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Nosocomial infectious diseases (e.g. influenza, pertussis) are a threat particularly for immunocompromised and vulnerable patients. Although vaccination of healthcare workers (HCWs) constitutes the most convenient and effective means to prevent nosocomial transmissions, vaccine uptake among HCWs remains unacceptably low. Worldwide, numerous studies have demonstrated that nurses have lower vaccination rates than physicians and that there is a relationship between receipt of vaccination by HCWs and knowledge. Measures to improve vaccination rates need to be profession-sensitive as well as specific in their approach in order to achieve sustained success.
The plaque reduction neutralization test (PRNT) is a preferred method for the detection of functional, SARS-CoV-2 specific neutralizing antibodies from serum samples. Alternatively, surrogate enzyme-linked immunosorbent assays (ELISAs) using ACE2 as the target structure for the detection of neutralization-competent antibodies have been developed. They are capable of high throughput, have a short turnaround time, and can be performed under standard laboratory safety conditions. However, there are very limited data on their clinical performance and how they compare to the PRNT. We evaluated three surrogate immunoassays (GenScript SARS-CoV-2 Surrogate Virus Neutralization Test Kit (GenScript Biotech, Piscataway Township, NJ, USA), the TECO® SARS-CoV-2 Neutralization Antibody Assay (TECOmedical AG, Sissach, Switzerland), and the Leinco COVID-19 ImmunoRank™ Neutralization MICRO-ELISA (Leinco Technologies, Fenton, MO, USA)) and one automated quantitative SARS-CoV-2 Spike protein-based IgG antibody assay (Abbott GmbH, Wiesbaden, Germany) by testing 78 clinical samples, including several follow-up samples of six BNT162b2 (BioNTech/Pfizer, Mainz, Germany/New York, NY, USA) vaccinated individuals. Using the PRNT as a reference method, the overall sensitivity of the examined assays ranged from 93.8 to 100% and specificity ranged from 73.9 to 91.3%. Weighted kappa demonstrated a substantial to almost perfect agreement. The findings of our study allow these assays to be considered when a PRNT is not available. However, the latter still should be the preferred choice. For optimal clinical performance, the cut-off value of the TECO assay should be individually adapted.
Purpose: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW).
Methods: The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed.
Results: n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p < 0.01). None of the patients had clinical symptoms that led to a suspected diagnosis of COVID-19 before PCR testing. The patients were either asymptomatic (n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9).
Conclusion: The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently “routine cases”, is highly recommended.
Human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in patient groups at risk. We have previously shown that the anti-CMV IgG seroprevalence in an urban region of Germany has changed over the last decades. Overall, a decline from 63.7 to 57.25% had been observed between 1988–1997 and 1998–2008 (p < 0,001). Here, we continuously follow the trends to the most recent decade 2009 to 2018. In a retrospective analysis, we determined the seroprevalence of CMV IgG antibodies in our patient cohort, stratified by gender and selected groups at risk (e.g., patients with HIV infection; women of childbearing age). The overall prevalence of anti-CMV IgG non-significantly declined further from 57.25% in 1998–2008 to 56.48% in 2009–2018 (p = 0.881). Looking at gender differences, overall CMV seroprevalence in males declined to 52.82% (from 55.54% in 1998–2008; p = 0.0254), while it non-significantly increased in females to 59.80%. The high seroprevalence in patients with a known HIV infection further increased from 87.46% in 1998–2008 to 92.93% in the current period (p = 0.9999). In women of childbearing age, no significant changes over the last three decades could be observed. The CMV seroprevalence in oncological patients was determined to be 60.64%. Overall, the former significant decline of CMV seroprevalence between the decades 1988–1997 and 1998–2008 in this urban region of Germany slowed down to a non-significant decrease of 0.77% (1998–2008 vs. 2009–2018). This might be an indicator that CMV seroprevalence has reached a plateau.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV diseas.
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.
Due to globally rising numbers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, resources for real-time reverse-transcription polymerase chain reaction (rRT-PCR)-based testing have been exhausted. In order to meet the demands of testing and reduce transmission, SARS-CoV-2 antigen-detecting rapid diagnostic tests (Ag-RDTs) are being considered. These tests are fast, inexpensive, and simple to use, but whether they detect potentially infectious cases has not been well studied. We evaluated three lateral flow assays (RIDA®QUICK SARS-CoV-2 Antigen (R-Biopharm), SARS-CoV-2 Rapid Antigen Test (Roche)), and NADAL® COVID-19 Ag Test (Nal von Minden GmbH, Regensburg, Germany) and one microfluidic immunofluorescence assay (SARS-CoV-2 Ag Test (LumiraDx GmbH, Cologne, Germany)) using 100 clinical samples. Diagnostic rRT-PCR and cell culture testing as a marker for infectivity were performed in parallel. The overall Ag-RDT sensitivity for rRT-PCR-positive samples ranged from 24.3% to 50%. However, for samples with a viral load of more than 6 log10 RNA copies/mL (22/100), typically seen in infectious individuals, Ag-RDT positivity was between 81.8% and 100%. Only 51.6% (33/64) of the rRT-PCR-positive samples were infectious in cell culture. In contrast, three Ag-RDTs demonstrated a more significant correlation with cell culture infectivity (61.8–82.4%). Our findings suggest that large-scale SARS-CoV-2 Ag-RDT-based testing can be considered for detecting potentially infective individuals and reducing the virus spread.
