The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most formidable challenge to humanity in a century. It is widely ...believed that prepandemic normalcy will never return until a safe and effective vaccine strategy becomes available and a global vaccination programme is implemented successfully. Here, we discuss the immunological principles that need to be taken into consideration in the development of COVID-19 vaccine strategies. On the basis of these principles, we examine the current COVID-19 vaccine candidates, their strengths and potential shortfalls, and make inferences about their chances of success. Finally, we discuss the scientific and practical challenges that will be faced in the process of developing a successful vaccine and the ways in which COVID-19 vaccine strategies may evolve over the next few years.
The term "original antigenic sin" (OAS) was first used in the 1960s to describe how one's first exposure to influenza virus shapes the outcome of subsequent exposures to antigenically related ...strains. In the decades that have passed, OAS-like responses have been shown to play an integral role in both protection from and susceptibility to infections. OAS may also have an important deterministic role in the differential efficacy of influenza vaccine responses observed for various age cohorts across seasons. In this article, we review how the understanding of OAS has progressed from its initial description and highlight important outstanding questions in need of further study.
Selective reactions on structures of high complexity can move beyond the mind’s eye and proof-of-principle. Enhanced understanding of noncovalent interactions and their interdependence, revealed ...through analysis of multiple parameters, should accelerate the discovery of efficient reactions in highly complex molecular environments.
The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a ...pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.
Display omitted
•Two trivalent adenoviral-vectored COVID-19 vaccines were developed and evaluated•Intranasal, but not intramuscular, immunization induces tripartite mucosal immunity•Intranasal immunization protects against ancestral and variant strains of SARS-CoV-2•Optimal protection requires B and T cell immunity and trained innate immunity
Respiratory mucosal immunization with a next-generation adenoviral-vectored trivalent COVID-19 vaccine expressing spike, nucleocapsid, and RdRp antigens, induces all-around protective mucosal immunity against SARS-CoV-2 via induction of systemic and local antibodies, lung-tissue-resident memory T cells, and trained alveolar macrophages.
Drift-barrier hypothesis and mutation-rate evolution Sung, Way; Ackerman, Matthew S; Miller, Samuel F ...
Proceedings of the National Academy of Sciences - PNAS,
11/2012, Letnik:
109, Številka:
45
Journal Article
Recenzirano
Odprti dostop
Mutation dictates the tempo and mode of evolution, and like all traits, the mutation rate is subject to evolutionary modification. Here, we report refined estimates of the mutation rate for a ...prokaryote with an exceptionally small genome and for a unicellular eukaryote with a large genome. Combined with prior results, these estimates provide the basis for a potentially unifying explanation for the wide range in mutation rates that exists among organisms. Natural selection appears to reduce the mutation rate of a species to a level that scales negatively with both the effective population size (N ₑ), which imposes a drift barrier to the evolution of molecular refinements, and the genomic content of coding DNA, which is proportional to the target size for deleterious mutations. As a consequence of an expansion in genome size, some microbial eukaryotes with large N ₑ appear to have evolved mutation rates that are lower than those known to occur in prokaryotes, but multicellular eukaryotes have experienced elevations in the genome-wide deleterious mutation rate because of substantial reductions in N ₑ.
Catalysts that control stereochemistry are prized tools in chemical synthesis. When an effective catalyst is found, it is often explored for other types of reactions, frequently under the auspices of ...different mechanisms. As successes mount, a unique catalyst scaffold may become viewed as “privileged”. However, the mechanistic hallmarks of privileged catalysts are not easily enumerated or readily generalized to genuinely different classes of reactions or substrates. We explored the concept of scaffold uniqueness with two catalyst types for an unusual atropisomer-selective cyclodehydration: (a) C 2-symmetric chiral phosphoric acids and (b) phosphothreonine-embedded, peptidic phosphoric acids. Pragmatically, both catalyst scaffolds proved fertile for enantioselective/atroposelective cyclodehydrations. Mechanistic studies revealed that the determinants of often equivalent and high atroposelectivity are different for the two catalyst classes. A data-descriptive classification of these asymmetric catalysts reveals an increasingly broad set of catalyst chemotypes, operating with different mechanistic features, that creates new opportunities for broad and complementary application of catalyst scaffolds in diverse substrate space.
