Skin manifestations after immunisation with an adjuvanted recombinant zoster vaccine, Germany, 2020.

BackgroundShortly after the launch of a novel adjuvanted recombinant zoster vaccine (RZV), Shingrix, cases of suspected herpes zoster (HZ) or zoster-like skin reactions following immunisation were reported.AimWe aimed to investigate if these skin manifestations after administration of RZV could be HZ.MethodsBetween April and October 2020, general practitioners (GP) reporting a suspected case of HZ or zoster-like skin manifestation after RZV vaccination to the Paul-Ehrlich-Institut, the German national competent authority, were invited to participate in the study. The GP took a sample of the skin manifestation, photographed it and collected patient information on RZV vaccination and the suspected adverse event. We analysed all samples by PCR for varicella-zoster virus (VZV) and herpes-simplex virus (HSV) and genotyped VZV-positive samples. In addition, cases were independently assessed by two dermatologists.ResultsEighty eligible cases were enrolled and 72 could be included in the analysis. Of the 72 cases, 45 were female, 33 were 60-69 years old, 32 had skin symptoms in the thoracic and 27 in the cervical dermatomes. Twenty-seven samples tested PCR positive for VZV (all genotyped as wild-type, WT), three for HSV-1 and five for HSV-2.ConclusionIt may be difficult to distinguish HZ, without a PCR result, from other zoster-like manifestations. In this study, VZV-PCR positive dermatomal eruptions occurring in the first weeks after immunisation with RZV were due to WT VZV, which is not unexpected as HZ is a common disease against which the vaccine is unlikely to provide full protection at this time.

The fourth vaccination with a non-SARS-CoV-2 variant adapted vaccine fails to increase the breadth of the humoral immune response.

Escape mutations in the spike protein of SARS-CoV-2 are a major reason for Omicron breakthrough infections. After basal vaccination only very low titers of Omicron neutralizing antibodies are present. However, booster vaccinations induce higher titers against the Omicron variant. The neutralization of the Delta and Omicron variants by sera obtained 6 months after 3rd vaccination and 2 weeks or 6 months after 4th vaccination with a monovalent RNA vaccine (Spikevax) was analyzed. It was observed for the Omicron variant that 6 months after the fourth vaccination, the titer returns to the same very low neutralizing capacity as 6 months after the third vaccination. The Delta variant neutralizing capacity wanes with a comparable kinetic although the titers are higher as compared to the Omicron variant. This indicates that the fourth vaccination with a monovalent vaccine based on the ancestral isolate neither affects the kinetic of the waning nor the breadth of the humoral response.

Rare cases of Guillain-Barré syndrome after COVID-19 vaccination, Germany, December 2020 to August 2021.

BackgroundGuillain-Barré syndrome (GBS) has been associated with vaccination against COVID-19.AimWe aimed to compare clinical characteristics and analyse excess GBS cases following administration of different COVID-19 and influenza vaccines in Germany versus the expected numbers estimated from pre-pandemic background incidence rates.MethodsWe analysed safety surveillance data reported to the German national competent authority between 27 December 2020 and 31 August 2021. GBS cases were validated according to Brighton Collaboration (BC) criteria. We conducted observed vs expected (OvE) analyses on cases fulfilling BC criteria levels 1 to 4 for all four European Medicines Agency-approved COVID-19 vaccines and for influenza vaccines.ResultsA total of 214 GBS cases after COVID-19 vaccination had been reported, of whom 156 were eligible for further analysis. Standardised morbidity ratio estimates 3-42 days after vaccination were 0.34 (95% confidence interval (CI): 0.25-0.44) for Comirnaty, 0.38 (95% CI: 0.15-0.79) for Spikevax, 3.10 (95% CI: 2.44-3.88) for Vaxzevria, 4.16 (95% CI: 2.64-6.24) for COVID-19 Vaccine Janssen and 0.60 (95% CI: 0.35-0.94) for influenza vaccines. Bilateral facial paresis was reported in 19.7% and 26.1% of the 156 GBS cases following vaccination with Vaxzevria and COVID-19 Vaccine Janssen, respectively, and only in 6% of cases exposed to Comirnaty.ConclusionThree and four times more GBS cases than expected were reported after vaccination with Vaxzevria and COVID-19 Vaccine Janssen, respectively, therefore GBS might be an adverse event of vector-based vaccines. Bifacial paresis was more common in cases with GBS following vaccination with vector-based than mRNA COVID-19 vaccines.