Background A procedure for including activity against enveloped viruses in the post-contamination treatment of hands has been recommended, but so far no European standard is available to implement it. In 2004, the German Robert Koch-Institute (RKI) and the German Association for the Control of Virus Disease (DVV) suggested that vaccinia virus and bovine viral diarrhea virus (BVDV) should be used as test viruses in a quantitative suspension test to determine the activity of a disinfectant against all enveloped viruses. Methods We have studied the activities of three commonly-used alcohol-based hand rubs (hand rub A, based on 45% propan-2-ol, 30% propan-1-ol and 0.2% mecetronium etilsulfate; hand rub B, based on 80% ethanol; hand rub C, based on 95% ethanol) against vaccinia virus and BVDV, and in addition against four other clinically relevant enveloped viruses: herpes simplex virus (HSV) types 1 and 2, and human and avian influenza A virus. The hand rubs were challenged with different organic loads at exposure time of 15, 30 and 60 s. According to the guidelines of both BGA/RKI and DVV, and EN 14476:2005, the reduction of infectivity of each test virus was measured on appropriate cell lines using a quantitative suspension test. Results All three alcohol-based hand rubs reduced the infectivity of vaccinia virus and BVDV by >= 4 log10-steps within 15 s, irrespective of the type of organic load. Similar reductions of infectivity were seen against the other four enveloped viruses within 15 s in the presence of different types of organic load. Conclusions Commonly used alcohol-based hand rubs with a total alcohol concentration >= 75% can be assumed to be active against clinically relevant enveloped viruses if they effectively reduce the infectivities of vaccinia virus and BVDV in a quantitative suspension test.
Background: To minimize the risk of disease transmission in cornea transplantation, donor screening for blood-derived viral infections is mandatory. Ideally, pre-mortem blood samples are used, but based on availability, cadaveric blood samples of cornea donors may also be used. However, serological and nucleic acid amplification tests (NATs) need to be validated for the use of cadaveric specimens.
Methods: Hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV) 1/2, and Treponema pallidum (syphilis)-specific serological and/or NAT assays were validated on different platforms (Abbott Alinity i, Alinity m, Roche Cobas 6800, and Roche Cobas AmpliPrep/Cobas TaqMan (CAP/CTM)) using (un)spiked paired pre- and post-mortem cornea donor blood samples from the same individual (up to 23.83 h after death) of 28 individuals in accordance with the specifications of the German Federal Institute for Vaccines and Biomedicines (Paul-Ehrlich-Institut [PEI]). In addition, routinely HBV-, HCV- and HIV-PCR-negative tested post-mortem blood samples of 24 individuals were used to assess NAT specificity.
Results: For the majority of serological parameters on the Abbott Alinity i (HBsAg, anti-HBc, anti-HBs, anti-HCV, anti-HIV, anti-HTLV 1/2, and anti-Treponema pallidum), ratios of generated test results of (un)spiked paired pre- and post-mortem blood samples differed ≤25%, with an agreement of qualitative pre- and post-mortem test results ranging from 91.2 to 100%. For NAT parameters (HBV, HCV, and HIV) on the Cobas 6800, Alinity m, and CAP/CTM, no significant deviation in virus concentrations (factor >5) of spiked pre- and post-mortem blood samples could be observed. Ct-values of corresponding internal controls did also not differ significantly (>1.5 Ct-values). In addition, no false-positive test results were generated when specificity was assessed.
Conclusion: Overall, fluctuations of test results for serological and NAT parameters in pre- and post-mortem blood samples examined in this study, were only limited and within the range of what is also observed when routinely testing fresh patient specimens. We conclude that all examined assays are eligible for the screening of blood samples taken up to about 24 h after the occurrence of death.
Oral swabs, sputum and blood samples from 18 patients with SARS-CoV-2 infection were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) testing. Whereas oral swabs or sputum from the lower respiratory tract were tested RT-PCR positive in all patients, RNAemia was neither detected in 3 patients without symptoms nor in 14 patients with flu-like symptoms, fever or pneumonia. The only patient with RNAemia suffered from acute respiratory distress syndrome (ARDS) and was artificially ventilated in an intensive care unit. Risk for SARS-CoV-2 transmission through blood components in asymptomatic SARS-CoV-2 infected individuals therefore seems negligible but further studies are needed.
Introduction: Healthcare workers (HCWs) are exposed to bloodborne pathogens (e.g., contaminated devices). In the healthcare environment, needlestick injuries (NSI) represent a major risk factor in the transmission of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Medical students are at risk of occupational exposure to bloodborne viruses following needlestick injuries during medical education. Reporting of needlestick injuries is an important step for initiating early prophylaxis or treatment. In the case of a bloodborne infection, pursuant to insure law could result in a claim. The objective of the present study was to describe occupational blood exposure of medical students through needlestick injuries.
Methods: Sixth-year medical students were invited to complete an anonymous questionnaire.
