Prevalence of IgG and IgM to SARS-CoV-2 and other human coronaviruses in The Democratic Republic of Congo, Sierra Leone and Uganda: A Longitudinal Study (preprint)

Objectives We assessed the prevalence of immunoglobulin G (IgG) and immunoglobulin M (IgM) against four endemic human coronaviruses (HCoVs) and two SARS-CoV-2 antigens, among vaccinated and unvaccinated staff at health care centres in Uganda, Sierra Leone, and the Democratic Republic of Congo (DRC). Methods Government health facility staff who had patient contact in Goma (DRC), Kambia District (Sierra Leone), and Masaka District (Uganda) were enrolled. Questionnaires and blood samples were collected at three timepoints over four months. Blood samples were analysed with the Luminex MAGPIX. Results Among unvaccinated participants, the prevalence of IgG/IgM antibodies against SARS-CoV-2 RBD or N-protein at enrolment was 70% in Goma (138/196), 89% in Kambia (112/126) and 89% in Masaka (190/213). IgG responses against endemic HCoVs at baseline were not associated with SAR-CoV-2 sero-acquisition during follow-up. Among vaccinated participants, those who had evidence of SARS-CoV-2 IgG/IgM at baseline tended to have higher IgG responses to vaccination compared to those SARS-CoV-2 seronegative at baseline, controlling for the time of sample collection since vaccination. Conclusions The high levels of natural immunity and hybrid immunity should be incorporated into both vaccination policy and prediction models of the impact of subsequent waves of infection in these settings.

Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey.

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.

Two Cases of Crimean-Congo Hemorrhagic Fever Detected in a Non-endemic Feast of Sacrifice

Crimean-Congo hemorrhagic fever (CCHF) is a viral zoonotic infectious disease transmitted by ticks, accompanied by fever, bleeding, myalgia, weakness and similar non-specific symptoms, and can have an acute and serious course. In this article, two CCHF cases seen during the Coronavirus disease-2019 (COVID-19) pandemic in a non-endemic province are described. The common feature of both cases; contact with animals in the endemic region during the feast of sacrifice, non-specific symptoms, liver function test, lactate dehydrogenase and creatine phosphokinase elevation, leukopenia and thrombocytopenia. Especially during the COVID-19 pandemic, tick and livestock contact of patients with non-specific symptoms should be questioned.

Crimean-Congo Hemorrhagic Fever Outbreak in Refugee Settlement during COVID-19 Pandemic, Uganda, April 2021.

Crimean-Congo hemorrhagic fever (CCHF) was detected in 2 refugees living in a refugee settlement in Kikuube district, Uganda. Investigations revealed a CCHF IgG seroprevalence of 71.3% (37/52) in goats within the refugee settlement. This finding highlights the need for a multisectoral approach to controlling CCHF in humans and animals in Uganda.

Crimean Congo Hemorrhagic Fever Epidemic During COVID-19 in Iraq: A “double whammy”? (preprint)

The Nairovirus causing the Crimean Congo Hemorrhagic Fever (CCHF) is transferred mainly via ticks and farm animals. Its incidence is spread over several countries broadly categorized into continents, including Europe, Asia, and Africa. This editorial is shedding light on this concerning pathogen and suggesting several strategies to tackle it.

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.

The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host's metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.

