Malaria is a vector-borne infectious disease that is widespread in tropical and subtropical regions, causing disease in approximately 400 million people and killing 1-3 million, most of them young children in Sub-Saharan Africa. It is one of the most common infectious diseases, caused by protozoan parasites of the genus Plasmodium. The most serious forms of the disease are caused by P. falciparum and P. vivax, but other related species (P. ovale, P. malariae, and sometimes P. knowlesi) can also infect humans. This group of human-pathogenic Plasmodium spp. is usually referred to as malaria parasites and are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms of anemia, as well as other general symptoms such as fever, chills, nausea, flu-like illness, and in severe cases, coma and death. No vaccine is currently available for malaria; preventative drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are often too expensive for most people living in endemic areas. Most adults from endemic areas have a degree of long-term recurrent infection and also of partial resistance, which reduces with time and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas (Joy et al., 2003; Escalante et al., 1998; Kaufman et al., 2005; Meis et al., 1983).
4. Microbial Pathogenesis
Malaria in humans develops via exoerythrocytic (hepatic) and erythrocytic phases. When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver. Within 30 minutes of being introduced into the human host, they infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 d. During this "dormant" time in the liver, the sporozoites are often referred to as "hypnozoites". Once in the liver, these organisms differentiate to yield thousands of merozoites which, following rupture of their host cells, escape into the blood and infect red blood cells, thus beginning the erythrocytic stage of the life cycle. The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell. Within the erythrocytes, the parasites multiply further, periodically breaking out of their hosts to invade fresh erythrocytes. Several such amplification cycles occur, resulting in the classical waves of fever. Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut, thereby defining the mosquito as the definitive host of the disease. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes, and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight (Talman et al., 2004; Bledsoe, 2005; Sturm et al., 2006).
5. Host Ranges and Animal Models
The vast majority of malaria cases occur in children under the age of 5 years; pregnant women are also especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of this disease since 1992. Precise statistics are unknown, as the majority of cases are undocumented. Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes from malaria increasing viral load and HIV infection increasing a person's susceptibility to malaria infection. Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur. The geographic distribution of malaria within large regions is complex, and malarial and malaria-free areas are often found close to each other. In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall (Breman, 2001; Greenwood et al., 2005; Hay et al., 2004).
6. Host Protective Immunity
Plasmodia are relatively protected from attack by the body's immune system because for most of its life cycle it resides within liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, P. falciparum displays adhesive proteins on the surface of the infected blood cells, causing blood cells to stick to the walls of small blood vessels, thereby sequestering the parasite from passage through the general circulation and the spleen and giving rise to hemorrhagic complications. Endothelial venules can be blocked by the attachment of masses of these infected red blood cells (RBCs). The blockage of these vessels causes placental and cerebral malaria. Although the RBC surface adhesive proteins (called PfEMP1, for Plasmodium falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and perhaps limitless versions within parasite populations (Chen et al., 2000; Adams et al., 2002).
Molecule Role Annotation :
Mice immunized with a refolded, recombinant, Plasmodium chabaudi AMA1 fragment (AMA1B) can withstand subsequent challenge with P. chabaudi adami (Xu et al., 2000).
Molecule Role Annotation :
Researchers produced a prototypic malaria vaccine based on a highly versatile self-assembling polypeptide nanoparticle (SAPN) platform that can repetitively display antigenic epitopes. Researchers used this platform to display a tandem repeat of the B cell immunodominant repeat epitope (DPPPPNPN)(2)D of the malaria parasite Plasmodium berghei circumsporozoite (CS) protein. Administered in saline, without the need for a heterologous adjuvant, the SAPN construct P4c-Mal conferred a long-lived, protective immune response to mice with a broad range of genetically distinct immune backgrounds including the H-2(b), H-2(d), and H-2(k) alleles. Mice were protected against an initial challenge of parasites up to 6 mo after the last immunization or for up to 15 mo against a second challenge after an initial challenge of parasites had successfully been cleared (Kaba et al., 2009).