Results: In our study, 58.8% (n=183/311) of medical students recalled at least one needlestick injury during their studies. Overall, 284 needlestick injuries were reported. Only 38.3% of medical students reported all NSI to the appropriate hospital personnel. The main reason (54.0%) for not reporting NSI was being ashamed of having an NSI.
Conclusions: Occupational exposure to blood is a common problem among medical students. Efforts are required to ensure greater awareness among medical students about the risk of bloodborne pathogens. Proper training in procedures and how to act in case of injury should be offered to reduce the number of needlestick injuries.
Aim: Our aim was to analyse the diagnostic workup of hospitalised infants with symptoms of congenital cytomegalovirus (CMV) infections.
Methods: This retrospective study was carried out at the University Hospital Frankfurt, Germany, from 2008 to 2017 on infants aged 4 weeks to 12 months presenting with neurological symptoms consistent with congenital CMV infections.
Results: We studied 117 infants, and workup data for CMV infections were available for 84%. Of these, 54% were immunoglobulin G‐ and immunoglobulin M‐seronegative for CMV or immunoglobulin G‐seropositive with no viral shedding. Congenital CMV infection was excluded in these cases. In 16%, the CMV workup was incomplete, precluding a definitive diagnosis. Dried blood spots (DBS) were requested from 30%. CMV polymerase chain reaction was negative in 19 of these 29 infants, and CMV deoxyribonucleic acid detection confirmed congenital CMV infections in six patients. DBS had been destroyed in line with German law in four cases. Congenital CMV infections were diagnosed (5%) or excluded (62%) in 67% of patients and unanswered in the remaining 33%.
Conclusion: Diagnoses of congenital CMV infections were widely considered and found in 5%. CMV was not stringently investigated in all patients or remained elusive due to German law on destroying DBS.
The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.
The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.
Background Medical students come into contact with infectious diseases early on their career. Immunity against vaccine-preventable diseases is therefore vital for both medical students and the patients with whom they come into contact. Methods The purpose of this study was to compare the medical history and serological status of selected vaccine-preventable diseases of medical students in Germany. Results The overall correlation between medical history statements and serological findings among the 150 students studied was 86.7 %, 66.7 %, 78 % and 93.3 % for measles, mumps, rubella and varicella, conditional on sufficient immunity being achieved after one vaccination. Conclusions Although 81.2 % of the students medical history data correlated with serological findings, significant gaps in immunity were found. Our findings indicate that medical history alone is not a reliable screening tool for immunity against the vaccine-preventable diseases studied.
Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues ribavirin and acyclovir. Omeprazole did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 μg/mL but increased the acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication in a dose-dependent manner. Omeprazole alone reduced HSV-1 and -2 titers [but not HSV-induced formation of cytopathogenic effects (CPE)] at concentrations ≥40 μg/mL. However, it exerted substantially stronger effects on acyclovir activity and also increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication. Omeprazole 80 μg/mL caused a 10.8-fold (Vero cells) and 47.7-fold (HaCaT cells) decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC50). In HSV-2-infected cells, omeprazole 80 μg/mL reduced the acyclovir IC50 by 7.3- (Vero cells) and 12.9-fold (HaCaT cells). In HaCaT cells, omeprazole 80 μg/mL reduced the HSV-1 titer in the presence of acyclovir 1 μg/mL by 1.6 × 105-fold and the HSV-2 titer in the presence of acyclovir 2 μg/mL by 9.2 × 103-fold. The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole increased the antiviral effects of acyclovir in a similar fashion as omeprazole, indicating this to be a drug class effect. In conclusion, proton pump inhibitors increase the anti-HSV activity of acyclovir and are candidates for antiviral therapies in combination with acyclovir, in particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications.
The demand to develop convergent technology platforms, such as bio-functionalized medical devices, is rapidly increasing. However, the loss of biological function of the effector molecules during sterilization represents a significant and general problem. Therefore, we have developed and characterized a nano-coating (NC) formulation capable of maintaining the functionality of proteins on biological-device combination products. As a proof of concept, the NC preserved the structural and functional integrity of an otherwise highly fragile antibody immobilized on polyurethane during deleterious sterilizing irradiation (≥ 25 kGy). The NC procedure enables straight-forward terminal sterilization of bio-functionalized materials while preserving optimal conditioning of the bioactive surface.
Multicentre comparison of quantitative PCR-based assays to detect SARS-CoV-2, Germany, March 2020
(2020)
Containment strategies and clinical management of coronavirus disease (COVID-19) patients during the current pandemic depend on reliable diagnostic PCR assays for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we compare 11 different RT-PCR test systems used in seven diagnostic laboratories in Germany in March 2020. While most assays performed well, we identified detection problems in a commonly used assay that may have resulted in false-negative test results during the first weeks of the pandemic.
