WO2024092112A2 - Procédé d'identification d'épitopes antigéniques chez plasmodium falciparum et leurs utilisations - Google Patents

Procédé d'identification d'épitopes antigéniques chez plasmodium falciparum et leurs utilisations Download PDF

Info

Publication number
WO2024092112A2
WO2024092112A2 PCT/US2023/077892 US2023077892W WO2024092112A2 WO 2024092112 A2 WO2024092112 A2 WO 2024092112A2 US 2023077892 W US2023077892 W US 2023077892W WO 2024092112 A2 WO2024092112 A2 WO 2024092112A2
Authority
WO
WIPO (PCT)
Prior art keywords
plasmodium
seq
nos
malaria
epitopes
Prior art date
Application number
PCT/US2023/077892
Other languages
English (en)
Other versions
WO2024092112A3 (fr
Inventor
Matthew B. LAURENS
Alexander John LAURENSON
Original Assignee
University Of Maryland, Baltimore
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Maryland, Baltimore filed Critical University Of Maryland, Baltimore
Publication of WO2024092112A2 publication Critical patent/WO2024092112A2/fr
Publication of WO2024092112A3 publication Critical patent/WO2024092112A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/002—Protozoa antigens
    • A61K39/015—Hemosporidia antigens, e.g. Plasmodium antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
    • C07K14/445—Plasmodium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/20—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans from protozoa
    • C07K16/205—Plasmodium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to the fields of bioinformatics and vaccine development. More specifically, the present invention relates to the identification, via bioinformatics, of epitopes for malaria vaccine antigens.
  • Plasmodium falciparum (Pf) is the most lethal parasite species of its genus to humans. P. falciparum has evaded successful vaccine development for many reasons, including redundant erythrocyte invasion mechanisms (1-3).
  • PfRH5- PfCyRPA-Pf-Ripr (RCR) complex is expressed on the Pf merozoite surface (3).
  • An RCR component, Pf merozoite Rh5 interacting protein (PfRipr) is nonredundant, highly conserved, and essential for erythrocyte invasion (FIG. 1 ) (5).
  • the present invention is directed to an immunogenic composition.
  • the composition comprises at least one synthetic peptide effective to initiate an immune response against a malaria parasite such as the human malaria parasites Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi.
  • the present invention is further directed to a method for treating malaria in a subject in need thereof.
  • an amount of the immunogenic composition described herein effective to initiate the immune response against the malaria parasite is administered to the subject.
  • the present invention is directed further to a multi-epitope vaccine.
  • the vaccine comprises a plurality of antigenic epitope sequences linked to form a vaccine construct effective to initiate an immune response against a component of a PfPCRCR complex in Plasmodium falciparum.
  • the present invention is directed further still to a method for blocking a malaria disease in a subject.
  • the multi-epitope vaccine described herein is administered to the subject in an amount effective to initiate an immune response against a Pf merozoite Rh5 interacting protein (PfRipr) to inhibit erythrocyte invasion by Plasmodium falciparum.
  • PfRipr Pf merozoite Rh5 interacting protein
  • the present invention is directed further still to a vaccine construct directed against a malarial erythrocyte invasion protein.
  • the vaccine construct comprises a multi-epitope composition of linked T-cell epitopes and B-cell epitopes with amino acid sequences shown in SEQ ID NOS: 1-18.
  • the present invention is directed further still to a vaccination method directed against malaria in a subject.
  • a component of a PfPCRCR complex in Plasmodium falciparum infecting the subject is contacted with an amount of the vaccine construct described herein effective to inhibit erythrocyte invasion thereby.
  • the present invention is directed further still to a method for designing a multiepitope vaccine construct directed against Plasmodium-caused human malaria in an endemic region.
  • a plurality of blood samples are obtained from human subjects with malaria living in the endemic region.
  • a Pf merozoite Rh5 interacting protein (PfRipr) in each of the blood samples is searched, via a bioinformatics algorithm, for T-cell epitopes with a binding affinity for MHC alleles.
  • B-cell linear epitopes and B-cell discontinuous epitopes are predicted, via algorithm, from 3- dimensional models of the PfRipr protein in each blood sample.
  • the T-cell epitopes with a high binding affinity for MHC alleles and the B-cell epitopes with a high protrusion index score are selected as candidate epitopes from which to design the multi-epitope vaccine construct.
  • the present invention is directed further still to a related method for designing a multi-epitope vaccine construct.
  • the method further comprises synthesizing peptides corresponding to amino acid sequences of the candidate T-cell epitopes shown in SEQ ID NOS: 1-14 and amino acid sequences of the candidate B-cell epitopes shown in SEQ ID NOS: 15-18 and linking a plurality of the peptides to form the multi-epitope vaccine construct.
  • FIG. 1 is a model of binding and insertion of RCR complex to erythrocyte surface.
  • FIG. 2 is a 3D model of PfRipr predicted via AlphaFold with labeled discontinuous B-cell.
  • the boxed sections A and B correspond to the discontinuous B- cell epitopes at F6 and T7, respectively.