Molecule Role Annotation :
We employed a P. berghei parasite line that expresses a heterologous CSP (CS) from P. falciparum in order to assess the role of the CSP in the protection conferred by vaccination with radiation-attenuated P. berghei parasites. Our data demonstrated that sterile immunity could be obtained despite the absence of immune responses specific to the CSP expressed by the parasite used for challenge (Grüner et al., 2007).
Molecule Role Annotation :
Study showed that immunization with irradiated sporozoites (IrrSpz) of a P. berghei line whose endogenous CS was replaced by that of P. yoelii conferred sterile protection against challenge with wild type P. berghei sporozoites (Mauduit et al., 2009).
Molecule Role Annotation :
A genetically attenuated parasite (GAP) with a mutation in the FabB/FabF gene is attenuated in mice by arresting in the late liver stage. It also conferred complete protection in mice from challenge with wild type Plasmodium (Butler et al., 2011).
Molecule Role Annotation :
Immunized animals were challenged in vivo with various parasite strains or clones of malaria. Immunization with the PfEMP1-DBL1 alpha domain abolished the PfEMP1-dependent sequestration of the homologous strain in immunized rats and substantially inhibited parasite adhesion in immunized monkeys. Protection against sequestration of heterologous parasite strains was also confirmed by direct or indirect challenge in the rat model (Moll et al., 2007).
Molecule Role Annotation :
Some of the S. sciureus monkeys immunized with MSP-3(212-380)-AS02 or GLURP(27-500)-alum were able to fully or partially control parasitaemia upon an experimental P. falciparum [Falciparum Uganda Palo Alto (FUP-SP) strain] blood-stage infection, and this protection was related to the prechallenge antibody titres induced. The data are indicative that MSP-3 and GLURP can induce protective immunity against an experimental P. falciparum infection using adjuvants that are acceptable for human use and this should trigger further studies with those new antigens (Carvalho et al., 2004).
Molecule Role Annotation :
Immunization of mice with subunit vaccines based on the Plasmodium yoelii 17kDa hepatocyte erythrocyte protein (PyHEP17), orthologue of Plasmodium falciparum exported protein 1 (PfExp1), induces antigen-specific immune responses and protects against sporozoite challenge (Dobaño and Doolan, 2007).
Molecule Role Annotation :
A monkey vaccination trial using a Plasmodium falciparum protein fraction containing antigens of 90-110 kDa is reported. Three monkeys out of five resisted a heavy challenge dose of highly virulent parasites. Hsp90 was found in the immunoprecipitates obtained with SERP antisera. Interestingly, the response to hsp90 correlated with protection, high antibody titres being found only in the protected monkeys (Bonnefoy et al., 1994).
Molecule Role Annotation :
Two large fragments of PfKbeta representing the N- and C-terminal halves were expressed in E. coli. The recombinant proteins were highly immunogenic in mice, and also found to be the target for immune response in natural infections of Plasmodium spp. Immunization with recombinant PfKbeta fragments was partially protective against a heterologous challenge infection in mice (Mohmmed et al., 2005).
Molecule Role Annotation :
In chimpanzees (Pan troglodytes), the primates most closely related to humans and that share a similar susceptibility to P. falciparum liver-stage infection, immunization with LSA-3 induced protection against successive heterologous challenges with large numbers of P. falciparum sporozoites (Daubersies et al., 2000).
Molecule Role Annotation :
Aotus monkeys were challenged with the virulent Vietnam Oak Knoll (FVO) strain of P. falciparum. Vaccination of A. nancymai with yMSP1(19) induced protective immune responses. Both of the A. nancymai vaccinated with yMSP1(19) self-resolved an otherwise lethal infection (Kumar et al., 1995).
