Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibit approximately 18-fold lower neutralization titers against Omicron. Convalescent sera from Alpha and Delta patients allow similar levels of breakthrough by Omicron. However, some Delta patients have relatively preserved neutralization efficacy, comparable to 3-month double BNT162b2 vaccination. Domain-wise analysis using chimeric spike revealed that this efficient evasion was, at least in part, caused by multiple mutations in the N-terminal domain. Omicron escapes the therapeutic cocktail of imdevimab and casirivimab, whereas sotrovimab, which targets a conserved region to avoid viral mutation, remains effective against Omicron. The ACE2 decoy is another virus-neutralizing drug modality that is free, at least in theory, from mutational escape. Deep mutational analysis demonstrated that, indeed, the engineered ACE2 overcomes every single-residue mutation in the receptor-binding domain, similar to immunized sera. Like previous SARS-CoV-2 variants, Omicron and some other sarbecoviruses showed high sensitivity against engineered ACE2, confirming the therapeutic value against diverse variants, including those that are yet to emerge.

COVID-19 REINFECTION BETWEEN DOSES OF VACCINATION: CASE REPORT IN A CITY OF BRAZIL’S SOUTHEAST

Vaccination against COVID-19 is happening worldwide, with most vaccines requiring 2 doses to reach its maximum potential. It is the most efficient measure to prevent new cases of COVID-19, both of infection and reinfection. This case reports the reinfection of a female receptionist at an urgent care facility, where the research group was testing and monitoring symptoms of patients with flu syndrome, in the city of Belo Horizonte, Minas Gerais, Brasil, where she reinfected between the two preconized doses. Her initial infection occurred in September 2020 and reinfection in February 2021, 14 days after the first dose - both confirmed by RT-PCR - with reportedly worse symptoms on the latter. We warn for the possibility of reinfection episodes even after the first dose of vaccination, differently from what literature stated so far, so that health agents can organize more effective security measures, in a context of viral mutation and of new strains.

511. Treatment with Molnupiravir in the MOVe-In and MOVe-Out Clinical Trials Results in an Increase in Transition Mutations Across the SARS-CoV-2 Genome

Background Molnupiravir (MOV), (MK-4482, EIDD-2801) is being clinically developed for the treatment of COVID-19 disease caused by SARS-CoV-2. MOV is the orally administered 5′-isobutyrate prodrug of the active, antiviral ribonucleoside analogue, N-hydroxycytidine (NHC, EIDD-1931) which inhibits viral replication by induction of mutations in the viral genome, leading to viral error catastrophe. In 2 clinical studies, hospitalized (MOVe-In) and non-hospitalized (MOVe-Out) participants were treated for 5 days with MOV and followed up to Day 29. Viral RNA isolated from nasal swab samples were sequenced to determine the rate, distribution and type of viral mutations observed after MOV treatment. Methods RNA isolated from nasopharangeal swab samples collected during study conduct was quantified by RT-PCR. Samples containing >22,000 copies/mL of RNA underwent complete genome NGS using the Ion AmpliSeq SARS-CoV-2 research panel and Ion Torrent sequencing. Mutation rates were calculated by determining the number of nucleotide changes observed across the entire genome at Day 3 and/or Day 5 compared to baseline. Results Combined data from both studies showed an increase of ~2-4 fold in the viral mutation rate post-baseline in MOV treated compared with placebo. Mutations were distributed across the entire genome with only a minority being observed in more than one sample. The most frequent mutations were transitions of C to U observed in the highest MOV dose group (800 mg/BID). Conclusion Consistent with the proposed mechanism of action of MOV, an increase in the rate of transition mutations in the virus was observed in post-baseline nasal swab samples from participants treated with MOV compared with placebo. Disclosures Julie Strizki, PhD, Merck & Co., Inc. (Employee, Shareholder) Jay Grobler, PhD, Merck & Co., Inc. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Shunbing Zhao, PhD, Merck & Co., Inc. (Employee, Shareholder) Diane Levitan, PhD, Merck & Co., Inc. (Employee, Shareholder) Alex Therien, PhD, Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Nicholas Murgolo, PhD, Merck & Co., Inc. (Employee, Shareholder)

The Fightback

This chapter discusses some of the barriers viruses must overcome in order to complete their life cycle. To survive, viruses must penetrate host cells before they can begin the process of reproducing their genetic material, and here again viruses appear remarkably resourceful. By carrying a molecular key on their surface, they can disguise themselves as normal body constituents, and latch on to and enter any cell which bears the complementary lock. As such, viruses infect only those cells which display the particular molecular lock that their key fits into, and this restriction dictates the type of cell a virus infects and therefore the symptoms it will cause. Since there are several hundred molecules to choose from, viruses cause a great variety of diseases. However, viruses are not fighting a one-sided battle. Even the simplest organisms have ways of dealing with viruses, but the sophistication and subtlety of the human immune system is unrivalled. The chapter then considers the vital role B and T cells play in the body’s defences. It also traces how viruses and their hosts have co-evolved. Finally, the chapter outlines the threats viruses may pose, including viral mutation and the use of viruses in biological warfare.

