Group Anna Färnert

Malaria

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.

Project descriptions

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

Team Sundling/Färnert

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.

 

Team members

 

Anna Färnert, Professor Senior Consultant, Head of Division

Akua Botwe, PhD student

Peter Jahnmatz, PhD student

Muhammad Asghar, PhD, Research Assistant Professor

Klara Sondén, MD, PhD, Post Doctoral Fellow

Andreas Wångdahl, MD, PhD student

Katja Wyss, MD, PhD student

Victor Yman, MD, PhD student

Christopher Sundling, PhD, Research Assistent Professor

Key publications

Obesity and Diabetes as Risk Factors for Severe Plasmodium falciparum Malaria: Results From a Swedish Nationwide Study.
Wyss K, Wångdahl A, Vesterlund M, Hammar U, Dashti S, Naucler P, et al
Clin. Infect. Dis. 2017 Sep;65(6):949-958

High Rate of Treatment Failures in Nonimmune Travelers Treated With Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Sweden: Retrospective Comparative Analysis of Effectiveness and Case Series.
Sondén K, Wyss K, Jovel I, Vieira da Silva A, Pohanka A, Asghar M, et al
Clin. Infect. Dis. 2017 Jan;64(2):199-206

Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection.
Portugal S, Tran T, Ongoiba A, Bathily A, Li S, Doumbo S, et al
Clin. Infect. Dis. 2017 03;64(5):645-653

Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.
Holmberg D, Franzén-Röhl E, Idro R, Opoka R, Bangirana P, Sellgren C, et al
Malar. J. 2017 07;16(1):303

Cord blood IgG and the risk of severe Plasmodium falciparum malaria in the first year of life.
Murungi L, Sondén K, Odera D, Oduor L, Guleid F, Nkumama I, et al
Int. J. Parasitol. 2017 02;47(2-3):153-162

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.
Zhao X, Howell K, He S, Brannan J, Wec A, Davidson E, et al
Cell 2017 May;169(5):891-904.e15

Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells.
Kräutler N, Suan D, Butt D, Bourne K, Hermes J, Chan T, et al
J. Exp. Med. 2017 05;214(5):1259-1267

Plasma cell and memory B cell differentiation from the germinal center.
Suan D, Sundling C, Brink R
Curr. Opin. Immunol. 2017 Apr;45():97-102

Oil-Fortified Maize Porridge Increases Absorption of Lumefantrine in Children with Uncomplicated Falciparum Malaria.
Mwebaza N, Jerling M, Gustafsson L, Silva A, Pohanka A, Obua C, et al
Basic Clin. Pharmacol. Toxicol. 2017 May;120(5):457-465

Parallel telomere shortening in multiple body tissues owing to malaria infection.
Asghar M, Palinauskas V, Zaghdoudi-Allan N, Valkiūnas G, Mukhin A, Platonova E, et al
Proc. Biol. Sci. 2016 Aug;283(1836):

Antibody acquisition models: A new tool for serological surveillance of malaria transmission intensity.
Yman V, White M, Rono J, Arcà B, Osier F, Troye-Blomberg M, et al
Sci Rep 2016 Feb;6():19472

An antigen-specific, four-color, B-cell FluoroSpot assay utilizing tagged antigens for detection.
Jahnmatz P, Bengtsson T, Zuber B, Färnert A, Ahlborg N
J. Immunol. Methods 2016 06;433():23-30

Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children.
Murungi L, Sondén K, Llewellyn D, Rono J, Guleid F, Williams A, et al
Infect. Immun. 2016 Apr;84(4):950-963

CD138 and CD31 Double-Positive Cells Comprise the Functional Antibody-Secreting Plasma Cell Compartment in Primate Bone Marrow.
Martinez-Murillo P, Pramanik L, Sundling C, Hultenby K, Wretenberg P, Spångberg M, et al
Front Immunol 2016 ;7():242

