Systems analysis and controlled malaria infection in Europeans and Africans elucidate naturally acquired immunity

Abstract

Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161 + CD4 + T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4 + T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.

Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial

“…As well as providing a platform for evaluation of candidate vaccines, a human-challenge model of S. pyogenes infection offers the unique opportunity to interrogate the dynamic host immune response to infection using samples collected before, during, and after development of disease. Human-challenge models have been established for other infectious pathogens such as Vibrio cholerae, Salmonella Typhi and Paratyphi, Streptococcus pneumoniae, respiratory syncytial virus and malaria, and have enormous potential to successfully guide vaccine development [11][12][13][14][15] . Recently, a new human-challenge model of S. pyogenes pharyngitis in healthy adults was established in an initial dose-finding clinical trial, after an extensive effort to select and characterise a challenge strain and develop a study protocol to protect participants and promote the model's clinical relevance [16][17][18] .…”

Cellular and antibody response in GMZ2-vaccinated Gabonese volunteers in a controlled human malaria infection trial

“…On the other hand, another explanation relying on the marked CD4 + T cell activity at baseline may provide a scenario where the saturated activation of T cells and/ or previous activation of dendritic cells (DCs) before vaccination may reflect the influence of the frequent natural exposure to P. falciparum [35]. It has also been shown that elevated levels of CD161 + CD4 + T cells and malaria-specific IFN-γ-production predicted protection against CHMI [36].…”

“…The targeted antigens included several biomarkers of exposure [42] and well-described malaria vaccine candidates. Associations between antibody breadth and protection, as well as responses to specific malaria antigens and protection, have been described in malaria-naïve volunteers immunized with sporozoites under chemoprophylaxis [36,43]. There, either patterns or specific antigens were associated with protection.…”

“…Despite these limitations, the study provides important insights on the difficulties to develop a malaria vaccine for malaria-endemic regions. Further exploration of the immunological aspects of naturally acquired immunity in endemic regions are a necessary step in the design and clinical development of any future malaria vaccine with an impact where it is most needed [36].…”

Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda?

“…Of these, Plasmodium falciparum (P. falciparum) and Plasmodium vivax (P. vivax) are more widely distributed [3]. In sub-Saharan Africa, P. falciparum is the cause of most malaria cases while P. vivax is reported to cause most of the malaria cases in Asia; P. falciparum cause more fatal disease [4].…”