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High Containment Laboratory, Public Health Agency of Sweden (The Swedish BSL4 laboratory)

2. Responsible public or private organization or company
Public Health Agency of Sweden
3. Location and postal address
Public Health Agency of Sweden, SE-17182 SOLNA, Sweden
4. Source(s) of financing of the reported activity, including indication if the activity is wholly or partly financed by the Ministry of Defence

The activities are financed through the Swedish Government (Ministry of Health and Social Affairs), and through governmental agencies such as Swedish Civil Contingencies Agency (MSB), Swedish Research Council (VR) and partly by the EU (research funds and the Innovative Medicines Initiative and funding through Joint Actions within European Health Program).

5. Number of maximum containment units5 within the research centre and/or laboratory, with an indication of their respective size (SqM):
BL 4 , 136.00 SqM
Two separate BSL4 units enclosing three laboratories.
6. Scope and general description of activities, including type(s) of micro-organisms and/or toxins as appropriate

The Public Health Agency of Sweden is a national expert authority with overall responsibility for public health questions at a national level. Our mission is to promote health, prevent illness and contribute to a sustainable society. There are no projects conducted related to biological defence, more than a strive to a better biological understanding of biological agents (see publication list below). The agency develops and maintain national diagnostic preparedness for highly pathogenic agents. Research results are published in international journals.

 

Risk group 4 agents

In the BSL4 containment units diagnostics and research regarding viruses from the following families are performed: Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, Nairoviridae, Orthomyxoviridae, Paramyxoviridae, Phenuiviridae and Poxviridae. Special emphasis is directed towards the Crimean-Congo haemorrhagic fever virus (CCHFV) and Ebola virus.

 

Methods for identification

Standard methods are used for identification of these microorganisms. Methods in use include molecular biological methods (including novel high throughput/high capacity methods), serological methods such as neutralization assays, cultivation/isolation and electron microscopy. Public Health Agency of Sweden also has capacity to culture virus in small rodents. The quality of diagnostic methods for many of the pathogens is assured through participation in quality assurance exercises and ring trials within international EC-funded networks.

The general goals are to improve laboratory diagnostics, laboratory capacity and basic knowledge of highly pathogenic agents. This includes the development of platforms for broad, efficient and reliable diagnostic methods, studies of virulence and pathogenesis and the establishment and use of animal models for use in diagnostics, treatment and vaccine development.

 

Public Health Agency of Sweden (PHAS): publications in 2021 related to high containment laboratory BSL3 and BSL4 activities at PHAS:

Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor. Capraz T, Kienzl NF, Laurent E, Perthold JW, Föderl-Höbenreich E, Grünwald-Gruber C, Maresch D, Monteil V, Niederhöfer J, Wirnsberger G, Mirazimi A, Zatloukal K, Mach L, Penninger JM, Oostenbrink C, Stadlmann J.Elife. 2021 Dec 20; 10:e73641. doi: 10.7554/eLife.73641. PMID: 34927585

 

Nucleoside-Modified mRNA Vaccines Protect IFNAR-/- Mice against Crimean-Congo Hemorrhagic Fever Virus Infection. Appelberg S, John L, Pardi N, Végvári Á, Bereczky S, Ahlén G, Monteil V, Abdurahman S, Mikaeloff F, Beattie M, Tam Y, Sällberg M, Neogi U, Weissman D, Mirazimi A.J Virol. 2022 Feb 9;96(3):e0156821. doi: 10.1128/JVI.01568-21. Epub 2021 Nov 24.PMID: 34817199

 

Access and benefit-sharing by the European Virus Archive in response to COVID-19. Sett S, Dos Santos Ribeiro C, Prat C, Haringhuizen G; European Virus Archive principal investigators, Scholz AH.Lancet Microbe. 2021 Nov 16. doi: 10.1016/S2666-5247(21)00211-1. Online ahead of print. PMID: 34806057.

 

Correction to: 2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales. Kuhn JH, Adkins S, Agwanda BR, Al Kubrusli R, Alkhovsky SV, Amarasinghe GK, Avšič-Županc T, Ayllón MA, Bahl J, Balkema-Buschmann A, Ballinger MJ, Basler CF, Bavari S, Beer M, Bejerman Net.al .Arch Virol. 2021 Dec;166(12):3567-3579. doi: 10.1007/s00705-021-05266-w.PMID: 34786611

 

