A longitudinal study on SARS-CoV-2 seroconversion, reinfection and neutralisation spanning several variant waves and vaccination campaigns, Heinsberg, Germany, April 2020 to November 2022.

BackgroundSince its emergence in December 2019, over 700 million people worldwide have been infected with SARS-CoV-2 up to May 2024. While early rollout of mRNA vaccines against COVID-19 has saved many lives, there was increasing immune escape of new virus variants. Longitudinal monitoring of population-wide SARS-CoV-2 antibody responses from regular sample collection irrespective of symptoms provides representative data on infection and seroconversion/seroreversion rates.AimTo examine adaptive and cellular immune responses of a German SARS-CoV-2 outbreak cohort through several waves of infection with different virus variants.MethodsUtilising a 31-month longitudinal seroepidemiological study (n = 1,446; mean age: 50 years, range: 2-103) initiated during the first SARS-CoV-2 superspreading event (February 2020) in Heinsberg, Germany, we analysed acute infection, seroconversion and virus neutralisation at five follow-up visits between October 2020 and November 2022; cellular and cross-protective immunity against SARS-CoV-2 Omicron variants were also examined.ResultsSARS-CoV-2 spike (S)-specific IgAs decreased shortly after infection, while IgGs remained stable. Both increased significantly after vaccination. We predict an 18-month half-life of S IgGs upon infection. Nucleocapsid (N)-specific responses declined over 12 months post-infection but increased (p < 0.0001) during Omicron. Frequencies of SARS-CoV-2-specific TNF-alpha+/IFN-gamma+ CD4+ T-cells declined over 12 months after infection (p < 0.01). SARS-CoV-2 S antibodies and neutralisation titres were highest in triple-vaccinated participants infected between April 2021 and November 2022 compared with infections between April 2020 and January 2021. Cross neutralisation against Omicron BQ.1.18 and XBB.1.5 was very low in all groups.ConclusionInfection and/or vaccination did not provide the population with cross-protection against Omicron variants.

Deficient Immune Response following SARS-CoV-2 Vaccination in Patients with Hepatobiliary Carcinoma: A Forgotten, Vulnerable Group of Patients.

Introduction: Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment. Methods: In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented. Results: In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log10 BAU/mL; 95% CI: 2.33-2.76; p < 0.01) than in patients in follow-up care (3.02 log10 BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; p < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed. Conclusion: Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.

Impaired immunogenicity after vaccination for SARS-CoV-2 in patients with gastrointestinal cancer: does tumor entity matter?

Background: SARS-CoV-2 immunogenicity in patients with gastrointestinal cancer (GI cancer) following second and third vaccination was analyzed. Methods: A total of 125 patients under active anticancer therapy or in follow-up care were included in this prospective study. Seroprevalence of SARS-CoV-2 anti-spike and surrogate neutralization antibodies (NABs) was measured. Results: Four weeks after second vaccination, adequate titers of SARS-CoV-2 anti-spike immunoglobulin G (IgG) [≥282.0 binding antibody units (BAU)/mL] were found in 62.2% of patients under treatment versus 96.3% of patients in follow-up care (P<0.01). Sufficient titers of SARS-CoV-2 surrogate NAB (≥85.0%) were found in 32.7% of patients under treatment versus 70.6% in follow-up care (P<0.01). Titers of SARS-CoV-2 anti-spike IgG were especially low in patients with colorectal cancer (CRC). For SARS-CoV-2 surrogate NAB, patients with hepatocellular carcinoma (HCC) and with pancreaticobiliary cancer showed the lowest titers (P<0.01). SARS-CoV-2 anti-spike IgG and SARS-CoV-2 surrogate NAB were associated with a correlation coefficient of 0.93. Reaching a titer of SARS-CoV-2 anti-spike IgG ≥482.0 BAU/mL, protective levels of SARS-CoV-2 surrogate NAB (≥85.0%) could be assumed. Following booster vaccination, all patients reached effective antibody titers. Conclusions: Patients with active GI cancer showed impaired immunogenicity after second SARS-CoV-2 vaccination which was overcome by booster vaccination. Our findings were tumor-related and pronounced in patients with CRC and HCC. Waning immunity over time and antibody escape phenomena by variant of concern Omicron must be considered in these especially vulnerable patients.