  • FIG. 3 is a schematic representation of a multi-epitope vaccine construct.
  • the articles “a” and “an” when used in conjunction with the term “comprising” in the claims and/or the specification, may refer to “one”, but it is also consistent with the meaning of “one or more”, “at least one”, and “one or more than one”. Some embodiments of the invention may consist of or consist essentially of one or more elements, components, method steps, and/or methods of the invention.
  • the term “about” refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated.
  • the term “about” generally refers to a range of numerical values (e.g., ⁇ 5- 10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result).
  • the term “about” may include numerical values that are rounded to the nearest significant figure.
  • multi-epitope vaccine refers to a collection of synthetic peptides with antigenic properties linked to form the vaccine.
  • immunogenic composition refers to a plurality of peptides or synthetic peptides so linked as to form an antigenic molecule effective to initiate or provoke an immune response.
  • an immunogenic composition comprising at least one synthetic peptide effective to initiate an immune response against a malaria parasite.
  • the malaria parasite may be Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi.
  • the immune response may be against a Pf merozoite Rh5 interacting protein (PfRipr).
  • the synthetic peptide may comprise an amino acid sequence shown in at least one of SEQ ID NOS: 1-6 or at least one of SEQ ID NOS: 7-14 or at least one of SEQ ID NOS: 15- 18 or a combination thereof.
  • the synthetic peptide may comprise the amino acid sequences shown in SEQ ID NOS: 1-18 in a linked construct.
  • a method for treating malaria in a subject in need thereof comprising administering to the subject an amount of the immunogenic composition, as described supra, effective to initiate an immune response against the malaria parasite.
  • a representative component of the PfPCRCR complex may be Pf merozoite Rh5 interacting protein (PfRipr).
  • the malaria parasite may be as described supra.
  • a multiepitope vaccine comprising a plurality of antigenic epitope sequences linked to form a vaccine construct effective to initiate an immune response against a component of a PfPCRCR complex in Plasmodium falciparum.
  • the component of the PfPCRCR complex may be Pf merozoite Rh5 interacting protein (PfRipr).
  • the plurality of antigenic epitopes in the vaccine construct may comprise a plurality of T-cell epitopes or a plurality of B-cell epitopes or a combination thereof.
  • the plurality of T-cell epitopes may comprise amino acid sequences shown in SEQ ID NOS: 1-14.
  • the plurality of B-cell epitopes may comprise amino acid sequences shown in SEQ ID NOS: 15-18.
  • the plurality of antigenic epitopes in the vaccine construct comprises amino acid sequences shown in SEQ ID NOS: 1-18.
  • a method for blocking a malaria disease in a subject comprising administering the multi-epitope vaccine, as described supra, to the subject in an amount effective to initiate an immune response against a Pf merozoite Rh5 interacting protein (PfRipr) to inhibit erythrocyte invasion by Plasmodium falciparum.
  • PfRipr Pf merozoite Rh5 interacting protein
  • a vaccine construct directed against a malarial erythrocyte invasion protein comprising a multiepitope composition of linked T-cell epitopes and B-cell epitopes with amino acid sequences shown in SEQ ID NOS: 1-18.
  • the erythrocyte invasion protein may be a Pf merozoite Rh5 interacting protein (PfRipr).
  • a vaccination method directed against malaria in a subject comprising contacting a component of a PfPCRCR complex in Plasmodium falciparum infecting the subject with an amount of the vaccine construct, as described supra, effective to inhibit erythrocyte invasion thereby.
  • the component of the PfPCRCR complex may be a Pf merozoite Rh5 interacting protein (PfRipr).
  • a method for designing a multi-epitope vaccine construct directed against Plasmodium-caused human malaria in an endemic region comprising obtaining a plurality of blood samples from human subjects with malaria living in the endemic region; searching, via a bioinformatics algorithm, a Pf merozoite Rh5 interacting protein (PfRipr) in each of the blood samples for T-cell epitopes with a binding affinity for MHC alleles; predicting, via algorithm, B-cell linear epitopes and B-cell discontinuous epitopes from 3- dimensional models of the PfRipr protein in each blood sample; and selecting the T- cell epitopes with a high binding affinity for MHC alleles and the B-cell epitopes with a high protrusion index score as candidate epitopes from which to design the multiepitope vaccine construct.
  • PfRipr Pf merozoite Rh5 interacting protein
  • the method may comprise synthesizing peptides corresponding to amino acid sequences of the candidate T-cell epitopes shown in SEQ ID NOS: 1-14 and amino acid sequences of the candidate B-cell epitopes shown in SEQ ID NOS: 15-18; and linking a plurality of the peptides to form the multi-epitope vaccine construct.
  • the multi-epitope vaccine may comprise a plurality of the peptides with amino acid sequences shown in SEQ ID NOS: 1-14 or a plurality of the peptides with amino acid sequences shown in SEQ ID NOS: 15-18 or a combination thereof of such pepetides.
  • the human malaria may be caused by Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi.
