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Functional Immuno-genetic Correlates of Immunity to Malaria

Functional Immuno-genetic Correlates of Immunity to Malaria

Project Lead(s)
DR. BRIGHT ADU (SENIOR RESEARCH FELLOW)
Senior Research Fellow
Project Background 

This is a South-driven capacity building research collaboration involving multiple (5) partners with the overall aim of building human and institutional capacity in the conduct of sustainable innovative malaria vaccine related research that will improve the general well-being of populations living in malaria endemic areas. The partners include Noguchi Memorial Institute for Medical Research, Kintampo Health Research Centre, Navrongo Health Research Centre in Ghana and Statens Serum Institut, Københavns Universitet in Denmark. Plasmodium falciparum (Pf) malaria is the leading cause of morbidity in Ghana, responsible for about 38% of all outpatient illnesses, 36% of all admissions, and 33% of all deaths in children under 5 years. Current intervention measures have contributed in reducing malaria morbidity and mortality, but long-term sustainability is not guaranteed. Vaccines against malaria therefore remain an important public health goal since vaccines have proven to be effective low-cost public health intervention tools with wide coverage. Vaccine candidates have been selected based on 1) association of malarial antibody titres with reduced risk of malaria in sero-epidemiological studies and 2) capacity of their anti-IgG preparations to inhibit parasite growth in vitro, either alone (GIA (Growth Inhibition Assay)) or in cooperation with monocytes or neutrophils (OP (Opsonic Phagocytosis)). In these studies, and in vaccine trial data analysis, all individuals are thought to benefit equally from naturally or vaccine induced protective antibodies. We hypothesized that protective malaria immunity is a result of interplay between antibodies and host genetic factors and that individuals do not benefit equally from protective antibodies due to polymorphisms in certain key genes.

Objectives/Research Areas 

The overall goal of the project is to build human and institutional capacity in the conduct of sustainable innovative malaria vaccine related research that will improve the general well-being of populations living in malaria endemic areas.  

 

Objectives 

  1. To conduct a longitudinal cohort study (LCS) in Danfa of the La-Nkwantanang Madina Municipality, a high malaria endemic region in Ghana and use an ongoing blood draw protocol to optimize OP and GIA bioassays
  2. 2. To assess antibody functionality in individuals naturally exposed to Pf and the interaction between antibodies and host genetic factors in relation to the risk of clinical malaria.
  3. 3. To assess the dynamics of Pf genetic variations that underlie the acquisition of immunity to malaria
  4. To conduct statistical modeling of age-specific risk of malaria and relative contributions of host, parasite and environmental associated factors to the risk of malaria
  5. 5. To assess antibody functionality in GMZ2 immunized individuals and the interaction between GMZ2 induced antibodies and host genetic factors in relation to the risk of malaria
  6. 6. To evaluate the anti-parasite activity of naturally acquired (LCS) and vaccine (GMZ2) induced IgG in the context of host genetic factors using OP
Key Findings 
  1. Opsonic phagocytosis activity correlates with protection against malaria 
  2. GMZ2 vaccine induced antibodies work in concert with naturally acquired antibodies to protect against malaria 
  3. The medium hinge region length of IgG3 is associated with increased risk against cerebral malaria  
  4. Increased breadth of malarial specific antibody response is associated with reduced risk of malaria. 
Ongoing Activities  