Analysis of Transfusion-Transmitted Bacterial Infections according to German Hemovigilance Data (2011-2020).

Introduction: Following the first assessment of the effects of safety measures taken against transfusion-transmitted bacterial infections (TTBI), the Paul-Ehrlich-Institut (PEI) decided to newly analyze risk minimization measures (RMM) using German hemovigilance data from 2011 to 2020, focusing on blood components, recipients, and bacterial strains. Materials and Methods: The PEI assessed the imputability of all reported serious adverse reactions (SAR) relying mainly on microbiological test results. Reporting rates (RR) of suspected, confirmed, and fatal confirmed TTBI were calculated and compared to the previous reporting 10-year period (2001-2010) using Poisson regression to estimate RR ratios (RRR). Furthermore, details on blood component age, patients' medical history, and bacterial pathogenicity were collected. Results: With respect to the previous 10-year period, the number of suspected TTBI increased (n = 403), while fewer cases were confirmed (n = 40); the number of deaths remained more or less unchanged (n = 8). The RR for suspected TTBI were 7.9, 18.7, and 1.6 cases per million units transfused for red blood cells (RBC), platelet concentrates (PC), and fresh frozen plasma (FFP), respectively. RRR showed a statistically significant 2.5-fold increase in the RR for suspected TTBI after RBC administration from 2001-2010 to the period under review (p < 0.0001). The RR for confirmed TTBI were 0.4, 5.0, and 0.0 cases per million units transfused for RBC, PC, and FFP, respectively. Compared to the period 2001-2010, there was a statistically significant decrease in the RR of confirmed TTBI by half for PC (p = 0.0052). The RR for confirmed PC-caused TTBI with fatal outcome was 1.4 cases per million units transfused. Regardless of type of blood product transfused and outcome of SAR, the majority of TTBI occurred after administration of a product at the end of shelf life (40.0%) and to recipients of advanced age (median age: 68.5 years) and/or with severe immunosuppression (72.5%) due to decreased myelopoiesis (62.5%). 72.5% of the involved bacteria had a middle/high human pathogenicity. Conclusion: Despite a significant decrease in confirmed TTBI following PC transfusion in Germany after implementation of RMM, the current manufacture of blood products can still not prevent TTBI with fatal outcomes. As demonstrated in various countries, RMM like bacterial screening or pathogen reduction may measurably improve the safety of blood transfusion.

Follow-Up of Plasma Donors after Quarantine Storage: Results of a 5-Year Survey in Germany.

Background and Objectives: In 1993, a quarantine storage of 6 months was introduced for plasma for transfusion and was reduced to 4 months in 2003, owing to the improvements of screening assays used in German blood establishments. The presented survey analyses the value of quarantine storage under the current screening conditions. Materials and Methods: From 2015 to 2019, we collected data on the total amount of released quarantine plasma as well as on the number of quarantine plasma not released due to a reactive screening test of a follow-up donation. Results: Responding establishments covered 84% of plasma units released within the sampled period. In 3,583,913 (99.98%) of the total 3,584,664 test pairs, all screening assays revealed a negative result, leading to plasma release from quarantine storage. In 442 out of the residual 751 cases, confirmed positive results for human immunodeficiency virus (24), hepatitis C virus (22), or hepatitis B virus (396) were obtained in the follow-up donations. Of them, 372 revealed negative ID-NAT results in their retain samples confirmed by using highly sensitive individual donor nucleic acid amplification technology. In 70 cases, no testing of retain samples was performed as plasma was released for fractionation. The maximum theoretical risk for an undetected human immunodeficiency virus, hepatitis C or B virus infection was less than 0.0001%. Conclusion: No positive donation were found under the current screening regime and the quarantine storage during the 5-year survey period. In view of the current type and sensitivity of screening tests in German blood establishments, the results allow a reassessment of the value of quarantine storage of plasma regarding duration and release modalities. Due to the more sensitive donor screening, shorter quarantine periods as well as dispensing quarantine storage can be discussed. A reduction in the safety standard of plasma transfusions need not be feared, and the availability of plasma for transfusions could be facilitated.