HIV-Associated Microbial Translocation May Affect Cytokine Production of CD56bright NK Cells via Stimulation of Monocytes.

The mechanisms involved in HIV-associated natural killer (NK) cell impairment are still incompletely understood. We observed HIV infection to be associated with increased plasma levels of IFABP, a marker for gut epithelial barrier dysfunction, and LBP, a marker for microbial translocation. Both IFABP and LBP plasma concentrations were inversely correlated with NK cell interferon-γ production, suggesting microbial translocation to modulate NK cell functions. Accordingly, we found lipopolysaccharide to have an indirect inhibitory effect on NK cells via triggering monocytes' transforming growth factor-ß production. Taken together, our data suggest increased microbial translocation to be involved in HIV-associated NK cell dysfunction.

SARS-CoV-2 in Environmental Samples of Quarantined Households.

The role of environmental transmission of SARS-CoV-2 remains unclear. Thus, the aim of this study was to investigate whether viral contamination of air, wastewater, and surfaces in quarantined households result in a higher risk for exposed persons. For this study, a source population of 21 households under quarantine conditions with at least one person who tested positive for SARS-CoV-2 RNA were randomly selected from a community in North Rhine-Westphalia in March 2020. All individuals living in these households participated in this study and provided throat swabs for analysis. Air and wastewater samples and surface swabs were obtained from each household and analysed using qRT-PCR. Positive swabs were further cultured to analyse for viral infectivity. Out of all the 43 tested adults, 26 (60.47%) tested positive using qRT-PCR. All 15 air samples were qRT-PCR-negative. In total, 10 out of 66 wastewater samples were positive for SARS-CoV-2 (15.15%) and 4 out of 119 surface samples (3.36%). No statistically significant correlation between qRT-PCR-positive environmental samples and the extent of the spread of infection between household members was observed. No infectious virus could be propagated under cell culture conditions. Taken together, our study demonstrates a low likelihood of transmission via surfaces. However, to definitively assess the importance of hygienic behavioural measures in the reduction of SARS-CoV-2 transmission, larger studies should be designed to determine the proportionate contribution of smear vs. droplet transmission.

Reconstruction of the origin of the first major SARS-CoV-2 outbreak in Germany.

The first major COVID-19 outbreak in Germany occurred in Heinsberg in February 2020 with 388 officially reported cases. Unexpectedly, the first outbreak happened in a small town with little to no travelers. We used phylogenetic analyses to investigate the origin and spread of the virus in this outbreak. We sequenced 90 (23%) SARS-CoV-2 genomes from the 388 reported cases including the samples from the first documented cases. Phylogenetic analyses of these sequences revealed mainly two circulating strains with 74 samples assigned to lineage B.3 and 6 samples assigned to lineage B.1. Lineage B.3 was introduced first and probably caused the initial spread. Using phylogenetic analysis tools, we were able to identify closely related strains in France and hypothesized the possible introduction from France.

Case Report: Infection With SARS-CoV-2 in the Presence of High Levels of Vaccine-Induced Neutralizing Antibody Responses.

We present a case of SARS-CoV-2 B.1. 525 infection in a healthcare worker despite the presence of highly neutralizing, multivariant-specific antibodies 7 weeks after full vaccination with the mRNA vaccine BNT162b2. We show that the virus replicated to high levels in the upper respiratory tract over the course of several days in the presence of strong antibody responses. The virus was readily propagatable in vitro, demonstrating the potential to transmit to others, bolstered by the fact that several household members were equally infected. This highlights the importance of protective measures even in vaccinated individuals.

Analysis of autoantibody spectrum and human herpesvirus 6 in adult patients with 'early' versus 'late' diagnosis of 'possible limbic encephalitis'.