Molecule Role Annotation :
Immunization with Plasmodium yoelii merozoite surface protein (PyMSP)-8 protects mice from lethal malaria but does not prevent infection (Petritus and Burns, 2008).
>AAC47502.1 merozoite surface protein 1, partial [Plasmodium berghei]
SGQSSTEPASTGTPSSGEVSTGTSTGGASAGVTNTGAATTGTSTGGASAGVTNTGAATTGTTGTGAATTG
TTGAEAVTTGNTGAEVTQVQIVPTLTPEEKKKKMDGLYAQI
Molecule Role :
Protective antigen
Molecule Role Annotation :
Mice vaccinated with recombinant rMSP1 (rPbMSP1), which was generated from Plasmodium berghei, in alum mounted significant protective immunity against challenge infection (P < 0.01). On day 121 after the booster, three out of ten mice immunized with rPbMSP1 in PBS survived parasite infection (P < 0.05) and eight out of ten mice vaccinated with r MSP1 in alum did (P < 0.01). Hence, immunization with MSP1 in alum obviously has conferred protective effects, which prevented death from P. berghei lethal infection in mice (P < 0.01) (Wan et al., 2007).
Molecule Role Annotation :
Researchers found that the cysteine-rich, carboxyl-terminal region of the MSP-1 protein from the rodent malarial parasite Plasmodium yoelii yoelii can be expressed in a native configuration as a fusion protein in Escherichia coli. This recombinant polypeptide elicits antibodies in mice which recognize the native parasite MSP-1. Most significantly, both inbred and outbred mice immunized with the fusion protein in Ribi adjuvant are partially and in some cases completely protected against challenge infection with an otherwise lethal parasite strain (Daly and Long, 1993).
Molecule Role Annotation :
Immunization of BALB/c mice and Aotus monkeys with PvMSP-1 induced IgG antibodies (titer > 10(6)) that cross-reacted with P. vivax parasites. Immunized monkeys displayed partial protection against a challenge with P. vivax blood stages (Valderrama-Aguirre et al., 2005).
Molecule Role Annotation :
Immunization with a recombinant yeast-expressed Plasmodium falciparum merozoite surface protein 3 (MSP3) protected Aotus nancymai monkeys against a virulent challenge infection (Tsai et al., 2009).
Molecule Role Annotation :
Oral immunization of mice with Escherichia coli-expressed Plasmodium yoelii merozoite surface protein 4/5 or the C-terminal 19-kDa fragment of merozoite surface protein 1 induced systemic antibody responses and protected mice against lethal malaria infection (Wang et al., 2004).
Molecule Role Annotation :
Genetically attenuated P36p-deficient Plasmodium berghei sporozoites provide protection against sporozoites challenge in mice (Douradinha et al., 2007).
>BAD97684.1 PF cell-traversal protein [Plasmodium falciparum]
MNALRRLPVICSFLVFLVFSNVLCFRGNNGHNSSSSLYNGSQFIEQLNNSFTSAFLESQSMNKIGDDLAE
TISNELVSVLQKNSPTFLESSFDIKSEVKKHAKSMLKELIKVGLPSFENLVAENVKPPKVDPATYGIIVP
VLTSLFNKVETAVGAKVSDEIWNYNSPDVSESEESLSDDFFD
Molecule Role :
Protective antigen
Molecule Role Annotation :
Immunization with PfCelTOS resulted in potent humoral and cellular immune responses and most importantly induced sterile protection against a heterologous challenge with P. berghei sporozoites in a proportion of both inbred and outbred mice (Bergmann-Leitner et al., 2010).
Molecule Role Annotation :
Mice immunized with r-Pfen (recombinant P. falciparum enolase protein) showed protection against a challenge with the 17XL lethal strain of the mouse malarial parasite Plasmodium yoelii (Pal-Bhowmick et al., 2007).
