Artificial intelligence and clinical data suggest the T cell-mediated SARS-CoV-2 nonstructural protein intranasal vaccines for global COVID-19 immunity

Seyran, Murat

doi:10.1016/j.vaccine.2022.06.052

Cited by 4 publications

(4 citation statements)

References 46 publications

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“…To reduce the possibility of inducing non-protective antibodies, RBD alone or in conjunction with the 76E1 epitope ( 18 ) can be displayed. In addition, including certain T cell epitopes as a peptide linker of the immunogen may also be necessary for the development of long-term T cell immunity to COVID-19 disease ( 83 , 84 ). Moreover, immunogen delivery would likely need to be through a more physiologically relevant route, i.e.…”

Section: Perspective On the Design Of Broadly Protective Vaccines For...mentioning

confidence: 99%

Pan-neutralizing, germline-encoded antibodies against SARS-CoV-2: Addressing the long-term problem of escape variants

Lunderberg

Dutta²,

Collier³

et al. 2022

Front. Immunol.

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Despite the initially reported high efficacy of vaccines directed against ancestral SARS-CoV-2, repeated infections in both unvaccinated and vaccinated populations remain a major global health challenge. Because of mutation-mediated immune escape by variants-of-concern (VOC), approved neutralizing antibodies (neutAbs) effective against the original strains have been rendered non-protective. Identification and characterization of mutation-independent pan-neutralizing antibody responses are therefore essential for controlling the pandemic. Here, we characterize and discuss the origins of SARS-CoV-2 neutAbs, arising from either natural infection or following vaccination. In our study, neutAbs in COVID-19 patients were detected using the combination of two lateral flow immunoassay (LFIA) tests, corroborated by plaque reduction neutralization testing (PRNT). A point-of-care neutAb LFIA, NeutraXpress™, was validated using serum samples from historical pre-COVID-19 negative controls, patients infected with other respiratory pathogens, and PCR-confirmed COVID-19 patients. Surprisingly, potent neutAb activity was mainly noted in patients generating both IgM and IgG against the Spike receptor-binding domain (RBD), in contrast to samples possessing anti-RBD IgG alone. We propose that low-affinity, high-avidity, germline-encoded natural IgM and subsequent generation of class-switched IgG may have an underappreciated role in cross-protection, potentially offsetting immune escape by SARS-CoV-2 variants. We suggest Reverse Vaccinology 3.0 to further exploit this innate-like defense mechanism. Our proposition has potential implications for immunogen design, and provides strategies to elicit pan-neutAbs from natural B1-like cells. Refinements in future immunization protocols might further boost long-term cross-protection, even at the mucosal level, against clinical manifestations of COVID-19.

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Section: Perspective On the Design Of Broadly Protective Vaccines For...mentioning

confidence: 99%

Pan-neutralizing, germline-encoded antibodies against SARS-CoV-2: Addressing the long-term problem of escape variants

Lunderberg

Dutta²,

Collier³

et al. 2022

Front. Immunol.

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“…One possible explanation may be immune evasion based on the indels in these hotspots. Previous studies that evaluated SARS-CoV-2 epitope reactivity indicated that non-structural proteins such as Nsp3 and ORF8 may be highly antigenic T cell epitopes [ 14 – 16 ]. It is reasonable to consider that mutations in these genes may contribute to immune evasion by SARS-related coronaviruses.…”

Section: Discussionmentioning

confidence: 99%

Insertion/deletion hotspots in the Nsp2, Nsp3, S1, and ORF8 genes of SARS-related coronaviruses

