{"paper_id":"30d6fda2-8d44-46bc-ae9d-7112c446177e","body_text":"Immature dendritic cell-targeting mRNA vaccine expressing PfCSP enhances protective immune responses against Plasmodium liver infection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Immature dendritic cell-targeting mRNA vaccine expressing PfCSP enhances protective immune responses against Plasmodium liver infection Prakash Srinivasan, Sean Yanik, Varsha Venkatesh, James Gordy, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4656309/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2025 Read the published version in npj Vaccines → Version 1 posted 10 You are reading this latest preprint version Abstract Resurgence in malaria has been noted in 2022 with 249 million clinical cases resulting in 608,000 deaths, mostly in children under five. Two vaccines, RTS, S, and more recently R21, targeting the circumsporozoite protein (CSP) are recommended by the WHO but are not yet widely available. Strong humoral responses to neutralize sporozoites before they can infect the hepatocytes are important for vaccine-mediated protection. Suboptimal protection conferred by these first-generation vaccines highlight the need for approaches to improve vaccine-induced immune responses. With the recent success of mRNA-LNP vaccines against COVID-19, there is growing interest in leveraging this approach to enhance malaria vaccines. Here, we present the development of a novel chemokine fusion mRNA vaccine aimed at boosting immune responses to PfCSP by targeting the immunogen to immature dendritic cells (iDC). Vaccination of mice with mRNA encoding full-length CSP fused to macrophage inflammatory protein 3 alpha (MIP3α) encapsulated within lipid nanoparticles (LNP) elicited robust CD4 + T cell responses and enhanced antibody titers against NANP repeat epitopes compared to a conventional CSP mRNA-LNP vaccine. Importantly, the CSP-MIP3α fusion vaccine provided significantly greater protection against liver infection upon challenge with P. berghei PfCSP transgenic sporozoites. This enhanced protection was associated with multifunctional CD4 + T cells levels and anti-NANP repeat titers. This study highlights the potential to augment immune responses to PfCSP through iDC targeting and bolster protection against malaria liver infection. Biological sciences/Microbiology Biological sciences/Microbiology/Vaccines/RNA vaccines Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Additional Declarations Competing interests : D.W. is named on a patent for a vaccine platform using nucleoside-modified mRNA in lipid nanoparticles. Y.T. is an employee of Acuitas Therapeutics, a company developing mRNA-LNP therapeutics. D.W. and M.-G.A. are named on patents describing lipid nanoparticles for delivering nucleic acid therapeutics, including mRNA, and the use of modified mRNA in lipid nanoparticles as a vaccine platform. RBM and JG have equity interests in a company involved in the development of a malaria vaccine. The other authors declare no competing interests . Supplementary Files YaniketalSupplementarydata.pdf Supplementary figure and figure legends Cite Share Download PDF Status: Published Journal Publication published 19 Feb, 2025 Read the published version in npj Vaccines → Version 1 posted Editorial decision: revise 30 Sep, 2024 Review # 2 received at journal 28 Sep, 2024 Reviewer # 2 agreed at journal 27 Sep, 2024 Review # 1 received at journal 29 Aug, 2024 Reviewer # 1 agreed at journal 19 Aug, 2024 Reviewers invited by journal 27 Jul, 2024 Editor assigned by journal 16 Jul, 2024 Submission checks completed at journal 05 Jul, 2024 First submitted to journal 03 Jul, 2024 Unknown event 03 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4656309\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":323306795,\"identity\":\"a75f26ca-e723-46f5-8d4e-c19bc1db05a7\",\"order_by\":0,\"name\":\"Prakash Srinivasan\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIie3OMQrCMBSA4RcCTsGscfAOkUJrqfQslUK7dnRwyOQZcoyCF4gEMqW6dvUGgquIREFwStwE809veN/jAcRiP5oCDiUF62YcTuqZ+Ia4UK9IIMnocNZdp3FyGAyDTbEWPpLLlmvJ9TRVx4aBbf2EjxPQhDc4VTZlaKcDyMk8CdoLR+4hRDWOrFAPjogAkssXqZmyybIybeIlGTX4Sm6spNIuxsu2mPsfe09MAVS+9U9CvedjsVjsX3sAaJg9qrNmyyMAAAAASUVORK5CYII=\",\"orcid\":\"https://orcid.org/0009-0007-8370-0553\",\"institution\":\"Johns Hopkins Bloomberg School of Public Health\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Prakash\",\"middleName\":\"\",\"lastName\":\"Srinivasan\",\"suffix\":\"\"},{\"id\":323306796,\"identity\":\"16a1a150-59d5-412c-8e77-d12cc43aafd4\",\"order_by\":1,\"name\":\"Sean Yanik\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Johns Hopkins 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Alameh\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-5672-6930\",\"institution\":\"University