>VUZ98878.1 cell traversal protein for ookinetes and sporozoites [Plasmodium vivax]
MHLFNKPPKGKMNKVNRVSIICAFLALFCFVNVLSLRGKSGSTASSSLEGGSEFSERIGNSLSSFLSESA
SLEVIGNELADNIANEIVSSLQKDSASFLQSGFDVKTQLKATAKKVLLEALKAALEPTEKIVASTIKPPR
VSEDAYFLLGPVVKTLFNKVEDVLHKPIPDTIWEYESKGSLEEEEAEDEFSDELLD
Molecule Role Annotation :
Deletion of P52 and P36 in Plasmodium yoelii were attenuated and provided protection against challenge in mice (Labaied et al., 2007).
>gi|23479924|gb|EAA16624.1| p36 protein [Plasmodium yoelii yoelii]
MSENSTIEGNDIGEKVAAIKKYLEAFDHQNEAKSIHGFVDLLKKINIKMAVFDFDLTLIGKHSGTCNIMC
GYIDKLNDIEDIGTSVTNAFKILSKRLYENNIKITVATFSDDEAIRYSKVKSPSLIAGEELIQHCIKHSN
CETKIERVYAYYPYYYKEPKKYMALGLKEPMSNDKSYHLKRIRNEFSVNINEIIFFDDDVKNCISAKKEG
YITFNVTGKKGFNFKDIKLMQ
Molecule Role :
Virmugen
Molecule Role Annotation :
A genetically attenuated parasite (GAP) with deletions in p52 and p36 are attenuated in mice. Mice immunized with the mutant were completely protected against challenge with wild type Plasmodium sporozoites (Labaied et al., 2007).
Molecule Role Annotation :
A genetically attenuated parasite (GAP) with deletions in p52 and p36 are attenuated in mice. Mice immunized with the mutant were completely protected against challenge with wild type Plasmodium sporozoites (Labaied et al., 2007).
Molecule Role Annotation :
Researchers constructed a new recombinant molecule of SERA5, namely SE36. Vaccination of Squirrel monkeys with SE36 protein and aluminium hydroxyl gel (SE36/AHG) conferred protection against high parasitemia and boosted serum anti-SE36 IgG after P. falciparum parasite challenge (Horii et al., 2010).
>gi|83315853|ref|XP_730972.1| early transcribed membrane protein [Plasmodium yoelii yoelii str. 17XNL]
MPQFFTCIIYINKYFRTNKKYMKVYKMNTLKVFFVFYVLYITTFFFNPCFCEDADYYSEIDDGALDSIDT
AIKKKKKRKSVAIALLSSGLVASVIGVLYYMYKSHNKGRHDWNKGFNFFPFNKQTEYKQPDGEKPSTSTK
YEEPLGVNKVNIKGKLKENNNDIDVPLKRFNTFMDNVKLAAKHHFSNLSNEQQKYLIKDYDYLRKIVQTL
DENKDVNISRAQEDIAVLGVEHFLKEQYQPK
Molecule Role :
Virmugen
Molecule Role Annotation :
Deletion of UIS3 in Plasmodium yoelii provided attenuation and full protection in mice by Pyuis3(-) sporozoites required at least 2 immunizations against challenges with infectious sporozoites (Tarun et al., 2007).
>gi|82753006|ref|XP_727503.1| hypothetical protein [Plasmodium yoelii yoelii str. 17XNL]
MNKRIFSLVCIALYTLLTVPAHCSEQEVSDVGNKSDEKNDIEYKRETQLKNTNSKDDRGFNCFNIFKKNK
RTQSHSYSKVPLTHPYNKITETSSNNNDSIHKIELLMEKIARYFLANHSEILKFLSNNKITEASSNNNDA
IHKVSLEMRKIMRELLEKSPEGLKLLSRLAEKLEKRPSNDKPSE
Molecule Role :
Virmugen
Molecule Role Annotation :
A UIS4 mutant of Plasmodium yoelii is attenuated and a single dose of Pyuis4(-) sporozoites conferred complete protection against challenges with infectious sporozoites (Tarun et al., 2007).
