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The development of effective and long-lasting malaria vaccines remains a key goal. Late-arresting genetically attenuated sporozoite (LA-GAP SPZ) vaccines, such as Pf∆mei2 (GA2), have shown strong protective potential. While GA2 delivered via mosquito bites has demonstrated up to 90% protection in humans, practical vaccine deployment will require alternative administration routes. Intravenous (IV) delivery of whole SPZ vaccines has been highly effective, but intradermal (ID) administration though easier, offers significantly reduced protection, with unclear underlying mechanisms. In this study, we used a Plasmodium berghei GA2 SPZ rodent model to compare immune responses following ID and IV immunization across multiple organs. ID immunization resulted in lower frequencies of CD8⁺ tissue-resident memory T cells (Trm) in the spleen (1.3%, p = 0.3), lungs (8.1%, p = 0.005) and liver (2.5%, p = 0.07), along with reduced activation markers (Granzyme A, Ki67, and KLRG1). In the liver, Granzyme B (p = < 0.0001) and perforin (p = < 0.0001) were significantly decreased after ID immunization, indicating diminished cytotoxic potential. Importantly, ID immunization induced a regulatory myeloid phenotype in the skin and skin-draining lymph nodes, marked by low CD86 and high PD-L1 expression, potentially impairing T cell priming. A similar regulatory profile in the liver suggests systemic immunosuppression. These findings highlight key immunological differences between ID and IV GA2 SPZ delivery and suggest that optimizing ID administration, such as adjusting injection volume to enhance sporozoite migration, may improve efficacy. Understanding how myeloid regulation and T-cell activation vary across organs is essential for enhancing malaria vaccine strategies.

Background Sporozoites (SPZ), the infective form of Plasmodium falciparum malaria, can be inoculated into the human host skin by Anopheline mosquitoes. These SPZ migrate at approximately 1 µm/s to find a blood vessel and travel to the liver where they infect hepatocytes and multiply. In the skin they are still low in number (50–100 SPZ) and vulnerable to immune attack by antibodies and skin macrophages. This is why whole SPZ and SPZ proteins are used as the basis for most malaria vaccines currently deployed and undergoing late clinical testing. Mosquitoes typically inoculate SPZ into a human host between 14 and 25 days after their previous infective blood meal. However, it is unknown whether residing time within the mosquito affects SPZ condition, infectivity or immunogenicity. This study aimed to unravel how the age of P . falciparum SPZ in salivary glands (14, 17, or 20 days post blood meal) affects their infectivity and the ensuing immune responses. Methods SPZ numbers, viability by live/dead staining, motility using dedicated sporozoite motility orienting and organizing tool software (SMOOT), and infectivity of HC-04.j7 liver cells at 14, 17 and 20 days after mosquito feeding have been investigated. In vitro co-culture assays with SPZ stimulated monocyte-derived macrophages (MoMɸ) and CD8 + T-cells, analysed by flow cytometry, were used to investigate immune responses. Results SPZ age did not result in different SPZ numbers or viability. However, a markedly different motility pattern, whereby motility decreased from 89% at day 14 to 80% at day 17 and 71% at day 20 was observed (p ≤ 0.0001). Similarly, infectivity of day 20 SPZ dropped to ~ 50% compared with day 14 SPZ (p = 0.004). MoMɸ were better able to take up day 14 SPZ than day 20 SPZ (from 7.6% to 4.1%, p = 0.03) and displayed an increased expression of pro-inflammatory CD80, IL-6 (p = 0.005), regulatory markers PDL1 (p = 0.02), IL-10 (p = 0.009) and cytokines upon phagocytosis of younger SPZ. Interestingly, co-culture of these cells with CD8 + T-cells revealed a decreased expression of activation marker CD137 and cytokine IFNγ compared to their day 20 counterparts. These findings suggest that older (day 17–20) P . falciparum SPZ are less infectious and have decreased immune regulatory potential. Conclusion Overall, this data is a first step in enhancing the understanding of how mosquito residing time affects P . falciparum SPZ and could impact the understanding of the P . falciparum infectious reservoir and the potency of whole SPZ vaccines.

