COVID-19 during pregnancy, maternal immune response and neonatal cell-specific immunity

Pathogens are a major threat to maternal health and the progression of pregnancy. The immune response during normally progressing pregnancies, primarily the suppression of inflammation, likely accounts for this high susceptibility of pregnant women to infections. An increased morbidity and mortality related to influenza, COVID-19 and malaria has been reported for pregnant women, compared to non-pregnant women. Especially influenza infections during pregnancy have been well studied, as humans are severely and recurrently affected by seasonal epidemics and random pandemics. Besides severe maternal symptoms such as acute cardiopulmonary events, pneumonia, and acute respiratory distress syndrome, maternal influenza infection also causes foetal complications, such as intrauterine growth restriction, preterm birth or even foetal death. However, vertical transmission of the influenza virus across the placenta and infection of the foetus has not been observed, suggesting that the pregnancy pathologies are maternally derived. In addition to influenza-mediated adverse conditions, the recent COVID-19 pandemic has underscored that infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) can also lead to severe illnesses in pregnant women, accompanied by a higher risk for foetal loss or preterm birth. Fortunately, with the ongoing pandemic, large cohort studies and meta-analyses revealed that vertical transmission and related fetal infection is a rare complication affecting only 1-3% of SARS-CoV-2 infections in pregnancy. These low risk for placental infection is likely due to the inefficient SARS-CoV-2 virus replication in placental tissues. Since understanding SARS-CoV-2-related pathogenicity during pregnancy is highly relevant, we initiated a study early in 2020, to which we have recruited more than 160 pregnant women with COVID-19. Our comprehensive placental analyses unearthed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection and in convalescent pregnant women. Furthermore, we could show inefficient SARS-CoV-2 replication in placental tissues in vitro, which provides a rationale for the low ex vivo viral expression. We detected specific SARS-CoV-2 T cell responses in mothers within a few days upon infection, which is undetectable in cord blood. Reports by others have shown that maternal SARS-CoV-2 during pregnancy may cause placental insufficiency, defined by increased perivillous fibrin deposition, histiocytic intervillositis and trophoblast necrosis. These changes can cause extensive placental damage leading to placental malperfusion and insufficiency that is incompatible with intrauterine survival. Considering that multiple SARS-CoV-2 variants of concern which emerged until today may affect pregnant women differently and bear a differential risk for pregnancy complication. This, continuous vigilance is needed in order to provide best protection of the highly vulnerable group of pregnant women and their unborn children. Trial registration number

NATURAL KILLER CELL-MEDIATED ADCC in SARS-CoV-2 INFECTION and VACCINATION

Background: COVID-19, caused by SARS-CoV-2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of Natural killer (NK) cells in COVID-19 remains poorly understood. Methods: We characterized NK cell-mediated SARS-CoV-2 antibody-dependent cellular cytotoxicity (ADCC) against SARS-CoV-2 spike-1 (S1) and nucleocapsid (NC) protein using NK cell degranulation (CD107a) and killing assays. Results: Serum samples from SARS-CoV-2 resolvers induced significant CD107a expression by NK cells in response to S1 and NC (p < 0.0001), while serum samples from SARS-CoV-2-negative individuals did not. Furthermore, serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals (p < 0.0001). As expected, vaccine-induced responses were directed against S1 and not against NC protein. S1-specific CD107a responses by NK cells were significantly correlated to NK cell-mediated killing of S1-expressing cells (r = 0.86, p = 1.82 x 10-6). Interestingly, screening of serum samples collected prior to the COVID-19 pandemic identified two individuals with cross-reactive antibodies against SARS-CoV-2 S1, which also induced degranulation of NK cells. Conclusion: These data demonstrate that antibodies induced by SARS-CoV-2 infection and anti-SARS-CoV-2 vaccines can trigger significant NK cell-mediated ADCC activity, and identify some cross-reactive ADCC activity against SARS-CoV-2 by endemic coronavirus-specific antibodies.

CD19+ B Lymphocytes Are Predictive for Anti-Sars-Cov-2 Vaccination Response in Multiple Myeloma Patients