of Pennsylvania\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mohamad-Gabriel\",\"middleName\":\"\",\"lastName\":\"Alameh\",\"suffix\":\"\"},{\"id\":323306800,\"identity\":\"ea6671c6-b3d2-4fad-9594-0613f1214352\",\"order_by\":5,\"name\":\"Jacob Meza\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Johns Hopkins School of Public Health\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jacob\",\"middleName\":\"\",\"lastName\":\"Meza\",\"suffix\":\"\"},{\"id\":323306801,\"identity\":\"b7eda98b-552c-4b6f-a536-6c4cfc642620\",\"order_by\":6,\"name\":\"Yangchen Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Johns Hopkins School of Public 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Tam\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0002-4083-5251\",\"institution\":\"Acuitas Therapeutics\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ying\",\"middleName\":\"\",\"lastName\":\"Tam\",\"suffix\":\"\"},{\"id\":323306805,\"identity\":\"f271a5d6-bbd4-4d17-95d4-9d02c660c39d\",\"order_by\":10,\"name\":\"Nattawat Chaiyawong\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Johns Hopkins School of Public Health\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Nattawat\",\"middleName\":\"\",\"lastName\":\"Chaiyawong\",\"suffix\":\"\"},{\"id\":323306806,\"identity\":\"5f826cba-3f11-4361-9d81-2075e9158978\",\"order_by\":11,\"name\":\"Deepti Sarkar\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Johns Hopkins University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Deepti\",\"middleName\":\"\",\"lastName\":\"Sarkar\",\"suffix\":\"\"},{\"id\":323306807,\"identity\":\"7dc074fa-49ad-4f16-9a87-0ea2dd614c1e\",\"order_by\":12,\"name\":\"Drew Weissman\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Pennsylvania\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Drew\",\"middleName\":\"\",\"lastName\":\"Weissman\",\"suffix\":\"\"},{\"id\":323306808,\"identity\":\"85dfc0f0-1f75-4035-9974-c43811e24ef1\",\"order_by\":13,\"name\":\"Richard Markham\",\"email\":\"\",\"orcid\":\"https://orcid.org/0000-0003-3527-9147\",\"institution\":\"Johns Hopkins Bloomberg School of Public Health\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Richard\",\"middleName\":\"\",\"lastName\":\"Markham\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-06-28 18:05:07\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-4656309/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4656309/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1038/s41541-025-01089-x\",\"type\":\"published\",\"date\":\"2025-02-19T05:00:00+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":59948469,\"identity\":\"eaaeb8d5-789d-4d2a-8328-604d3325b822\",\"added_by\":\"auto\",\"created_at\":\"2024-07-09 16:38:18\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":132236,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eAntibody responses and protection from liver stage infection following standard 3-dose mRNA vaccination. (A) Design of CSP and MIP3a-CSP constructs. Representations of protein sequences for full length CSP, the MIP3a -CSP construct, and the CSP construct used in the approved RTS,S vaccine are shown. Both CSP and MIP3a-CSP sequences contain the CSP C-terminal domain containing important T cell epitopes, CSP junctional region, and central repeat region of CSP with 1/4/38 copies of NPDP/NVDP/NANP respectively. For comparison, the RTS,S construct contains 0/0/19 copies of NPDP/NVDP/NANP respectively. In the MIP3a-CSP construct, the human MIP3a gene was fused to the N-terminus of 3D7 PfCSP gene via a 14 amino acid linker sequence. The tPA signal sequence is located at the N terminus of the MIP3a gene in this construct. (B) In the first challenge study, C57BL/6J mice (n=5/grp) were immunized 3x at two-week intervals with 10ug MIP3a-CSP LNP-mRNA or CSP LNP-mRNA. Two weeks after the 3rd immunization, vaccinated and naïve mice were challenged with 3000 Pb PfCSP-luc intravenously delivered sporozoites. Forty-two h after infection, parasite liver loads, measured by luminescence, were captured. (C-D) Full length recombinant CSP specific (C) and NANP6 peptide specific (D) antibody titers in mouse serum are shown. Endpoint titers (OD450 = 1) were used to quantify antibody titers for both groups. Data points are individual mice (n = 5) performed in duplicate, with horizontal lines representing mean values. Ordinary one-way ANOVAs with Tukey’s test for multiple comparisons were performed to compare differences between groups. (E) Titer ratios of anti-full length CSP antibodies to anti-NANP6 antibodies are shown, with horizontal lines representing mean values. An ordinary one-way ANOVA with Tukey’s test for multiple comparisons was performed to compare differences between groups. (F) NANP specific 