III. Vaccine Information
1. Ad-MVA PvCelTOS
a. Type:
Recombinant vector vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Human
d. Antigen
PvCelTOS: cell-traversal protein for ookinetes and sporozoites of P. vivax. A protein important for parasite traversal of host cells both for ookinetes in the mosquito and for sporozoites. (Alves et al., 2017)
(Ad): ChAd63: recombinant chimpanzee adenoviral vector 63 (MVA): MVA: modified vaccinia virus Ankara (Alves et al., 2017)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
PvCelTOS (Ad): Recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS. PvCelTOS (MVA): Recombinant modified vaccinia virus Ankara (MVA) expressing PvCelTOS **PvCelTOS (Ad) is the primary vaccination, and PvCelTOS (MVA) is the booster. (Alves et al., 2017)
i.
Mouse Response
Vaccination Protocol:
3 groups of mice were used, each group includes 6 mice. Mice were intramuscularly inject prime immune 1*10^8 IU ChAd63-PvCelTOS, then intramuscularly injected one of the boosters 8 weeks later: 1*10^6 PFU per ml of 1) PvCelTOS (MVA), 2) PvCelTOS (VLPs), 3) PvCelTOS (protein) (Alves et al., 2017)
Immune Response:
Humoral: anti-PvCelTOS antibody levels significantly increased after vaccination in both types of mice. Antibody responses were boosted with all three vaccine platforms. Cellular: CD-1: Mice in Ad-MVA group had significantly higher TNF-α levels (2.93% ± 0.72% comparing to 0.98% ± 0.42%) and IFN-γ levels(3.46% ± 0.699% and 1.36% ± 0.52%). No significant difference in IL-2 levels. The total anti-PvCelTOS cellular responses were low after background values subtraction (1.9% for TNF-α and 2.1% for IFN-γ. Only the value of IFN-γ significantly higher (P < 0.0001)). BALB/c: All immunization regimens substantially higher levels of TNF-α- and IFN-γ-producing CD3+/CD8+ cells. (Alves et al., 2017)
Challenge Protocol:
Same prime-boost vaccination performed (6 mice in each BALB/c group, 10 mice in each CD1 group). Three set of mice were each challenged with 1000 sporozoits of 1) Pb-PvCelTOS (P. berghei expressing P. vivax CelTOS), 2) Wild-type P.berghei, and 3) Pb-PfCelTOS (P. berghei sporozoites expressing P. falciparum CelTOS). Sporozoits were intravenous injected 10 days after booster. Efficacy was determined by measuring the prepatent period (the time to reach 1% parasitemia after challenge). (Alves et al., 2017)
Efficacy:
Pb-PvCelTOS: CD1: Ad-MVA provided 10% sterile protection, not significantly higher than the control BALB/c: no vaccination regimen conferred any protective efficacy even though it induced protective cellular and humoral immune responses. Pb-PfCelTOS: no protective immunity in CD1 mice. Wild-type P. berghei: no protective immunity from any immunization regimen in CD1 mice. (Alves et al., 2017)
PvCelTOS: cell-traversal protein for ookinetes and sporozoites of P. vivax. A protein important for parasite traversal of host cells both for ookinetes in the mosquito and for sporozoites. (Alves et al., 2017)
PvCelTOS (Ad): Recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS. PvCelTOS (protein): PvCelTOS expressed as a protein using HEK293T cells, a eukaryotic cell expression system. **PvCelTOS (Ad) is the primary vaccination, and PvCelTOS (protein) is the booster. (Alves et al., 2017)
Vaccination Protocol:
3 groups of mice were used, each group includes 6 mice. Mice were intramuscularly inject prime immune 1*10^8 IU ChAd63-PvCelTOS, then intramuscularly injected one of the boosters 8 weeks later: 1*10^6 PFU per ml of 1) PvCelTOS (MVA), 2) PvCelTOS (VLPs), 3) PvCelTOS (protein) (Alves et al., 2017)
Immune Response:
Humoral: anti-PvCelTOS antibody levels significantly increased after vaccination in both types of mice. Antibody responses were boosted with all three vaccine platforms, and boosting with protein in the Matrix-M adjuvant consistently elicited the highest titers. Cellular: CD-1: Mice in Ad-protein group had no significant cellular responses. BALB/c: All immunization regimens substantially higher levels of TNF-α- and IFN-γ-producing CD3+/CD8+ cells. (Alves et al., 2017)
