SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies. HighlightsO_LISARS-CoV-2 undergoes rapid evolution in an immunocompromised, chronically infected cancer patient, overcoming neutralization by two monoclonal antibody cocktail treatments C_LIO_LIReceptor binding domain (RBD) mutations emerging after monoclonal antibody treatment enable effective escape from neutralization in the absence of adaptive immunity C_LIO_LISome emerging mutations are predicted to disrupt immunomodulatory viral proteins, including prevention of ORF8 homodimerization, mis-localization of ORF3a in host cells and alteration of the host-suppressive function of NSP1 C_LI

Immunosuppression as a hub for SARS-CoV-2 mutational drift

Newly emerging SARS-CoV-2 variants of concern (VOCs) play a major role in the persistence of the coronavirus disease 2019 (COVID-19) pandemic. While these VOCs are characterized by extraordinary evolutionary leaps and evasion from previously acquired immunity, their origins remain mostly unknown. In this study, we paired electronic health records of individuals infected with SARS-CoV-2 to viral whole-genome sequences, to assess effects of host clinical parameters and immunity on the intra-host evolution of SARS-CoV-2. We found small, albeit significant differences in SARS-CoV-2 intra-host diversity, which depended on host parameters such as vaccination status and smoking. Viral genomes showed a significant difference in the early course of disease in only one of 31 immunosuppressed patients, a recently vaccinated woman aged in her 70s. We highlight the unusually mutated viral genome obtained from this woman, which harbored near-complete truncating of the accessory protein ORF3a. Our findings suggest only minor influence of host parameters on the SARS-CoV-2 intra-host evolutionary rate and trajectory, with even the majority of immunosuppressed persons carrying fairly unremarkable viral genomes. We hypothesize that major evolutionary steps, such as those observed in VOCs, are rare occurrences, even among immunodeficient hosts. HighlightsO_LIIntra-host viral diversity is modestly affected by host clinical parameters, such as vaccination status and smoking. C_LIO_LIThe emergence and fixation of high-impact SARS-CoV-2 mutations in immunosuppressed hosts are rare, and not exclusive to patients with prolonged viral shedding. C_LIO_LIWe identified a rare stop-gain mutation, leading to near-complete truncating of ORF3a, in an immunosuppressed woman recently vaccinated against COVID-19. C_LI

Elevated expression of RGS2 may underlie reduced olfaction in COVID-19 patients

Anosmia is common in COVID-19 patients, lasting for weeks or months following recovery. The biological mechanism underlying olfactory deficiency in COVID-19 does not involve direct damage to nasal olfactory neurons, which do not express the proteins required for SARS-CoV-2 infection. A recent study suggested that anosmia results from downregulation of olfactory receptors. We hypothesized that anosmia in COVID-19 may also reflect SARS-CoV-2 infection-driven elevated expression of regulator of G protein signaling 2 (RGS2), a key regulator odorant receptor, thereby silencing their signaling. To test our hypothesis, we analyzed gene expression of nasopharyngeal swabs from SARS-CoV-2 positive patients and non-infected controls (two published RNA-sequencing datasets, 580 individuals). Our analysis found upregulated RGS2 expression in SARS-CoV-2 positive patients (FC=14.5, Padj=1.69e-05 and FC=2.4; Padj=0.001, per dataset). Additionally, RGS2 expression was strongly correlated with PTGS2, IL1B, CXCL8, NAMPT and other inflammation markers with substantial upregulation in early infection. These observations suggest that upregulated expression of RGS2 may underlie anosmia in COVID-19 patients. As a regulator of numerous G-protein coupled receptors, RGS2 may drive further neurological symptoms of COVID-19. Studies are required for clarifying the cellular mechanisms by which SARS-CoV-2 infection drives the upregulation of RGS2 and other genes implicated in inflammation. Insights on these pathways may assist in understanding anosmia and additional neurological symptoms reported in COVID-19 patients.

Antibody response to SARS-CoV-2 infection and BNT162b2 vaccine in Israel

Neutralizing antibodies targeting the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) block viral entry to host cells, preventing disease and further spread of the pathogen. The presence of SARS-CoV-2 antibodies in serum is a reliable indicator of infection, used epidemiologically to estimate the prevalence of infection and clinically as a measurement of an antigen-specific immune response. In this study, we analyzed serum Spike protein-specific IgG antibodies from 26,170 samples, including convalescent individuals who had coronavirus disease 2019 (COVID-19) and recipients of the BNT162b2 vaccine. We find distinct serological patterns in COVID-19 convalescent and vaccinated individuals, correlated with age and gender and the presence symptoms.

Ethnic differences in SERPINA1 allele frequencies may partially explain national differences in COVID-19 fatality rates

COVID-19 infection and fatality rates vary considerably between countries. We present preliminary evidence that these variations may in part reflect ethnic differences in the frequencies of polymorphic alleles of SERPINA1, coding for alpha-1 antitrypsin, the major blood serine protease inhibitor.

COVID-19 diagnosis prediction by symptoms of tested individuals: a machine learning approach

MotivationEffective screening of SARS-CoV-2 enables quick and efficient diagnosis of COVID-19 and can mitigate the burden on healthcare systems. Prediction models that combine several features to estimate the risk of infection have been developed in hopes of assisting medical staff worldwide in triaging patients when allocating limited healthcare resources. ResultsWe established a machine learning approach that trained on records from 51,831 tested individuals (of whom 4,769 were confirmed COVID-19 cases) while the test set contained data from the following week (47,401 tested individuals of whom 3,624 were confirmed COVID-19 cases). Our model predicts COVID-19 test results with high accuracy using only eight features: gender, whether age is above 60, known contact with an infected individual, and five initial clinical symptoms. SummaryOverall, based on the nationwide data publicly reported by the Israeli Ministry of Health, we developed a model that detects COVID-19 cases by simple features accessed by asking basic questions. Our framework can be used, among other considerations, to prioritize testing for COVID-19 when allocating limited testing resources. AvailabilityAll data used in this study was retrieved from the Israeli Ministry of Health website. Contactyazeed@tauex.tau.ac.il, nshomron@tauex.tau.ac.il