27 avidity indices are shown for antibodies from CSP and MIP3a-CSP groups. Dots represent avidity indices of individual mice. The avidity index was calculated using the following equation ((OD 1 titer in chaotropic agent)/(OD 1 titer in PBS)*100). A two-tailed unpaired t test was performed to determine p values. Bars represent mean \\u003cstrong\\u003e±\\u003c/strong\\u003e SEM. (G) Luminescence values for each mouse in naïve, CSP and MIP3a-CSP groups were calculated in photons/sec, with horizontal lines representing group means. An ordinary one-way ANOVA with Tukey’s test for multiple comparisons was performed to compare differences between groups. (H) Percent inhibition of liver infection was calculated relative to naïve, sporozoite challenged mice. Data is again shown for individual animals, with horizontal lines representing mean values. A two-tailed unpaired t test was used to compare groups.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Screenshot20240709122239.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4656309/v1/d259ff8d5e27009b8c529e42.png\"},{\"id\":59948468,\"identity\":\"ffd4ae89-9e06-4ecc-bfe9-a35b125af565\",\"added_by\":\"auto\",\"created_at\":\"2024-07-09 16:38:18\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":179409,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eT cell responss in mice following mRNA dose de-escalation and delayed boosting. (A) C57BL/6J mice (n=7/grp) were immunized 3x with 25μg, 15μg, and finally 5μg of MIP3a-CSP LNP-mRNA or CSP LNP-mRNA. In this delayed dosing experiment, the 2nd and 3rd immunizations occurred 2 and 8 weeks after the first immunization respectively. Splenocytes were harvested from each mouse 42h after challenge for usage in T cell stimulation assays. (B-C) Cells were stained, run on flow cytometry, and gated for CD4+ (B) or CD8+ (C) T cells. Median fluorescence intensities of CD4+ IFNγ+ (B) and CD8+ IFNγ+ (C) T cells are shown (left). The percentage of IFN-γ+ cells among CD4+ cells (B) and CD8+ cells (C) are also shown (right). Horizontal lines indicate group means. Ordinary one-way ANOVAs with Tukey’s test for multiple comparisons were performed to compare differences between groups. (D-E) Cells were stained, run on flow cytometry, and gated for CD4+ T cells. Median fluorescence intensities of CD4+ TNFa+ cells (D) and CD4+ IL2+ cells (E) are shown (left). The percentage of TNFa+ (D) or IL2+ cells (E) among CD4+ cells are also shown (right). Horizontal lines indicate group means. Ordinary one-way ANOVAs with Tukey’s test for 28 multiple comparisons were performed to compare differences between groups. (F-G) The percentage of CD4+ or CD8+ (G) T cells that were IFNγ, TNFa, and IL-2 triple positive (left axis) or IFNγ, TNFa double positive are shown (right axis). Horizontal lines indicate group means. Ordinary one-way ANOVAs with Tukey’s test for multiple comparisons were performed to compare differences between groups.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Screenshot20240709122317.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4656309/v1/43d70a61a5a3014a3942c437.png\"},{\"id\":59948470,\"identity\":\"26f6a0a6-84f8-47aa-9963-fb9bcfd7f32f\",\"added_by\":\"auto\",\"created_at\":\"2024-07-09 16:38:18\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":125689,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eAntibody responses and protection from liver stage infection following mRNA dose de-escalation and delayed boosting. (A) Full length recombinant CSP antibody titer in mice sera. (B) NANP6 peptide-specific antibody titer in mousesera. Endpoint titers (OD450 = 1) were used to quantify antibody titers for both groups. Data points are individual mice (n = 7) performed in duplicate, with horizontal lines representing mean values. Two-tailed unpaired t tests were performed to compare differences between groups. (C) Titer ratios of anti-full length CSP antibodies to anti-NANP6 antibodies are shown, with horizontal lines representing mean values. A two-tailed unpaired t test was performed to compare differences between groups. Data is shown as mean \\u003cstrong\\u003e±\\u003c/strong\\u003e SEM with individual points representing individual mice performed in duplicate. (D-E) Full length recombinant CSP specific (D) and NANP6 peptide specific (E) avidity indices are shown for antibodies from CSP and MIP3a-CSP vaccinated mice. Dots represent avidity indices of individual mice performed in duplicate. The avidity index was calculated using the following equation ((OD 1 titer in chaotropic agent)/(OD 1 titer in PBS)*100). Two-tailed unpaired t tests were performed to determine p values. Bars represent mean \\u003cstrong\\u003e±\\u003c/strong\\u003e SEM. (F) The IgG1/(IgG2a+IgG2c) ratio of CSPFL specific and NANP6 specific