Challenge Protocol:
Same prime-boost vaccination performed (6 mice in each BALB/c group, 10 mice in each CD1 group). Three set of mice were each challenged with 1000 sporozoits of 1) Pb-PvCelTOS (P. berghei expressing P. vivax CelTOS), 2) Wild-type P.berghei, and 3) Pb-PfCelTOS (P. berghei sporozoites expressing P. falciparum CelTOS). Sporozoits were intravenous injected 10 days after booster. Efficacy was determined by measuring the prepatent period (the time to reach 1% parasitemia after challenge). (Alves et al., 2017)
Efficacy:
Pb-PvCelTOS: CD1: 30% sterile protection, significantly higher than control. BALB/c: no vaccination regimen conferred any protective efficacy even though it induced protective cellular and humoral immune responses. Pb-PfCelTOS: 20% protection in CD1 mice, significantly higher than control. Wild-type P. berghei: no protective immunity from any immunization regimen in CD1 mice. *Regardless of the parasite line, Ad-protein induced the highest levels of protection. (Alves et al., 2017)
3. Ad-VLPs PvCelTOS
a. Type:
Recombinant vector vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Human
d. Antigen
PvCelTOS: cell-traversal protein for ookinetes and sporozoites of P. vivax. A protein important for parasite traversal of host cells both for ookinetes in the mosquito and for sporozoites. (Alves et al., 2017)
PvCelTOS (Ad): Recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS. PvCelTOS (VLPs): PvCelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs) **PvCelTOS (Ad) is the primary vaccination, and PvCelTOS (VLPs) is the booster. (Alves et al., 2017)
i.
Mouse Response
Vaccination Protocol:
3 groups of mice were used, each group includes 6 mice. Mice were intramuscularly inject prime immune 1*10^8 IU ChAd63-PvCelTOS, then intramuscularly injected one of the boosters 8 weeks later: 1*10^6 PFU per ml of 1) PvCelTOS (MVA), 2) PvCelTOS (VLPs), 3) PvCelTOS (protein) (Alves et al., 2017)
Immune Response:
Humoral: anti-PvCelTOS antibody levels significantly increased after vaccination in both types of mice. Antibody responses were boosted with all three vaccine platforms. Cellular: CD-1: Mice in Ad-VLPs group had no significant cellular responses. BALB/c: All immunization regimens substantially higher levels of TNF-α- and IFN-γ-producing CD3+/CD8+ cells. (Alves et al., 2017)
Challenge Protocol:
Same prime-boost vaccination performed (6 mice in each BALB/c group, 10 mice in each CD1 group). Three set of mice were each challenged with 1000 sporozoits of 1) Pb-PvCelTOS (P. berghei expressing P. vivax CelTOS), 2) Wild-type P.berghei, and 3) Pb-PfCelTOS (P. berghei sporozoites expressing P. falciparum CelTOS). Sporozoits were intravenous injected 10 days after booster. Efficacy was determined by measuring the prepatent period (the time to reach 1% parasitemia after challenge). (Alves et al., 2017)
Efficacy:
Pb-PvCelTOS: CD1: 30% sterile protection, significantly higher than control. BALB/c: no vaccination regimen conferred any protective efficacy even though it induced protective cellular and humoral immune responses. Pb-PfCelTOS: no protective immunity in CD1 mice. Wild-type P. berghei: no protective immunity from any immunization regimen in CD1 mice. (Alves et al., 2017)
4. AMA 49-CPE
a. Type:
Virosome-formulated synthetic peptides
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
A virosome-formulated P. falciparum protein derived synthetic peptide antigen (Genton et al., 2007)
e. Gene Engineering of
AMA1 from P. falciparum 3D7
Type:
Conjugate vaccine preparation
Description:
AMA 49-CPE is prepared as an apical membrane antigen-1 (AMA-1) derived synthetic phospatidylethanolamine (PE)-peptide conjugate (Genton et al., 2007)
AMA 49-CPE is an apical membrane antigen-1 (AMA-1) derived synthetic phospatidylethanolamine (PE)-peptide conjugate that serves as a malaria vaccine (Genton et al., 2007)
h.
