Anna Färnert Group

Malaria remains a major global health problem and new tools are needed to reduce malaria morbidity and mortality and eventually reach the goals of elimination. Development of an efficacious vaccine will require further understanding of how natural immunity to malaria is acquired and maintained. Our group is particularly interested in the importance of the extensive diversity of parasite antigens and mechanisms involved in the maintenance of protection. The molecular and sero-epidemiology of malaria is studied in a longitudinal population cohort in areas of varying transmission in Sub-Saharan Africa.

Moreover, immune responses are studied in depth in a cohort of patients successfully treated for malaria and prospectively followed in Sweden, thus without risk of reinfection. Immunological memory is studied in the context of different infections and vaccines. In addition, we assess long term effects of malaria and other infections on the host including ageing biology. In a nation wide study of malaria in Sweden we investigate host factors, such as comorbidities, in relation to the risk of severe malaria, with aim to improve the clinical management and prevention of malaria.

Acquisition and maintenance of immunity to malaria:

• Molecular epidemiology of malaria: Understanding how natural immunity to malaria develops in populations living in endemic areas can guide the development of vaccines and other malaria interventions. Molecular and immunological tools are used to investigate the epidemiology of malaria in populations with different degrees of exposure. The genetic diversity of parasite antigens is studied in relation to disease and immune responses, in closely followed population cohorts in areas of different transmission. We have previously shown that individuals in endemic areas that are persistently infected with multiple parasite clones are at reduced risk of clinical malaria and also have broader antibody responses. Current projects investigate the importance of repeated and chronic infections to the maintenance of otherwise short lived antibody responses, as well as the importance of the extensive genetic diversity of parasite antigens for the acquisition clinical protection against malaria.

Clinical epidemiology and management of malaria:

• The outcome of a malaria infection is largely affected by the acute clinical management. In addition to the morbidity and mortality due to acute disease, malaria might also have longterm consequences on health. As part of a nationwide study in Sweden, we assess factors affecting severe malaria including maintenance of immunity and comorbidities such as diabetes and obesity. By using national health registers and individual medical record data we study acute and longterm effect of malaria in relation to host factors. In addition, we study the epidemiology of malaria in in a longitudinally followed population in Tanzania. These projects focus on clinical aspects of malaria, including prognostic factors, diagnostics and therapy, with the overall aim to improve the management and prevention of malaria.

Malaria and vaccine immunology:

• Mechanistic insights into the control of long-lived humoral immunity: Vaccines work by stimulating the immune system with components of pathogens without experiencing a fullblown infection. However, although the protective effect of most licensensed vaccines is very high, the durability of the protection varies widely between vaccines. The tick-borne encephalitis virus (TBEV) vaccine, e.g. needs to be boosted every three to five years while the measles vaccine generally generates protective immunity for the life-time of the individual. Live vaccines, such as the measles vaccine, generally induce immunity that lasts longer compared to inactivated- or subunit vaccines, such as the TBEV or tetanus vaccines, as they more closely mimick the natural infection. However, not all natural infections lead to long-lasting immunity. Individuals that were previously immune to malaria disease can become susceptible again after staying in non-endemic regions for a few years, indicating that malaria-specific immunity is very short-lived.It is currently unclear why there is such a difference in the longevity of immunity and this is an important problem to solve, so that current and future vaccines can be improved and generate longer lasting immunity. To increase our understanding of the mechanisms that govern longevity of an immune response we use molecular approaches to investigate antigen-specific immune cells at different time-points after vaccination or infection that induce long- or short-lived immunity. This approach enable us to better understand how the immune cells are programmed in the context of long- vs short-lived immunity, and thereby help guide future vaccine efforts.

• Changes to the immune landscape after malaria infection: Malaria infection is associated with a strong activation of the innate immune response. This activation is characterized by high levels of interferon gamma, which is characteristic of a Th1 immune response. The innate signal type and strength is important inshaping the size and direction of the adaptive immune response. In recent years, it has become clear that the strong Th1 signal observed during malaria infection may have implications for the longevity and reactivation of the adaptive immune response. Current projects investigate the immune landscape in individuals that experience malaria for the first time, or that have experienced malaria previously. Using mass cytometry, we have found that the innate and adaptive immune profiles differ in the monocyte, T cell, NK cell, and B cell compartments between the groups, findings that are currently being investigated further.

