Anaphylactic reactions after COVID-19 vaccination in Germany.

. For the COVID-19 vaccines used in Germany, severe allergic (anaphylactic) reactions after vaccination have been reported in very rare cases. While Comirnaty and Spikevax are mRNA vaccines, Vaxzevria and Jcovden comprise vector vaccines, and Nuvaxovid a recombinant spike protein vaccine. The reporting rate of anaphylaxis after mRNA vaccination was higher in females receiving their first vaccination dose, with 0.97 and 1.12 reports per 100,000 vaccinations for Comirnaty and Spikevax, respectively, compared with vaccinated males and subsequent vaccinations. The Paul-Ehrlich-Institut (PEI) investigated 106 responses of 321 cases of confirmed anaphylactic reactions concerning subsequent allergy testing and revaccination with a COVID-19 vaccine. The collected data indicate that only a small proportion of cases (22%) were IgE-mediated reactions. A large proportion (73%) of patients could be revaccinated under precautionary measures without recurrence of anaphylaxis. The pathomechanism of the majority of anaphylactic reactions remains unclear and should be investigated in further studies.

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%).

Laboratory confirmed vaccine-induced immune thrombotic thrombocytopenia: Retrospective analysis of reported cases after vaccination with ChAdOx-1 nCoV-19 in Germany.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse event of SARS-CoV-2 vaccination. We describe the characteristics of patients reported in Germany based on the Brighton Collaboration (BC) case definition criteria for Thrombosis and Thrombocytopenia Syndrome (TTS) and focus on patients with complete anti-platelet factor 4 (PF4)-antibody laboratory work up. METHODS: The adverse drug reaction database of the Paul-Ehrlich Institute was queried for TTS cases following ChAdOx1 nCoV-19 vaccination from February 1, until May 21, 2021. Cases with reports from the Greifswald laboratory were analysed in detail. FINDINGS: PF4 antibody tests were available for 69 suspected TTS cases reported to the Paul-Ehrlich Institute, of whom 52 patients fulfilled the BC case definition; 37 (71%) women, 15 (29%) men, median age 46·0 years (interquartile range 31·0-60·3 years). Cerebral venous sinus thrombosis was confirmed in 37 (71%), (additional) multiple thromboses in 19 (37%) patients. Twelve patients died. Non-survivors showed lower platelet counts compared to survivors (median nadir 15,000/µL vs 49,000/µL; p<0·0001). Combined anti-PF4/heparin IgG ELISA and PF4-dependent platelet activation testing yielded sensitivity of 96% (95% confidence interval 87-100%) and specificity of 77% (50-93%) for TTS. Four patients with thrombocytopenia but without thrombosis presented with severe headache or cerebral bleeding, explaining the lower specificity. INTERPRETATION: VITT has high mortality and can present with isolated thrombocytopenia, severe headache, and bleeding. Demonstration of platelet activating anti-PF4 IgG has high sensitivity for TTS and captures a wider spectrum of clinically relevant VITT than the current BC case definition. FUNDING: Deutsche Forschungsgemeinschaft: 374031971-TRR240; Domagk-Programm Universitätsmedizin Greifswald.

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.

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.

Accelerated Development of COVID-19 Vaccines: Technology Platforms, Benefits, and Associated Risks.

Multiple preventive COVID-19 vaccines have been developed during the ongoing SARS coronavirus (CoV) 2 pandemic, utilizing a variety of technology platforms, which have different properties, advantages, and disadvantages. The acceleration in vaccine development required to combat the current pandemic is not at the expense of the necessary regulatory requirements, including robust and comprehensive data collection along with clinical product safety and efficacy evaluation. Due to the previous development of vaccine candidates against the related highly pathogenic coronaviruses SARS-CoV and MERS-CoV, the antigen that elicits immune protection is known: the surface spike protein of SARS-CoV-2 or specific domains encoded in that protein, e.g., the receptor binding domain. From a scientific point of view and in accordance with legal frameworks and regulatory practices, for the approval of a clinic trial, the Paul-Ehrlich-Institut requires preclinical testing of vaccine candidates, including general pharmacology and toxicology as well as immunogenicity. For COVID-19 vaccine candidates, based on existing platform technologies with a sufficiently broad data base, pharmacological-toxicological testing in the case of repeated administration, quantifying systemic distribution, and proof of vaccination protection in animal models can be carried out in parallel to phase 1 or 1/2 clinical trials. To reduce the theoretical risk of an increased respiratory illness through infection-enhancing antibodies or as a result of Th2 polarization and altered cytokine profiles of the immune response following vaccination, which are of specific concern for COVID-19 vaccines, appropriate investigative testing is imperative. In general, phase 1 (vaccine safety) and 2 (dose finding, vaccination schedule) clinical trials can be combined, and combined phase 2/3 trials are recommended to determine safety and efficacy. By applying these fundamental requirements not only for the approval and analysis of clinical trials but also for the regulatory evaluation during the assessment of marketing authorization applications, several efficacious and safe COVID-19 vaccines have been licensed in the EU by unprecedentedly fast and flexible procedures. Procedural and regulatory-scientific aspects of the COVID-19 licensing processes are described in this review.