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  1. Article ; Online: Emulsion and liposome-based adjuvanted R21 vaccine formulations mediate protection against malaria through distinct immune mechanisms.

    Reinke, Sören / Pantazi, Eirini / Chappell, Gabrielle R / Sanchez-Martinez, Alexandra / Guyon, Romain / Fergusson, Joannah R / Salman, Ahmed M / Aktar, Anjum / Mukhopadhyay, Ekta / Ventura, Roland A / Auderset, Floriane / Dubois, Patrice M / Collin, Nicolas / Hill, Adrian V S / Bezbradica, Jelena S / Milicic, Anita

    Cell reports. Medicine

    2023  Volume 4, Issue 11, Page(s) 101245

    Abstract: Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the ... ...

    Abstract Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%-100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different T
    MeSH term(s) Animals ; Mice ; Liposomes ; Th1 Cells ; Emulsions ; Adjuvants, Immunologic/pharmacology ; Malaria Vaccines ; Malaria/prevention & control
    Chemical Substances Liposomes ; Emulsions ; Adjuvants, Immunologic ; Malaria Vaccines
    Language English
    Publishing date 2023-10-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-3791
    ISSN (online) 2666-3791
    DOI 10.1016/j.xcrm.2023.101245
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  2. Article ; Online: Screening of viral-vectored P. falciparum pre-erythrocytic candidate vaccine antigens using chimeric rodent parasites.

    Kolli, Surendra Kumar / Salman, Ahmed M / Ramesar, Jai / Chevalley-Maurel, Severine / Kroeze, Hans / Geurten, Fiona G A / Miyazaki, Shinya / Mukhopadhyay, Ekta / Marin-Mogollon, Catherin / Franke-Fayard, Blandine / Hill, Adrian V S / Janse, Chris J

    PloS one

    2021  Volume 16, Issue 7, Page(s) e0254498

    Abstract: To screen for additional vaccine candidate antigens of Plasmodium pre-erythrocytic stages, fourteen P. falciparum proteins were selected based on expression in sporozoites or their role in establishment of hepatocyte infection. For preclinical evaluation ...

    Abstract To screen for additional vaccine candidate antigens of Plasmodium pre-erythrocytic stages, fourteen P. falciparum proteins were selected based on expression in sporozoites or their role in establishment of hepatocyte infection. For preclinical evaluation of immunogenicity of these proteins in mice, chimeric P. berghei sporozoites were created that express the P. falciparum proteins in sporozoites as an additional copy gene under control of the uis4 gene promoter. All fourteen chimeric parasites produced sporozoites but sporozoites of eight lines failed to establish a liver infection, indicating a negative impact of these P. falciparum proteins on sporozoite infectivity. Immunogenicity of the other six proteins (SPELD, ETRAMP10.3, SIAP2, SPATR, HT, RPL3) was analyzed by immunization of inbred BALB/c and outbred CD-1 mice with viral-vectored (ChAd63 or ChAdOx1, MVA) vaccines, followed by challenge with chimeric sporozoites. Protective immunogenicity was determined by analyzing parasite liver load and prepatent period of blood stage infection after challenge. Of the six proteins only SPELD immunized mice showed partial protection. We discuss both the low protective immunogenicity of these proteins in the chimeric rodent malaria challenge model and the negative effect on P. berghei sporozoite infectivity of several P. falciparum proteins expressed in the chimeric sporozoites.
    MeSH term(s) Animals ; Antibodies, Protozoan/immunology ; Antibodies, Protozoan/metabolism ; Antigens, Protozoan/immunology ; Antigens, Protozoan/metabolism ; Erythrocytes/metabolism ; Female ; Malaria Vaccines/therapeutic use ; Malaria, Falciparum/genetics ; Malaria, Falciparum/immunology ; Malaria, Falciparum/parasitology ; Mice ; Mice, Inbred BALB C ; Plasmodium falciparum/metabolism ; Plasmodium falciparum/pathogenicity ; Protozoan Proteins/metabolism ; Ribosomal Protein L3 ; Sporozoites/pathogenicity
    Chemical Substances Antibodies, Protozoan ; Antigens, Protozoan ; Malaria Vaccines ; Protozoan Proteins ; Ribosomal Protein L3 ; Rpl3 protein, mouse
    Language English
    Publishing date 2021-07-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0254498
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  3. Article ; Online: Production of a high purity, C-tagged hepatitis B surface antigen fusion protein VLP vaccine for malaria expressed in Pichia pastoris under cGMP conditions.

    Mukhopadhyay, Ekta / Brod, Florian / Angell-Manning, Philip / Green, Nicola / Tarrant, Richard D / Detmers, Frank J / Bolam, Emma J / Baleanu, Ioana N / Hobson, Mark / Whale, Gary / Morris, Susan J / Ashfield, Rebecca / Gilbert, Sarah C / Jin, Jing / Draper, Simon J / Moyle, Sarah P / Berrie, Eleanor L / Hill, Adrian V S

    Biotechnology and bioengineering

    2022  Volume 119, Issue 10, Page(s) 2784–2793

    Abstract: Virus-like particles (VLPs) induce strong humoral and cellular responses and have formed the basis of some currently licensed vaccines. Here, we present the method used for the production of R21, a VLP-based anti-sporozoite malaria vaccine, under current ...

