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Normark, Johan
Publications (10 of 32) Show all publications
Fernández, L., Rosvall, M., Normark, J., Fällman, M. & Avican, K. (2024). Co-PATHOgenex web application for assessing complex stress responses in pathogenic bacteria. Microbiology Spectrum, 12(1), Article ID e02781-23.
Open this publication in new window or tab >>Co-PATHOgenex web application for assessing complex stress responses in pathogenic bacteria
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2024 (English)In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 12, no 1, article id e02781-23Article in journal (Refereed) Published
Abstract [en]

Pathogenic bacteria encounter various stressors while residing in the host. They respond through intricate mechanisms of gene expression regulation, ensuring their survival and adaptation. Understanding how bacteria adapt to different stress conditions through regulatory processes of specific genes requires exploring complex transcriptional responses using gene co-expression networks. We employed a large transcriptome data set comprising 32 diverse human bacterial pathogens exposed to the same 11 host-mimicking stress conditions. Using the weighted gene co-expression network analysis algorithm, we generated bacterial gene co-expression networks. By associating modular eigengene expression with specific stress conditions, we identified gene co-expression modules and stress-specific stimulons, including genes with unique expression patterns under specific stress conditions. Suggesting a new potential role of the frm operon in responding to bile stress in enteropathogenic bacteria demonstrates the effectiveness of our approach. We also revealed the regulation of streptolysin S genes, involved in the production, processing, and export of streptolysin S, a toxin responsible for the beta-hemolytic phenotype of group A Streptococcus. In a comparative analysis of stress responses in three Escherichia coli strains from the core transcriptome, we revealed shared and unique expression patterns across the strains, offering insights into convergent and divergent stress responses. To help researchers perform similar analyses, we created the user-friendly web application Co-PATHOgenex. This tool aids in deepening our understanding of bacterial adaptation to stress conditions and in deciphering complex transcriptional responses of bacterial pathogens.IMPORTANCEUnveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition. Unveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition.

Place, publisher, year, edition, pages
American Society for Microbiology, 2024
Keywords
stress responses, bacterial pathogens, gene co-expression, stimulon, gene regulation, RNA-seq, transcriptomics
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-217963 (URN)10.1128/spectrum.02781-23 (DOI)001110226300001 ()38019016 (PubMedID)2-s2.0-85182501386 (Scopus ID)
Funder
Swedish Research Council, 2021-02466The Kempe FoundationsSwedish Research Council, 2018-02855Knut and Alice Wallenberg Foundation, 2016.0063
Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2024-01-25Bibliographically approved
Wigren, J., Vikström, L., Rosendal, E., Gröning, R., Gwon, Y.-D., Nilsson, E., . . . Forsell, M. N. E. (2023). At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study. Eurosurveillance, 28(13), Article ID 2200432.
Open this publication in new window or tab >>At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study
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2023 (English)In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, no 13, article id 2200432Article in journal (Refereed) Published
Abstract [en]

Background: The current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture for testing is usually performed by trained staff at healthcare centres. Long travel distances to healthcare centres in rural regions may introduce a bias of testing towards relatively large communities with closer access. Rural regions are therefore often not represented in population-based data.

Aim: The aim of this retrospective cohort study was to develop and implement a strategy for at-home testing in a rural region of Sweden during spring 2021, and to evaluate its role to provide equal health care for its inhabitants.

Methods: We developed a sensitive method to measure antibodies to the S-protein of SARS-CoV-2 and optimised this assay for clinical use together with a strategy of at-home capillary blood sampling.

Results: We demonstrated that our ELISA gave comparable results after analysis of capillary blood or serum from SARS-CoV-2-experienced individuals. We demonstrated stability of the assay under conditions that reflected temperature and humidity during winter or summer. By assessment of capillary blood samples from 4,122 individuals, we could show both feasibility of the strategy and that implementation shifted the geographical spread of testing in favour of rural areas.

Conclusion: Implementation of at-home sampling enabled citizens living in remote rural areas access to centralised and sensitive laboratory antibody tests. The strategy for testing used here could therefore enable disease control authorities to get rapid access to information concerning immunity to infectious diseases, even across vast geographical distance.