Herpes genitalis is caused mainly by herpes simplex virus type 2 (HSV-2) and to a lesser extent but with increasing frequency, by herpes simplex virus type 1 (HSV-1). Today, the diagnosis of genital herpes is based "on laboratory methods. Serology is useful to distinguish primary infection from latent infection and for seroepidemiological investigations. Newer type-specific antibody tests based on single recombinant or purified viral antigens have a higher sensitivity and specificity for detecting anti HSV-2 antibodies. The tests also allow the discrimination between HSV-1 or -2 specific antibodies. Since serology is not able to recognize reactivation, isolation in cell culture remains the standard. If cell culture is not available or optimal transport is not possible and rapid results are needed, direct antigen detection, or in selected cases, the highly sensitive and specific PCR should be used.
Influenza A (H1N1) 2009 : impact on Frankfurt in due consideration of health care and public health
(2010)
Background: In April 2009 a novel influenza A H1N1/2009 virus was identified in Mexico and in the United States which quickly spread around the world. Most of the countries established infection surveillance systems in order to track the number of (laboratory-confirmed) H1N1 cases, hospitalizations and deaths. Methods: The impact of the emergence of the novel pandemic (H1N1) 2009 virus on Frankfurt was statistically evaluated by the Health Protection Authority, City of Frankfurt am Main. Vaccination rates of the health care workers (HCWs) of the University Hospital Frankfurt were measured by the Occupational Health Service. Results: Although the virulence of pandemic (H1N1) 2009 seems to be comparable with seasonal influenza, a major patient load and wave of hospital admissions occurred in the summer of 2009. Even though the 2009 vaccination rate of the University Hospital Frankfurt (seasonal influenza [40.5%], swine flu [36.3%]) is better than the average annual uptake of influenza vaccine in the German health care system (approximately 22% for seasonal and 15% for swine flu), vaccination levels remain insufficient. However, physicians were significantly (p < 0.001) more likely to have been vaccinated against swine flu and seasonal influenza than nurses. Conclusions: The outbreak of the pandemic (H1N1) 2009 in April 2009 provided a major challenge to health services around the world. Nosocomial transmission of H1N1/2009 has been documented. Present experience should be used to improve pandemic preparedness plans and vaccination programs ought to target as many HCWs as possible.
The long-term effect of protection by two doses of SARS-CoV-2 vaccination in patients receiving chronic intermittent hemodialysis (CIHD) is an urging question. We investigated the humoral and cellular immune response of 42 CIHD patients who had received two doses of SARS-CoV-2 vaccine, and again after a booster vaccine with mRNA-1273 six months later. We measured antibody levels and SARS-CoV-2-specific surrogate neutralizing antibodies (SNA). Functional T cell immune response to vaccination was assessed by quantifying interferon-γ (IFN-γ) and IL-2 secreting T cells specific for SARS-CoV-2 using an ELISpot assay. Our data reveal a moderate immune response after the second dose of vaccination, with significantly decreasing SARS-CoV-2-specific antibody levels and less than half of the study group showed neutralizing antibodies six months afterwards. Booster vaccines increased the humoral response dramatically and led to a response rate of 89.2% for antibody levels and a response rate of 94.6% for SNA. Measurement in a no response/low response (NR/LR) subgroup of our cohort, which differed from the whole group in age and rate of immunosuppressive drugs, indicated failure of a corresponding T cell response after the booster vaccine. We strongly argue in favor of a regular testing of surrogate neutralizing antibodies and consecutive booster vaccinations for CIHD patients to provide a stronger and persistent immunity.
Background In October 2007, the working group CEN/TC 216 of the European Committee for standardisation suggested that the Sabin oral poliovirus vaccine type 1 strain (LSc-2ab) presently used for virucidal tests should be replaced by another attenuated vaccine poliovirus type 1 strain, CHAT. Both strains were historically used as oral vaccines, but the Sabin type 1 strain was acknowledged to be more attenuated. In Germany, vaccination against poliomyelitis was introduced in 1962 using the oral polio vaccine (OPV) containing Sabin strain LSc-2ab. The vaccination schedule was changed from OPV to an inactivated polio vaccine (IPV) containing wild polio virus type 1 strain Mahoney in 1998. In the present study, we assessed potential differences in neutralising antibody titres to Sabin and CHAT in persons with a history of either OPV, IPV, or OPV with IPV booster. Methods Neutralisation poliovirus antibodies against CHAT and Sabin 1 were measured in sera of 41 adults vaccinated with OPV. Additionally, sera from 28 children less than 10 years of age and immunised with IPV only were analysed. The neutralisation assay against poliovirus was performed according to WHO guidelines. Results The neutralisation activity against CHAT in adults with a complete OPV vaccination series was significantly lower than against Sabin poliovirus type 1 strains (Wilcoxon signed-rank test P < 0.025). In eight sera, the antibody titres measured against CHAT were less than 8, although the titre against Sabin 1 varied between 8 and 64. Following IPV booster, anti-CHAT antibodies increased rapidly in sera of CHAT-negative adults with OPV history. Sera from children with IPV history neutralised CHAT and Sabin 1 strains equally. Conclusion The lack of neutralising antibodies against the CHAT strain in persons vaccinated with OPV might be associated with an increased risk of reinfection with the CHAT polio virus type 1, and this implies a putative risk of transmission of the virus to polio-free communities. We strongly suggest that laboratory workers who were immunised with OPV receive a booster vaccination with IPV before handling CHAT in the laboratory.
Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a read-out for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in a broad range of cell culture models, independently of cytopathogenic effect formation. Compared to other cell culture models, the Caco-2 subline Caco-2-F03 displayed superior performance, as it possesses a stable SARS-CoV-2 susceptible phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of PHGDH, CLK-1, and CSF1R. The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the HK2 inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false positive hits.
Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a readout for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in numerous cell culture models, independently of cytopathogenic effect formation. Compared to other models, the Caco-2 subline Caco-2-F03 displayed superior performance. It possesses a stable SARS-CoV-2 susceptibility phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1,796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of phosphoglycerate dehydrogenase (PHGDH), CDC like kinase 1 (CLK-1), and colony stimulating factor 1 receptor (CSF1R). The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the hexokinase II (HK2) inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2-F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false-positive hits.
Objectives: Regarding reactogenicity and immunogenicity, heterologous COVID-19 vaccination regimens are considered as an alternative to conventional immunization schemes.
Methods: Individuals receiving either heterologous (ChAdOx1-S [AstraZeneca, Cambridge, UK]/BNT162b2 [Pfizer-BioNTech, Mainz, Germany]; n = 306) or homologous (messenger RNA [mRNA]-1273 [Moderna, Cambridge, Massachusetts, USA]; n = 139) vaccination were asked to participate when receiving their second dose. Reactogenicity was assessed after 1 month, immunogenicity after 1, 3, and/or 6 months, including a third dose, through SARS-CoV-2 antispike immunoglobulin G, surrogate virus neutralization test, and a plaque reduction neutralization test against the Delta (B.1.167.2) and Omicron (B.1.1.529; BA.1) variants of concern.
Results: The overall reactogenicity was lower after heterologous vaccination. In both cohorts, SARS-CoV-2 antispike immunoglobulin G concentrations waned over time with the heterologous vaccination demonstrating higher neutralizing activity than homologous mRNA vaccination after 3 months to low neutralizing levels in the Delta plaque reduction neutralization test after 6 months. At this point, 3.2% of the heterologous and 11.4% of the homologous cohort yielded low neutralizing activity against Omicron. After a third dose of an mRNA vaccine, ≥99% of vaccinees demonstrated positive neutralizing activity against Delta. Depending on the vaccination scheme and against Omicron, 60% to 87.5% of vaccinees demonstrated positive neutralizing activity.
Conclusion: ChAdOx1-S/BNT162b2 vaccination demonstrated an acceptable reactogenicity and immunogenicity profile. A third dose of an mRNA vaccine is necessary to maintain neutralizing activity against SARS-CoV-2. However, variants of concern-adapted versions of the vaccines would be desirable.
Background: Hundreds of West African healthcare workers (HCW) have become ill with Ebola virus disease (EVD) and died during the recent outbreak. The occurrence of occupational infections in laboratories could be due to the lack of use of personal protective equipment, the failure to implement specific regulations about the use of equipment and how to work with hazardous materials. Our study attempted to assess the information as well as training level of HCW of a German high level isolation unit and their concern over an occupationally acquired EVD.
Methods: During the recent Ebola virus outbreak a survey was conducted among HCWs, using an anonymous questionnaire.
Results: Although 70% of our total study population stated that they have all the information needed to care for Ebola patients, only 18.2% of laboratory workers and 29.4% of the HCW of the virology department felt sufficiently trained. The HCW rated the Internet (64.3%) and the daily press (54.3%) as the most important sources of information. Medical literature (45.7%) and official institutions (40.4%) were rated less often.
Conclusions: Formulated pointedly, the HCW turned to popular science to get the information they need to feel safe. Further in house training regarding practical skills and reference to scientific literature would be a better solution to ensure workplace safety.
Evaluation of stability and inactivation methods of SARS-CoV-2 in context of laboratory settings
(2021)
The novel coronavirus SARS-CoV-2 is the causative agent of the acute respiratory disease COVID-19, which has become a global concern due to its rapid spread. Laboratory work with SARS-CoV-2 in a laboratory setting was rated to biosafety level 3 (BSL-3) biocontainment level. However, certain research applications in particular in molecular biology require incomplete denaturation of the proteins, which might cause safety issues handling contaminated samples. In this study, we evaluated lysis buffers that are commonly used in molecular biological laboratories for their ability to inactivate SARS-CoV-2. In addition, viral stability in cell culture media at 4 °C and on display glass and plastic surfaces used in laboratory environment was analyzed. Furthermore, we evaluated chemical and non-chemical inactivation methods including heat inactivation, UV-C light, addition of ethanol, acetone-methanol, and PFA, which might be used as a subsequent inactivation step in the case of insufficient inactivation. We infected susceptible Caco-2 and Vero cells with pre-treated SARS-CoV-2 and determined the tissue culture infection dose 50 (TCID50) using crystal violet staining and microscopy. In addition, lysates of infected cells and virus containing supernatant were subjected to RT-qPCR analysis. We have found that guanidine thiocyanate and most of the tested detergent containing lysis buffers were effective in inactivation of SARS-CoV-2, however, the M-PER lysis buffer containing a proprietary detergent failed to inactivate the virus. In conclusion, careful evaluation of the used inactivation methods is required especially for non-denaturing buffers. Additional inactivation steps might be necessary before removal of lysed viral samples from BSL-3.