Long-term outcome of patients with vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis.

We present the long-term outcomes of 44 patients who developed cerebral venous sinus thrombosis after vaccination with the adenoviral vector ChAdOx1 nCoV-19 COVID-19 vaccine. Assessment of the Extended Glasgow Outcome Scale was performed within 3-6 months after the initial hospital admissions. Patient outcomes ranged from good recovery (13 patients, 29.6%) to moderate disability (11 patients, 25.0%) and severe disability or vegetative state (6 patients, 13.6%). Fatal outcomes were reported in 14 patients (31.8%).

The SARS-CoV-2 Variant Omicron Is Able to Escape Vaccine-Induced Humoral Immune Responses, but Is Counteracted by Booster Vaccination.

The SARS-CoV-2 variant Omicron has spread world-wide and is responsible for rapid increases in infections, including in populations with high vaccination rates. Here, we analysed in the sera of vaccinated individuals the antibody binding to the receptor-binding domain (RBD) of the spike protein and the neutralization of wild-type (WT), Delta (B.1.617.2), and Omicron (B.1.1.529; BA.1) pseudotyped vectors. Although sera from individuals immunized with vector vaccines (Vaxzevria; AZ and COVID-19 Janssen, Ad26.COV2.S; J&J) were able to bind and neutralize WT and Delta, they showed only background levels towards Omicron. In contrast, mRNA (Comirnaty; BNT) or heterologous (AZ/BNT) vaccines induced weak, but detectable responses against Omicron. While RBD-binding antibody levels decreased significantly six months after full vaccination, the SARS-CoV-2 RBD-directed avidity remained constant. However, this still coincided with a significant decrease in neutralization activity against all variants. A third booster vaccination with BNT significantly increased the humoral immune responses against all tested variants, including Omicron. In conclusion, only vaccination schedules that included at least one dose of mRNA vaccine and especially an mRNA booster vaccination induced sufficient antibody levels with neutralization capacity against multiple variants, including Omicron.

Quantitative and Qualitative Difference in Antibody Response against Omicron and Ancestral SARS-CoV-2 after Third and Fourth Vaccination.

Waning immunity against SARS-CoV-2 and the emergence of variants, especially of the most distant variant, Omicron, affect titers of neutralizing antibodies in the sera of vaccinated individuals. Thus, two vaccinations with the mRNA vaccine BNT162b fail to induce neutralizing antibodies against the Omicron variant. A first booster vaccination increases Omicron-RBD-binding IgG and IgA and neutralizing capacity. In comparison, the Wuhan isolate titers of the Omicron variant binding antibodies are 8.5 lower. After a third vaccination, induction of Omicron-RBD- and Wuhan-RBD-binding antibodies follows the same kinetic. Five to six months after the third vaccination, there are still Omicron-RBD-binding antibodies detectable, but 35.9 percent of the analyzed sera fail to neutralize the Omicron variant, while all sera efficiently neutralize the Delta isolate. In the case of the Wuhan-RBD, a significantly larger number of stable antigen-antibody complexes is formed than in Omicron-RBD. A fourth vaccination with mRNA-1273 temporarily restores levels of Omicron-, Delta- and Wuhan-specific antibodies. Comparing different booster strategies revealed that the breadth of the immune response is not affected by the vaccination regimen. Taken together, these data indicate that booster vaccinations (third and fourth dose) increase the breadth of the immune response, but there is a qualitative difference of antibodies with respect to the stability of antigen-antibody complexes and persistence of antibody titers.