Place, publisher, year, edition, pages
European Centre for Disease Control and Prevention (ECDC), 2023
Keywords
coronavirus disease (COVID-19), laboratory, surveillance, Sweden
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-206673 (URN)10.2807/1560-7917.ES.2023.28.13.2200432 (DOI)000971868200003 ()36995373 (PubMedID)2-s2.0-85151573640 (Scopus ID)
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-09-05Bibliographically approved
Möller, M., Borg, K., Janson, C., Lerm, M., Normark, J. & Niward, K. (2023). Cognitive dysfunction in post-COVID-19 condition: mechanisms, management, and rehabilitation. Journal of Internal Medicine, 294(5), 563-581
Open this publication in new window or tab >>Cognitive dysfunction in post-COVID-19 condition: mechanisms, management, and rehabilitation
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2023 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Journal of Internal Medicine, ISSN 0954-6820, Vol. 294, no 5, p. 563-581Article, review/survey (Refereed) Published
Abstract [en]

The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors, possible mechanisms, and management strategies for cognitive dysfunction in post-COVID-19 condition (PCC). Prolonged cognitive dysfunction is one of the most common impairments in PCC, affecting between 17% and 28% of the individuals more than 12 weeks after the infection and persisting in some cases for several years. Cognitive dysfunctions can be manifested as a wide range of symptoms including memory impairment, attention deficit, executive dysfunction, and reduced processing speed. Risk factors for developing PCC, with or without cognitive impairments, include advanced age, preexisting medical conditions, and the severity of acute illness. The underlying mechanisms remain unclear, but proposed contributors include neuroinflammation, hypoxia, vascular damage, and latent virus reactivation not excluding the possibility of direct viral invasion of the central nervous system, illustrating complex viral pathology. As the individual variation of the cognitive impairments is large, a neuropsychological examination and a person-centered multidimensional approach are required. According to the World Health Organization, limited evidence on COVID-19-related cognitive impairments necessitates implementing rehabilitation interventions from established practices of similar conditions. Psychoeducation and compensatory skills training are recommended. Assistive products and environmental modifications adapted to individual needs might be helpful. In specific attention- and working memory dysfunctions, cognitive training—carefully monitored for intensity—might be effective for people who do not suffer from post-exertional malaise. Further research is crucial for evidence-based interventions specific to COVID-19-related cognitive impairments.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
cognition, fatigue, long-haul COVID, post-acute COVID-19 syndrome, SARS-CoV-2
National Category
General Practice
Identifiers
urn:nbn:se:umu:diva-215229 (URN)10.1111/joim.13720 (DOI)001074081200001 ()37766515 (PubMedID)2-s2.0-85173092163 (Scopus ID)
Available from: 2023-10-17 Created: 2023-10-17 Last updated: 2023-12-20Bibliographically approved
Ahmad, I., Edin, A., Granvik, C., Kumm Persson, L., Tevell, S., Månsson, E., . . . Normark, J. (2023). High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19. Frontiers In Public Health, 11, Article ID 1104267.
Open this publication in new window or tab >>High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19
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2023 (English)In: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, article id 1104267Article in journal (Refereed) Published
Abstract [en]

Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
COVID-19, EQ-5D, long-COVID, PACS, Post COVID-19 condition (PCC), post-acute COVID syndrome (PACS), SARS-CoV-2
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-205360 (URN)10.3389/fpubh.2023.1104267 (DOI)000937266000001 ()36817925 (PubMedID)2-s2.0-85148359690 (Scopus ID)
Funder
Nyckelfonden, OLL-938628Nyckelfonden, OLL-961416Region Västmanland, 20201009Swedish Research Council, 2020-06235Swedish Heart Lung Foundation, 20200325Swedish Heart Lung Foundation, 20210078Knut and Alice Wallenberg Foundation, VC-2020-0015Umeå UniversityRegion Västerbotten, RV-938855Region Värmland, LIVFOU-939646
Available from: 2023-03-29 Created: 2023-03-29 Last updated: 2023-10-30
Gröning, R., Dernstedt, A., Ahlm, C., Normark, J., Sundström, P. & Forsell, M. N. E. (2023). Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption. Frontiers in Immunology, 14, Article ID 1219560.
Open this publication in new window or tab >>Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1219560Article in journal (Refereed) Published
Abstract [en]

Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
B cell immunology, COVID-19, multiple sclerosis, rituximab, vaccination
National Category
Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-212992 (URN)10.3389/fimmu.2023.1219560 (DOI)37575257 (PubMedID)2-s2.0-85167514064 (Scopus ID)
Funder
Region Västerbotten, RV-969133Swedish Research Council, 2020-0625Swedish Research Council, 2021-04665Knut and Alice Wallenberg Foundation, VA-2021-0018Knut and Alice Wallenberg Foundation, VA-2022-0008Science for Life Laboratory, SciLifeLab
Available from: 2023-08-18 Created: 2023-08-18 Last updated: 2024-01-17Bibliographically approved
Björsell, T., Sundh, J., Lange, A., Ahlm, C., Forsell, M. N. E., Tevell, S., . . . Cajander, S. (2023). Risk factors for impaired respiratory function post COVID-19: a prospective cohort study of nonhospitalized and hospitalized patients. Journal of Internal Medicine, 293(5), 600-614
Open this publication in new window or tab >>Risk factors for impaired respiratory function post COVID-19: a prospective cohort study of nonhospitalized and hospitalized patients
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2023 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 293, no 5, p. 600-614Article in journal (Refereed) Published
Abstract [en]

Background: Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3–6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. Methods: Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DLCO), was performed 3–6 months after hospital discharge or study enrollment (for nonhospitalized patients). Breathlessness (defined as ≥1 according to the modified Medical Research Council scale) and functional exercise capacity (1-min sit-to-stand test; 1-MSTST) were assessed. Results: Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DLCO were significantly lower in patients with severe COVID-19. Among hospitalized patients, 20% had reduced DLCO, versus 4% in nonhospitalized. Breathlessness was found in 40.6% of the participants and was associated with impaired DLCO. A pathological desaturation or heart rate response was observed in 17% of participants during the 1-MSTST. However, this response was not associated with reduced DLCO. Conclusion: Reduced DLCO was the major respiratory impairment 3–6 months following COVID-19, with hospitalization as the most important risk factor. The lack of association between impaired DLCO and pathological physiological responses to exertion suggests that these physiological responses are not primarily related to decreased lung function.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
breathlessness, COVID-19, diffusion capacity, post-acute COVID-19 syndrome, spirometry
National Category
Respiratory Medicine and Allergy General Practice
Identifiers
urn:nbn:se:umu:diva-205377 (URN)10.1111/joim.13614 (DOI)000936826900001 ()36815689 (PubMedID)2-s2.0-85148632325 (Scopus ID)
Funder
Nyckelfonden, OLL-938628Nyckelfonden, OLL-961416Swedish Research Council, 2020-06235Swedish Research Council, 2016-06514Swedish Heart Lung Foundation, 20200325Swedish Heart Lung Foundation, 20210078Knut and Alice Wallenberg Foundation, VC-2020-0015Umeå University, RV‐938855Region Västerbotten, RV-938855Region Värmland, LIVFOU-939646
Available from: 2023-03-24 Created: 2023-03-24 Last updated: 2023-07-14Bibliographically approved
Vasiliu, A., Köhler, N., Altpeter, E., Ægisdóttir, T. R., Amerali, M., de Oñate, W. A., . . . Lange, C. (2023). Tuberculosis incidence in foreign-born people residing in European countries in 2020. Eurosurveillance, 28(42), Article ID 2300051.
Open this publication in new window or tab >>Tuberculosis incidence in foreign-born people residing in European countries in 2020
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2023 (English)In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, no 42, article id 2300051Article in journal (Refereed) Published
Abstract [en]

Background: European-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.

Aim: We aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.

Methods: The Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.

Results: Data on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.

Conclusions: Country of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Place, publisher, year, edition, pages
European Centre for Disease Prevention and Control (ECDC), 2023
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-215670 (URN)10.2807/1560-7917.es.2023.28.42.2300051 (DOI)37855907 (PubMedID)2-s2.0-85175586861 (Scopus ID)
Available from: 2023-10-24 Created: 2023-10-24 Last updated: 2023-12-01Bibliographically approved
Vikström, L., Fjällström, P., Gwon, Y.-D., Sheward, D. J., Wigren-Byström, J., Evander, M., . . . Forsell, M. N. E. (2023). Vaccine-induced correlate of protection against fatal COVID-19 in older and frail adults during waves of neutralization-resistant variants of concern: an observational study. The Lancet Regional Health: Europe, 30, Article ID 100646.
Open this publication in new window or tab >>Vaccine-induced correlate of protection against fatal COVID-19 in older and frail adults during waves of neutralization-resistant variants of concern: an observational study
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2023 (English)In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 30, article id 100646Article in journal (Refereed) Published
Abstract [en]

Background: To inform future preventive measures including repeated vaccinations, we have searched for a clinically useful immune correlate of protection against fatal COVID-19 among nursing homes residents.