  • bioinformatic approaches to antigenic epitope identification directed against the Pf merozoite Rh5 interacting protein (PfRipr) component of the PfPCRCR complex of Plasmodium falciparum specific to regions endemic with malaria are also provided.
  • immunogenic compositions and vaccines, preferably multiepitope vaccines, designed from the identified candidate epitopes with high immunogenic potential may be applied to a broader database of PfRipr sequences from other malaria endemic regions to ensure broad applicability of results.
  • bioinformatic approaches may be applied to identifying antigenic epitopes for any of the other four human parasite species of malaria that are Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, or Plasmodium knowlesi.
  • the immunogenic compositions and multi-epitope vaccines comprise or consist of a plurality of peptides or synthetic peptides with sequences corresponding to the candidate epitope sequences linked, if necessary, with a plurality of linkers well-known and standard in the art (see FIG. 3).
  • the peptides may be synthesized or otherwise obtained by methods known in the art.
  • the peptides comprise or consist of a plurality of T-cell epitope sequences, a plurality of B-cell epitope sequences or, preferably, a combination of both T-cell and B-cell epitope sequences.
  • the peptides may have the T-cell amino acid sequences shown in SEQ ID NOS: 1-14 and the B-cell amino acid sequences shown in SEQ ID NOS: 15-18 to form a multi-epitope vaccine with an amino acid sequence of SEQ ID NO: 19 that is a combination of all of SEQ ID NOS: 1-18
  • the immunogenic compositions, vaccines and multi-epitope vaccines may be used to treat malaria by initiating immune responses against, in a non-limiting example, Plasmodium falciparum.
  • the compositions and vaccines provided herein are effective to inhibit or prevent transmission of the malaria parasite by stopping erythrocyte invasion.
  • the compositions and vaccines are directed against the Pf merozoite Rh5 interacting protein (PfRipr) required for erythrocyte invasion.
  • the immunogenic compositions and multi-epitope vaccines may be administered by means as known in the art.
  • One of skill in the art is well able to determine dosage and route of administration depending on, inter alia, the age of the subject.
  • WGS whole genome sequence
  • Predicted binders were sorted using MHC allele recognition as a metric of the epitope’s promiscuity of binding across the different MHC allele profiles included in the search. Epitopes with the highest MHC allele recognition in their respective class were further filtered based on sequence conservation, predicted antigenic identity, and predicted allergenicity (10-12).
  • B-cell receptor and antibody epitope predictions use 3D protein structures as inputs to model linear and discontinuous epitope-binding.
  • tertiary structures of all 56 samples were predicted using SWISS-MODEL (13-15).
  • 3D structures of sample PfRipr used to predict B-cell linear and discontinuous epitopes via ElliPro were used to model residue accessibility (16).
  • Epitopes filtered to include predicted binders in all 56 samples were sorted by the Protrusion Index score. Top-scoring epitopes were further filtered based on conservation, predicted antigenic identity, and predicted allergenicity (10-12).
  • the candidate epitopes and vaccine constructs comprising the same are validated by known methods of in silico protein stabilization and docking simulations, in vitro HLA binding and T-cell activation assays, and in vivo transgenic mouse models.
  • Candidate T-cell epitopes are divided into MHC class I epitopes, i.e., type HLA- A, HLA-B and HLA-C, and MHC class II epitopes, i.e., DRB1 and DQA1-DQB1 , shown in Tables 2 and 3, respectively.
  • B-cell epitopes Table 3 lists those peptide sequences with a high degree of recognition for linear and discontinuous B-cell epitopes (FIG. 2).
  • FIG. 3 is a schematic representation of a multi-epitope vaccine construct (SEQ ID NO: 19) comprising the peptide sequences of SEQ ID NOS: 1-18 corresponding to the candidate epitopes.
  • FliC is added to the N-terminus to stimulate and to amplify an immune response (17).
  • the EAAAK linker (SEQ ID NO: 20) is used to separate the bifunctional fusion protein domains (18).
  • AAY linkers are used to amplify MHC I and II epitopes and to prevent junctional epitope binding (19).
  • GPGPG linkers (SEQ ID NO: 21 ) between B-cell epitopes function to minimize junctional epitopes and to retain conformational-dependent immunogenicity (20).
  • a six amino acid histidine HHHHHH (SEQ ID NO: 22) was added to the C-terminus to aid during lab purification processes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des procédés d'identification d'épitopes antigéniques contre le parasite du paludisme Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, et Plasmodium knowlesi dans des régions endémiques pour le paludisme. L'invention concerne également des compositions immunogènes, des vaccins et des vaccins multi-épitopes construits à partir des épitopes antigéniques identifiés et des procédés de traitement du paludisme chez un sujet, bloquant la transmission du paludisme chez un sujet et initiant des réponses immunitaires contre la protéine interagissant avec le mérozoïte Pf Rh5 (PfRipr) et inhibant l'invasion des érythrocytes.
PCT/US2023/077892 2022-10-27 2023-10-26 Procédé d'identification d'épitopes antigéniques chez plasmodium falciparum et leurs utilisations WO2024092112A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263419749P 2022-10-27 2022-10-27
US63/419,749 2022-10-27