New onset temporal seizures are increasingly encountered in adult patients. Many of those fulfill diagnostic criteria for possible or definite limbic encephalitis (LE). LE is associated with autoantibodies (autoABs) against neuronal surface structures ('neuronal' autoABs), 'onconeuronal' or GAD65. AutoABs can emerge in a paraneoplastic setting. However, by far not all patients with possible/definite LE have an oncological history. AutoABs have also found to arise in the context of viral encephalitis. Rare associations between autoAB-positive LE and human herpes virus 6 (HHV-6) infection have been as well reported. Our present analysis was dedicated to learn about potentially different autoAB spectra and HHV-6 detection rates in adult-onset temporal seizure patients with possible LE and largely different time spans between first seizure events and referral to a tertiary epileptological center due to pharmacoresistent seizures. We scrutinized serum/CSF samples obtained from adults with 'early diagnosis' of possible LE (≤ 30 months after first seizure event; n = 94) versus a patient group with 'late diagnosis' of possible LE (≥ 97 months; n = 45) for the presence of autoABs and HHV-6 DNA. AutoABs were detected in CSF and/or serum samples (n = 20) in 21.3 % of the early diagnosis patients with the highest abundance of anti-LGI1 (n = 8), significantly more frequent than in the late diagnosis group (autoAB positive: n = 4 (8.9 %); *p < 0.05, Fisher's Exact Test). Quantitative PCR revealed viral HHV-6 DNA in only one serum sample of the early diagnosis cohort but no evidence in corresponding CSF samples or in any sample of the late diagnosis group. The present data demonstrate a higher incidence of distinct autoABs in adults with early diagnosis of possible LE. The distinct spectra of autoABs have to be taken into account in the differential diagnosis of possible LE patients with short versus more sustained duration of temporal seizure activity.

Detectable SARS-CoV-2 RNAemia in Critically Ill Patients, but Not in Mild and Asymptomatic Infections.

BACKGROUND: The SARS-CoV-2 pandemic has challenged many of our current routine practices in the treatment and care of patients. Given the critical importance of blood donation and transfusion we analyzed 92 blood samples of individuals infected with SARS-CoV-2 stratified by symptoms. STUDY DESIGN AND METHODS: We therefore tested blood samples for SARS-CoV-2 via RT-PCR targeting the E gene. In addition, we tested each blood sample for anti-SARS-CoV-2 IgG antibodies via ELISA and performed plaque reduction neutralization tests. RESULTS: SARS-CoV-2 RNA was absent in the blood of mild to asymptomatic patients (57 individuals) and only detectable in individuals with severe COVID-19 who were admitted to the intensive care unit (35 individuals) (n = 6/92 [6.5%]; p = 0.023 Fisher's exact test). Interestingly, anti-spike IgG antibodies were not significantly higher in intensive care unit patients compared to mild patients, but we found that their neutralizing capacity was disproportionately increased (p < 0.001). CONCLUSION: Our observations support the hypothesis that there are no potential hazards from blood or plasma transfusion of SARS-CoV-2-positive individuals with mild flu-like symptoms and more importantly of asymptomatic individuals.

SARS-CoV-2 seroconversions and chains of infection in healthcare professionals in a German maximum care provider (The CoSHeP study).