Methods: We performed repeated capillary blood sampling with analysis of S-binding IgG in an open cohort of nursing home residents in Sweden. We analyzed immunological and registry data from 16 September 2021 to 31 August 2022 with follow-up of deaths to 30 September 2022. The study period included implementation of the 3rd and 4th mRNA monovalent vaccine doses and Omicron virus waves.

Findings: A total of 3012 nursing home residents with median age 86 were enrolled. The 3rd mRNA dose elicited a 99-fold relative increase of S-binding IgG in blood and corresponding increase of neutralizing antibodies. The 4th mRNA vaccine dose boosted levels 3.8-fold. Half-life of S-binding IgG was 72 days. A total 528 residents acquired their first SARS-CoV-2 infection after the 3rd or the 4th vaccine dose and the associated 30-day mortality was 9.1%. We found no indication that levels of vaccine-induced antibodies protected against infection with Omicron VOCs. In contrast, the risk of death was inversely correlated to levels of S-directed IgG below the 20th percentile. The death risk plateaued at population average above the lower 35th percentile of S-binding IgG.

Interpretation: In the absence of neutralizing antibodies that protect from infection, quantification of S-binding IgG post vaccination may be useful to identify the most vulnerable for fatal COVID-19 among the oldest and frailest. This information is of importance for future strategies to protect vulnerable populations against neutralization resistant variants of concern.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Correlate of protection, COVID-19, Immune monitoring of vulnerable populations, Longevity of vaccination, Open cohort study, Vaccination, Vulnerable population
National Category
Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-208263 (URN)10.1016/j.lanepe.2023.100646 (DOI)2-s2.0-85156247971 (Scopus ID)
Funder
Swedish Research CouncilScience for Life Laboratory, SciLifeLabKnut and Alice Wallenberg FoundationVinnovaSwedish Association of Local Authorities and RegionsFamiljen Erling-Perssons Stiftelse
Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-07-14Bibliographically approved
Kaku, C. I., Champney, E. R., Normark, J., Garcia, M., Johnson, C. E., Ahlm, C., . . . Walker, L. M. (2022). Broad anti–SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination. Science, 375(6584), 1041-1047
Open this publication in new window or tab >>Broad anti–SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination
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2022 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 375, no 6584, p. 1041-1047Article in journal (Refereed) Published
Abstract [en]

Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1: ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273–booste participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relativ to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2022
National Category
Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-193058 (URN)10.1126/science.abn2688 (DOI)000764236900049 ()35143256 (PubMedID)2-s2.0-85125682798 (Scopus ID)
Available from: 2022-03-21 Created: 2022-03-21 Last updated: 2023-09-05Bibliographically approved
Staessen, J. A., Wendt, R., Yu, Y.-L., Kalbitz, S., Thijs, L., Siwy, J., . . . Beige, J. (2022). Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study. The Lancet Digital Health, 4(10), e727-e737
Open this publication in new window or tab >>Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study
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2022 (English)In: The Lancet Digital Health, E-ISSN 2589-7500, Vol. 4, no 10, p. e727-e737Article in journal (Refereed) Published
Abstract [en]

Background: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker.

Methods: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country.

Findings: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1–3 in 445 (44%) participants, 4–5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05–2·92) unadjusted and 1·67 (1·34–2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60–2·01) when unadjusted and 1·63 (1·41–1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6–77·1%) for mortality (threshold 0·47) and 67·4% (64·4–70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5–95% percentile interval 0·730–1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04).

Interpretation: The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1–4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs. Funding: German Federal Ministry of Health.

Place, publisher, year, edition, pages
Elsevier, 2022
National Category
Urology and Nephrology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-199891 (URN)10.1016/S2589-7500(22)00150-9 (DOI)000879907700006 ()36057526 (PubMedID)2-s2.0-85138444259 (Scopus ID)
Available from: 2022-10-03 Created: 2022-10-03 Last updated: 2023-09-05Bibliographically approved
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