Professional antigen-presenting cells (APCs), like macrophages (M[PHI]s) and dendritic cells (DCs), are central players in the induction of natural and vaccine-induced immunity to malaria, yet very little is known about the interaction of SPZ with human APCs. Intradermal delivery of whole-sporozoite vaccines reduces their effectivity, possibly due to dermal immunoregulatory effects. Therefore, understanding these interactions could prove pivotal to malaria vaccination. We investigated human APC responses to recombinant circumsporozoite protein (recCSP), SPZ and anti-CSP opsonized SPZ both in monocyte derived MoDCs and MoM[PHI]s. Both MoDCs and MoM[PHI]s readily took up recCSP but did not change phenotype or function upon doing so. SPZ are preferentially phagocytosed by MoM[PHI]s instead of DCs and phagocytosis greatly increased after opsonization. Subsequently MoM[PHI]s show increased surface marker expression of activation markers as well as tolerogenic markers such as Programmed Death-Ligand 1 (PD-L1). Additionally they show reduced motility, produce interleukin 10 and suppressed interferon gamma (IFN[gamma]) production by antigen specific CD8.sup.+ T cells. Importantly, we investigated phenotypic responses to SPZ in primary dermal APCs isolated from human skin explants, which respond similarly to their monocyte-derived counterparts. These findings are a first step in enhancing our understanding of pre-erythrocytic natural immunity and the pitfalls of intradermal vaccination-induced immunity.

Latent infection with cytomegalovirus (CMV) is assumed to contribute to the age-associated decline of the immune system. CMV induces large changes in the T-cell pool and may thereby affect other immune responses. CMV is expected to impact especially older adults, who are already at higher risk of severe disease and hospitalization upon infections such as influenza virus (IAV) infection. Here, we investigated the impact of CMV infection on IAV-specific CD8 + T-cell frequencies in healthy individuals (n=96) and the response to IAV infection in older adults (n=72). IAV-specific memory T-cell frequencies were lower in healthy CMV + older individuals compared to healthy CMV - older individuals. Upon acute IAV infection, CMV serostatus or CMV-specific antibody levels were not negatively associated with IAV-specific T-cell frequencies, function, phenotype or T-cell receptor repertoire diversity. This suggests that specific T-cell responses upon acute IAV infection are not negatively affected by CMV. In addition, we found neither an association between CMV infection and inflammatory cytokine levels in serum during acute IAV infection nor between cytokine levels and the height of the IAV-specific T-cell response upon infection. Finally, CMV infection was not associated with increased severity of influenza-related symptoms. In fact, CMV infection was even associated with increased IAV-specific T-cell responses early upon acute IAV infection. In conclusion, although associated with lower frequencies of memory IAV-specific T cells in healthy individuals, CMV infection does not seem to hamper the induction of a proper T-cell response during acute IAV infection in older adults.

Despite promising results in malaria-naïve individuals, whole sporozoite (SPZ) vaccine efficacy in malaria-endemic settings has been suboptimal. Vaccine hypo-responsiveness due to previous malaria exposure has been posited as responsible, indicating the need for SPZ vaccines of increased immunogenicity. To this end, we here demonstrate a proof-of-concept for altering SPZ immunogenicity, where supramolecular chemistry enables chemical augmentation of the parasite surface with a TLR7 agonist-based adjuvant (SPZ-SAS(CL307)). In vitro , SPZ-SAS(CL307) remained well recognized by immune cells and induced a 35-fold increase in the production of pro-inflammatory IL-6 (p < 0.001). More promisingly, immunization of mice with SPZ-SAS(CL307) yielded improved SPZ-specific IFN-γ production in liver-derived NK cells (percentage IFN-γ + cells 11.1 ± 1.8 vs. 9.4 ± 1.5%, p < 0.05), CD4 + T cells (4.7 ± 4.3 vs. 1.8 ± 0.7%, p < 0.05) and CD8 + T cells (3.6 ± 1.4 vs. 2.5 ± 0.9%, p < 0.05). These findings demonstrate the potential of using chemical augmentation strategies to enhance the immunogenicity of SPZ-based malaria vaccines.