Persistence of infectious SARS-CoV-2 particles for up to 37 days in patients with mild COVID-19.

BACKGROUND: People suffering from COVID-19 are typically considered non-infectious 14 days after diagnosis if symptoms have disappeared for at least 48 h. We describe three patients who independently acquired their infection. These three patients experienced mild COVID-19 and completely recovered symptomatically within 10 days, but remained PCR-positive in deep pharyngeal samples for at least 38 days. We attempted to isolate virus from pharyngeal swabs to investigate whether these patients still carried infectious virus. METHODS: Infectious virus was amplified in Vero E6 cells and characterized by electron microscopy and WGS. The immune response was investigated by ELISA and peptide arrays. RESULTS: In all three cases, infectious and replication-competent virus was isolated and amplified in Vero E6 cells. Virus replication was detected by RT-PCR and immunofluorescence microscopy. Electron microscopy confirmed the formation of intact SARS-CoV-2 particles. For a more detailed analysis, all three isolates were characterized by whole-genome sequencing (WGS). The sequence data revealed that the isolates belonged to the 20A or 20C clade, and two mutations in ORF8 were identified among other mutations that could be relevant for establishing a long-term infection. Characterization of the humoral immune response in comparison to patients that had fully recovered from mild COVID-19 revealed a lack of antibodies binding to sequential epitopes of the receptor-binding domain (RBD) for the long-term infected patients. CONCLUSION: Thus, a small portion of COVID-19 patients displays long-term infectivity and termination of quarantine periods after 14 days, without PCR-based testing, should be reconsidered critically.

Analysis of BNT162b2- and CVnCoV-elicited sera and of convalescent sera toward SARS-CoV-2 viruses.

BACKGROUND: The mRNA vaccine BNT162b2 (Comirnaty, BioNTech/Pfizer) and the vaccine candidate CVnCoV (Curevac) each encode a stabilized spike protein of SARS-CoV2 as antigen but differ with respect to the nature of the mRNA (modified versus unmodified nucleotides) and the mRNA amount (30 µg versus 12 µg RNA). This study characterizes antisera elicited by these two vaccines in comparison to convalescent sera. METHODS: Sera from BNT162b2 vaccinated healthcare workers, and sera from participants of a phase I trial vaccinated with 2, 4, 6, 8, or 12 µg CVnCoV and convalescent sera from hospitalized patients were analyzed by ELISA, neutralization tests, surface plasmon resonance (SPR), and peptide arrays. RESULTS: BNT162b2-elicited sera and convalescent sera have a higher titer of spike-RBD-specific antibodies and neutralizing antibodies as compared to the CVnCoV-elicited sera. For all analyzed sera a reduction in binding and neutralizing antibodies was found for the lineage B.1.351 variant of concern. SPR analyses revealed that the CVnCoV-elicited sera have a lower fraction of slow-dissociating antibodies. Accordingly, the CVnCoV sera almost fail to compete with the spike-ACE2 interaction. The significance of common VOC mutations K417N, E484K, or N501Y focused on linear epitopes was analyzed using a peptide array approach. The peptide arrays showed a strong difference between convalescent sera and vaccine-elicited sera. Specifically, the linear epitope at position N501 was affected by the mutation and elucidates the escape of viral variants to antibodies against this linear epitope. CONCLUSION: These data reveal differences in titer, neutralizing capacity, and affinity of the antibodies between BNT162b2- and CVnCoV-elicited sera, which could contribute to the apparent differences in vaccine efficacy.

Comirnaty-Elicited and Convalescent Sera Recognize Different Spike Epitopes.

