Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated with AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants.

BACKGROUND: We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of SARS-CoV-2 variants identified from breakthrough infections in the PROVENT pre-exposure prophylaxis trial (NCT04625725). METHODS: Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles. RESULTS: At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough COVID-19 cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and non-breakthrough cases. CONCLUSION: Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure.

Chapter 10 - Challenges in designing antiviral agents

Among the microorganisms, viruses have the simplest of structures. Despite this, they are the cause of a number of diseases, wherein the discovery of new antivirals is one of the most difficult tasks in medicinal chemistry. There are several approved drugs for numerous pathological conditions caused by viral agents. At the same time, there is a significant lack of effective treatments. Furthermore, many diseases remain without any specific treatment, due to several factors that make it difficult. In this context, this chapter addresses the main difficulties encountered in the discovery of antiviral agents, as well as some analogs that could overcome such limitations, which can be useful against herpes, influenza, coronavirus, human immunodeficiency virus, hepatitis B, dengue, Ebola, and Lassa. In fact, one of the main limitations for designing new antivirals is related to the rapid emergence of virus resistance to drugs. Thus, there is considerable need for new scaffolds that can overcome this enormous challenge. Furthermore, low bioavailability of nucleoside analogs and low quality in vitro assays are among the major limitations found currently. Finally, we hope that this chapter encourages medicinal chemists around the world to find possibilities to overcome these limitations by developing new methodologies for testing compounds and designing new chemical agents that could represent future treatments for these diseases.

Current Trend of Virology in the Post COVID-19 Era with Related Topic-Based Tweet Analysis

In light of current trends in virology, we performed social media analysis of 13 main topics in the area of virology and ranked these topics with metrics such as users, posts, engagement, and influence. These metrics were monitored against the 13 keywords on Twitter for the same period (i.e., from 27 November to 6 December 2021) for benchmarking purposes. The 13 main topics were "virological Science", " preventive vaccines", "therapeutic vaccines", "viral pathogenesis", "viral immunology", "antiviral strategies", "virus structure", "virus expression", "viral resistance", "emerging viruses", "interspecies transmission", "viruses and cancer" and " viral diseases". "viral diseases" recorded the highest number of users (i.e., 905 users) and the highest number of post (i.e., about 1K posts). The second-highest number of posts were monitored to be on "therapeutic vaccines" with 729 posts from 691 users. In terms of engagement, "viral diseases" (3.4 K) were found to be on the top followed by "viruses and cancer" (3.1K). Lastly, in terms of influence, "viral diseases" recorded 9.0 million influences followed by 6.6 million influences on "emerging viruses". In summary, "viral diseases" was found to be the most engaging and influential topic highest with the highest number of posts from most of the tweet users. In relation to trending hashtags in virology, #COVID19 recorded the highest number of hashtags, followed by # omicron, #sarscov2, #publichealth, #omicronvarient, #wuhan, #originofcovid, #fauci and #epidemiology. Word clouds showing the main area of discussion were also generated for these 13 main topics.

Genetic susceptibility to viral disease in humans.

BACKGROUND: During the past decades, studies on patients with severe viral infections have revealed rare inborn errors of immunity (IEIs) underlying these diseases. This has led to important new insights into the molecular genetics and immunological mechanisms governing susceptibility to viral infection in humans. OBJECTIVES: Herein, the current knowledge on major IEIs predisposing to severe or chronic viral infections are described and discussed, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined. SOURCES: The review is based on a broad literature search, including relevant studies primarily based on patients, supported by experimental molecular models in vitro or in mice, to characterize the pathophysiological mechanism governing these disease conditions. CONTENT: Current concepts and principles of genetic predisposition to viral infections in humans are described with a major focus on defects related to innate immune responses and new concepts of constitutive immune mechanisms. The topic therefore spans from seminal studies on the human genetics of herpesvirus infections in the central nervous system, severe influenza, and disease after vaccination with live attenuated viral vaccines, to genetic resistance to viral infection. IMPLICATIONS: Past and present studies of patients with IEIs conferring vulnerability to viral infections have taught us important lessons on protective innate and adaptive antiviral immunity in humans. Such knowledge also has important clinical implications, allowing development of prophylactic and therapeutic solutions to prevent or dampen the clinical consequences of insufficient or dysregulated antiviral immunity in patients. Collectively, such measures are likely to improve patient management at an individualized level and help societies reduce the disease burden from viral infections.

Loss-of-function mutations in IFNAR2 in COVID-19 severe infection susceptibility.

Recent COVID-19 (coronavirus disease 2019) host genetics studies suggest enrichment of mutations in genes involved in the regulation of type I and type III interferon (IFN) immunity in patients with severe COVID-19 infection. We performed whole-genome sequencing analysis of samples obtained from patients participating in the ongoing ODYSSEY phase 3 study of hospitalised patients with severe COVID-19 infection receiving supplemental oxygen support. We focused on burden testing of categories of rare and common loss-of-function (LOF) variants in all of the IFN pathway genes, specifically with MAF < 0.1% and MAF < 1%. In a model including LOF and missense variants (MAF < 1%), we report a significant signal in both INFAR1 and IFNAR2. We report carriers of rare variants in our COVID-19 cohort, including a stop-gain IFNAR2 (NM_000874:exon9:c.C966A:p.Y322X) amongst carriers of several other IFNAR rare nonsynonymous variants. Furthermore, we report an increased allelic frequency of common IFNAR2 variants in our data, reported also by the COVID-19 Host Genetics Initiative.

Targeting SARS-CoV-2 receptors as a means for reducing infectivity and improving antiviral and immune response: an algorithm-based method for overcoming resistance to antiviral agents.

The ongoing severe acute respiratory syndrome pandemic caused by the novel coronavirus 2 (SARS-CoV-2) is associated with high morbidity and mortality rates, and it has created a pressing global need for effective antiviral therapies against it. COVID-19 disease pathogenesis is characterized by an initial virus-mediated phase, followed by inappropriate hyperactivation of the immune system leading to organ damage. Targeting of the SARS-CoV-2 viral receptors is being explored as a therapeutic option for these patients. In this paper, we summarize several potential receptors associated with the infectivity of SARS-CoV-2 and discuss their association with the immune-mediated inflammatory response. The potential for the development of resistance towards antiviral drugs is also presented. An algorithm-based platform to improve the efficacy of and overcome resistance to viral receptor blockers through the introduction of personalized variability is described. This method is designed to ensure sustained antiviral effectiveness when using SARS-CoV-2 receptor blockers.