Drug repurposing for COVID-19: current evidence from randomized controlled adaptive platform trials and living systematic reviews.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic resulted in a race to develop effective treatments largely through drug repurposing via adaptive platform trials on a global scale. Drug repurposing trials have focused on potential antiviral therapies aimed at preventing viral replication, anti-inflammatory agents, antithrombotic agents and immune modulators through a number of adaptive platform trials. Living systematic reviews have also enabled evidence synthesis and network meta-analysis as clinical trial data emerge globally. SOURCES OF DATA: Recent published literature. AREAS OF AGREEMENT: Corticosteroids and immunomodulators that antagonize the interleukin-6 (IL-6) receptor have been shown to play a critical role in modulating inflammation and improving clinical outcomes in hospitalized patients. Inhaled budesonide reduces the time to recovery in older patients with mild-to-moderate COVID-19 managed in the community. AREAS OF CONTROVERSY: The clinical benefit of remdesivir remains controversial with conflicting evidence from different trials. Remdesivir led to a reduction in time to clinical recovery in the ACTT-1 trial. However, the World Health Organization SOLIDARITY and DISCOVERY trial did not find a significant benefit on 28-day mortality and clinical recovery. GROWING POINTS: Other treatments currently being investigated include antidiabetic drug empagliflozin, antimalarial drug artesunate, tyrosine kinase inhibitor imatinib, immunomodulatory drug infliximab, antiviral drug favipiravir, antiparasitic drug ivermectin and antidepressant drug fluvoxamine. AREAS TIMELY FOR DEVELOPING RESEARCH: The timing of therapeutic interventions based on postulated mechanisms of action and the selection of clinically meaningful primary end points remain important considerations in the design and implementation of COVID-19 therapeutic trials.

Low Prevalence of HEV Infection and No Associated Risk of HEV Transmission from Mother to Child among Pregnant Women in Vietnam.

Infections with HEV in low- and middle-income countries (LMICs) are associated with increased rates of preterm birth, miscarriage, and stillbirth. The aim of the present study was to investigate HEV infections in pregnant women and the possibility of mother-to-child transmission, and associated outcomes. A total of 183 pregnant women in their third trimester were recruited and followed until delivery. Anti-HEV IgG and IgM were determined via enzyme-linked immunosorbent assay (ELISA), and HEV nucleic acids were detected in stool and cord blood samples. HEV genotypes were identified by Sanger sequencing, and phylogenetic analyses were performed. Mother-to-child transmission and associated adverse outcomes were not observed. Only 2% of patients (n = 4/183) tested positive for anti-HEV IgM, and 8% (n = 14/183) tested positive for anti-HEV IgG antibodies. Cord blood (n = 150) analysis showed that there was no IgM detected, while 4% (n = 6/150) tested positive for anti-HEV IgG, which was consistent with mothers testing positive for anti-HEV IgG. Nucleic acid tests for HEV RNA yielded 2% (n = 4/183) from the serum and stool of pregnant women, and none from cord blood. The HEV isolates belonged to the genotype HEV-3a, with 99% homology with humans and 96% with pigs. No association was found between the risk of HEV infection and pregnancy outcomes or HEV transmission from mother to child. HEV-3 infections of zoonotic origin in pregnancy might have eventually resolved without complications.

Middle East respiratory syndrome coronavirus-a 10-year (2012-2022) global analysis of human and camel infections, genomic sequences, lineages, and geographical origins.

OBJECTIVES: The World Health Organization priority zoonotic pathogen Middle East respiratory syndrome (MERS) coronavirus (CoV) has a high case fatality rate in humans and circulates in camels worldwide. METHODS: We performed a global analysis of human and camel MERS-CoV infections, epidemiology, genomic sequences, clades, lineages, and geographical origins for the period January 1, 2012 to August 3, 2022. MERS-CoV Surface gene sequences (4061 bp) were extracted from GenBank, and a phylogenetic maximum likelihood tree was constructed. RESULTS: As of August 2022, 2591 human MERS cases from 26 countries were reported to the World Health Organization (Saudi Arabia, 2184 cases, including 813 deaths [case fatality rate: 37.2%]) Although declining in numbers, MERS cases continue to be reported from the Middle East. A total of 728 MERS-CoV genomes were identified (the largest numbers were from Saudi Arabia [222: human = 146, camels = 76] and the United Arab Emirates [176: human = 21, camels = 155]). A total of 501 'S'-gene sequences were used for phylogenetic tree construction (camels [n = 264], humans [n = 226], bats [n = 8], other [n=3]). Three MERS-CoV clades were identified: clade B, which is the largest, followed by clade A and clade C. Of the 462 clade B lineages, lineage 5 was predominant (n = 177). CONCLUSION: MERS-CoV remains a threat to global health security. MERS-CoV variants continue circulating in humans and camels. The recombination rates indicate co-infections with different MERS-CoV lineages. Proactive surveillance of MERS-CoV infections and variants of concern in camels and humans worldwide, and development of a MERS vaccine, are essential for epidemic preparedness.