Many of the approved SARS-CoV-2 vaccines are based on a stabilized variant of the spike protein. This raises the question of whether the immune response against the stabilized spike is identical to the immune response that is elicited by the native spike in the case of a SARS-CoV-2 infection. Using a peptide array-based approach, we analysed the binding of antibodies from Comirnaty-elicited, convalescent, and control sera to the peptides covering the spike protein. A total of 37 linear epitopes were identified. A total of 26 of these epitopes were almost exclusively recognized by the convalescent sera. Mapping these epitopes to the spike structures revealed that most of these 26 epitopes are masked in the pre-fusion structure. In particular, in the conserved central helix, three epitopes that are only exposed in the post-fusion conformation were identified. This indicates a higher spike-specific antibody diversity in convalescent sera. These differences could be relevant for the breadth of spike-specific immune response.

Blood Donation-Related Adverse Reactions: Results of an Online Survey among Donors in Germany (2018).

INTRODUCTION: According to German legislation, reports of suspected serious adverse reactions (AR) associated with the donation of blood and its components are continuously being evaluated by the Paul-Ehrlich-Institut. This survey aimed at providing a more complete picture of the AR associated with the donation of blood and blood components. MATERIALS AND METHODS: Eligible donors had the opportunity to anonymously report all AR occurring during or after their last donation by completing an online questionnaire. Reported AR were classified according to the Standard for Surveillance of Complications Related to Blood Donation. Donors' self-assessment of AR seriousness was compared with the official severity classification as laid down by German legislation. Besides a descriptive statistical analysis, a multiple logistic analysis was performed to identify risk factors for AR. RESULTS: A total of 8,138 data records were evaluated. Slightly more males (57.9%) participated in the survey and, except for donors aged ≥60 years, all age groups were equally represented. The majority of participants were whole blood donors (85.4%), repeat donors (97.2%), and stayed under observation in the blood establishment (BE) for more than 5 min (63.1%) after donation. Most participants did not report any reaction (72.5%), whereas 2,237 reported at least one AR (27.5%), 475 of whom underwent apheresis and 1,762 donated whole blood. Most AR occurred after leaving the BE (64.4%). Only a minority of participants required medical treatment (5.1%) or assessed the experienced AR as serious (3.9%). The most frequently reported donor AR were haematoma and other local reactions (57.6%). Vasovagal reactions without and with loss of consciousness were developed in 17 and 2% of the participants, respectively, whilst 7.6% experienced citrate reactions. New AR (i.e., allergic reactions and symptoms associated with iron deficiency) were reported as well. The occurrence of AR was linked to risk factors (i.e., female gender, young age, first-time donation, and thrombocytapheresis). DISCUSSION: This survey yielded a more comprehensive AR spectrum, revealed a prolonged time to symptom onset, and identified risk factors for AR. This novel information could be implemented in an amended informed consent addressing common and rare AR.

Prospective Long-term Follow-up of Autologous Chondrocyte Implantation With Periosteum Versus Matrix-Associated Autologous Chondrocyte Implantation: A Randomized Clinical Trial.