Virus-Derived DNA Forms Mediate the Persistent Infection of Tick Cells by Hazara Virus and Crimean-Congo Hemorrhagic Fever Virus. Salvati MV, Salaris C, Monteil V, Del Vecchio C, Palù G, Parolin C, Calistri A, Bell-Sakyi L, Mirazimi A, Salata C.J Virol. 2021 Nov 23;95(24):e0163821. doi: 10.1128/JVI.01638-21. Epub 2021 Oct 6.PMID: 34613808

 

Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants. Wirnsberger G, Monteil V, Eaton B, Postnikova E, Murphy M, Braunsfeld B, Crozier I, Kricek F, Niederhöfer J, Schwarzböck A, Breid H, Sanchez Jimenez A, Bugajska-Schretter A, Dohnal A, Ruf C, Gugenberger R, Hagelkruys A, Montserrat N, Holbrook MR, Oostenbrink C, Shoemaker RH, Mirazimi A, Penninger JM.bioRxiv. 2021 Sep 10:2021.09.10.459744. doi: 10.1101/2021.09.10.459744. Preprint. PMID: 34545368

 

2021 Taxonomic update of phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales. Kuhn JH, Adkins S, Agwanda BR, Al Kubrusli R, Alkhovsky SV, Amarasinghe GK, et.al. Arch Virol. 2021 Dec;166(12):3513-3566. doi: 10.1007/s00705-021-05143-6.PMID: 34463877

 

Atypical Genetic Basis of Pyrazinamide Resistance in Monoresistant Mycobacterium tuberculosis. Samuel J Modlin, Tyler Marbach , Jim Werngren, Mikael Mansjö, Sven E Hoffner, Faramarz Valafar. Antimicrob Agents Chemother. 2021 May 18;65(6):e01916-20. doi: 10.1128/AAC.01916-20.  Print 2021 May 18.

 

Genotypic Resistance of Pyrazinamide but Not Minimum Inhibitory Concentration Is Associated With Longer Time to Sputum Culture Conversion in Patients With Multidrug-resistant Tuberculosis. Johanna Kuhlin, Lina Davies Forsman, Mikael Mansjö, Michaela Jonsson Nordvall, Maria Wijkander, Charlotta Wagrell, Jerker Jonsson, Ramona Groenheit, Jim Werngren, Thomas Schön, Judith Bruchfeld. Clin Infect Dis . 2021 Nov 2;73(9):e3511-e3517.  doi: 10.1093/cid/ciaa1509.

 

Detection of Pyrazinamide Heteroresistance in Mycobacterium tuberculosis. Jim Werngren, Mikael Mansjö, Mikaela Glader, Sven Hoffner, Lina Davies Forsman. Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0072021. doi: 10.1128/AAC.00720-21. Epub 2021 Aug 17. PMID: 34181476.

 

Whole-genome sequencing differentiates relapse from re-infection in TB. A Nikolenka, M Mansjö, A Skrahina, H Hurevich, V Grankov, S Nikisins, M Dara, S Ehsani, R Groenheit. Int J Tuberc Lung Dis. 2021 Dec 1;25(12):995-1000. doi: 10.5588/ijtld.21.0274. PMID: 34886929.

 

Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity. Rao Muvva J, Ahmed S, Rekha RS, Kalsum S, Groenheit R, Schön T, Agerberth B, Bergman P, Brighenti S. J Infect Dis. 2021 Jul 15;224(2):332-344.

 

Impact of the COVID-19 pandemic on tuberculosis laboratory services in Europe. ERLTB-Net-2 study participants, Nikolayevskyy V, Holicka Y, van Soolingen D, van der Werf MJ, Ködmön C, Surkova E, Hillemann D, Groenheit R; Cirillo D. Eur Respir J. 2021 Jan 5;57(1):2003890.

 

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.  Hu Y, Zheng X, Davies Forsman L, Ning Z, Chen C, Gao Y, Zhang Z, Lu W, Werngren J, Bruchfeld J, Hoffner S, Xu B. Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study. Clin Microbiol Infect. 2021 Dec;27(12):1805-1813. doi: 10.1016/j.cmi.2021.04.001. Epub 2021 Apr 23. PMID: 33895338.

 

Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China. Davies Forsman L, Niward K, Kuhlin J, Zheng X, Zheng R, Ke R, Hong C, Werngren J, Paues J, Simonsson USH, Eliasson E, Hoffner S, Xu B, Alffenaar JW, Schön T, Hu Y, Bruchfeld J. Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China. Eur Respir J. 2021 Mar 11;57(3):2003463. doi: 10.1183/13993003.03463-2020. PMID: 33154028.