antibodies in CSP and MIP3a-CSP LNP-mRNA vaccinated groups are shown. P values were calculated using two-tailed unpaired t tests. Dots represent the ratio of antibody isotypes of individual mice performed in duplicate, and horizontal bars represent mean values of each group. (G) Luminescence values for each mouse in naïve, CSP and MIP3a-CSP 29 groups were calculated in photons/sec, with horizontal lines representing group means. An ordinary one-way ANOVA with Tukey’s test for multiple comparisons was performed to compare differences between groups. (H) Percent inhibition of liver infection was calculated relative to naïve, sporozoite challenged mice. Data is again shown for individual animals, with horizontal lines representing mean values. A two-tailed unpaired t test was used to compare groups.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Screenshot20240709122330.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4656309/v1/76e8eee3b62da10fede1a0a0.png\"},{\"id\":59948471,\"identity\":\"f1c3fa12-72af-4f95-8c0f-2a8bdf36d0c0\",\"added_by\":\"auto\",\"created_at\":\"2024-07-09 16:38:18\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":92410,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eImmunological Correlates of Protection. (A) Relationship between log10 NANP6 peptide antibody titers (y-axis) and % inhibition of liver stage parasitemia relative to naïve, sporozoite challenged mice (x-axis). Unfilled and filled symbols represent single mice from challenge studies 1 and 2 (standard regimen and delayed, dose de-escalation regimen) respectively. Squares represent mice from the MIP3a-CSP LNP-mRNA vaccinated group, circles represent mice from the CSP LNP-mRNA vaccinated group, and triangles represent mice from the rCSPFL vaccinated group. P values were calculated using Spearman’s ranked correlation coefficient. (B-D) Relationship between inhibition of liver stage parasitemia (x-axis) and the percentage of IFNγ+ cells among CD4+ cells (B), the percentage of IFNγ, TNFa, and IL-2 triple positive cells among CD4+ cells (C), and the percentage of IFNγ, TNFa, and IL-2 triple positive CD8+ cells (D). Circles represent mice from the CSP vaccinated group, and squares represent mice from the MIP3a-CSP vaccinated group. P values were calculated using\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Screenshot20240709122339.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4656309/v1/f1eb80bcad68376d98cfc067.png\"},{\"id\":76740658,\"identity\":\"629a32dd-403c-4b1c-9160-aecbf42cf52e\",\"added_by\":\"auto\",\"created_at\":\"2025-02-20 08:15:47\",\"extension\":\"pdf\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":793246,\"visible\":true,\"origin\":\"\",\"legend\":\"Article File\",\"description\":\"\",\"filename\":\"Yaniketalmanuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4656309/v1_covered_1d24c4df-5a52-4a87-8b2b-94432efa0d15.pdf\"},{\"id\":59948472,\"identity\":\"d56a81c8-4e40-46d2-96f1-5d38a8c8f102\",\"added_by\":\"auto\",\"created_at\":\"2024-07-09 16:38:18\",\"extension\":\"pdf\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":419180,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSupplementary figure and figure legends\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"YaniketalSupplementarydata.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4656309/v1/6eb4e537c0049b8ffb4c8052.pdf\"}],\"financialInterests\":\"\\u003cp\\u003e\\u003cem\\u003eCompeting interests\\u003c/em\\u003e: D.W. is named on a patent for a \\u003cem\\u003evaccine\\u003c/em\\u003e platform using nucleoside-modified mRNA in lipid nanoparticles. Y.T. is an employee of Acuitas Therapeutics, a company developing mRNA-LNP therapeutics. D.W. and M.-G.A. are named on patents describing lipid nanoparticles for delivering nucleic acid therapeutics, including mRNA, and the use of modified mRNA in lipid nanoparticles as a \\u003cem\\u003evaccine\\u003c/em\\u003e platform. RBM and JG have equity interests in a company involved in the development of a malaria \\u003cem\\u003evaccine.\\u003c/em\\u003e The other authors declare no \\u003cem\\u003ecompeting interests\\u003c/em\\u003e.\\u003c/p\\u003e\",\"formattedTitle\":\"Immature dendritic cell-targeting mRNA vaccine expressing PfCSP enhances protective immune responses against Plasmodium liver infection\",\"fulltext\":[],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":false,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":true,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":true,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"npj-vaccines\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"npjvaccines\",\"sideBox\":\"Learn more about [npj Vaccines](http://www.nature.com/npjvaccines/)\",\"snPcode\":\"41541\",\"submissionUrl\":\"https://submission.springernature.com/new-submission/41541/3?