BACKGROUND: Matrix-associated autologous chondrocyte implantation (MACI) is a further development of the original autologous chondrocyte implantation periosteal flap technique (ACI-P) for the treatment of articular cartilage defects. PURPOSE: We aimed to establish whether MACI or ACI-P provides superior long-term outcomes in terms of patient satisfaction, clinical assessment, and magnetic resonance imaging (MRI) evaluation. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 21 patients with cartilage defects at the femoral condyle were randomized to MACI (n = 11) or ACI-P (n = 10) between the years 2004 and 2006. Patients were assessed for subjective International Knee Documentation Committee (IKDC) score, Lysholm and Gillquist score, Tegner Activity Score, and 36-Item Short Form Health Survey (SF-36) preoperatively (T0), at 1 and 2 years postoperatively (T1, T2), and at the final follow-up 8 to 11 years after surgery (T3). Onset of osteoarthritis was determined using the Kellgren-Lawrence score and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, and delayed gadolinium-enhanced MRI of cartilage was used to evaluate the cartilage. Adverse events were recorded to assess safety. RESULTS: There were 16 patients (MACI, n = 9; ACI-P, n = 7) who were reassessed on average 9.6 years after surgery (76% follow-up rate). The Lysholm and Gillquist score improved in both groups after surgery and remained elevated but reached statistical significance only in ACI-P at T1 and T2. IKDC scores increased significantly at all postoperative evaluation time points in ACI-P. In MACI, IKDC scores showed a significant increase at T1 and T3 when compared with T0. In the majority of the patients (10/16; MACI, 5/9; ACI-P, 5/7) a complete defect filling was present at the final follow-up as shown by the MOCART score, and 1 patient in the ACI-P group displayed hypertrophy of the repair tissue, which represents 6% of the whole study group and 14.3% of the ACI-P group. Besides higher SF-36 vitality scores in ACI-P at T3, no significant differences were seen in clinical scores and MRI scores between the 2 methods at any time point. Revision rate was 33.3% in MACI and 28.6% in ACI-P at the last follow-up. CONCLUSION: Our long-term results suggest that first- and third-generation ACI methods are equally effective treatments for isolated full-thickness cartilage defects of the knee. With the number of participants available, no significant difference was noted between MACI and ACI-P at any time point. Interpretation of our data has to be performed with caution due to the small sample size, which was further limited by a loss to follow-up of 24%.

SARS-CoV-2 asymptomatic and symptomatic patients and risk for transfusion transmission.

Oral swabs, sputum, and blood samples from 18 asymptomatic and symptomatic patients with SARS-CoV-2 infection were examined using RT-PCR testing in order to assess the risk of transfusion-related transmission. In asymptomatic patients as well as patients with flu-like symptoms and fever, no SARS-CoV-2 RNA could be detected in the blood or serum despite a clearly positive result in all throat swabs. As patients with symptoms of infectious disease will not be admitted to blood donation, the risk for transfusion transmission of SARS-CoV-2 seems to be negligible.

Retrospective multicenter matched case-control study on the risk factors for intussusception in infants less than 1 year of age with a special focus on rotavirus vaccines - the German Intussusception Study.

Studies associate rotavirus vaccination with intussusception. In Germany, a retrospective multicenter matched case-control study was performed to identify risk factors for intussusception with a special focus on rotavirus vaccines. Children with place of birth and residence in Germany who had been treated for intussusception from 2010 to 2014 and who had been less than 1 year old at the time of intussusception were recruited. Case report forms were independently validated by two pediatricians according to the criteria of intussusception defined by the Brighton Collaboration (BC). Cases with the highest diagnostic certainty (level 1) were matched with population-based controls by age, gender, federal state, and place of residence. Information on vaccine exposures originated from vaccination certificates. One hundred and sixteen cases were matched with 272 controls. A significantly increased adjusted odds ratio (aOR) for intussusception (5.74, 95% CI: 1.51-21.79) was detected in individuals immunized with rotavirus vaccine dose 1 prior to symptom onset as compared to non-exposed individuals. Age at the start of the rotavirus immunization series did not modify the risk of intussusception. The odds for intussusception were not increased postdose 2 and 3 as well as any dose. One further risk factor for intussusception, family history of intussusception (aOR 3.26, 95% CI 1.09 - 9.77) was identified. Breastfeeding was found to have a protective effect (aOR 0.54, 95% CI 0.33 - 0.88). Rotavirus vaccine dose 1 was associated with a 5.7-fold increased risk to develop intussusception regardless of age at immunization whereas the overall risk for intussusception in the first year of life was not increased.

Detection of hepatitis B virus infection in German blood donors 2008-2015.