 

Multicentre testing of the EUCAST broth microdilution reference method for MIC determination on Mycobacterium tuberculosis. Schön T, Werngren J, Machado D, Borroni E, Wijkander M, Lina G, Mouton J, Matuschek E, Kahlmeter G, Giske C, Santin M, Cirillo DM, Viveiros M, Cambau E. Multicentre testing of the EUCAST broth microdilution reference method for MIC determination on Mycobacterium tuberculosis. Clin Microbiol Infect. 2021 Feb;27(2):288.e1-288.e4. doi: 10.1016/j.cmi.2020.10.019. Epub 2020 Oct 24. PMID: 33198949.

 

Additional drug resistance for Mycobacterium tuberculosis during turnaround time for drug-susceptibility testing in China: A multicenter observational cohort study. Zhu J, Bao Z, Xie Y, Werngren J, Hu Y, Davies Forsman L, Bruchfeld J, Hoffner S. Additional drug resistance for Mycobacterium tuberculosis during turnaround time for drug-susceptibility testing in China: A multicenter observational cohort study. Int J Infect Dis. 2021 Jul;108:81-88. doi: 10.1016/j.ijid.2021.04.027. Epub 2021 Apr 16. PMID: 33862209.

 

Cranberry (Vaccinium macrocarpon) Extract Impairs Nairovirus Infection by Inhibiting the Attachment to Target Cells. Mirandola M, Salvati MV, Rodigari C, Appelberg KS, Mirazimi A, Maffei ME, Gribaudo G, Salata C.Pathogens. 2021 Aug 13;10(8):1025. doi: 10.3390/pathogens10081025.PMID: 34451488 

 

The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and Other Human Coronaviruses. Calistri A, Luganini A, Mognetti B, Elder E, Sibille G, Conciatori V, Del Vecchio C, Sainas S, Boschi D, Montserrat N, Mirazimi A, Lolli ML, Gribaudo G, Parolin C. Microorganisms. 2021 Aug 14;9(8):1731. doi: 10.3390/microorganisms9081731.PMID: 34442810 

 

Presence of antibodies to Crimean Congo haemorrhagic fever virus in sheep in Tunisia, North Africa. Khamassi Khbou M, Romdhane R, Bouaicha Zaafouri F, Bouajila M, Sassi L, Appelberg SK, Schulz A, Mirazimi A, Groschup MH, Rekik M, Benzarti M, Gharbi M.Vet Med Sci. 2021 Nov;7(6):2323-2329. doi: 10.1002/vms3.597. Epub 2021 Aug 14.PMID: 34390548 

 

Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites. Hoffmann D, Mereiter S, Jin Oh Y, Monteil V, Elder E, Zhu R, Canena D, Hain L, Laurent E, Grünwald-Gruber C, Klausberger M, Jonsson G, Kellner MJ, Novatchkova M, Ticevic M, Chabloz A, Wirnsberger G, Hagelkruys A, Altmann F, Mach L, Stadlmann J, Oostenbrink C, Mirazimi A, Hinterdorfer P, Penninger JM.EMBO J. 2021 Oct 1;40(19):e108375. doi: 10.15252/embj.2021108375. Epub 2021 Aug 23.PMID: 34375000 

 

Diagnosis and Pathogenesis of Nairobi Sheep Disease Orthonairovirus Infections in Sheep and Cattle. Hartlaub J, Gutjahr B, Fast C, Mirazimi A, Keller M, Groschup MH.Viruses. 2021 Jun 27;13(7):1250. doi: 10.3390/v13071250.PMID: 34199054 

 

A super-potent tetramerized ACE2 protein displays enhanced neutralization of SARS-CoV-2 virus infection. Miller A, Leach A, Thomas J, McAndrew C, Bentley E, Mattiuzzo G, John L, Mirazimi A, Harris G, Gamage N, Carr S, Ali H, Van Montfort R, Rabbitts T.Sci Rep. 2021 May 19;11(1):10617. doi: 10.1038/s41598-021-89957-z.PMID: 34012108 

 

Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells. Chen X, Saccon E, Appelberg KS, Mikaeloff F, Rodriguez JE, Vinhas BS, Frisan T, Végvári Á, Mirazimi A, Neogi U, Gupta S.Cell Death Discov. 2021 May 18;7(1):114. doi: 10.1038/s41420-021-00487-z.PMID: 34006825

 

Cell-type-resolved quantitative proteomics map of interferon response against SARS-CoV-2. Saccon E, Chen X, Mikaeloff F, Rodriguez JE, Szekely L, Vinhas BS, Krishnan S, Byrareddy SN, Frisan T, Végvári Á, Mirazimi A, Neogi U, Gupta S.iScience. 2021 May 21;24(5):102420. doi: 10.1016/j.isci.2021.102420. Epub 2021 Apr 20.PMID: 33898942 