    Abstract Virus-like particles (VLPs) induce strong humoral and cellular responses and have formed the basis of some currently licensed vaccines. Here, we present the method used for the production of R21, a VLP-based anti-sporozoite malaria vaccine, under current Clinical Good Manufacturing Practice regulations (cGMP). Previous preclinical studies in BALB/c mice showed that R21 produced almost complete protection against sporozoite challenge with transgenic Plasmodium berghei parasites. Here, we have modified the preclinical production process to enable the production of sufficient quantities of highly pure, clinical-grade material for use in human clinical trials. The R21 construct was re-engineered to include a C-tag to allow affinity-based separation from the major contaminant alcohol oxidase 1 (AOX 1, ~74 kDa). To our knowledge, this is the first use of C-tag technology to purify a VLP vaccine candidate for use in human clinical trials. The R21 vaccine has shown high-level efficacy in an African Phase IIb trial, and multiple clinical trials are underway to assess the safety and efficacy of the vaccine. Our findings support the future use of C-tag platform technologies to enable cGMP-compliant biomanufacturing of high purity yeast-expressed VLP-based vaccines for early phase clinical trials when clinical grade material is required in smaller quantities in a quick time frame.
    MeSH term(s) Animals ; Hepatitis B Surface Antigens/genetics ; Hepatitis B Surface Antigens/metabolism ; Humans ; Malaria/prevention & control ; Malaria Vaccines/genetics ; Malaria Vaccines/metabolism ; Mice ; Mice, Inbred BALB C ; Pichia/genetics ; Saccharomycetales ; Vaccines, Virus-Like Particle ; Viral Vaccines
    Chemical Substances Hepatitis B Surface Antigens ; Malaria Vaccines ; Vaccines, Virus-Like Particle ; Viral Vaccines
    Language English
    Publishing date 2022-07-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 280318-5
    ISSN 1097-0290 ; 0006-3592
    ISSN (online) 1097-0290
    ISSN 0006-3592
    DOI 10.1002/bit.28181
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.

    Datoo, Mehreen S / Natama, Magloire H / Somé, Athanase / Traoré, Ousmane / Rouamba, Toussaint / Bellamy, Duncan / Yameogo, Prisca / Valia, Daniel / Tegneri, Moubarak / Ouedraogo, Florence / Soma, Rachidatou / Sawadogo, Seydou / Sorgho, Faizatou / Derra, Karim / Rouamba, Eli / Orindi, Benedict / Ramos Lopez, Fernando / Flaxman, Amy / Cappuccini, Federica /
    Kailath, Reshma / Elias, Sean / Mukhopadhyay, Ekta / Noe, Andres / Cairns, Matthew / Lawrie, Alison / Roberts, Rachel / Valéa, Innocent / Sorgho, Hermann / Williams, Nicola / Glenn, Gregory / Fries, Louis / Reimer, Jenny / Ewer, Katie J / Shaligram, Umesh / Hill, Adrian V S / Tinto, Halidou

    Lancet (London, England)

    2021  Volume 397, Issue 10287, Page(s) 1809–1818

    Abstract: Background: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African ... ...

    Abstract Background: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy.
    Methods: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724.
    Findings: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later.
    Interpretation: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy.
    Funding: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.
    MeSH term(s) Adjuvants, Immunologic/administration & dosage ; Antibodies, Protozoan/immunology ; Burkina Faso ; Double-Blind Method ; Female ; Hepatitis B Surface Antigens ; Humans ; Immunogenicity, Vaccine ; Infant ; Malaria/prevention & control ; Malaria Vaccines/therapeutic use ; Malaria, Falciparum/prevention & control ; Male ; Nanoparticles/administration & dosage ; Proportional Hazards Models ; Protozoan Proteins/immunology ; Saponins/administration & dosage ; Treatment Outcome ; Vaccines, Virus-Like Particle/therapeutic use
    Chemical Substances Adjuvants, Immunologic ; Antibodies, Protozoan ; Hepatitis B Surface Antigens ; Malaria Vaccines ; Matrix-M ; Protozoan Proteins ; Saponins ; Vaccines, Virus-Like Particle ; circumsporozoite protein, Protozoan
    Language English
    Publishing date 2021-05-05
    Publishing country England
    Document type Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 3306-6
    ISSN 1474-547X ; 0023-7507 ; 0140-6736
    ISSN (online) 1474-547X
    ISSN 0023-7507 ; 0140-6736
    DOI 10.1016/S0140-6736(21)00943-0
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    Ua VI Zs.5: Show issues Location:
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