.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

Bone turnover markers can predict healing time in medication-related osteonecrosis of the jaw.

OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) is a severe and difficult-to-treat adverse event of bone-modifying agents. Therefore predictive strategies determining patients at risk for a prolonged healing duration are needed to optimize treatment. Thus, the present study evaluates whether or not bone turnover markers can be used to predict the healing duration in MRONJ patients. MATERIALS AND METHODS: The present study is a retrospective data analysis of patients suffering from MRONJ and positive histology for Actinomyces spp., who were identified at the General Hospital Vienna from 2014 to 2018. During the first visit, the patients' demographics and levels of bone formation parameters were compiled. Healing times were analysed by Cox regression in dependence on these factors. RESULTS: A total of 52 patients were identified who fulfilled the inclusion criteria. The indication for bone-modifying agents was breast cancer (n = 21), prostate cancer (n = 14), multiple myeloma (n = 6) and other malignant diseases (n = 11). In 43 (82.7%) of our patients, we were able to document complete mucosal healing. Furthermore, patients who responded faster to therapy showed higher levels of C-telopeptide (P < 0.05), osteocalcin (P < 0.05) and bone-specific alkaline phosphatase (P < 0.05), but lower levels of 1.25-dihydroxyvitamin D (P < 0.05) than slower responding patients. No correlation was found regarding parathyroid hormone or calcitonin levels. Interestingly, patients who had a slower response were less likely to report dental procedures, but more likely to report a history of chemotherapy. CONCLUSION: CTX and osteocalcin levels may be used for predicting healing duration for MRONJ.

SARS-CoV-2 seroprevalence in oncology healthcare professionals and patients with cancer at a tertiary care centre during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 outbreak, healthcare professionals (HCP) are at the frontline of clinical management and at increased risk for infection. The SARS-CoV-2 seroprevalence of oncological HCP and their patients has significant implications for oncological care. METHODS: HCP and patients with cancer at the Division of Oncology, Medical University of Vienna were included between 21 March and 4 June and tested for total antibodies against SARS-CoV-2 employing the Roche Elecsys Anti-SARS-CoV-2 immunoassay. Reactive samples were confirmed or disproved by the Abbott SARS-CoV-2 IgG test. Additionally, a structured questionnaire regarding basic demographic parameters, travel history and COVID-19-associated symptoms had to be completed by HCP. RESULTS: 146 subjects (62 HCP and 84 patients with cancer) were enrolled. In the oncological HCP cohort, 20 (32.3%) subjects were medical oncologists, 28 (45.2%) nurses at our ward and 14 (22.6%) fulfil other functions such as study coordinators. In the patient cohort, most individuals are on active anticancer treatment (96.4%). 26% of the HCP and 6% of the patients had symptoms potentially associated with COVID-19 since the end of February 2020. However, only in 2 (3.2%) HCP and in 3 (3.6%) patients, anti-SARS-Cov-2 total antibodies were detected. The second assay for anti-SARS-Cov-2 IgG antibodies confirmed the positive result in all HCP and in 2 (2.4%) patients, suggesting an initial assay's unspecific reaction in one case. In individuals with a confirmed test result, an active COVID-19 infection was documented by a positive SARS-CoV-2 RNA PCR test. CONCLUSION: Specific anti-SARS-CoV-2 antibodies were found solely in persons after a documented SARS-CoV-2 viral infection, thus supporting the test methods' high sensitivity and specificity. The low prevalence of anti-SARS-CoV-2 antibodies in our cohorts indicates a lack of immunity against SARS-CoV-2. It highlights the need for continued strict safety measures to prevent uncontrolled viral spread among oncological HCPs and patients with cancer.

Incidence and characteristics of invasive fungal diseases in allogeneic hematopoietic stem cell transplant recipients: a retrospective cohort study.

BACKGROUND: Allogeneic hematopoietic stem cell transplant (HSCT) recipients experience an increased risk for invasive fungal diseases (IFDs). METHODS: This retrospective cohort study at the Medical University of Vienna aspired to assess the incidence, characteristics and the outcome of IFDs as well as the associated risk factors in a setting where only 43 % of patients were given systemic antifungal prophylaxis during aplasia. IFDs were classified as probable or proven according to the EORTC/MSG consensus group. All adult patients (n = 242) receiving an allogeneic HSCT at the University Hospital of Vienna from January 2009 to December 2013 were enrolled. RESULTS: The primary outcome of this study was the one-year incidence for IFDs after HSCT, which was 10.3 % (25/242). Overall 28 patients experienced an IFD - 20 probable and 8 proven - with invasive aspergillosis being the predominant IFD (n = 18), followed by invasive candidiasis (n = 7) and pneumocystis pneumonia (n = 3). Patients with an IFD were more likely to be admitted to an intensive care unit (64 % versus 12 %, p < 0.0001) and had a significantly higher mortality in the first year after HSCT (48 % versus 25 %, p = 0.02). Multivariate regression analysis revealed that intensified immunosuppressive therapy (high-dose cortisone and basiliximab or etanercept) because of severe graft-versus-host disease (adjusted odds ratio (AOR) 3.6, p = 0.01) and transplant-associated microangiopathy (AOR 3.7, p = 0.04) were associated with an increased risk for IFD, while antifungal prophylaxis given during aplasia and post-engraftment was associated with a decreased risk (AOR 0.3, p = 0.02). CONCLUSIONS: We documented a one-year incidence for IFDs of 10.3 % and no selection of rare pathogens at a centre with moderate use of antifungal prophylaxis. Intensified immunosuppressive therapy and transplant-associated microangiopathy were significant risk factors for IFDs.