Is SARS CoV-2 viral mutation leading us to a virtual world?

not available Bangladesh Journal of Medical Science Vol.20(5) 2021 p.185-187

Tinjauan Molekuler dan Epidemiologi Mutasi pada Virus SARS-CoV-2

The SARS-CoV-2 virus which is the cause of the COVID-19 pandemic since the end of 2019 has undergone many mutations that gave rise to several variants of concern (VOC) with higher transmission, virulence, and ability to evade the immune system than the initial variant (wild-type). Until now, there are four variants included in the VOC of the virus, namely alpha, beta, gamma and delta variants. The increased transmission and virulence of these VOCs were associated with mutational changes in the spike protein, which is the structure of the virus that plays a role in binding to host cells. In this article, we conduct a literature review on VOCs from the SARS-CoV-2 virus related to mutations that occur and their impact on the viral binding process. To gain an understanding of the impact of mutations in these variants, we also reviewed the structure of the spike protein and the process of viral entry into host cells. Keywords: viral mutation, variants of concern (VOC), COVID-19, SARS-CoV-2.

Mutation signatures inform the natural host of SARS-CoV-2

The before-outbreak evolutionary history of SARS-CoV-2 is enigmatic because it shares only ~96% genomic similarity with RaTG13, the closest relative so far found in wild animals (horseshoe bats). Since mutations on single-stranded viral RNA are heavily shaped by host factors, the viral mutation signatures can in turn inform the host. By comparing publically available viral genomes we here inferred the mutations SARS-CoV-2 accumulated before the outbreak and after the split from RaTG13. We found the mutation spectrum of SARS-CoV-2, which measures the relative rates of 12 mutation types, is 99.9% identical to that of RaTG13. It is also similar to that of two other bat coronaviruses but distinct from that evolved in non-bat hosts. The viral mutation spectrum informed the activities of a variety of mutation-associated host factors, which were found almost identical between SARS-CoV-2 and RaTG13, a pattern difficult to create in laboratory. All the findings are robust after replacing RaTG13 with RshSTT182, another coronavirus found in horseshoe bats with ~93% similarity to SARS-CoV-2. Our analyses suggest SARS-CoV-2 shared almost the same host environment with RaTG13 and RshSTT182 before the outbreak.

SARS-CoV-2 Infectivity and Severity of COVID-19 According to SARS-CoV-2 Variants: Current Evidence

Background: We conducted this review to summarize the relation between viral mutation and infectivity of SARS-CoV-2 and also the severity of COVID-19 in vivo and in vitro. Method: Articles were identified through a literature search until 31 May 2021, in PubMed, Web of Science and Google Scholar. Results: Sixty-three studies were included. To date, most studies showed that the viral mutations, especially the D614G variant, correlate with a higher infectivity than the wild-type virus. However, the evidence of the association between viral mutation and severity of the disease is scant. A SARS-CoV-2 variant with a 382-nucleotide deletion was associated with less severe infection in patients. The 11,083G > U mutation was significantly associated with asymptomatic patients. By contrast, ORF1ab 4715L and S protein 614G variants were significantly more frequent in patients from countries where high fatality rates were also reported. The current evidence showed that variants of concern have led to increased infectivity and deteriorating epidemiological situations. However, the relation between this variant and severity of COVID-19 infection was contradictory. Conclusion: The COVID-19 pandemic continues to spread worldwide. It is necessary to anticipate large clinical cohorts to evaluate the virulence and transmissibility of SARS-CoV-2 mutants.

The total number and mass of SARS-CoV-2 virions

Quantitatively describing the time course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within an infected individual is important for understanding the current global pandemic and possible ways to combat it. Here we integrate the best current knowledge about the typical viral load of SARS-CoV-2 in bodily fluids and host tissues to estimate the total number and mass of SARS-CoV-2 virions in an infected person. We estimate that each infected person carries 109 to 1011 virions during peak infection, with a total mass in the range of 1 μg to 100 μg, which curiously implies that all SARS-CoV-2 virions currently circulating within human hosts have a collective mass of only 0.1 kg to 10 kg. We combine our estimates with the available literature on host immune response and viral mutation rates to demonstrate how antibodies markedly outnumber the spike proteins, and the genetic diversity of virions in an infected host covers all possible single nucleotide substitutions.