By JoAnne Chan, Burnet Institute, Australia
A persisting problem in the quest of developing an effective malaria vaccine is our limited understanding of why potent anti-malarial immunity is difficult to generate and is not long-lasting. Individuals who live in malaria-endemic countries gradually develop antibodies that protect against symptomatic disease, suggesting that the development of a malaria vaccine is highly feasible, and some success has been achieved. However, vaccines to-date have failed to reach the desired efficacy that is required for strong public health impact against malaria. This is due in part to the lack of fundamental knowledge regarding the mechanisms of anti-malarial immunity, which hampers our ability to develop a highly efficacious and long-lasting vaccine.
Our group has recently identified how antibody development is regulated by cellular immune mechanisms, specifically revealing the role of specialized immune cells known as T follicular helper (Tfh) cells. These cells play a central role in inducing and regulating the development of antibodies. They can be grouped into different subsets and their activation and proliferation profiles impact the generation of protective antibodies. However, there have been limited studies on the role of Tfh cells in human P. falciparum malaria.
Here, we used a novel and powerful approach of a human challenge model where healthy Australian adults agreed to be infected with malaria. This was performed within laboratory-controlled conditions at QIMR-Berghofer Institute. This innovative approach enables the study of immune responses without the influence of prior malaria exposure or other co-morbidities. Participants were infected with a low dose of malaria parasites, monitored for the development of parasitemia and treated prior to the onset of symptoms. Samples were collected at specific time points for the duration of the study and all participants were treated to clear parasites upon study completion.
We showed that Tfh cells activate following experimental malaria infection, with distinct profiles within the different subsets. The Th2-Tfh subset activated early during peak infection, while Th1-Tfh cells activate a week after peak infection and treatment. Importantly, we provide evidence for an association between Th2-Tfh cell activation and the induction of functional human antibodies that protect against malaria. In contrast we found that Th1-Tfh activation was not associated with antibodies but instead with plasma cells which has been shown to be detrimental in the development of immunity.
Our work contrasts the role of different Tfh cell subsets in regulating antibody production and inform the development of malaria vaccines that target Th2-Tfh to boost antibody induction using effective vaccine adjuvants. This discovery contributes important new insights into the advancement of malaria vaccines which are critical to achieve elimination. Vaccine strategies that better activate Th2-TfH may lead to better efficacy.
Figure: Schematic summary of study design and TfH cell types and activation that were associated with antibody responses. (From Chan JA et al, Cell Reports Medicine, 2020, Dec 22;1(9):100157)