Abstract
Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.
Highlights
Whether a vaccine generates an immune response that results in protection from infection or disease depends in part on the preimmunization status and capacities of the vaccinated individual’s immune system[1]
Despite the wide-ranging clinical trial conditions, our results indicate that protection against post-immunization malaria challenge is associated with innate immune system activation and a moderately elevated inflammatory state prior to immunization, including higher expression in genes associated with Toll-like receptors (TLRs) signaling and other inflammatory pathways
A differential expression analysis comparing the transcriptomes of all protected participants (n = 38) and all nonprotected participants (n = 46) pooled from the trials revealed no genes with statistically significant differences in transcript abundance using an FDR-adjusted P-value cutoff of 0.1
Summary
Whether a vaccine generates an immune response that results in protection from infection or disease depends in part on the preimmunization status and capacities of the vaccinated individual’s immune system[1]. Identifying preimmunization correlates of protection, offers opportunities for illuminating the immunological pathways that promote or attenuate protective vaccine responses, for identifying avenues whereby the immune system can be influenced to respond effectively, and for developing personalized approaches that predict vaccine efficacy on an individual or group basis. Despite the wide-ranging clinical trial conditions, our results indicate that protection against post-immunization malaria challenge is associated with innate immune system activation and a moderately elevated inflammatory state prior to immunization, including higher expression in genes associated with TLR signaling and other inflammatory pathways These results echo molecular- and pathway-level preimmunization correlates of malaria protection derived from previous analyses on narrower sets of clinical trials[19,21]. They highlight specific immunological pathways that may play critical roles in the development of effective malaria vaccine-elicited responses and offer potential targets for manipulating the immune system into a state that promotes such responses
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