SARS-CoV-2 B.1.214.1, B.1.214.2 and B.1.620 are predominant lineages between December 2020 and July 2021 in the Republic of Congo.

Background: : SARS-CoV-2 variants have been emerging and are shown to increase transmissibility, pathogenicity, and decreased vaccine efficacies. The objective of this study was to determine the distribution, prevalence, and dynamics of SARS-CoV-2 variants circulating in Brazzaville, the Republic of Congo (ROC). Methods: : Between December 2020 and July 2021, a total of n=600 oropharyngeal specimens collected in the community were tested for COVID-19. Of the samples tested, 317 (53%) were SARS-CoV-2 positive. All samples that had a threshold of Ct <30 (n=182) were sequenced by next-generation sequencing (NGS), and all complete sequenced genomes were submitted to GISAID; lineages were assigned using pangolin nomenclature and a phylogenetic tree was reconstructed. In addition, the global prevalence of the predominant lineages was analysed using data from GISAID and Outbreak databases. Results: : A total of 15 lineages circulated with B.1.214.2 (26%), B.1.214.1 (19%) and B.1.620 (18%) being predominant. The variants of concern (VOC) alpha (B.1.1.7) (6%) and for the first time in June delta (B.1.617.2) (4%) were observed. In addition, the B.1.214.1 lineage first reported from ROC was observed to be spreading locally and regionally. Phylogenetic analysis suggests that the B.1.620 variant (VUM) under observation may have originated from either Cameroon or the Central African Republic. SARS-CoV-2 lineages were heterogeneous, with the densely populated districts of Poto-Poto and Moungali likely the epicenter of spread. Conclusion: : Longitudinal monitoring and molecular surveillance across time and space are critical to understanding viral phylodynamics, which could have important implications for transmissibility and impact infection prevention and control measures.

How to (ab)use a COVID-19 antigen rapid test with soft drinks?

With reasonably good specificity and sensitivity, the speed and convenience of COVID-19 antigen tests have led to self-testing in schools, offices, and universities in the European Union (EU). Although self-testing can be beneficial and increase the accessibility to testing, there are potential ways to confound a positive COVID-19 lateral flow test. We observed that all soft drinks, energy drinks, alcoholic beverages (vodka, whiskey, and brandy), commercially bottled mineral water, and carbonated mineral water caused the appearance of a red test line. However, when equal volumes of the buffer and the respective beverages are mixed, there are no false-positive test lines. Deceitful methods may easily lead to misuse of COVID-19 antigen rapid tests and lead to false-positive results; however, this does not prove that these tests are unreliable when performed correctly.

Host genetic loci LZTFL1 and CCL2 associated with SARS-CoV-2 infection and severity of COVID-19.

OBJECTIVES: Host genetic factors contribute to the variable severity of COVID-19. We examined genetic variants from genome-wide association studies and candidate gene association studies in a cohort of patients with COVID-19 and investigated the role of early SARS-CoV-2 strains in COVID-19 severity. METHODS: This case-control study included 123 COVID-19 cases (hospitalized or ambulatory) and healthy controls from the state of Baden-Wuerttemberg, Germany. We genotyped 30 single nucleotide polymorphisms, using a custom-designed panel. Cases were also compared with the 1000 genomes project. Polygenic risk scores were constructed. SARS-CoV-2 genomes from 26 patients with COVID-19 were sequenced and compared between ambulatory and hospitalized cases, and phylogeny was reconstructed. RESULTS: Eight variants reached nominal significance and two were significantly associated with at least one of the phenotypes "susceptibility to infection", "hospitalization", or "severity": rs73064425 in LZTFL1 (hospitalization and severity, P <0.001) and rs1024611 near CCL2 (susceptibility, including 1000 genomes project, P = 0.001). The polygenic risk score could predict hospitalization. Most (23/26, 89%) of the SARS-CoV-2 genomes were classified as B.1 lineage. No associations of SARS-CoV-2 mutations or lineages with severity were observed. CONCLUSION: These host genetic markers provide insights into pathogenesis and enable risk classification. Variants which reached nominal significance should be included in larger studies.

SARS-CoV-2 viral dynamics of the first 1000 sequences from Vietnam and neighbouring ASEAN countries.