Fatal skin and pulmonary infection caused by Hormographiella aspergillata in a leukaemic patient: case report and literature overview.

Invasive systemic fungal infections are a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation. We report the case of a fatal infection with Hormographiella aspergillata in a patient undergoing allogenic peripheral blood stem cell transplantation for acute myeloid leukaemia.

A prospective analysis of invasive candidiasis following cardiac surgery: severity markers are predictive.

AIM: Invasive Candida infections (ICI) in intensive care unit (ICU) patients are associated with high mortality. A 2-year prospective study was performed to improve clinical decision making in long-term ICU patients after cardiac surgery. METHODS: Demographic, clinical and physiological data, the incidence of ICI and Candida colonisation scores were analysed. To assess severity of illness the new simplified acute physiology score (SAPS II score), the European system for cardiac operative risk evaluation (EuroSCORE) and the sequential organ failure assessment (SOFA) score were calculated. To define independent risk factors univariate and multivariate Cox-regression analyses with time-dependent covariates were calculated. RESULTS: One hundred and sixty-nine cardiac surgery patients with ICU admittance ≥ 4 days out of 513 admittances were enrolled. Ten patients had proven ICI. In the multivariate analysis the SOFA score (HR = 1.29, p = 0.009) was associated with proven ICI. In 71 patients receiving empiric antifungal therapy for presumptive but unproven ICI the SOFA score (HR = 1.18, p = 0.029) and corrected Candida colonisation index (HR 11.08; p = 0.030) were significantly associated to ICI. Neither SAPS II score nor EuroScore were associated with ICI in either patient group. The mortality rate of patients receiving empiric antifungal therapy was significantly lower compared to that of patients with proven ICI (36.6% vs. 80%, respectively). CONCLUSION: Time-associated SOFA score assessing acute organ failure was the only independent risk factor for proven ICI. Cardiovascular procedures did not confer risk to develop ICI. Empiric antifungal therapy may be warranted in severely ill cardiac surgery patients.

Pandemic whole-virion, Vero-cell-derived, adjuvant-free influenza A H1N1 vaccine in patients with solid tumors and hematologic malignancies receiving concurrent anticancer treatment: Immunogenicity, tolerability, and acceptability during the pandemic situation.

Patients with malignancies are considered to be at increased risk of acquiring influenza. Because of higher complication and case fatality rates, preventive measures such as vaccination are of great interest. The objective of this study was to assess the acceptability, tolerability and immunogenicity of an adjuvant-free whole-virion pandemic influenza A (H1N1) vaccine in cancer patients with ongoing anticancer treatment during a 'pandemic situation'. Adult patients with hematologic malignancies or solid tumors and concurrent cytotoxic, targeted, and/or hormone therapy were recruited during the influenza A (H1N1) pandemic in 2009/2010 and were offered free vaccine. Antibody titers were measured using virus-specific hemagglutination inhibition assay and ELISA. Among 285 patients with solid tumors who were offered vaccination during their therapy, 260 (91.2%) declined and 25 (8.8%) accepted. Seventeen patients with hematologic malignancies were also vaccinated during therapy; 23 healthy individuals served as a control group. When measured using hemagglutination-inhibition assays, rates of seroprotection, seroconversion, and geometric mean titer ratios after the second vaccination were 96%, 70%, and 4.1 respectively among the healthy individuals, 90%, 52%, and 4.3 among patients with solid tumors, and 67%, 13%, and 1.5 among patients with hematologic malignancies during therapy (P<0.05). When measured using ELISA, seropositivity differed significantly among the three groups after the second vaccination: healthy individuals 74%, patients with solid tumors 57%, those with hematologic malignancies 13% (P<0.001). The vaccine was well tolerated. Our results demonstrate a low uptake of the well tolerated adjuvant-free influenza A (H1N1) vaccine by cancer patients receiving anticancer treatment during the pandemic of 2009/2010. Among the vaccinated patients, the immune response was weaker than that in healthy individuals. The immune response in patients with hematological malignancies was low. Two doses of vaccine are needed in these immunosuppressed patients.