Abstract Background Travellers infected with Schistosoma spp. might be pauci- or even asymptomatic on first presentation. Therefore, schistosomiasis may remain undiagnosed in this population. Active infection, as evidenced by the presence of the tissue-dwelling worm, can be demonstrated via the detection of adult worm-derived circulating anodic antigen (CAA) utilising a robust well-described lateral flow-(LF) based test applying background-free up-converting reporter particles (UCP). In this prospective study, we assessed the diagnostic value of serum and urine UCP-LF CAA test in comparison with two Schistosoma-specific serological assays detecting antibodies against adult worm antigen-immuno fluorescence assay (AWA-IFA) and against soluble egg antigen–enzyme-linked immunosorbent assay (SEA-ELISA) antigens in travellers. Methods Samples were collected from 106 Dutch travellers who reported freshwater contact in sub-Saharan Africa and who were recruited up to 2 years after return. Subjects were asked to complete a detailed questionnaire on travel history, water contact, signs and symptoms compatible with schistosomiasis. Results Two travellers were positive by serum CAA and an additional one by urine CAA. A total of 22/106 (21%) samples were antibody positive by AWA-IFA and 9/106 (9%) by SEA-ELISA. At follow-up 6 weeks and 6 months after praziquantel treatment, all seropositives remained antibody positive whereas CAA was cleared. Seropositivity could not be predicted by the type of fresh water-related activity, country visited or symptoms reported. Conclusion The low number of UCP-LF CAA positives suggests that in travellers, active infections often do not establish or have very low worm burden. Based on our high seroconversion rates, we conclude that the AWA-IFA assay is the most sensitive test to detect schistosome exposure. Given the lack of predictive symptoms or risk factors, we recommend schistosomiasis screening at least by serology in all travellers with reported freshwater contact in high-endemic areas.

Chimeric rodent malaria parasites with the endogenous circumsporozoite protein ( csp ) gene replaced with csp from the human parasites Plasmodium falciparum ( Pf ) and P. vivax ( Pv ) are used in preclinical evaluation of CSP vaccines. Chimeric rodent parasites expressing Pf CSP have also been assessed as whole sporozoite (WSP) vaccines. Comparable chimeric P. falciparum parasites expressing CSP of P. vivax could be used both for clinical evaluation of vaccines targeting Pv CSP in controlled human P. falciparum infections and in WSP vaccines targeting P. vivax and P. falciparum . We generated chimeric P. falciparum parasites expressing both Pf CSP and Pv CSP. These Pf - Pv CSP parasites produced sporozoite comparable to wild type P. falciparum parasites and expressed Pf CSP and Pv CSP on the sporozoite surface. Pf - Pv CSP sporozoites infected human hepatocytes and induced antibodies to the repeats of both Pf CSP and Pv CSP after immunization of mice. These results support the use of Pf - Pv CSP sporozoites in studies optimizing vaccines targeting Pv CSP.

Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose–exposure–response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoites in malaria-naive, healthy volunteers. This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study performed in Leiden, Netherlands. Malaria-naive, healthy adults aged 18–45 years were divided into five cohorts and randomly assigned (3:1) to receive cabamiquine or placebo. Randomisation was done by an independent statistician using codes in a permuted block schedule with a block size of four. Participants, investigators, and study personnel were masked to treatment allocation. A single, oral dose regimen of cabamiquine (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 h (early liver-stage) or 96 h (late liver-stage) after DVI. The primary endpoints based on a per-protocol analysis set were the number of participants who developed parasitaemia within 28 days of DVI, time to parasitaemia, number of participants with documented parasite blood-stage growth, clinical symptoms of malaria, and exposure–efficacy modelling. The impact of cabamiquine on liver stages was evaluated indirectly by the appearance of parasitaemia in the blood. The Clopper–Pearson CI (nominal 95%) was used to express the protection rate. The secondary outcomes were safety and tolerability, assessed in those who had received DVI and were administered one dose of the study intervention. The trial was prospectively registered on ClinicalTrials.gov (NCT04250363). Between Feb 17, 2020 and April 29, 2021, 39 healthy participants were enrolled (early liver-stage: 30 mg [n=3], 60 mg [n=6], 80 mg [n=6], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=6]; late liver-stage: 60 mg [n=3], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=3]). A dose-dependent causal chemoprophylactic effect was observed, with four (67%) of six participants in the 60 mg, five (83%) of six participants in the 80 mg, and all three participants in the 100 and 200 mg cabamiquine dose groups protected from parasitaemia up to study day 28, whereas all participants in the pooled placebo and 30 mg cabamiquine dose group developed parasitaemia. A single, oral dose of 100 mg cabamiquine or higher provided 100% protection against parasitaemia when administered during early or late liver-stage malaria. The median time to parasitaemia in those with early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of cabamiquine, respectively, compared with 10 days for the pooled placebo. All participants with positive parasitaemia showed documented blood-stage parasite growth, apart from one participant in the pooled placebo group and one participant in the 30 mg cabamiquine group. Most participants did not exhibit any malaria symptoms in both the early and late liver-stage groups, and those reported were mild in severity. A positive dose–exposure–efficacy relationship was established across exposure metrics. The median maximum concentration time was 1–6 h, with a secondary peak observed between 6 h and 12 h in all cabamiquine dose groups (early liver-stage). All cabamiquine doses were safe and well tolerated. Overall, 26 (96%) of 27 participants in the early liver-stage group and ten (83·3%) of 12 participants in the late liver-stage group reported at least one treatment-emergent adverse event (TEAE) with cabamiquine or placebo. Most TEAEs were of mild severity, transient, and resolved without sequelae. The most frequently reported cabamiquine-related TEAE was headache. No dose-related trends were observed in the incidence, severity, or causality of TEAEs. The results from this study show that cabamiquine has a dose-dependent causal chemoprophylactic activity. Together with previously demonstrated activity against the blood stages combined with a half-life of more than 150 h, these results indicate that cabamiquine could be developed as a single-dose monthly regimen for malaria prevention. The healthcare business of Merck KGaA, Darmstadt, Germany.

The development of effective and long-lasting malaria vaccines remains a key goal. Late-arresting genetically attenuated sporozoite (LA-GAP SPZ) vaccines, such as Pf∆mei2 (GA2), have shown strong protective potential. While GA2 delivered via mosquito bites has demonstrated up to 90% protection in humans, practical vaccine deployment will require alternative administration routes. Intravenous (IV) delivery of whole SPZ vaccines has been highly effective, but intradermal (ID) administration though easier, offers significantly reduced protection, with unclear underlying mechanisms. In this study, we used a Plasmodium berghei GA2 SPZ rodent model to compare immune responses following ID and IV immunization across multiple organs. ID immunization resulted in lower frequencies of CD8⁺ tissue-resident memory T cells (Trm) in the spleen (1.3%, p = 0.3), lungs (8.1%, p = 0.005) and liver (2.5%, p = 0.07), along with reduced activation markers (Granzyme A, Ki67, and KLRG1). In the liver, Granzyme B (p = < 0.0001) and perforin (p = < 0.0001) were significantly decreased after ID immunization, indicating diminished cytotoxic potential. Importantly, ID immunization induced a regulatory myeloid phenotype in the skin and skin-draining lymph nodes, marked by low CD86 and high PD-L1 expression, potentially impairing T cell priming. A similar regulatory profile in the liver suggests systemic immunosuppression. These findings highlight key immunological differences between ID and IV GA2 SPZ delivery and suggest that optimizing ID administration, such as adjusting injection volume to enhance sporozoite migration, may improve efficacy. Understanding how myeloid regulation and T-cell activation vary across organs is essential for enhancing malaria vaccine strategies.