Objective: The regional distribution and transmissibility of existing COVID-19 variants of concern (VOC) has led to concerns about increasing transmission, given the ability of VOCs to evade immunity as breakthrough infections become more prevalent. Methods: SARS-CoV-2 genomes (n = 277) were sequenced and analysed alongside all available genomes from Vietnam and ASEAN countries to understand the phylodynamics. The observed lineages were assigned using Pangolin nomenclature, and spread patterns were investigated. Results: Between January and November 8, 2021, VOCs, including alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2), were observed across the ASEAN countries. While alpha and delta were the major VOCs in nine ASEAN countries, delta was predominant. The alpha VOC was first reported by Singapore, beta by Malaysia, gamma by the Philippines, and delta by Singapore. Of the first 1000 genomes analysed from Vietnam, alpha and delta were the most represented, with delta being the dominant VOC from May 2021. The delta variant was introduced in early January 2021, and formed a large cluster within the representative genomes. Conclusion: Spatial and temporal monitoring of SARS-CoV-2 variants is critical to the understanding of viral phylodynamics, and will provide useful guidance to policy makers for infection prevention and control.

Evaluation of SARS-CoV-2 diagnostics and risk factors associated with SARS-CoV-2 infection in Zambia.

OBJECTIVES: To conduct a diagnostic validation study of SARS-CoV-2 diagnostic kits. METHODS: We compared SARS-CoV-2 diagnostic test results from 3 RT-PCR assays used by the Zambian government between November 2020 and February 2021 (Panther Fusion assay, Da An Gene's 2019-nCoV RNA kit and Maccura's PCR Kit) with the Altona RealStar RT-PCR kit which served as the gold standard. We also evaluated results from rapid antigen testing and whether comorbidities were linked with increased odds of infection. RESULTS: We recruited 244 participants, 61% (149/244) were positive by at least 1 PCR assay. Da An Gene, Maccura, and Panther Fusion assays had sensitivities of 0.0% (95% confidence interval [CI] 0%-41%), 27.1% (95% CI 15%-42%), and 76% (95% CI 65%-85%), respectively, but specificity was low (<85% for all 3 assays). HIV and TB were not associated with SARS-CoV-2, whereas female sex (OR 0.5 [0.3-0.9], p = 0.026) and chronic pulmonary disease (0.1 [0.0-0.8], p = 0.031) were associated with lower odds of SARS-CoV-2 infection. Of 44 samples, 84% sequenced were Beta variant. CONCLUSIONS: The RT-PCR assays evaluated did not meet WHO recommended minimum sensitivity of 80%. Local diagnostic validation studies should be embedded within preparedness plans for future outbreaks to improve the public health response.

Emergence of B.1.1.318 SARS-CoV-2 viral lineage and high incidence of alpha B.1.1.7 variant of concern in the Republic of Gabon.

OBJECTIVE: Variants of concern (VOCs) associated with relatively high transmissibility appear to be rapidly spreading in Gabon. Therefore, it is imperative to understand the distribution of several VOCs in the population, which could have implications for transmissibility and vaccine efficacy. METHODS: Between February and May 2021, SARS-CoV-2 genomes were sequenced using the Oxford nanopore MinION method and the respective genome diversity was elucidated. Phylogenetic analysis was performed and genomes were classified using pangolin lineages. RESULTS: The results highlighted an increase (46%) in the alpha VOC (B.1.1.7) in the Gabonese population over the study period. In addition, an increase (31%) in the B.1.1.318 lineage, which is associated with high transmission and impaired vaccine efficacy (D614G+E484K+Y144del), was detected. CONCLUSION: With the second wave ongoing, these findings highlight the need for surveillance of the SARS-CoV-2 genome in the Republic of Gabon and should provide useful guidance to policymakers in selecting an appropriate vaccine for this population.

Host genetic factors determining COVID-19 susceptibility and severity.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.

Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 : A phase 1 randomized clinical trial.

BACKGROUND: We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV­2 spike (S) protein encapsulated in lipid nanoparticles (LNP). METHODS: This is an interim analysis of a dosage escalation phase 1 study in healthy 18-60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV­2 S­protein and receptor binding domain (RBD), and SARS-CoV­2 neutralizing titers (MN50). RESULTS: In 245 volunteers who received 2 CVnCoV vaccinations (2 µg, n = 47, 4 µg, n = 48, 6 µg, n = 46, 8 µg, n = 44, 12 µg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S­protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S­protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 µg group. Responses to 12 µg were comparable to those observed in convalescent sera from known COVID-19 patients. CONCLUSION: In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 µg dosages elicited levels of immune responses that overlapped those observed in convalescent sera.