Human Response
Host Strain:
healthy Caucasian volunteers aged 18-45 years
Immune Response:
50 microg antigen dose was associated with a higher mean antibody titer and seroconversion rate than the 10 microg dose (Genton et al., 2007)
Side Effects:
11/46 study participants reported 16 vaccine related local AEs of being in pain (Genton et al., 2007)
5. AMA1-C1Alhydrogel
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
AMA1-C1(Malkin et al., 2005): Apical membrane antigen 1. An 83-kDa antigen that may be involved in the process of erythrocyte invasion (Hodder et al., 2001).
e. Gene Engineering of
AMA1 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
An equal mixture of recombinant proteins based on sequences from the FVO and 3D7 P. falciparum, expressed in Pichia pastoris and adsorbed on Alhydrogel. (Malkin et al., 2005)
Vaccination Protocol:
Open-label, dose-escalating phase 1 clinical trial Ten volunteers in each of three dose groups (5 μg, 20 μg, and 80 μg of AMA1-C1) were vaccinated by a 0.5-ml intramuscular injection on study days 0, 28, and 180 (Malkin et al., 2005).
Immune Response:
Anti-AMA1 IgG antibodies: Two weeks after the second vaccination, 20%, 55%, and 89% individuals in 5-μg, 20-μg, and 80-μg groups respectively had detectable antibody responses to AMA1-3D7, and 20%, 55%, and 78% had detectable antibody responses to AMA1-FVO. There was significant dose-response relationship for both responses in the all groups on day 42. Antibody levels declined and became undetectable in 53% responders for the AMA1-3D7 and 43% responders for AMA1-FVO on ay180. 92% individuals boosted their antibody levels two weeks after the third vaccination, . Antibody responses from the 5-μg, 20-μg, and 80-μg groups were 153, 1,041, and 978 U on average for AMA-3D7 and 113, 649, and 712 U on average for AMA-FVO. A relationship was found between antigen dose and antibody response to AMA1-FVO two weeks after the third vaccination. Antibody level declined on day 364. (Malkin et al., 2005) Significant AMA specific inhibition of both P. falciparum 3D7 and FVO growth was achieved in the in vitro growth inhibition assay. (Malkin et al., 2005)
Side Effects:
Mild or moderate headaches, nausea, malaise and localized myalgia. (Malkin et al., 2005)
6. AMA1-C1Alhydrogel + CPG 7909
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
AMA1-C1 (NIAID, 2006): Apical membrane antigen 1. An 83-kDa antigen that may be involved in the process of erythrocyte invasion (Hodder et al., 2001).
e. Gene Engineering of
AMA1 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
An equal mixture of recombinant proteins based on sequences from the FVO and 3D7 P. falciparum, expressed in Pichia pastoris and adsorbed on Alhydrogel. (Malkin et al., 2005)
Vaccination Protocol:
Double blind Phase 1 trial 24 participants were randomly assigned to one of the two groups: 12 volunteers will receive two doses of 80 microgram AMA1-C1/Alhydrogel + 500 microgram CPG; 12 volunteers will receive 80 microgram AMA1-C1/Alhydrogel, both at a 1-month dosing interval. (NIAID, 2006)
ChAd63: Chimpanzee adenovirus: vector for prime vaccination (Hou et al., 2022), MVA: modified vaccinia Ankara: vector for booster vaccination (Hou et al., 2022)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Prime-boosting vaccine that use different vectors: ChAd63 PvDBP is the prime vaccination and MVA PvDBP is the booster. (Hou et al., 2022)
i.