Surface disinfectants are part of broader preventive strategies preventing the transmission of bacteria, fungi and viruses in medical institutions. To evaluate their virucidal efficacy, these products must be tested with appropriate model viruses with different physico-chemical properties under conditions representing practical application in hospitals.
The aim of this study was to evaluate a quantitative carrier assay. Furthermore, different putative model viruses like adenovirus type 5 (AdV-5) and different animal parvoviruses were evaluated with respect to their tenacity and practicability in laboratory handling. To evaluate the robustness of the method, some of the viruses were tested in parallel in different laboratories in a multi-center study. Different biocides, which are common active ingredients of surface disinfectants, were used in the test. After drying on stainless steel discs as the carrier, model viruses were exposed to different concentrations of three alcohols, peracetic acid (PAA) or glutaraldehyde (GDA), with a fixed exposure time of 5 minutes. Residual virus was determined after treatment by endpoint titration.
All parvoviruses exhibited a similar stability with respect to GDA, while AdV-5 was more susceptible. For PAA, the porcine parvovirus was more sensitive than the other parvoviruses, and again, AdV-5 presented a higher susceptibility than the parvoviruses. All parvoviruses were resistant to alcohols, while AdV-5 was only stable when treated with 2-propanol. The analysis of the results of the multi-center study showed a high reproducibility of this test system.
In conclusion, two viruses with different physico-chemical properties can be recommended as appropriate model viruses for the evaluation of the virucidal efficacy of surface disinfectants: AdV-5, which has a high clinical impact, and murine parvovirus (MVM) with the highest practicability among the parvoviruses tested.
BACKGROUND: There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV) is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV) or the modified vaccinia Ankara strain (MVA).
METHODS: Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining.
RESULTS: The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min.
CONCLUSIONS: Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV.
Herpes simplex virus type 2 (HSV-2) is the main cause of herpes genitalis, a recurrent sexually transmitted disease. By the use of routine Serologie methods (complement fixation test, enzyme immunoassay), virus carriers are difficult to identify because of strong antibody cross reactions with antigens of HSV-1 which is ubiquitously spread throughout the population. We introduce a microtechnique Western blot system loaded with HSV-1 and HSV-2 type-specific and common antigens on separated nitrocellulose strips. By the simultaneous evaluation of Immunologie reactions with both strips, the occurrence of HSV-2 specific antibodies can be sensitively detected in serum specimens containing antibodies to HSV-1. A total of 158 serum specimens were analyzed and the results obtained by Western blot were compared to those of a screening ELISA and virus isolation performed with smears of herpes lesions.
An agreement of 97.9 % was assessed between Western blot and virus isolation to detect an HSV-1 and HSV-2 infection. Less specific serologic results were produced by the screening ELISA on HSV-2 antibodies which correlated in 85.4 % (41/48) with virus isolation and typing. Concerning HSV-2 antibody testing, Western blot and ELISA showed an overall agreement in 89.8 % of the sera investigated.
As shown by our data, the HSV type specific Western blot proved to be a specific, reproducible and standardized technique. It can be utilized for both sero-epidemiological surveys and determination of the HSV immune status.
Postmortem detection of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) after the exhumation of a corpse can become important, e.g. in the case of subsequent medical malpractice allegations. To date, data on possible detection periods [e.g. by reverse transcription polymerase chain reaction (RT-PCR)] or on the potential infectivity of the virus after an exhumation are rare. In the present study, these parameters were examined in two cases with a time span of approximately 4 months between day of death and exhumation. Using SARS-CoV-2 RT-PCR on swabs of both lungs and the oropharynx detection was possible with cycle threshold (Ct) values of about 30 despite signs of beginning decay. RT-PCR testing of perioral and perinasal swabs and swabs collected from the inside of the body bag, taken to estimate the risk of infection of those involved in the exhumation, was negative. Cell culture-based infectivity testing was negative for both, lung and oropharyngeal swabs. In one case, RT-PCR testing at the day of death of an oropharyngeal swab showed almost identical Ct values as postmortem testing of an oropharyngeal swab, impressively demonstrating the stability of viral RNA in the intact corpse. However, favorable climatic conditions in the grave have to be taken into account, as it was wintertime with constant low temperatures. Nevertheless, it was possible to demonstrate successful postmortem detection of SARS-CoV-2 infection following exhumation even after months in an earth grave.
Background: Europe was certified to be polio-free in 2002 by the WHO. However, wild polioviruses remain endemic in India, Pakistan, Afghanistan, and Nigeria, occasionally causing polio outbreaks, as in Tajikistan in 2010. Therefore, effective surveillance measures and vaccination campaigns remain important. To determine the poliovirus immune status of a German study population, we retrospectively evaluated the seroprevalence of neutralizing antibodies (NA) to the poliovirus types 1, 2 and 3 (PV1, 2, 3) in serum samples collected from 1,632 patients admitted the University Hospital of Frankfurt am Main, Germany, in 2001, 2005 and 2010.
Methods: Testing was done by using a standardized microneutralization assay.