Crimean-Congo hemorrhagic fever (CCHF) is an emerging disease that is increasingly spreading to new populations. The condition is now endemic in almost 30 countries in sub-Saharan Africa, South-Eastern Europe, the Middle East and Central Asia. CCHF is caused by a tick-borne virus and can cause uncontrolled bleeding. It has a mortality rate of up to 40%, and there are currently no vaccines or effective treatments available. All viruses depend entirely on their hosts for reproduction, and they achieve this through hijacking the molecular machinery of the cells they infect. However, little is known about how the CCHF virus does this and how the cells respond. To understand more about the relationship between the cell's metabolism and viral replication, Neogi, Elaldi et al. studied immune cells taken from patients during an infection and one year later. The gene activity of the cells showed that the virus prefers to hijack processes known as central carbon and energy metabolism. These are the main regulator of the cellular energy supply and the production of essential chemicals. By using cancer drugs to block these key pathways, Neogi, Elaldi et al. could reduce the viral reproduction in laboratory cells. These findings provide a clearer understanding of how the CCHF virus replicates inside human cells. By interfering with these processes, researchers could develop new antiviral strategies to treat the disease. One of the cancer drugs tested in cells, 2-DG, has been approved for emergency use against COVID-19 in some countries. Neogi, Elaldi et al. are now studying this further in animals with the hope of reaching clinical trials in the future.

Crimean Congo hemorrhagic fever in the COVID-19 pandemic: a case study (preprint)

In the COVID-19 pandemic, the overlap of clinical features between the other viral infections, make a reliable diagnosis difficult in the initial stage of illness. We describe the first confirmed case of CCHF in Tehran province during this year, who first misdiagnosed as COVID-19 infection.

Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir (preprint)

Remdesivir (RDV) is a direct antiviral agent that is approved in several countries for the treatment of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RDV exhibits broad-spectrum antiviral activity against positive-sense RNA viruses, e.g., SARS-CoV-2 and hepatitis C virus (HCV) and non-segmented negative-sense RNA viruses, e.g., Nipah virus (NiV), while several segmented negative-sense RNA viruses such as influenza (Flu) virus or Crimean-Congo hemorrhagic fever virus (CCHFV) are not sensitive to the drug. The reasons for this apparent pattern are unknown. Here, we expressed and purified representative RNA-dependent RNA polymerases (RdRp) and studied three biochemical parameters that have been associated with the inhibitory effects of RDV-triphosphate (TP): (i) selective incorporation of the nucleotide substrate RDV-TP, (ii) the effect of the incorporated RDV-monophosphate (MP) on primer extension, and (iii) the effect of RDV-MP in the template during incorporation of the complementary UTP. The results of this study revealed a strong correlation between antiviral effects and efficient incorporation of RDV-TP. Delayed chain-termination is heterogeneous and usually inefficient at higher NTP concentrations. In contrast, template-dependent inhibition of UTP incorporation opposite the embedded RDV-MP is seen with all polymerases. Molecular modeling suggests a steric conflict between the 1'-cyano group of RDV-MP and conserved residues of RdRp motif F. We conclude that future efforts in the development of nucleotide analogues with a broader spectrum of antiviral activities should focus on improving rates of incorporation while capitalizing on the inhibitory effects of a bulky 1'-modification.

Cross-Reactivity of SARS-CoV-2 Laboratory Diagnostics to Endemic Diseases in Africa: A Diagnostic Accuracy Study (preprint)

