Published November 2018
RTS,S induces antibodies with complement fixing ability
The most advanced Malaria vaccine in development is RTS,S, a subunit vaccine containing a fragment of CSP, the dominant antigen on the sporozoite surface. Epidemiological studies show that anti-CSP antibody titer is a correlate of protection after RTS,S immunization. However, it is unclear how specifically antibodies can block blood stage development.
In work presented at the ASP, Liriye Kurtovic and colleagues found that anti-CSP IgG induced by RTS,S showed potent complement fixation capabilities, although a substantial decline of C1q fixing ability was observed in follow-up months after vaccination. In my view, mechanistic insights into how antibodies prevent P. falciparum infection are highly valuable since they may pave the road towards more rationale vaccine design. However, whether the complement-binding activity of RTS,S-induced antibodies is required for the vaccine`s protective effect was not addressed in the presented research, although it has been shown before that complement fixation to CSP can inhibit sporozoite movement and may lead to sporozoite death.
T-bet impedes acquisition of humoral immunity during blood stage Malaria
Ly and colleagues presented results that point towards the T-bet transcription factor as a potential cause for the slow acquisition adaptive immunity to Malaria. Utilizing the P. berhei/ANKA model and mice with CD4 T-cell or B-cell specific T-bet knockout, they show improved Tfh-cell development (CD4 T-cell specific T-bet K.O.) and germinal center responses (B-cell specific T-bet K.O.) during infection. Both Tfh-cell development and germinal center responses are critical to the establishment of strong humoral immunity.
Inflammatory cytokines such as INFy and IL-12 induce T-bet expression in many cell types. This observation prompts Ly et. al to hypothesize that excessive inflammation during infection impedes the acquisition of protective humoral immunity by over-induction of T-bet. Although many open questions about T-bet function in general remain, it is conceivable that T-bet dysregulation during Malaria infection contributes to slow acquisition of humoral immunity in mice. The talk showed again that inflammation is a “double-edged sword” in (Malaria) infection and how little is understood about its role in the acquisition of adaptive immunity.
Whole parasite blood stage vaccination
A recently revisited idea for vaccination is the injection of whole, parasitized red blood cells. At the ASP meeting, Danielle Stanisic stated that high antigenic variability of blood-stage Malaria is one of the reasons that no subunit vaccine has been able to reach the desired efficacies. Consequently, she proposed the use of whole, parasitized red blood cells, arguing that a broader array of antigens available to the immune system will produce a broader, more efficacious adaptive immune response. She also noted that the immune response against the injected red blood cells has to be qualitatively different from that mounted during natural infection. She suggested using only small doses of iRBCs for vaccination and simultaneous treatment with blood-stage targeted drugs.
I think this is a promising line of research. Importantly, if we knew why the immune response during natural infection does not lead to protective immunity, we could apply this knowledge to circumvent potential Malaria-mediated immune-modulation during vaccination with parasitized whole RBCs.
Drug-induced immunomodulation in Malaria research
Haylay Joseph gave a stimulating talk discussing possible confounding effects of chloroquine and pyrimethamine in Malaria immunology research. Both drugs are routinely used in mouse models of Malaria infection to prevent fatalities. However, drug-treated control mice are rarely included although immunomodulatory effects of chloroquine have been described. Interestingly, the group from WHEI found that drug-treated control animals showed severe defects in the development of antigen presenting B cells compared to untreated control mice. This discrepancy strongly warrants the use of drug-treated control animals.
Biomedical experimentation has seen a rise in complexity in the last decades. This has allowed for breakthrough discoveries, but it should also caution us to the increasing number of potential confounding factors. These factors can make it difficult to draw meaningful conclusions from generated data, especially in absence of suitable controls. In my opinion, the experiments done by Haylay Joseph and colleagues highlight this issue and once again remind us to use appropriate controls.
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