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Background The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. Methods We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications. Results In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d -dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms. Conclusions Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.
Background We developed a heterologous COVID-19 vaccine consisting of two components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of two formulations (frozen and lyophilised) of this vaccine. Methods We did two open, non-randomised phase 1/2 studies at two hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18–60 years to both studies. In phase 1 of each study, we administered intramuscularly on day 0 either one dose of rAd26-S or one dose of rAd5-S and assessed the safety of the two components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered intramuscularly a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (number of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concentration) and change in neutralising antibodies (detected with a SARS-CoV-2 neutralisation assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875. Findings Between June 18 and Aug 3, 2020, we enrolled 76 participants to the two studies (38 in each study). In each study, nine volunteers received rAd26-S in phase 1, nine received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titres were 14 703 with the frozen formulation and 11 143 with the lyophilised formulation, and neutralising antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilised formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2·5% CD4+ and 1·3% CD8+ with the frozen formulation, and a median cell proliferation of 1·3% CD4+ and 1·1% CD8+ with the lyophilised formulation. Interpretation The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19. Funding Ministry of Health of the Russian Federation.
Originalliteratur Voysey M, Clemens SAC, Madhi SA et al on behalf of the Oxford COVID Vaccine Trial Group (2020) Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 10.1016/S0140-6736(20)32661-1 Polack FP, Thomas SJ, Kitchin N et al for the C4591001 Clinical Trial Group (2020) Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 10.1056/NEJMoa2034577 Seit der ersten beschriebenen Infektion mit dem „severe acute respiratory syndrome coronavirus 2“ (SARS-CoV-2) im Dezember 2019 hat sich die „coronavirus disease 2019“ (COVID-19) zu einer Pandemie entwickelt, deren Symptomatik vom asymptomatischen Verlauf bis hin zum akuten Lungen- und Multiorganversagen und Tod reicht. Hoffnung, die Pandemie in den Griff zu bekommen, bringen die neu entwickelten, kurz vor der Zulassung stehenden (Stand 21.12.2020) Impfstoffe. Derzeit sind 52 Impfstoffe in der klinischen Prüfung, die sich hinsichtlich der Wirkweise teils deutlich unterscheiden. So nutzt AZD1222 ein Schimpansenadenovirus als Vektor für SARS-CoV-2-Proteine, Sputnik V [5] zwei unterschiedliche Adenoviren als Vektoren, bei der ersten Impfung rAd26 und bei der zweiten rAd5. Der NVX-CoV2373-Impfstoff [4] ist ein rekombinanter Nanopartikelimpfstoff, der aus dem SARS-CoV-2-Wildtyp-Spike hergestellt wurde, während mRNA-1273 [3] die Boten-RNA des Spike-Proteins von SARS-CoV‑2 als Induktor nutzt und BNT162b2 ein lipidnanopartikelformulierter nukleosidmodifizierter RNA-Impfstoff ist, der das SARS-CoV-2-Spike-Protein in voller Länge codiert. Ziel der im Folgenden vorgestellten Studien war es, die Wirksamkeit einer Impfung von Probanden bezüglich der Prävention einer COVID-19-Infektion zu verifizieren.
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