Introduction: Up to now,reliable results regarding the efficacy of anti-SARS-CoV-2 vaccines in patients with multiple myeloma (MM), especially under current myeloma-directed therapy, are scarcely available. Here, we report an analysis describing the level of post-vaccination antibody titers after the 1 stand 2 ndanti-SARS-CoV-2 vaccination depending on therapy, remission status, and B- and T-cell numbers in patients with MM and related plasma cell neoplasia. Methods: This observational single-center study included patients aged ≥18 years with diagnoses of MM, monoclonal gammopathies of clinical significance (MGCS), or systemic light-chain amyloidosis (AL) who were eligible for Anti-SARS-CoV-2 vaccination according to the International Myeloma Society recommendations. Patients with prior COVID-19 infections were excluded. Samples were analyzed for the presence of SARS-CoV-2 specific antibodies using the quantitative anti-spike IgG (SARS-CoV-2 spike RBD IgG, cut off ≥ 0.8 BAU/ml) according to manufacturer's recommendations. SARS-CoV-2 spike protein antibody titer (SP-AbT) were evaluated after at least 7 days after the 1 stand 2 ndvaccination, respectively. This study was performed between January 1 - July 15, 2021, at the University Medical Center Hamburg-Eppendorf, Germany, as part of the COVIDOUT trial (NCT04779346). All patients provided written informed consent. Aims of this study were to evaluate a possible correlation between SP-AbT and CD19+ B lymphocyte count, as well as to identify other factors impacting vaccination response. Results: 82 patients who received SARS-CoV-2 vaccines (including 67 patients with mRNA-, 8 with vector-based vaccines and 4 heterologous vaccinations) were included. 74 patients had diagnosis of MM, 4 of MGCS/smoldering MM and 4 of AL. Median age was 68 years (range 35-85) and 49 patients were male. In total, 37 patients (45.1%) received anti-CD38- and 2 (2.4%) anti-SLAMF7-targeting therapies at the time of vaccination, 52 (63.4%) patients received immunomodulatory drug (IMID)-based treatments and 13 patients (15.9%) were under active surveillance. 59% of patients had newly diagnosed and 41% refractory or relapsed disease. In total, 75.6% of all patients were in deep remissions (very good partial remission or better). Assessment of anti-SARS-CoV-2 antibody titers took place in median 23 days (range [r] 8-63 days) after the 1 stand 21 days (r: 6-53) after the 2 ndvaccination. A positive SARS-CoV-2 SP-AbT was detected in 31.9% of assessable patients with an overall median SP-AbT of 0 BAU/ml (r: 0-10328, mean 202.36) after the 1 stvaccination and increased up to 88.9% (median SP-AbT of 216.87 BAU/ml, r: 0-25720, mean 2139.29) after 2 ndvaccination. Of the patients not showing positive SP-AbT after the 1 stvaccination, 80.9% became positive after 2 ndvaccination, while 19.1 % remained negative. Median SP-AbT titer was significantly lower compared to patients who became positive already after 1 stvaccination (51.04 vs. 2191.87 BAU/ml, p<0.0001). Regarding immune status, a CD19+ B cell count of median 33.5/µl (r: 1-696/µl) was seen in the overall patient cohort;in patients with negative SP-AbT, median CD19+ B cell numbers were significantly lower compared to patients with positive titers (median CD19+ B cells: 2.0 vs. 52.5/µl, p=0.005). Overall, CD19+ B lymphocyte numbers correlate significantly with positive SP-AbT results and were identified as predictive factor in multivariate analysis. The previously suggested threshold of 30 CD19+ B cells/µl as being predictive for SP-AbT development could be validated. SP-AbT concentration was significantly lower with older age. Furthermore, median SP-AbT were significantly lower in patients with current anti-CD38 directed therapy (median SP-AbT: 1085.4 vs. 62.05 BAU/ml, p < 0.005). Conclusions: In spite of immunodeficiency and immunosuppressive therapy, most MM patients develop SP-AbT. However, about 11% of MM patients failed to develop SP-AbT after full vaccination, and thus remain on risk for COVID-19. Higher counts of CD19+ B lymphocytes, ith a threshold of 30 CD19+ B lymphocytes/µl, are predictive for SP-AbT formation and may further help to identify patients at higher risk of insufficient vaccination response in whom control of vaccination success and potential third vaccination are particularly important. Disclosures: Bokemeyer: GlaxoSmithKline: Research Funding;Inside: Research Funding;IO Biotech: Research Funding;Eisai: Research Funding;Daiichi Sankyo: Research Funding;Gilead Sciences: Research Funding;Blueprint Medicine: Research Funding;BerGenBio: Research Funding;Janssen-Cilag: Research Funding;Isofol Medical: Research Funding;AOK Health insurance: Consultancy;GSO: Consultancy;Bayer Schering Pharma: Consultancy;Gylcotope GmbH: Research Funding;ADC Therapeutics: Research Funding;Apellis Pharmaceuticals: Research Funding;Amgen: Research Funding;Alexion Pharmaceuticals: Research Funding;Agile Therapeutics: Research Funding;Merck Serono: Consultancy, Other: Travel accomodation;Lilly/ImClone: Consultancy;Merck Sharp Dohme: Consultancy, Honoraria;AstraZeneca: Honoraria, Research Funding;BMS: Honoraria, Other: Travel accomodation, Research Funding;Bayer: Honoraria, Research Funding;Roche: Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Other: Travel accomodation;Merck KGaA: Honoraria;Abbvie: Research Funding;Boehringer Ingelheim: Research Funding;Celgene: Research Funding;Astellas: Research Funding;Karyopharm Therapeutics: Research Funding;Lilly: Research Funding;Millenium: Research Funding;MSD: Research Funding;Nektar: Research Funding;Rafael Pharmaceuticals: Research Funding;Springworks Therapeutics: Research Funding;Taiho Pharmaceutical: Research Funding;Pfizer: Other. Sinn: Incyte: Honoraria, Research Funding;Pfizer: Honoraria;Servier: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Research Funding;Astra Zenica: Consultancy, Research Funding;MSD: Consultancy, Research Funding;Sanofi: Consultancy;Bayer: Research Funding;BMS: Honoraria, Research Funding. Leypoldt: GSK: Consultancy, Other: Meeting attendance;Sanofi: Consultancy;Abbvie: Other: Meeting attendance. Weisel: Adaptiv Biotec: Consultancy;Abbvie: Consultancy;BMS: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;GSK: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Karyopharm: Honoraria;Novartis: Honoraria;Oncopeptides: Consultancy, Honoraria;Pfizer: Honoraria;Roche: Honoraria;Takeda: Honoraria;Sanofi: Consultancy, Honoraria, Research Funding.