Publications (2)

Publication Number Publication Date
WO2024092112A2 true WO2024092112A2 (fr) 2024-05-02
WO2024092112A3 WO2024092112A3 (fr) 2024-05-30

Family

ID=90832087

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/077892 WO2024092112A2 (fr) 2022-10-27 2023-10-26 Procédé d'identification d'épitopes antigéniques chez plasmodium falciparum et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2024092112A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884101B2 (en) * 2010-11-09 2018-02-06 The Walter And Eliza Hall Institute For Medical Research Treatment and prevention of malaria
EP2796147A1 (fr) * 2013-04-24 2014-10-29 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Nouveaux vaccins contre les Apicomplexa pathogènes

Also Published As

Publication number Publication date
WO2024092112A3 (fr) 2024-05-30

Similar Documents

Publication Publication Date Title
Chaudhury et al. The biological function of antibodies induced by the RTS, S/AS01 malaria vaccine candidate is determined by their fine specificity
Feng et al. Abundance of intrinsically unstructured proteins in P. falciparum and other apicomplexan parasite proteomes
Patarroyo et al. Structural and immunological principles leading to chemically synthesized, multiantigenic, multistage, minimal subunit-based vaccine development
Doolan et al. Utilization of genomic sequence information to develop malaria vaccines
Lu et al. Profiling the humoral immune responses to Plasmodium vivax infection and identification of candidate immunogenic rhoptry-associated membrane antigen (RAMA)
Stern et al. HLA-DR: molecular insights and vaccine design
Jaenisch et al. High-density peptide arrays help to identify linear immunogenic B-cell epitopes in individuals naturally exposed to malaria infection*[S]
Chaturvedi et al. Strategies & recent development of transmission-blocking vaccines against Plasmodium falciparum
Alaeddine et al. Reduced infection and protection from clinical signs of cerebral neosporosis in C57BL/6 mice vaccinated with recombinant microneme antigen NcMIC1
Thompson et al. PTRAMP; a conserved Plasmodium thrombospondin-related apical merozoite protein
Fonseca et al. A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119
Kengne-Ouafo et al. Immune responses to the sexual stages of Plasmodium falciparum parasites
de Jong et al. Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes
Leitner et al. Role of opsonophagocytosis in immune protection against malaria
Verma et al. Antigen discovery, bioinformatics and biological characterization of novel immunodominant Babesia microti antigens
Khan et al. Immune escape and immune camouflage may reduce the efficacy of RTS, S vaccine in Malawi
Vaughan et al. Meta‐analysis of immune epitope data for all Plasmodia: overview and applications for malarial immunobiology and vaccine‐related issues
Wahl et al. How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein
Raghavan et al. Antibodies to repeat-containing antigens in Plasmodium falciparum are exposure-dependent and short-lived in children in natural malaria infections
Heide et al. Detection of EXP1-specific CD4+ T cell responses directed against a broad range of epitopes including two promiscuous MHC class II binders during acute plasmodium falciparum malaria
López et al. The in Vitro Antigenicity of Plasmodium vivax Rhoptry Neck Protein 2 (Pv RON2) B-and T-Epitopes Selected by HLA-DRB1 Binding Profile
WO2024092112A2 (fr) Procédé d'identification d'épitopes antigéniques chez plasmodium falciparum et leurs utilisations
Arévalo-Pinzón et al. Plasmodium vivax cell traversal protein for ookinetes and sporozoites (CelTOS) Functionally restricted regions are involved in specific host-pathogen interactions
Dieng et al. Genetic variations of Plasmodium falciparum circumsporozoite protein and the impact on interactions with human immunoproteins and malaria vaccine efficacy
Cheng et al. Clinical expression and antigenic profiles of a Plasmodium vivax vaccine candidate: merozoite surface protein 7 (PvMSP-7)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23883747

Country of ref document: EP

Kind code of ref document: A2