Relapse of Plasmodium vivax and Plasmodium ovale malaria with and without primaquine treatment in a non-endemic area.
Wångdahl A, Sondén K, Wyss K, Stenström C, Björklund D, Zhang J, Hervius Askling H, Carlander C, Hellgren U, Färnert A
Clin Infect Dis 2021 Jul;():

Clinical phenotypes and outcomes of SARS-CoV-2, influenza, RSV and seven other respiratory viruses: a retrospective study using complete hospital data.
Hedberg P, Karlsson Valik J, van der Werff S, Tanushi H, Requena Mendez A, Granath F, Bell M, Mårtensson J, Dyrdak R, Hertting O, Färnert A, Ternhag A, Naucler P
Thorax 2021 Jul;():

Enhanced virulence of Plasmodium falciparum in blood of diabetic patients.
Ch’ng JH, Moll K, Wyss K, Hammar U, Rydén M, Kämpe O, Färnert A, Wahlgren M
PLoS One 2021 ;16(6):e0249666

Determinants of the varied profiles of Plasmodium falciparum infections among infants living in Kintampo, Ghana.
Botwe AK, Oppong FB, Gyaase S, Owusu-Agyei S, Asghar M, Asante KP, Färnert A, Osier F
Malar J 2021 May;20(1):240

Memory B-Cell Responses Against Merozoite Antigens After Acute Plasmodium falciparum Malaria, Assessed Over One Year Using a Novel Multiplexed FluoroSpot Assay.
Jahnmatz P, Sundling C, Yman V, Widman L, Asghar M, Sondén K, Stenström C, Smedman C, Ndungu F, Ahlborg N, Färnert A
Front Immunol 2020 ;11():619398

Malaria and risk of lymphoid neoplasms and other cancer: a nationwide population-based cohort study.
Wyss K, Granath F, Wångdahl A, Djärv T, Fored M, Naucler P, Färnert A
BMC Med 2020 10;18(1):296

Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season.
Andrade CM, Fleckenstein H, Thomson-Luque R, Doumbo S, Lima NF, Anderson C, Hibbert J, Hopp CS, Tran TM, Li S, Niangaly M, Cisse H, Doumtabe D, Skinner J, Sturdevant D, Ricklefs S, Virtaneva K, Asghar M, Homann MV, Turner L, Martins J, Allman EL, N’Dri ME, Winkler V, Llinás M, Lavazec C, Martens C, Färnert A, Kayentao K, Ongoiba A, Lavstsen T, Osório NS, Otto TD, Recker M, Traore B, Crompton PD, Portugal S
Nat Med 2020 12;26(12):1929-1940

Profiles of Plasmodium falciparum infections detected by microscopy through the first year of life in Kintampo a high transmission area of Ghana.
Botwe AK, Owusu-Agyei S, Asghar M, Hammar U, Oppong FB, Gyaase S, Dosoo D, Jakpa G, Boamah E, Twumasi MF, Osier F, Färnert A, Asante KP
PLoS One 2020 ;15(10):e0240814

Persistent transmission of Plasmodium malariae and Plasmodium ovale species in an area of declining Plasmodium falciparum transmission in eastern Tanzania.
Yman V, Wandell G, Mutemi DD, Miglar A, Asghar M, Hammar U, et al
PLoS Negl Trop Dis 2019 May;13(5):e0007414

B cell profiling in malaria reveals expansion and remodelling of CD11c+ B cell subsets.
Sundling C, Rönnberg C, Yman V, Asghar M, Jahnmatz P, Lakshmikanth T, et al
JCI Insight 2019 Apr;5():

Malaria in Eritrean migrants newly arrived in seven European countries, 2011 to 2016.
Sondén K, Rolling T, Wångdahl A, Ydring E, Vygen-Bonnet S, Kobbe R, et al
Euro Surveill. 2019 Jan;24(5):

Antibody responses to merozoite antigens after natural Plasmodium falciparum infection: kinetics and longevity in absence of re-exposure.
Yman V, White MT, Asghar M, Sundling C, Sondén K, Draper SJ, et al
BMC Med 2019 01;17(1):22

KILchip v1.0: A Novel Plasmodium falciparum Merozoite Protein Microarray to Facilitate Malaria Vaccine Candidate Prioritization.
Kamuyu G, Tuju J, Kimathi R, Mwai K, Mburu J, Kibinge N, et al
Front Immunol 2018 ;9():2866

Cutaneous, mucocutaneous and visceral leishmaniasis in Sweden from 1996-2016: a retrospective study of clinical characteristics, treatments and outcomes.
Glans H, Dotevall L, Söbirk SK, Färnert A, Bradley M
BMC Infect. Dis. 2018 Dec;18(1):632

The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels.
Algady W, Louzada S, Carpenter D, Brajer P, Färnert A, Rooth I, et al
Am. J. Hum. Genet. 2018 11;103(5):769-776

Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational Study.
Reuling IJ, de Jong GM, Yap XZ, Asghar M, Walk J, van de Schans LA, et al
EBioMedicine 2018 Oct;36():131-139

Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo.
Parigi SM, Czarnewski P, Das S, Steeg C, Brockmann L, Fernandez-Gaitero S, et al
Sci Rep 2018 01;8(1):154

Cellular aging dynamics after acute malaria infection: A 12-month longitudinal study.
Asghar M, Yman V, Homann MV, Sondén K, Hammar U, Hasselquist D, et al
Aging Cell 2018 02;17(1):

Detection of Malaria Parasites After Treatment in Travelers: A 12-months Longitudinal Study and Statistical Modelling Analysis.
Vafa Homann M, Emami SN, Yman V, Stenström C, Sondén K, Ramström H, et al
EBioMedicine 2017 Nov;25():66-72