Brain pathology of COVID-19

Coronavirus disease 2019 (COVID-19) is caused by the infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS) where it leads to CNS dysfunction (Neuro COVID-19). Mechanisms of SARS-CoV-2 neuropathogenesis including the targeting of the brain and elucidation of the sequence of events underlying CNS damage are only poorly understood. We and others have investigated this by neuropathological deep phenotyping using morphological methods and molecular neuropathology in representative cohorts of patients dying from/with COVID-19 and in adequate control cohorts. Our studies show that Neuro COVID-19 is characterized by a compartmentalized and region-specific perivascular glial and neuroinflammatory response with activation of microglia which is found in nearly all patients dying from/with COVID-19. Conversely, SARS-CoV-2 and SARS-CoV-2 viral proteins can only be found in low amounts in a subset of COVID-19 patients' brains. In the presentation, it will be illustrated how neuropathological deep phenotyping can contribute to elucidate disease mechanisms in Neuro COVID-19.

SARS-CoV-2 Reinfection in a Healthcare Worker Despite the Presence of Detectable Neutralizing Antibodies

So far, only a few reports about reinfections with SARS-CoV-2 have been published, and they often lack detailed immunological and virological data. We report about a SARS-CoV-2 reinfection with a genetically distinct SARS-CoV-2 variant in an immunocompetent female healthcare worker that has led to a mild disease course. No obvious viral escape mutations were observed in the second virus variant. The infectious virus was shed from the patient during the second infection episode despite the presence of neutralizing antibodies in her blood. Our data indicate that a moderate immune response after the first infection, but not a viral escape, did allow for reinfection and live virus shedding.

An automated room disinfection system using ozone is highly active against surrogates for SARS-CoV-2.

BACKGROUND: The presence of coronaviruses on surfaces in the patient environment is a potential source of indirect transmission. Manual cleaning and disinfection measures do not always achieve sufficient removal of surface contamination. This increases the importance of automated solutions in the context of final disinfection of rooms in the hospital setting. Ozone is a highly effective disinfectant which, combined with high humidity, is an effective agent against respiratory viruses. Current devices allow continuous nebulization for high room humidity as well as ozone production without any consumables. AIM: In the following study, the effectiveness of a fully automatic room decontamination system based on ozone was tested against bacteriophage Φ6 (phi 6) and bovine coronavirus L9, as surrogate viruses for the pandemic coronavirus SARS-CoV-2. METHODS: For this purpose, various surfaces (ceramic tile, stainless steel surface and furniture board) were soiled with the surrogate viruses and placed at two different levels in a gas-tight test room. After using the automatic decontamination device according to the manufacturer's instructions, the surrogate viruses were recovered from the surfaces and examined by quantitative cultures. Then, reduction factors were calculated. FINDINGS: The ozone-based room decontamination device achieved virucidal efficacy (reduction factor >4 log10) against both surrogate organisms regardless of the different surfaces and positions confirming a high activity under the used conditions. CONCLUSION: Ozone is highly active against SARS-CoV-2 surrogate organisms. Further investigations are necessary for a safe application and efficacy in practice as well as integration into routine processes.

Evidence for systematic autopsies in COVID-19 positive deceased: Case report of the first German investigated COVID-19 death.

Forensic medicine and pathology involve specific health risks, whereby health workers are dealing with microorganisms, cells or parasites, which are referred to as biological agents. Biological agents are divided into four categories according to § 3 of the Biological Agents Ordinance. The newly identified coronavirus, severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2) that has spread rapidly around the world is placed into category 3 of the Biological Agents Ordinance, meaning pathogens that can cause serious illnesses in humans and may pose a risk to workers. The Robert Koch Institute, the German government's central scientific institution in the field of biomedicine issued the announcement, that aerosol-producing measures (including autopsies) of SARS-CoV­2 infected bodies should be avoided, despite the fact that autopsies are an important source of understanding the pathomorphological course of new diseases. The first German case of death due to a proven SARS-CoV­2 infection is presented with global multifocal reticular consolidation in the post-mortem computed tomography (CT) scan, a macroscopic and microscopic viral pneumonia and viral RNA of SARS-CoV­2 in pharyngeal mucosa and lung tissue.