Background: Serology is a great tool to assess the level of immunity against SARS-CoV-2 in settings with limited access to molecular diagnostics. However, African populations displays a particular immunological profile with massive circulation of infectious agents from different aetiologies that can affect assays performance.Methods: We evaluated the OMEGA Diagnostics COVID-19 ELISA-IgG and the ID Screen® SARS-CoV-2-N IgG Indirect in Senegal using a panel of 636 blood samples covering several African-endemic diseases and healthy donors to determine test sensitivity and specificity. The sensitivity panel of sera includes 461 serum samples collected from 91 patients hospitalized for COVID-19 disease. COVID-19 cases were confirmed by qRT-PCR and samples were collected on an interval of three days until viral clearance. In addition, 272 sera obtained from COVID-19 negative individuals were selected from a well-documented biobank of sera collected before the COVID-19 outbreak.Finding: High-cross reactivity have been found in individuals with a history of exposure to Chikungunya, HIV, malaria (Plasmodium falciparum), rheumatoid factor as well as healthy donors with respective specificities of 55%, 41.8%, 70%, 70% and 75%. ELISA experiments with commercial assays targeting either SARS-CoV-2 Nucleocapsid protein and Spike 2 protein or nucleocapsid protein only suggest that cross-reactivity might be directed against Spike 2 protein and not Nucleocapsid protein. Further samples characterisation reveals that anti-malaria IgG is the leading cause of such poor specificities, but exposure to other diseases contributed as well.Interpretation: We anticipate that COVID-19 seroprevalence can be biased if assays are not contextualized. Since malaria is endemic in African settings, we propose that a particular attention must be given in serological surveillance of COVID-19 or anti-SARS-CoV-2 antibodies quantification as vaccines are being rolled out.FundingUK Foreign, Commonwealth and Development Office/Wellcome Trust Joint Initiative for Research in Epidemic Preparedness and Response (JIREP grant number 220764/Z/20/Z).Funding Information: UK Foreign, Commonwealth and Development Office/Wellcome Trust Joint Initiative for Research in Epidemic Preparedness and Response (JIREP grant number 220764/Z/20/Z).Declaration of Interests: JRAF was an employee of Mologic Ltd, which was the development partner of one of the ELISAs adopted in this study. The remaining authors declare no competing interest.Ethics Approval Statement: Pre-COVID-19 samples for malaria (PCR), dengue, yellow fever, Zika, Chikungunya, Influenza A/B, HIV, rheumatoid arthritis and samples tested negative for the same diseases and also Crimean Congo haemorrhagic fever, West Nile fever encephalitis and Rift Valley fever were part of national public health surveillance program of the Senegalese Ministry of Social Action and Health performed in collaboration with Institut Pasteur de Dakar. Therefore, consultation with ethics committee was not required. Pre-COVID-19 samples for malaria endemic areas were from a longitudinal cohort survey performed in Dielmo village and approved by the Senegalese National Ethics Committee for Research in Health (reference number 00000007/MSAS/CNERS/Sec 26 January 2021). Samples from COVID-19 RT-PCR positive patients were obtained from a multicentre cohort survey approved by the Senegalese National Ethics Committee for Research in Health (reference number 00000068/MSAS/CNERS/Sec, 10 April 2020).

Novel application of capture-recapture methods to estimate the completeness of contact tracing during a large outbreak of Ebola Virus Disease, Democratic Republic of Congo, 2018-2020 (preprint)

Despite its critical role in containing outbreaks, the efficacy of contact tracing (CT), measured as the sensitivity of case detection, remains an elusive metric. We estimated the sensitivity of CT by applying unilist capture-recapture methods on data from the 2018-2020 outbreak of Ebola virus disease in the Democratic Republic of Congo. We applied different distributional assumptions to the zero-truncated count data to estimate the number of unobserved cases with a) any contacts and b) infected contacts, to compute CT sensitivity. Geometric distributions were the best fitting models. Our results indicate that CT efforts identified almost all (n=792, 99%) of the cases with any contacts, but only half (n=207, 48%) of the cases with infected contacts, suggesting that CT efforts performed well at identifying contacts during the listing stage, but performed poorly during the contact follow-up stage. We discuss extensions to our work and potential applications for the current COVID-19 pandemic.

Association Between Severity Grading Score And Acute Phase Reactants In Patients With Crimean Congo Hemorrhagic Fever.

As the COVID-19 pandemic continues, countries still have to struggle with their endemic diseases such as Crimean-Congo hemorrhagic fever (CCHF). Severity grading score (SGS) is a practical approach and may shed light on the course of the CCHF, whose pathogenesis is not clearly understood, and have no effective treatments. It is aimed to assess the association between SGS and acute phase reactants (APR). Laboratory-confirmed patients were categorized by severity scores, and the relationship between APR and SGS was evaluated. A significant correlation between SGS and C-reactive protein (CRP) was found (p < 0.001). High SGS was associated with mortality and high CRP levels were used to predict the mortality at the beginning of the hospital admission. To predict the outcome of the disease and for appropriate patient management, SGS and APR can be used simultaneously.