Potential associations of selected polymorphic genetic variants with COVID-19 disease susceptibility and severity (preprint)

In this study, we analyzed the potential associations of selected laboratory and anamnestic parameters, as well as 12 genetic polymorphisms (SNPs), with clinical COVID-19 occurrence and severity in 869 hospitalized patients. The SNPs analyzed by qPCR were selected based on population-wide genetic (GWAS) data previously indicating association with the severity of COVID-19. We confirmed the associations of disease with several clinical laboratory and anamnestic parameters and found an unexpected association between less severe disease and the loss of smell and taste. In most cases, selected SNP analysis supported earlier results by indicating genetic associations with hospitalization and disease severity, while the potential role of some previously unrecognized polymorphisms has also been observed. A genetic association was indicated between the presence of a reduced-function ABCG2 transporter variant and a less severe disease, which was also observed in diabetic patients. Our current results, which should be reinforced by larger studies, indicate that together with laboratory and anamnestic parameters, genetic polymorphisms may have predictive value for the clinical occurrence and severity of COVID-19.

Virus neutralizing antibody responses after two doses of BBIBP-CorV (Sinopharm, Beijing CNBG) vaccine (preprint)

Background Limited information is available on the effectiveness of the BBIBP-CorV (Sinopharm, Beijing CNBG) vaccine, especially in the elderly, despite the fact that it is approved in more than 50 countries. Methods Virus neutralizing antibody titres, as a rapidly available but highly predictive surrogate marker, were measured after two doses of the BBIBP-CorV vaccine in 450 subjects. Results were analyzed in a multivariable model accounting for age, sex and time since the administration of the second dose of the vaccine. Findings Sex and time since the second dose had little association with the antibody titres. Age, however, was highly relevant: measurable antibody levels were present in about 90% of individuals below the age of 50, but antibody production after BBIBP-CorV vaccination was strongly reduced with increasing age. A large number of elderly subjects, reaching 25% at 60 years, and up to 50% at ages over 80, were found not to produce any protective antibody. Interpretation Neutralizing antibody titre, as a correlate of protection for COVID-19 disease susceptibility, should help to evaluate the effectiveness of the BBIBP-CorV vaccine. Results suggest that proper measures should be undertaken to prevent a potential outbreak of COVID-19 in BBIBP-CorV vaccinated but eventually unprotected elderly individuals. Funding No specific funding was used to carry out the study. Research in context Evidence before this study The BBIBP-CorV (Sinopharm, Beijing CNBG) vaccine was found to be effective, but the Phase 3 trial included few women, almost no elderly subject and no subject with preexisting medical condition. It is therefore especially important to monitor the real-world effectiveness of this vaccine, however when searching Pubmed for (Sinopharm OR BBIBP-CorV) AND vaccine AND (effectiveness OR efficacy OR antibody OR titre) in text words with no language or date restriction and with translation of the terms enabled, we found no such published study. The most rapid way to generate such evidence is the assessment of antibody response which was found to be highly predictive for disease susceptibility. This is of crucial importance as the vaccine is approved in more than 50 countries, and hundreds of millions have already been vaccinated with many planned to be vaccinated in the near future with this vaccine. Added value of this study Virus neutralizing antibody titres were measured after two doses of the BBIBP-CorV vaccine in 450 subjects. Results were analyzed in a multivariable model accounting for age, sex and time since the administration of the second dose of the vaccine. We found that sex and time since the second dose had little association with the antibody titres. Age, however, was highly relevant: while the vast majority of those below 50 years had measurable antibody levels, this rate quickly dropped with increasing age. In subjects aged 60 years, quarter, in those above 80 almost half had no detectable neutralizing antibody. Implications of all the available evidence The real-world effectiveness of the BBIBP-CorV vaccine should be carefully monitored. Elderly subjects are especially prone to produce no protective antibody after vaccination. This should be monitored, and proper measures should be undertaken to prevent a potential outbreak of COVID-19 in BBIBP-CorV vaccinated but eventually unprotected elderly individuals.

Interactions of Anti-COVID-19 Drug Candidates With Hepatic Transporters May Cause Liver Toxicity and Affect Drug Metabolism (preprint)

Transporters in the human liver play a major role in the metabolism of endo-and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake or expel various compounds into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the relevant key transporters in the hepatocytes. These transporters included the ABCB11/BSEP, ABCC2/MRP2, and MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, OCT1, OATP1B1, OATP1B3, and NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited the ABCB11/BSEP and MATE1 exporters, as well as the OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited ABCC4/MRP4, OATP1B1/1B3, MATE1 and OCT1. Thus, these agents may cause severe drug-drug interactions and drug-induced liver injury. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the variable interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.

A repurposed, blood gene signature is associated with poor outcomes in SARS-CoV-2 (preprint)

Poor outcomes after SARS-CoV-2 infection are difficult to predict. Survivors may develop pulmonary fibrosis. We previously identified a 52-gene signature in peripheral blood, predictive of mortality in Idiopathic Pulmonary Fibrosis. In this study, we analyzed this signature in SARS-CoV-2 infected individuals and identified genomic risk profiles with significant differences in outcomes. Analysis of single cell expression data shows that monocytes, red blood cells, neutrophils and dendritic cells are the cellular source of the high risk gene signature.

Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters (preprint)

In the COVID-19 epidemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied together with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, here we examined the interactions of the repurposed drugs with the key human multidrug transporters, present in the major tissue barriers and strongly affecting pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine, the antihelmintic ivermectin, and the proposed antiviral compounds, ritonavir, lopinavir, favipiravir and remdesivir with the ABCB1/Pgp, ABCG2/BCRP and ABCC1/MRP1 exporters, as well as the OATP2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning for the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.