2022

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The genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains many insertions/deletions (indels) from the genomes of other SARS-related coronaviruses. Some of the identified indels have recently reported to involve relatively long segments of 10–300 consecutive bases and with diverse RNA sequences around gaps between virus species, both of which are different characteristics from the classical shorter in-frame indels. These non-classical complex indels have been identified in non-structural protein 3 (Nsp3), the S1 domain of the spike (S), and open reading frame 8 (ORF8). To determine whether the occurrence of these non-classical indels in specific genomic regions is ubiquitous among broad species of SARS-related coronaviruses in different animal hosts, the present study compared SARS-related coronaviruses from humans (SARS-CoV and SARS-CoV-2), bats (RaTG13 and Rc-o319), and pangolins (GX-P4L), by performing multiple sequence alignment. As a result, indel hotspots with diverse RNA sequences of different lengths between the viruses were confirmed in the Nsp2 gene (approximately 2500–2600 base positions in the overall 29,900 bases), Nsp3 gene (approximately 3000–3300 and 3800–3900 base positions), N-terminal domain of the spike protein (21,500–22,500 base positions), and ORF8 gene (27,800–28,200 base positions). Abnormally high rate of point mutations and complex indels in these regions suggest that the occurrence of mutations in these hotspots may be selectively neutral or even benefit the survival of the viruses. The presence of such indel hotspots has not been reported in different human SARS-CoV-2 strains in the last 2 years, suggesting a lower rate of indels in human SARS-CoV-2. Future studies to elucidate the mechanisms enabling the frequent development of long and complex indels in specific genomic regions of SARS-related coronaviruses would offer deeper insights into the process of viral evolution.

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“…The significance of the reconstruction of molecular mechanisms of pathogen-host interactions, including the approaches involving metabolomic analysis, is dictated by the serious problem of emerging drug resistance of viruses due to the high mutation rates of their genomes. The pharmacological influence over the functions of host genes, which are exploited by the virus for the benefit of its life cycle, may result in the development of new generation therapies 52 . One can expect that drug resistance to such therapies will be considerably lower, than to those drugs, which target the viral enzymes and genomes.…”

Section: Discussionmentioning

confidence: 99%

Plasma metabolomics and gene regulatory networks analysis reveal the role of nonstructural SARS-CoV-2 viral proteins in metabolic dysregulation in COVID-19 patients

Иванисенко

Gaisler

Basov

et al. 2022

Sci Rep

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Metabolomic analysis of blood plasma samples from COVID-19 patients is a promising approach allowing for the evaluation of disease progression. We performed the metabolomic analysis of plasma samples of 30 COVID-19 patients and the 19 controls using the high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometric detection (LC–MS/MS). In our analysis, we identified 103 metabolites enriched in KEGG metabolic pathways such as amino acid metabolism and the biosynthesis of aminoacyl-tRNAs, which differed significantly between the COVID-19 patients and the controls. Using ANDSystem software, we performed the reconstruction of gene networks describing the potential genetic regulation of metabolic pathways perturbed in COVID-19 patients by SARS-CoV-2 proteins. The nonstructural proteins of SARS-CoV-2 (orf8 and nsp5) and structural protein E were involved in the greater number of regulatory pathways. The reconstructed gene networks suggest the hypotheses on the molecular mechanisms of virus-host interactions in COVID-19 pathology and provide a basis for the further experimental and computer studies of the regulation of metabolic pathways by SARS-CoV-2 proteins. Our metabolomic analysis suggests the need for nonstructural protein-based vaccines and the control strategy to reduce the disease progression of COVID-19.

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Artificial intelligence and clinical data suggest the T cell-mediated SARS-CoV-2 nonstructural protein intranasal vaccines for global COVID-19 immunity

Cited by 4 publications

References 46 publications

Pan-neutralizing, germline-encoded antibodies against SARS-CoV-2: Addressing the long-term problem of escape variants

Pan-neutralizing, germline-encoded antibodies against SARS-CoV-2: Addressing the long-term problem of escape variants

Insertion/deletion hotspots in the Nsp2, Nsp3, S1, and ORF8 genes of SARS-related coronaviruses

Plasma metabolomics and gene regulatory networks analysis reveal the role of nonstructural SARS-CoV-2 viral proteins in metabolic dysregulation in COVID-19 patients

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