Data analysis and manuscript writing 

Key Publications  
  1. Dassah S, Adu B, Tiendrebeogo RW, Singh SK, Arthur FKN, Sirima SB, Theisen M. GMZ2 Vaccine-Induced Antibody Responses, Naturally Acquired Immunity and the Incidence of Malaria in Burkinabe Children. Front Immunol. 2022;13:899223. doi: 10.3389/fimmu.2022.899223. eCollection 2022. PubMed PMID: 35720297; PubMed Central PMCID: PMC9200992.  
  2. Kyei-Baafour E, Kusi KA, Arthur FKN, Sarkodie-Addo T, Theisen M, Dodoo D, Adu B. Association of Immunoglobulin G3 Hinge Region Length Polymorphism With Cerebral Malaria in Ghanaian Children. J Infect Dis. 2022 May 16;225(10):1786-1790. doi: 10.1093/infdis/jiab548. PubMed PMID: 34718631.  
  3. León-Lara X, Yang T, Fichtner AS, Bruni E, von Kaisenberg C, Eiz-Vesper B, Dodoo D, Adu B, Ravens S. Evidence for an Adult-Like Type 1-Immunity Phenotype of Vδ1, Vδ2 and Vδ3 T Cells in Ghanaian Children With Repeated Exposure to Malaria. Front Immunol. 2022;13:807765. doi: 10.3389/fimmu.2022.807765. eCollection 2022. PubMed PMID: 35250979; PubMed Central PMCID: PMC8891705. 
  4. Garcia-Senosiain A, Kana IH, Singh S, Das MK, Dziegiel MH, Hertegonne S, Adu B, Theisen M. Neutrophils dominate in opsonic phagocytosis of P. falciparum blood-stage merozoites and protect against febrile malaria. Commun Biol. 2021 Aug 19;4(1):984. doi: 10.1038/s42003-021-02511-5. PubMed PMID: 34413459; PubMed Central PMCID: PMC8376957.  
  5. Dassah S, Adu B, Sirima SB, Mordmüller B, Ngoa UA, Atuguba F, Arthur FKN, Mensah BA, Kaddumukasa M, Bang P, Kremsner PG, Mategula D, Flach C, Milligan P, Theisen M. Extended follow-up of children in a phase2b trial of the GMZ2 malaria vaccine. Vaccine. 2021 Jul 13;39(31):4314-4319. doi: 10.1016/j.vaccine.2021.06.024. Epub 2021 Jun 24. PubMed PMID: 34175127.  
  6. Adu B, Issahaque QA, Sarkodie-Addo T, Kumordjie S, Kyei-Baafour E, Sinclear CK, Eyia-Ampah S, Owusu-Yeboa E, Theisen M, Dodoo D. Microscopic and Submicroscopic Asymptomatic Plasmodium falciparum Infections in Ghanaian Children and Protection against Febrile Malaria. Infect Immun. 2020 Sep 18;88(10). doi: 10.1128/IAI.00125-20. Print 2020 Sep 18. PubMed PMID: 32719157; PubMed Central PMCID: PMC7504941. 
  7. Dwomoh D, Adu B, Dodoo D, Theisen M, Iddi S, Gerds TA. Evaluating the predictive performance of malaria antibodies and FCGR3B gene polymorphisms on Plasmodium falciparum infection outcome: a prospective cohort study. Malar J. 2020 Aug 27;19(1):307. doi: 10.1186/s12936-020-03381-8. PubMed PMID: 32854708; PubMed Central PMCID: PMC7450914. 
  8. Garcia-Senosiain A, Kana IH, Singh SK, Chourasia BK, Das MK, Dodoo D, Singh S, Adu B, Theisen M. Peripheral Merozoite Surface Proteins Are Targets of Naturally Acquired Immunity against Malaria in both India and Ghana. Infect Immun. 2020 Mar 23;88(4). doi: 10.1128/IAI.00778-19. Print 2020 Mar 23. PubMed PMID: 31964745; PubMed Central PMCID: PMC7093125. 
  9. Kana IH, Singh SK, Garcia-Senosiain A, Dodoo D, Singh S, Adu B, Theisen M. Breadth of Functional Antibodies Is Associated With Plasmodium falciparum Merozoite Phagocytosis and Protection Against Febrile Malaria. J Infect Dis. 2019 Jun 19;220(2):275-284. doi: 10.1093/infdis/jiz088. PubMed PMID: 30820557. 
  10. Kana IH, Adu B, Tiendrebeogo RW, Singh SK, Dodoo D, Theisen M. Naturally Acquired Antibodies Target the Glutamate-Rich Protein on Intact Merozoites and Predict Protection Against Febrile Malaria. J Infect Dis. 2017 Feb 15;215(4):623-630. doi: 10.1093/infdis/jiw617. PubMed PMID: 28329101. 
Community Engagement Activities  
Organisation of Inter-Junior High Schools Health Quiz competition An Inter-Junior High Schools Quiz competition was organised on malaria mainly based on findings from the functional immunogenetics project and general knowledge education on how to prevent malaria within the study communities. A total of 12 Junior High Schools in the Oyarifa circuit of the La Nkwatanang- Madina Municipality competed in the two-day event held on July 10 and 12, 2019 at the Oyarifa Presbyterian School. Agape International School from Otinibi emerged as champions of the quiz. All finalists were brought on an educational visit to the Noguchi Memorial Institute for Medical Research where they had the opportunity to tour the laboratories and meet with scientists. The objective of the program was to breakdown research findings to the level of the layperson and engage young Junior High Students as agents to disseminate findings to the grassroots of the communities. The objective of the educational tour of the laboratories was to stir up more interest in science and research at the basic school level by exposing the students to real scientific research environment, equipment, and practices.
Team 
Internal Collaborator(s) 
Prof. Daniel Dodoo
Dr. Kwadwo Asamoah Kusi
Dr. Anita Ghansah
Dr. Linda Amoah
External Collaborator(s) 
Prof. Michael Theisen, Statens Serum Institute, Copenhagen, Denmark
Prof. Thomas Alexander Gerds, University of Copenhagen, Copenhagen, Denmark
Dr. Kwaku Poku Asante, Kintampo Health Research Centre, Kintampo, Ghana
Dr. Frank Atuguba, Navrongo Health Research Centre, Navrongo, Ghana
Funder(s) 
Ministry of Foreign Affairs of Denmark