Longitudinal monitoring of laboratory markers characterizes hospitalized and ambulatory COVID-19 patients.

Early detection of severe forms of COVID-19 is absolutely essential for timely triage of patients. We longitudinally followed-up two well-characterized patient groups, hospitalized moderate to severe (n = 26), and ambulatory mild COVID-19 patients (n = 16) at home quarantine. Human D-dimer, C-reactive protein (CRP), ferritin, cardiac troponin I, interleukin-6 (IL-6) levels were measured on day 1, day 7, day 14 and day 28. All hospitalized patients were SARS-CoV-2 positive on admission, while all ambulatory patients were SARS-CoV-2 positive at recruitment. Hospitalized patients had higher D-dimer, CRP and ferritin, cardiac troponin I and IL-6 levels than ambulatory patients (p < 0.001, p < 0.001, p = 0.016, p = 0.035, p = 0.002 respectively). Hospitalized patients experienced significant decreases in CRP, ferritin and IL-6 levels from admission to recovery (p < 0.001, p = 0.025, and p = 0.001 respectively). Cardiac troponin I levels were high during the acute phase in both hospitalized and ambulatory patients, indicating a potential myocardial injury. In summary, D-dimer, CRP, ferritin, cardiac troponin I, IL-6 are predictive laboratory markers and can largely determine the clinical course of COVID-19, in particular the prognosis of critically ill COVID-19 patients.

Host factors facilitating SARS-CoV-2 virus infection and replication in the lungs.

SARS-CoV-2 is the virus causing the major pandemic facing the world today. Although, SARS-CoV-2 primarily causes lung infection, a variety of symptoms have proven a systemic impact on the body. SARS-CoV-2 has spread in the community quickly infecting humans from all age, ethnicities and gender. However, fatal outcomes have been linked to specific host factors and co-morbidities such as age, hypertension, immuno-deficiencies, chronic lung diseases or metabolic disorders. A major shift in the microbiome of patients suffering of the coronavirus disease 2019 (COVID-19) have also been observed and is linked to a worst outcome of the disease. As many co-morbidities are already known to be associated with a dysbiosis of the microbiome such as hypertension, diabetes and metabolic disorders. Host factors and microbiome changes are believed to be involved as a network in the acquisition of the infection and the development of the diseases. We will review in detail in this manuscript, the immune response toward SARS-CoV-2 infection as well as the host factors involved in the facilitation and worsening of the infection. We will also address the impact of COVID-19 on the host's microbiome and secondary infection which also worsen the disease.

A call to caution when hydroxychloroquine is given to elderly patients with COVID-19.

INTRODUCTION: Use of hydroxychloroquine in patients with coronavirus disease 2019 (COVID-19) was widespread and uncontrolled until recently. Patients vulnerable to severe COVID-19 are at risk of hydroxychloroquine interactions with co-morbidities and co-medications contributing to detrimental, including fatal, adverse treatment effects. METHODS: A retrospective survey was undertaken of health conditions and co-medications of patients with COVID-19 who were pre-screened for enrolment in a randomized, double-blind, placebo-controlled hydroxychloroquine multi-centre trial. RESULTS: The survey involved 305 patients [median age 71 (interquartile range 59-81) years]. The majority of patients (n = 279, 92%) considered for inclusion in the clinical trial were not eligible, mainly due to safety concerns caused by health conditions or co-medications. The most common were QT-prolonging drugs (n = 188, 62%) and haematologic/haemato-oncologic diseases (n = 39, 13%) which prohibited the administration of hydroxychloroquine. In addition, 165 (54%) patients had health conditions and 167 (55%) patients were on co-medications that did not prohibit the use of hydroxychloroquine but had a risk of adverse interactions with hydroxychloroquine. The most common were diabetes (n = 86, 28%), renal insufficiency (n = 69, 23%) and heart failure (n = 58, 19%). CONCLUSION: The majority of hospitalized patients with COVID-19 had health conditions or took co-medications precluding safe treatment with hydroxychloroquine. Therefore, hydroxychloroquine should be administered with extreme caution in elderly patients with COVID-19, and only in clinical trials.

COVID-19 and syndemic challenges in 'Battling the Big Three': HIV, TB and malaria.

Indirect effects of the COVID-19 pandemic have the potential to seriously undermine the health system in sub-Saharan Africa with an increase in the incidences of malaria, tuberculosis (TB) and HIV infections. Based on current evidence in the African region the collateral impact of COVID-19 on the "big three diseases" shall be addressed in the following.