Results: Level of immunity to PV1 ranged between 84.2% (95%CI: 80.3-87.5), 90.4% (88.3-92.3) and 87.5% (85.4-88.8) in 2001, 2005 and 2010. For PV2, we found 90.8% (87.5-90.6), 91.3% (89.3-93.1) and 89.8% (88.7-90.9), in the same period. Seroprevalence to PV3 was 76.6% (72.2-80.6), 69.8% (66.6-72.8) and 72.9% (67.8-77.5) in 2001 and 2005 and 2010, respectively. In 2005 and 2010 significant lower levels of immunity to PV3 in comparison to PV1 and 2 were observed. Since 2001, immunity to PV3 is gradually, but not significantly decreasing.
Conclusion: Immunity to PV3 is insufficient in our cohort. Due to increasing globalization and worldwide tourism, the danger of polio-outbreaks is not averted - even not in developed countries, such as Germany. Therefore, vaccination remains necessary.
In resource-limited or point-of-care settings, rapid diagnostic tests (RDTs), that aim to simultaneously detect HIV antibodies and p24 capsid (p24CA) antigen with high sensitivity, can pose important alternatives to screen for early infections. We evaluated the performance of the antibody and antigen components of the old and novel version of the Determine™ HIV-1/2 Ag/Ab Combo RDTs in parallel to quantifications in a fourth-generation antigen/antibody immunoassay (4G-EIA), p24CA antigen immunoassay (p24CA-EIA), immunoblots, and nucleic acid quantification. We included plasma samples of acute, treatment-naïve HIV-1 infections (Fiebig stages I–VI, subtypes A1, B, C, F, CRF02_AG, CRF02_AE, URF) or chronic HIV-1 and HIV-2 infections. The tests’ antigen component was evaluated also for a panel of subtype B HIV-1 transmitted/founder (T/F) viruses, HIV-2 strains and HIV-2 primary isolates. Furthermore, we assessed the analytical sensitivity of the RDTs to detect p24CA using a highly purified HIV-1NL4-3 p24CA standard. We found that 77% of plasma samples from acutely infected, immunoblot-negative HIV-1 patients in Fiebig stages II–III were identified by the new RDT, while only 25% scored positive in the old RDT. Both RDTs reacted to all samples from chronically HIV-1-infected and acutely HIV-1-infected patients with positive immunoblots. All specimens from chronically infected HIV-2 patients scored positive in the new RDT. Of note, the sensitivity of the RDTs to detect recombinant p24CA from a subtype B virus ranged between 50 and 200 pg/mL, mirrored also by the detection of HIV-1 T/F viruses only at antigen concentrations tenfold higher than suggested by the manufacturer. The RTD failed to recognize any of the HIV-2 viruses tested. Our results indicate that the new version of the Determine™ HIV-1/2 Ag/Ab Combo displays an increased sensitivity to detect HIV-1 p24CA-positive, immunoblot-negative plasma samples compared to the precursor version. The sensitivity of 4G-EIA and p24CA-EIA to detect the major structural HIV antigen, and thus to diagnose acute infections prior to seroconversion, is still superior.
As the current SARS-CoV-2 pandemic continues, serological assays are urgently needed for rapid diagnosis, contact tracing and for epidemiological studies. So far, there is little data on how commercially available tests perform with real patient samples and if detected IgG antibodies provide protective immunity. Focusing on IgG antibodies, we demonstrate the performance of two ELISA assays (Euroimmun SARS-CoV-2 IgG & Vircell COVID-19 ELISA IgG) in comparison to one lateral flow assay ((LFA) FaStep COVID-19 IgG/IgM Rapid Test Device) and two in-house developed assays (immunofluorescence assay (IFA) and plaque reduction neutralization test (PRNT)). We tested follow up serum/plasma samples of individuals PCR-diagnosed with COVID-19. Most of the SARS-CoV-2 samples were from individuals with moderate to severe clinical course, who required an in-patient hospital stay.
For all examined assays, the sensitivity ranged from 58.8 to 76.5% for the early phase of infection (days 5-9) and from 93.8 to 100% for the later period (days 10-18) after PCR-diagnosed with COVID-19. With exception of one sample, all positive tested samples in the analysed cohort, using the commercially available assays examined (including the in-house developed IFA), demonstrated neutralizing (protective) properties in the PRNT, indicating a potential protective immunity to SARS-CoV-2. Regarding specificity, there was evidence that samples of endemic coronavirus (HCoV-OC43, HCoV-229E) and Epstein Barr virus (EBV) infected individuals cross-reacted in the ELISA assays and IFA, in one case generating a false positive result (may giving a false sense of security). This need to be further investigated.