INTRODUCTION: The CoSHeP study provides novel data on SARS-CoV-2 seroconversion rates in healthcare professionals (HP) at risk at the University Hospital Bonn, a maximum healthcare provider in a region of 900.000 inhabitants. METHODS: Single-center, longitudinal observational study investigating rate of SARS-CoV-2 IgG seroconversion in HP at 2 time-points. SARS-CoV-2 IgG was measured with Roche Elecsys Anti-SARS-CoV-2 assay. RESULTS: Overall, 150 HP were included. Median age was 35 (range: 19-68). Main operational areas were intensive care unit (53%, n = 80), emergency room (31%, n = 46), and infectious disease department (16%, n = 24). SARS-CoV-2-IgG was detected in 5 participants (3%) at inclusion in May/June 2020, and in another 11 participants at follow-up (December 2020/ January 2021). Of the 16 seropositive participants, 14 had already known their SARS-CoV-2 infection because they had performed a PCR-test previously triggered by symptoms. Trailing chains of infection by self-assessment, 31% (n = 5) of infections were acquired through private contacts, 25% (n = 4) most likely through semi-private contacts during work. 13% (n = 2) were assumed to result through contact with contagious patients, further trailing was unsuccessful in 31% (n = 5). All five participants positive for SARS-CoV-2 IgG at inclusion remained positive with a median of 7 months after infection. DISCUSSION: Frontline HP caring for hospitalized patients with COVID-19 are at higher risk of SARS-CoV-2 infections. Noteworthy, based upon identified chains of infection most of the infections were acquired in private environment and semi-private contacts during work. The low rate of infection through infectious patients reveals that professional hygiene standards are effective in preventing SARS-CoV-2 infections in HP. Persisting SARS-CoV-2-IgG might indicate longer lasting immunity supporting prioritization of negative HP for vaccination.

Fast Detection of SARS-CoV-2 RNA Directly from Respiratory Samples Using a Loop-Mediated Isothermal Amplification (LAMP) Test.

The availability of simple SARS-CoV-2 detection methods is crucial to contain the COVID-19 pandemic. This study examined whether a commercial LAMP assay can reliably detect SARS-CoV-2 genomes directly in respiratory samples without having to extract nucleic acids (NA) beforehand. Nasopharyngeal swabs (NPS, n = 220) were tested by real-time reverse transcription (RT)-PCR and with the LAMP assay. For RT-PCR, NA were investigated. For LAMP, NA from 26 NPS in viral transport medium (VTM) were tested. The other 194 NPS were analyzed directly without prior NA extraction (140 samples in VTM; 54 dry swab samples stirred in phosphate buffered saline). Ten NPS were tested directly by LAMP using a sous-vide cooking unit. The isothermal assay demonstrated excellent specificity (100%) but moderate sensitivity (68.8%), with a positive predictive value of 1 and a negative predictive value of 0.65 for direct testing of NPS in VTM. The use of dry swabs, even without NA extraction, improved the analytical sensitivity; up to 6% of samples showed signs of inhibition. LAMP could be performed successfully with a sous-vide cooking unit. This technique is very fast, requires little laboratory resources, and can replace rapid antigen tests or verify reactive rapid tests on-site.

Infection fatality rate of SARS-CoV2 in a super-spreading event in Germany.

A SARS-CoV2 super-spreading event occurred during carnival in a small town in Germany. Due to the rapidly imposed lockdown and its relatively closed community, this town was seen as an ideal model to investigate the infection fatality rate (IFR). Here, a 7-day seroepidemiological observational study was performed to collect information and biomaterials from a random, household-based study population. The number of infections was determined by IgG analyses and PCR testing. We found that of the 919 individuals with evaluable infection status, 15.5% (95% CI:[12.3%; 19.0%]) were infected. This is a fivefold higher rate than the reported cases for this community (3.1%). 22.2% of all infected individuals were asymptomatic. The estimated IFR was 0.36% (95% CI:[0.29%; 0.45%]) for the community and 0.35% [0.28%; 0.45%] when age-standardized to the population of the community. Participation in carnival increased both infection rate (21.3% versus 9.5%, p < 0.001) and number of symptoms (estimated relative mean increase 1.6, p = 0.007). While the infection rate here is not representative for Germany, the IFR is useful to estimate the consequences of the pandemic in places with similar healthcare systems and population characteristics. Whether the super-spreading event not only increases the infection rate but also affects the IFR requires further investigation.

Herpes Simplex Virus Type 2 Is More Difficult to Neutralize by Antibodies Than Herpes Simplex Virus Type 1.