We report a simple and rapid saliva‐based SARS‐CoV‐2 antigen test that utilizes a newly developed dimeric DNA aptamer, denoted as DSA1N5, that specifically recognizes the spike proteins of the ...wildtype virus and its Alpha and Delta variants with dissociation constants of 120, 290 and 480 pM, respectively, and binds pseudotyped lentiviruses expressing the wildtype and alpha trimeric spike proteins with affinity constants of 2.1 pM and 2.3 pM, respectively. To develop a highly sensitive test, DSA1N5 was immobilized onto gold electrodes to produce an electrochemical impedance sensor, which was capable of detecting 1000 viral particles per mL in 1:1 diluted saliva in under 10 min without any further sample processing. Evaluation of 36 positive and 37 negative patient saliva samples produced a clinical sensitivity of 80.5 % and specificity of 100 % and the sensor could detect the wildtype virus as well as the Alpha and Delta variants in the patient samples, which is the first reported rapid test that can detect any emerging variant of SARS‐CoV‐2.
Rapid and simple: an electrochemical sensor, based on a high‐affinity dimeric DNA aptamer for the SARS‐CoV‐2 spike protein was developed to detect the wildtype and Alpha and Delta variant in unprocessed saliva samples in 10 minutes, providing a detection limit of 1000 copies mL−1, clinical sensitivity of 80.5 % and specificity of 100 %.
Rapid antimicrobial susceptibility testing (AST) is urgently needed for informing treatment decisions and preventing the spread of antimicrobial resistance resulting from the misuse and overuse of ...antibiotics. To date, no phenotypic AST exists that can be performed within a single patient visit (30 min) directly from clinical samples. We show that AST results can be obtained by using digital nucleic acid quantification to measure the phenotypic response of
present within clinical urine samples exposed to an antibiotic for 15 min. We performed this rapid AST using our ultrafast (~7 min) digital real-time loop-mediated isothermal amplification (dLAMP) assay area under the curve (AUC), 0.96 and compared the results to a commercial (~2 hours) digital polymerase chain reaction assay (AUC, 0.98). The rapid dLAMP assay can be used with SlipChip microfluidic devices to determine the phenotypic antibiotic susceptibility of
directly from clinical urine samples in less than 30 min. With further development for additional pathogens, antibiotics, and sample types, rapid digital AST (dAST) could enable rapid clinical decision-making, improve management of infectious diseases, and facilitate antimicrobial stewardship.
Context guides perception by influencing stimulus saliency. Accordingly, in visual cortex, responses to a stimulus are modulated by context, the visual scene surrounding the stimulus. Responses are ...suppressed when stimulus and surround are similar but not when they differ. The underlying mechanisms remain unclear. Here, we use optical recordings, manipulations, and computational modeling to show that disinhibitory circuits consisting of vasoactive intestinal peptide (VIP)-expressing and somatostatin (SOM)-expressing inhibitory neurons modulate responses in mouse visual cortex depending on similarity between stimulus and surround, primarily by modulating recurrent excitation. When stimulus and surround are similar, VIP neurons are inactive, and activity of SOM neurons leads to suppression of excitatory neurons. However, when stimulus and surround differ, VIP neurons are active, inhibiting SOM neurons, which leads to relief of excitatory neurons from suppression. We have identified a canonical cortical disinhibitory circuit that contributes to contextual modulation and may regulate perceptual saliency.
•Visual context modulates the response of SOM oppositely to all other V1 neurons•The VIP-SOM disinhibitory circuit controls the impact of context on V1 responses•The VIP-SOM disinhibitory circuit controls V1 by modulating recurrent excitation•As we predict by modeling, silencing of VIP neurons reduces contextual modulation
Context provides meaning by influencing perception. In the visual world, context is the visual environment surrounding a visual scene. Here, Keller et al. report that a canonical disinhibitory circuit controls the response of mouse visual cortex to a visual stimulus depending on the context within which that stimulus is presented.
When H3N2 replaced H1N1 as the dominant influenza A subtype during the 2018-2019 season, the pattern of age-specific incidence shifted due to the lingering effects of antigenic imprinting. The ...characteristic shape that imprinting leaves on influenza susceptibility could foster important advances in understanding and predicting the epidemiology of influenza.
PDF