 

Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly. Krenn V, Bosone C, Burkard TR, Spanier J, Kalinke U, Calistri A, Salata C, Rilo Christoff R, Pestana Garcez P, Mirazimi A, Knoblich JA.Cell Stem Cell. 2021 Aug 5;28(8):1362-1379.e7. doi: 10.1016/j.stem.2021.03.004. Epub 2021 Apr 9.PMID: 33838105

 

Experimental Challenge of Sheep and Cattle with Dugbe Orthonairovirus, a Neglected African Arbovirus Distantly Related to CCHFV. Hartlaub J, von Arnim F, Fast C, Mirazimi A, Keller M, Groschup MH.Viruses. 2021 Feb 26;13(3):372. doi: 10.3390/v13030372.PMID: 33652845 

 

Serological and molecular study of Crimean-Congo Hemorrhagic Fever Virus in cattle from selected districts in Uganda. Balinandi S, von Brömssen C, Tumusiime A, Kyondo J, Kwon H, Monteil VM, Mirazimi A, Lutwama J, Mugisha L, Malmberg M.J Virol Methods. 2021 Apr;290:114075. doi: 10.1016/j.jviromet.2021.114075. Epub 2021 Jan 27.PMID: 33515661

 

Generation of enzymatically competent SARS-CoV-2 decoy receptor ACE2-Fc in glycoengineered Nicotiana benthamiana. Castilho A, Schwestka J, Kienzl NF, Vavra U, Grünwald-Gruber C, Izadi S, Hiremath C, Niederhöfer J, Laurent E, Monteil V, Mirazimi A, Wirnsberger G, Stadlmann J, Stöger E, Mach L, Strasser R.Biotechnol J. 2021 Jun;16(6):e2000566. doi: 10.1002/biot.202000566. Epub 2021 Feb 12.PMID: 33481336 

 

A DNA-based vaccine protects against Crimean-Congo haemorrhagic fever virus disease in a Cynomolgus macaque model. Hawman DW, Ahlén G, Appelberg KS, Meade-White K, Hanley PW, Scott D, Monteil V, Devignot S, Okumura A, Weber F, Feldmann H, Sällberg M, Mirazimi A. Nat Microbiol. 2021 Feb;6(2):187-195. doi: 10.1038/s41564-020-00815-6. Epub 2020 Nov 30.PMID: 33257849 

 

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, Ottaviani S, Shen JX, Sommerauer C, Tiseo G, Ghiadoni L, Virdis A, Monzani F, Rizos LR, Forfori F, Avendaño Céspedes A, De Marco S, Carrozzi L, Lena F, Sánchez-Jurado PM, Lacerenza LG, Cesira N, Caldevilla Bernardo D, Perrella A, Niccoli L, Méndez LS, Matarrese D, Goletti D, Tan YJ, Monteil V, Dranitsaris G, Cantini F, Farcomeni A, Dutta S, Burley SK, Zhang H, Pistello M, Li W, Romero MM, Andrés Pretel F, Simón-Talero RS, García-Molina R, Kutter C, Felce JH, Nizami ZF, Miklosi AG, Penninger JM, Menichetti F, Mirazimi A, Abizanda P, Lauschke VM. Sci Adv. 2021 Jan 1;7(1):eabe4724. doi: 10.1126/sciadv.abe4724. Print 2021 Jan. PMID: 33187978 

 

Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection. Monteil V, Dyczynski M, Lauschke VM, Kwon H, Wirnsberger G, Youhanna S, Zhang H, Slutsky AS, Hurtado Del Pozo C, Horn M, Montserrat N, Penninger JM, Mirazimi A.EMBO Mol Med. 2021 Jan 11;13(1):e13426. doi:10.15252/emmm.202013426. Epub 2020 Dec 14.PMID: 33179852 

 

Robust humoral and cellular immune responses and low risk for reinfection at least eight months following asymptomatic to mild COVID-19. Havervall, S., H. Ng, A. Jernbom Falk, N. Greilert-Norin, A. Månberg, U. Marking, I. Laurén, L. Gabrielsson, A.-C. Salomonsson, K, Aguilera, M. Kihlgren, M. Månsson, A. Rosell, C. Hellström, E. Andersson, J. Olofsson, L. Skoglund, J. Yousef, E. Pin, M. Lord, M. Hedhammar, H. Tegel, P. Dönnes, M. Phillipson, P. Nilsson*, J. Klingström*, S. Mangsbo*, S. Hober*, and C. Thålin*. *Shared last author. Journal of Internal Medicine 291: 72-80. 2022.