\",\"title\":\"npj Vaccines\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"NPJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4656309/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4656309/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eResurgence in malaria has been noted in 2022 with 249\\u0026nbsp;million clinical cases resulting in 608,000 deaths, mostly in children under five. Two vaccines, RTS, S, and more recently R21, targeting the circumsporozoite protein (CSP) are recommended by the WHO but are not yet widely available. Strong humoral responses to neutralize sporozoites before they can infect the hepatocytes are important for vaccine-mediated protection. Suboptimal protection conferred by these first-generation vaccines highlight the need for approaches to improve vaccine-induced immune responses. With the recent success of mRNA-LNP vaccines against COVID-19, there is growing interest in leveraging this approach to enhance malaria vaccines. Here, we present the development of a novel chemokine fusion mRNA vaccine aimed at boosting immune responses to PfCSP by targeting the immunogen to immature dendritic cells (iDC). Vaccination of mice with mRNA encoding full-length CSP fused to macrophage inflammatory protein 3 alpha (MIP3α) encapsulated within lipid nanoparticles (LNP) elicited robust CD4\\u0026thinsp;+\\u0026thinsp;T cell responses and enhanced antibody titers against NANP repeat epitopes compared to a conventional CSP mRNA-LNP vaccine. Importantly, the CSP-MIP3α fusion vaccine provided significantly greater protection against liver infection upon challenge with \\u003cem\\u003eP. berghei\\u003c/em\\u003e PfCSP transgenic sporozoites. This enhanced protection was associated with multifunctional CD4\\u0026thinsp;+\\u0026thinsp;T cells levels and anti-NANP repeat titers. This study highlights the potential to augment immune responses to PfCSP through iDC targeting and bolster protection against malaria liver infection.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Immature dendritic cell-targeting mRNA vaccine expressing PfCSP enhances protective immune responses against Plasmodium liver infection\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-07-09 16:38:13\",\"doi\":\"10.21203/rs.3.rs-4656309/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"revise\",\"date\":\"2024-09-30T08:04:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"This content is not available.\",\"date\":\"2024-09-28T14:24:29+00:00\",\"index\":2,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2024-09-27T07:15:55+00:00\",\"index\":2,\"fulltext\":\"This content is not available.\"},{\"type\":\"editorInvitedReview\",\"content\":\"This content is not available.\",\"date\":\"2024-08-29T19:56:17+00:00\",\"index\":1,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2024-08-19T18:53:21+00:00\",\"index\":1,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-07-28T00:43:58+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-07-17T00:58:57+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-07-05T19:47:59+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"npj Vaccines\",\"date\":\"2024-07-03T17:22:40+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksFailed\",\"content\":\"\",\"date\":\"2024-07-03T15:15:46+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"npj-vaccines\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"npjvaccines\",\"sideBox\":\"Learn more about [npj Vaccines](http://www.nature.com/npjvaccines/)\",\"snPcode\":\"41541\",\"submissionUrl\":\"https://submission.springernature.com/new-submission/41541/3?\",\"title\":\"npj Vaccines\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"NPJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"42f876ff-05b9-441c-be36-2eca6c320f54\",\"owner\":[],\"postedDate\":\"July 9th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":34196228,\"name\":\"Biological sciences/Microbiology\"},{\"id\":34196229,\"name\":\"Biological sciences/Microbiology/Vaccines/RNA vaccines\"}],\"tags\":[],\"updatedAt\":\"2025-02-20T08:15:40+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-4656309\",\"link\":\"https://doi.org/10.1038/s41541-025-01089-x\",\"journal\":{\"identity\":\"npj-vaccines\",\"isVorOnly\":false,\"title\":\"npj Vaccines\"},\"publishedOn\":\"2025-02-19 05:00:00\",\"publishedOnDateReadable\":\"February 19th, 2025\"},\"versionCreatedAt\":\"2024-07-09 16:38:13\",\"video\":\"\",\"vorDoi\":\"10.1038/s41541-025-01089-x\",\"vorDoiUrl\":\"https://doi.org/10.1038/s41541-025-01089-x\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4656309\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4656309\",\"identity\":\"rs-4656309\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}