High-Resolution Longitudinal Study of HIV-1 Env Vaccine-Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence.
Wang Y, Sundling C, Wilson R, O'Dell S, Chen Y, Dai K, et al
J. Immunol. 2016 05;196(9):3729-43

HIV-1 Vaccine-elicited Antibodies Reverted to Their Inferred Naive Germline Reveal Associations between Binding Affinity and in vivo Activation.
Dai K, Khan S, Wang Y, He L, Guenaga J, Ingale J, et al
Sci Rep 2016 Feb;6():20987

CTI special feature on innate immune responses and vaccine design.
Sundling C, Sandgren K
Clin Transl Immunology 2016 Aug;5(8):e96

Multiple clinical episodes of Plasmodium falciparum malaria in a low transmission intensity setting: exposure versus immunity.
Rono J, Färnert A, Murungi L, Ojal J, Kamuyu G, Guleid F, et al
BMC Med 2015 May;13():114

Asymptomatic Multiclonal Plasmodium falciparum Infections Carried Through the Dry Season Predict Protection Against Subsequent Clinical Malaria.
Sondén K, Doumbo S, Hammar U, Vafa Homann M, Ongoiba A, Traoré B, et al
J. Infect. Dis. 2015 Aug;212(4):608-16

Duration of residency in a non-endemic area and risk of severe malaria in African immigrants.
Färnert A, Wyss K, Dashti S, Naucler P
Clin. Microbiol. Infect. 2015 May;21(5):494-501

Chronic infection. Hidden costs of infection: chronic malaria accelerates telomere degradation and senescence in wild birds.
Asghar M, Hasselquist D, Hansson B, Zehtindjiev P, Westerdahl H, Bensch S
Science 2015 Jan;347(6220):436-8

Epidemiology of malaria in a village in the Rufiji River Delta, Tanzania: declining transmission over 25 years revealed by different parasitological metrics.
Färnert A, Yman V, Homann M, Wandell G, Mhoja L, Johansson M, et al
Malar. J. 2014 Nov;13():459

High incidence of Plasmodium vivax malaria in newly arrived Eritrean refugees in Sweden since May 2014.
Sonden K, Castro E, Törnnberg L, Stenstrom C, Tegnell A, Farnert A
Euro Surveill. 2014 Sep;19(35):

Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria.
Rono J, Osier F, Olsson D, Montgomery S, Mhoja L, Rooth I, et al
Clin. Infect. Dis. 2013 Nov;57(10):1409-16

Long-lived Plasmodium falciparum specific memory B cells in naturally exposed Swedish travelers.
Ndungu F, Lundblom K, Rono J, Illingworth J, Eriksson S, Färnert A
Eur. J. Immunol. 2013 Nov;43(11):2919-29

Plasmodium falciparum infection patterns since birth and risk of severe malaria: a nested case-control study in children on the coast of Kenya.
Lundblom K, Murungi L, Nyaga V, Olsson D, Rono J, Osier F, et al
PLoS ONE 2013 ;8(2):e56032

Bacterial coinfections in travelers with malaria: rationale for antibiotic therapy.
Sandlund J, Naucler P, Dashti S, Shokri A, Eriksson S, Hjertqvist M, et al
J. Clin. Microbiol. 2013 Jan;51(1):15-21

Transmission-dependent tolerance to multiclonal Plasmodium falciparum infection.
Färnert A, Williams T, Mwangi T, Ehlin A, Fegan G, Macharia A, et al
J. Infect. Dis. 2009 Oct;200(7):1166-75

Plasmodium falciparum population dynamics: only snapshots in time?
Färnert A
Trends Parasitol. 2008 Aug;24(8):340-4

 

Contact

Professor/senior physician

Anna Färnert

Phone: +46-(0)8-517 752 85
Organizational unit: Group A Färnert
E-mail: Anna.Farnert@ki.se

MD, PhD, Principal Investigator

Anna Färnert

Work:+46 (0)8-517 752 85

E-mail:Anna.Farnert@ki.se