BACKGROUND AND OBJECTIVES: Assessment of HBV-NAT testing compared to HBsAg and anti-HBc screening in German blood establishments for the period 2008-2015. MATERIALS AND METHODS: Blood donations screened for HBsAg and anti-HBc along with HBV-NAT were evaluated. Sensitivity of HBsAg and HBV-NAT tests was compared in 30 HBV seroconversion panels and with the viral load of the NAT-only cases. Residual risk for HBV in the WP was modelled. RESULTS: A total of 45 270 111 donations were evaluated. There were 29 NAT-only cases in the HBsAg-negative HBV-WP, one by ID-NAT and 28 by MP-NAT. MP-NAT, on average, showed higher sensitivity than HBsAg testing: MP-NAT-LoD of 146 IU/ml vs. 362 IU/ml HBV DNA for positive HBsAg detection (range 135-1502 IU/ml), resulting in 3·1 days (range 2·0-4·8 days) earlier HBV detection. Viral loads of the NAT-only cases confirmed the sensitivity of the HBV tests in the seroconversion study. One HBsAg-negative case was due to a new HBsAg mutant combination. There was one HBsAg-reactive only case. In addition, HBV incidence in the HBV-WP included 41 HBsAg-/HBV-NAT-positives and three HBV transmission cases. The residual risk for HBsAg was estimated to be 1:1 619 419-1 268 474 compared to 1:2 793 365-2 134 702 for MP-NAT. Within chronic HBV (HBsAg-/anti-HBc-positive and MP-NAT-negative) 70% were ID-NAT positive at low viral load (median 20 IU/ml). Among anti-HBc-only, supplementary ID-NAT detected 23 occult HBV infections. CONCLUSIONS: In the HBV-WP, MP-NAT provided a higher sensitivity than HBsAg testing, obtained a considerably higher yield and reduced the risk for HBV transmission. In later HBV stages, anti-HBc screening and HBV-ID-NAT intercepted potentially infectious donations.

Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients-A Known Issue of Unknown Origin.

There is a broad range of factor products approved in Germany for haemophilia A treatment. Since the introduction of recombinant coagulation factor VIII (FVIII) products in the 1990s, there has been substantial debate whether there is a difference in inhibitor incidence between single FVIII products or product classes. Neither haemophilia registries nor clinical studies, including a randomised controlled clinical trial, provided a consistent and definite answer. The reasons were mainly related to methodological challenges in conducting controlled studies in a rare disease. In this analysis, the most relevant epidemiological challenges and main problems were examined, including study bias, potential overlap of individual studies and advanced development of therapy and methods in the course of time. Meta-analyses on two levels showed that therapies using recombinant products resulted in different event rates when compared to plasma-derived products. These results are accompanied by substantial study heterogeneity evidenced by Cochran's Q tests. Only three studies have been identified that meet the standards of current clinical guidance. To finally resolve this ongoing and disputable safety issue of replacement therapy, collaboration among registry owners, academia and regulators must be fostered.

Safety profile of rubella vaccine administered to pregnant women: A systematic review of pregnancy related adverse events following immunisation, including congenital rubella syndrome and congenital rubella infection in the foetus or infant.

BACKGROUND: Data on the safety of inadvertent rubella vaccination in pregnancy is important for rubella vaccination programs aimed at preventing congenital rubella syndrome. METHODS: The association between monovalent rubella or combination vaccinations in or shortly before pregnancy and potential harm to the foetus was examined by conducting a systematic review and meta-analysis using fixed effect methods and simulation. RESULTS: Four cohort studies of inadvertently vaccinated and unvaccinated women were found, 15 cohorts of pregnant women who were rubella susceptible at time of inadvertent vaccination and 9 cohort studies with no information on susceptibility and case series. No case of vaccine associated congenital rubella syndrome (CRS) was identified. Cohort studies with an unvaccinated comparison group were limited in number and size, and based on these only a theoretical additional risk of 6 or more cases of CRS per 1000 vaccinated women (0% observed, upper 95% CI 0.6%) could be excluded. Based on cohorts of vaccinated rubella susceptible pregnant women a maximum theoretical risk of 1 CRS case in 1008 vaccinated women (0% observed, upper 95% CI 0.099%) was estimated. Asymptomatic rubella vaccine virus infection of the neonate was also noted (fixed effects estimate of risk overall 1.74%, 95% CI 1.21, 2.28). CONCLUSION: There is no evidence that CRS is caused by rubella-containing vaccines but transplacental vaccine virus infection can occur. CRS is effectively prevented by vaccination, thus the risk/benefit balance is unequivocally in favour of vaccination. The data confirm previous recommendations that inadvertent vaccination during pregnancy is not an indication for termination of pregnancy.

