Antigen-stimulated PBMC transcriptional protective signatures for malaria immunization

Abstract

<jats:p>Identifying immune correlates of protection and mechanisms of immunity accelerates and streamlines the development of vaccines. RTS,S/AS01E, the most clinically advanced malaria vaccine, has moderate efficacy in African children. In contrast, immunization with sporozoites under antimalarial chemoprophylaxis (CPS immunization) can provide 100% sterile protection in naïve adults. We used systems biology approaches to identifying correlates of vaccine-induced immunity based on transcriptomes of peripheral blood mononuclear cells from individuals immunized with RTS,S/AS01E or chemoattenuated sporozoites stimulated with parasite antigens in vitro. Specifically, we used samples of individuals from two age cohorts and three African countries participating in an RTS,S/AS01E pediatric phase 3 trial and malaria-naïve individuals participating in a CPS trial. We identified both preimmunization and postimmunization transcriptomic signatures correlating with protection. Signatures were validated in independent children and infants from the RTS,S/AS01E phase 3 trial and individuals from an independent CPS trial with high accuracies (&gt;70%). Transcription modules revealed interferon, NF-κB, Toll-like receptor (TLR), and monocyte-related signatures associated with protection. Preimmunization signatures suggest that priming the immune system before vaccination could potentially improve vaccine immunogenicity and efficacy. Last, signatures of protection could be useful to determine efficacy in clinical trials, accelerating vaccine candidate testing. Nevertheless, signatures should be tested more extensively across multiple cohorts and trials to demonstrate their universal predictive capacity.</jats:p>

The Case for the Development of a Chagas Disease Vaccine: Why? How? When?

“…While the confirmation of earlier results is encouraging, a major limitation of these approaches is that they remain limited in the breadth of the immune response assessed. Therefore, more integrative approaches from system immunology, such as those used for malaria, influenza, or yellow fever vaccines [70][71][72], may help reach a more comprehensive understanding of responses to vaccines and the correlates for protection against T. cruzi.…”

A guide to investigating immune responses elicited by whole‐sporozoite pre‐erythrocytic vaccines against malaria

“…IFN- ELISpot or IFN-/TNF-/IL-2 detection through ICS (see below) [37,39,52,55]. Resting of PBMCs after thawing and before assessment of T cell phenotype or function is thus favored, and is often performed for the evaluation of cellular responses in Wsp PE malaria vaccines clinical trials [18,30,[56][57][58][59].…”

“…A comprehensive analysis of antigen-specific cellular responses after vaccination is essential to understand the potency and efficacy of vaccine candidates, and may contribute to the identification of immune correlates of protection [18,30,56,90,91]. In contrast to the thorough investigation of lymphoid and non-lymphoid tissue-associated cellular responses that is possible in animal model studies, human T cell function is largely assessed through peripheral blood collection.…”

“…The evaluation of Wsp PE vaccine-induced immunogenicity involves the culture of volunteers' PBMCs with stimuli associated with the different stages of the Plasmodium parasite's life cycle (Table 3). These stimuli vary in complexity, and may include recombinant proteins or peptides (individual or pooled) [12,18,46,56,58,60], homologous [9,10,12,18,30,44,46,57,58,60,[63][64][65]73,74,94] or heterologous [65] sporozoites, and homologous [14,20,30,[44][45][46][47]57,64,73,74,93,95] or heterologous [20,47] Plasmodiuminfected red blood cells (RBCs). Sporozoites and infected RBCs can be purified and cryopreserved prior to use in the in vitro assays (see references in Table 3).…”

The host targeting effect of chloroquine in malaria

“…However, chloroquine has been used as an autophagy inhibitor in experimental studies investigating host autophagy in hepatocytes during sporozoite development [ 36 ]. On the other hand, the protection against Plasmodium parasites has been shown in animal and human experimental studies when individuals are immunized with infectious sporozoites under the cover of chloroquine chemoprophylaxis [ 37 •• , 38 , 39 • ]. Although the role of chloroquine in these studies was to suppress following blood stage parasites, whether chloroquine induces autophagy inhibition or exerts an immunomodulatory effect has not been elucidated.…”