 

Mravinacova, S., M. Jönsson, W. Christ, J. Klingström, J. Yousef, C. Hellström, M. Hedhammar, S. Havervall, C. Thålin, E. Pin, H. Tegel, P. Nilsson, A. Månberg, and S. Hober. A cell-free high throughput assay for assessment of SARS-CoV-2 neutralising antibodies. New Biotechnology 66: 46-52. 2022.

 

Havervall, S., U. Marking, N. Greilert-Norin, H. Ng, M. Gordon, A.-C. Salomonsson, C. Hellström, E. Pin, K. Blom, S. Mangsbo, M. Phillipson, J. Klingström, S. Hober, P. Nilsson, M. Åberg, and C. Thålin. Antibody responses after a single dose of ChAdOx1 nCoV-19 vaccine in healthcare workers previously infected with SARS-CoV-2.EBioMedicine 70: 103523. 2021. IF 8.143

 

Normark, J., L. Vikström, Y.-D. Gwon, I.-L. Persson, A. Edin, T. Björsell, A. Dernstedt, W. Christ, S. Tevell, M. Evander, J. Klingström, C. Ahlm, and M. Forsell. Heterologous ChAdOx-1:mRNA-1273 Vaccination.New England Journal of Medicine 385: 1049-1051. 2021.

 

Kerkman, P.F., A. Dernstedt, L. Tadala, E. Mittler, M. Dannborg, C. Sundling, K. T. Maleki, J. Tauriainen, A. Tuiskunen-Bäck, J. Wigren Byström, P. Ocaya, T. Thunberg, R. Jangra, G. Román-Sosa, P. Guardado-Calvo, F. A. Rey, J. Klingström, K. Chandran, A. Puhar, C. Ahlm, and M. N. E. Forsell. Generation of plasma cells and CD27-IgD- B cells during hantavirus infection is associated with distinct pathological findings. Clinical & Translational Immunology 10: e1313. 2021.

 

Dieterle, M. E., C. Solà-Riera, C, Ye, S. M. Goodfellow, E. Mittler, E. Kasikci, S. B. Bradfute, J. Klingström, R. K. Jangra, and K. Chandran. Genetic depletion studies inform receptor usage by virulent hantaviruses in human endothelial cells. eLife 10: e69708. 2021.

 

Glans, H., S. Gredmark-Russ, M. Olausson, S. Falck-Jones, R. Varnaite, W. Christ, K. T. Maleki, M. Lind Karlberg, S. Broddesson, R. Falck-Jones, M. Bell, N. Johansson, A. Färnert, A. Smed-Sörensen, J. Klingström, and A. Bråve. Shedding of infectious SARS-CoV-2 by hospitalized COVID-19 patients in relation to serum antibody responses. BMC Inf Dis 21: 494. 2021.

 

Lagerqvist, N., K.T. Maleki, J. Verner-Carlsson, M. Olausson, J. Dillner, J. Wigren, T. Monsen, M. Forsell, J. Eriksson, G. Bogdanovic, S. Muschiol, J. Ljunggren, J. Repo, T. Kjerstadius, S. Muradrasoli, M. Brytting, Å. Szekely Björndal, T. Åkerlund, C. Nilsson, and J. Klingström. Evaluation of eleven SARS-CoV-2 antibody tests by using samples from patients with defined IgG antibody titers. Scientific Reports 11: 7614. 2021.

 

Maleki, K.T., J. Tauriainen, M. García, P. F. Kerkman, W. Christ, J. Dias, J. Wigren Byström, E. Leeansyah, M. N. Forsell, H.-G. Ljunggren, C. Ahlm, N. K. Björkström, J. K. Sandberg, and J. Klingström. MAIT cell activation is associated with disease severity markers in acute hantavirus infection. Cell Reports Medicine 2: 100220. 2021.

 

Vangeti, S., T. Strandin, S. Liu, J. Tauriainen, A. Räisänen-Sokolowski, L. Cabrera, A. Hassinen, S. Mäkelä, J. Mustonen, A. Vaheri, O. Vapalahti, J. Klingström, and A. Smed-Sörensen. Monocyte subset redistribution from blood to kidneys in patients with Puumalavirus caused hemorrhagic fever with renal syndrome. PLoS Pathogens 17: e1009400. 2021.

 

 

 

 

                  

 

(4) For facilities with maximum containment units participating in the national biological defence research and development programme, please fill in name of facility and mark "Declared in accordance with Form A, part 2 (iii)".

(5) In accordance with the latest edition of the WHO Laboratory Biosafety Manual, or equivalent.