Infections with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are a global health burden. Besides painful oral or genital lesions in otherwise healthy subjects, both viruses can cause devastating morbidity and mortality in immune-compromised and immune-immature individuals. The latter are particularly susceptible to a disseminated, life-threatening disease. Neutralizing antibodies (NAb) constitute a correlate of protection from disease, and are promising candidates for the prophylactic or therapeutic treatment of severe HSV infections. However, a clinical vaccine trial suggested that HSV-2 might be more resistant to NAbs than HSV-1. In the present study, we investigated the antiviral efficacy of the well-characterized humanized monoclonal antibody (mAb) hu2c against HSV-2, in a NOD/SCID immunodeficiency mouse model. Despite the fact that hu2c recognizes a fully conserved epitope and binds HSV-1 and HSV-2 glycoprotein B with equal affinity, it was much less effective against HSV-2 in vitro and in NOD/SCID mice. Although intravenous antibody treatment prolonged the survival of HSV-2-infected mice, complete protection from death was not achieved. Our data demonstrate that HSV-2 is more resistant to NAbs than HSV-1, even if the same antibody and antigen are concerned, making the development of a vaccine or therapeutic antibodies more challenging.

When polyuria does not stop: a case report on an unusual complication of hantavirus infection.

BACKGROUND: The clinical features, course and outcome of hantavirus infection is highly variable. Symptoms of the central nervous system may occur, but often present atypically and diagnostically challenging. Even though the incidence of hantavirus infection is increasing worldwide, this case is the first to describe diabetes insipidus centralis as a complication of hantavirus infection in the Western world. CASE PRESENTATION: A 49-year old male presenting with severe headache, nausea and photophobia to our neurology department was diagnosed with acute haemorrhage in the pituitary gland by magnetic resonance imaging. In the following days, the patient developed severe oliguric acute kidney failure. Diagnostic workup revealed a hantavirus infection, so that the pituitary haemorrhage resulting in hypopituitarism was seen as a consequence of hantavirus-induced hypophysitis. Under hormone replacement and symptomatic therapy, the patient's condition and kidney function improved considerably, but significant polyuria persisted, which was initially attributed to recovery from kidney injury. However, water deprivation test revealed central diabetes insipidus, indicating involvement of the posterior pituitary gland. The amount of urine production normalized with desmopressin substitution. CONCLUSION: Our case report highlights that neurological complications of hantavirus infection should be considered in patients with atypical clinical presentation.

A cross-sectional study on risk factors for infection with Parvovirus B19 and the association with anaemia in a febrile paediatric population in Ghana.

Parvovirus B19 (B19V) occurs globally and can cause severe anaemia. The role of co-infections with Plasmodium falciparum (P. falciparum) has been controversially discussed. The study aimed to determine prevalence and severity of B19V infection, and the effect of co-infections on the risk for anaemia. Between November 2013 and April 2015 a total of 1186 hospital visits of children with fever admitted to a hospital in Ghana were recorded. Malaria, B19V and additional diagnostics for fever causes were performed. Recent B19V infection was defined as PCR and/or IgM positivity. Risk factors for a B19V infection and for anaemia were analysed. The prevalence of anaemia was compared between children with/without B19V infection, stratified for the presence of malaria. B19V IgM/PCR was positive in 6.4% (n = 76; 40 IgM + , 30 PCR + , 6 IgM + and PCR +). Among the B19V cases 60.5% had a simultaneous P. falciparum infection. B19V IgM positivity but not PCR positivity was associated with moderate-severe anaemia (OR = 2.6; 95%-CI: 1.3-5.3; P < 0.01 vs. OR = 0.9; 95%-CI: 0.4-1.8; P = 0.70). P. falciparum and IgM positive B19V infection were independent risk factors for anaemia with no evidence of effect modification. Our data show a significant association between B19V infection, defined as IgM but not PCR positivity, and moderate-severe anaemia. A multiplicative effect of B19V and P. falciparum infection was not found.

Drug Resistance Spread in 6 Metropolitan Regions, Germany, 2001-20181.

We analyzed 1,397 HIV-1 pol sequences of antiretroviral therapy-naive patients in a total of 7 university hospitals in Bonn, Cologne, Frankfurt, Hamburg, Hannover, and Munich, Germany. Phylogenetic and network analysis elucidated numerous cases of shared drug resistance mutations among genetically linked patients; K103N was the most frequently shared mutation.