Effectiveness of blood donor screening by HIV, HCV, HBV-NAT assays, as well as HBsAg and anti-HBc immunoassays in Germany (2008-2015).

BACKGROUND AND OBJECTIVES: In Germany, in addition to standard blood donor screening, further mandatory tests were introduced for HCV-RNA, HIV-1-RNA and for anti-HBc. Screening for HBV-DNA is optional. This study investigates the benefits of these additional tests for the detection of HIV, HCV, and HBV infections among German blood donors. MATERIALS AND METHODS: From 2008 to 2015 we collected data on blood donations exclusively testing NAT positive (NAT yield) or reactive in only one of the screening assays. Assuming a Poisson distribution, we calculated NAT yield/reactive only rates on a per donation basis (number of yield/reactive only cases divided by the number of donations tested in the period under review) with 95% confidence intervals. RESULTS: Responding establishments covered 95% of the donations. We identified 20 HIV-1-NAT, 61 HCV-NAT and 29 HBV-NAT yield cases among approximately 46 million blood donations tested corresponding to 0·43 HIV-1 NAT, 1·32 HCV-NAT, and 0·64 HBV-NAT yield cases per million blood donations tested. For one HBsAg reactive only case and 23 anti-HBc reactive only cases in repeat donors, infection was confirmed by ID-NAT which translates into 0·02 and 0·55 cases per million donations tested. During the 8-year-observation period, one HIV-1, no HCV and four HBV transmissions associated with donations in the viremic pre-seroconversion window period were reported. CONCLUSION: Annually, NAT screening alone detected 2·5 HIV-1, 7·6 HCV, and 3·6 HBV infectious donations; anti-HBc screening alone identified 2·9 infectious donations of repeat donors with occult HBV infection. Overall, the survey results support that the currently practiced donor HIV/HCV/HBV screening strategy in Germany does ensure a high standard of blood safety.

[Postvaccinal complications and management of suspected cases]. / Impfkomplikationen und der Umgang mit Verdachtsfällen.

In all developed countries there is the possibility to protect oneself from vaccine-preventable diseases. However, not all individuals make use of this option. It is precisely in highly developed countries where a trend to vaccination hesitancy is noticeable, i. e. reluctance to get oneself or one's children vaccinated. The reasons why this is so are many, but the most important reason is the fear of postvaccinal complications, especially of those that imply sequelae or those with fatal outcomes.Whereas there are some proven associations between vaccination and adverse drug reaction, for example febrile seizures after the measles-mumps-rubella (MMR) vaccination, other hypotheses can be refuted, for example autism after the MMR vaccination. On one hand, this article gives an overview of known postvaccinal complications with indication of a causal association with vaccination and on the other hand addresses hypotheses of potential adverse drug reactions that have been refuted by pharmacoepidemiological studies.Only the scientific debate of these hypotheses, which are repeatedly discussed, especially on social media, can contribute to corroborating or refuting a potential causal association. If evidence for a causal association grows, e. g. intussusception, the relevant authorities (e.g. Paul Ehrlich Institute, European Medicines Agency) will take risk-minimizing measures. If studies and meta-analyses do not reveal any evidence of a causal association, a targeted information strategy will be required in order to prevent myths from circulating, vaccination coverages from declining, and infectious diseases from spreading.