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) serological assays are urgently needed for rapid diagnosis, contact tracing, and for epidemiological studies. So far, there is limited data on how commercially available tests perform with real patient samples, and if positive tested samples show neutralizing abilities. Focusing on IgG antibodies, we demonstrate the performance of two enzyme‐linked immunosorbent assay (ELISA) assays (Euroimmun SARS‐CoV‐2 IgG and Vircell COVID‐19 ELISA IgG) in comparison to one lateral flow assay (FaStep COVID‐19 IgG/IgM Rapid Test Device) and two in‐house developed assays (immunofluorescence assay [IFA] and plaque reduction neutralization test [PRNT]). We tested follow up serum/plasma samples of individuals polymerase chain reaction‐diagnosed with COVID‐19. Most of the SARS‐CoV‐2 samples were from individuals with moderate to the severe clinical course, who required an in‐patient hospital stay. For all examined assays, the sensitivity ranged from 58.8 to 76.5% for the early phase of infection (days 5‐9) and from 93.8% to 100% for the later period (days 10‐18).
Characterization of neonates born to mothers with SARS-CoV-2 infection: review and meta-analysis
(2020)
Characterization of neonates born to mothers with SARS-CoV-2 infection has been partially carried out. There has been no systematic review providing a holistic neonatal presentation including possible vertical transmission. A systematic literature search was performed using PubMed, Google Scholar and Web of Science up to June, 6 2020. Studies on neonates born to mothers with SARS-CoV-2 infection were included. A binary random effect model was used for prevalence and 95% confidence interval. 32 studies involving 261 neonates were included in meta-analysis. Most neonates born to infected mothers did not show any clinical abnormalities (80.4%). Clinical features were dyspnea in 11 (42.3%) and fever in 9 newborns (19.1%). Of 261 neonates, 120 neonates were tested for infection, of whom 12 (10.0%) tested positive. Swabs from placenta, cord blood and vaginal secretion were negative. Neonates are mostly non affected by the mother's SARS-CoV-2 infection. The risk of vertical transmission is low.
Background: Vaccinia virus strain Lister Elstree (VACV) is a test virus in the DVV/RKI guidelines as representative of the stable enveloped viruses. Since the potential risk of laboratory-acquired infections with VACV persists and since the adverse effects of vaccination with VACV are described, the replacement of VACV by the modified vaccinia Ankara strain (MVA) was studied by testing the activity of different chemical biocides in three German laboratories. Methods: The inactivating properties of different chemical biocides (peracetic acid, aldehydes and alcohols) were tested in a quantitative suspension test according to the DVV/RKI guideline. All tests were performed with a protein load of 10% fetal calf serum with both viruses in parallel using different concentrations and contact times. Residual virus was determined by endpoint dilution method. Results: The chemical biocides exhibited similar virucidal activity against VACV and MVA. In three cases intra-laboratory differences were determined between VACV and MVA - 40% (v/v) ethanol and 30% (v/v) isopropanol are more active against MVA, whereas MVA seems more stable than VACV when testing with 0.05% glutardialdehyde. Test accuracy across the three participating laboratories was high. Remarkably inter-laboratory differences in the reduction factor were only observed in two cases. Conclusions: Our data provide valuable information for the replacement of VACV by MVA for testing chemical biocides and disinfectants. Because MVA does not replicate in humans this would eliminate the potential risk of inadvertent inoculation with vaccinia virus and disease in non-vaccinated laboratory workers.
Medical students are exposed to infectious diseases during the course of their clinical training. Unfortunately, vaccination rates among medical students remain insufficient. However, immunizations against vaccine-preventable diseases should be carried out before the students enter clinical courses. This is vital in order to prevent nosocomial infections. We screened 366 medical students in their first clinical year for hospital-related viral diseases. Serum samples were collected between April and May 2007. Antibody testing was carried out using commercial ELISA systems against measles, mumps, rubella, varicella, hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV). Overall, 63.9% (n=234) of the students were sufficiently vaccinated against HBV. In contrast, 31.7% (n=116) had not received any HBV vaccine dosage, and 4.4% (n=16) had not completed the full vaccine cycle (<3 dosage). Remarkably, two students showed serological markers of resolved HBV infection. In addition, one student was HCV-positive and one was HIV-positive, respectively. The following seronegative rates were found: measles (7.9%), mumps (17.5%), rubella (6.5%), and varicella (2.2%). Further work is needed to identify optimal strategies for improving vaccination rates among medical students. It is imperative to identify and limit possible disparities in immunity of vaccine-preventable diseases before initial patient contact. With regard to the primary diagnosis of serious virus diseases including HBV, HCV and HIV, medical students should be screened for these blood borne pathogens.
With respect to nosocomial influenza infections, the welfare of patients is best served by high rates of staff immunity against influenza. However, data from the Centers of Disease Control (CDC) in the USA and the Robert Koch-Institute (RKI) in Germany indicate that most of health care workers (HCWs) choose not to be vaccinated. Under voluntary influenza immunization standards, institutional influenza outbreaks occur every flu season. The question about the legality of implementation mandatory flu vaccination for HCWs is an ongoing debate, which covers several different positions.
To characterize the attitudes of German HCWs toward mandatory influenza immunization, an anonymous questionnaire was offered to HCWs of the University Hospital in Frankfurt/Main / Germany. Our study showed that almost 70% of the respondents would accept mandatory influenza vaccination.
In our opinion an annual influenza vaccination should be required for HCWs who care for immunocompromised patients and residents in long-term care if there will be a failure of voluntary vaccination programs. An informed declination should be obtained from employees who decline vaccination and these HCWs ought to work in uncritical areas of patient care.