Human Response
Vaccination Protocol:
Non-randomized, Phase IIa study. Group 1 participants received 5 x 10^10 vp ChAd63 PvDBP and 2 x 10^8 pfu MVA PvDBP 8 weeks later, followed by CHMI 2–4 weeks later. Group 2 received one dose of 5 x 10^10 vp ChAd63 PvDBP, and 12-18 months later received a second dose of 5 x 10^10 vp ChAd63 PvDBP and 8 weeks later 2 x 10^8 pfu MVA PvDBP. Group 3 participants received 5 x 10^10 vp ChAd63 PvDBP and 2 x 10^8 pfu MVA PvDBP 8 weeks later, followed by CHMI 2–4 weeks later. Group 3 participants received the first dose 2 years later than participants in group 1 and had CHMI at the same time with participants in Group 2. (Hou et al., 2022)
Challenge Protocol:
CHMI 2–4 weeks after booster vaccination (Hou et al., 2022)
Efficacy:
All volunteers developed parasitemia. There was no significant difference in PMR or LCP compared to the controls. (Hou et al., 2022)
ChAd63: replication-deficient chimpanzee adenovirus: vector for prime vaccination (Sheehy et al., 2012); MVA: attenuated orthopoxvirusmodified vaccinia virus Ankara: vector for booster vaccination (Sheehy et al., 2012)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Prime-boosting combination that use the same antigen but different vectors: ChAd63 MSP1 is the prime vaccination and MVA MSP1 is the booster.(Sheehy et al., 2012)
Vaccination Protocol:
Phase Ia, open-label, non-randomized blood stage malaria vaccine trial Participants were divided into two groups: Group 1 (eight volunteers) received 5 × 10^9 viral particles ChAd63 AMA1 diluted in 0.9% NaCl and administered in 300 µL as primary vaccination, and four of these received 5 × 10^8 pfu MVA AMA1 undiluted and administered in 200 µL as booster 56 days later. Group 2 (8 volunteers) received 5 × 10^10 viral particles ChAd63 AMA1 undiluted and administered in 300 µL as primary vaccination, and four of these received MVA AMA1 as booster 56 days later: one received 2.5×10^8 pfu undiluted and administered in 100 µL, and the rest (three volunteers) received 1.25×10^8 pfu undiluted and administered in 50 µL. (Sheehy et al., 2012)
Immune Response:
Cellular: peak of IFN-γ SFC response at day 14, no significant difference between the two groups (921 vs 933 SFU/million PBMCs in higher vs lower group). Responses contracted by day 56. After MVA MSP1: responses were significantly boosted, stronger response in the highest dose group (7186 vs 2631SFU/million PBMCs in 5×10^8 group vs lower dose group).CD4+ and CD8+ responses were detectable: CD8+ upregulated CD107a expression and produced IFN-γ and TNFα, and CD4+ produced high levels of TNFα.
Humoral: serum IgG antibody response detectable. Peak of antibody responses against AMA1 at day 28, significantly stronger responses in the higher dose group (109 vs 37 AU). Response declined slowly but was maintained at day 90. After MVA MSP1: responses were significantly boosted and reached peak at day 84, no significant difference between the lower dose groups and the highest dose group (1709 vs 949 AU). Response declined but was maintained at day 140 (971 vs 547 AU). (Sheehy et al., 2012)
Side Effects:
Local: swelling, pruritus, warmth, erythema, and pain. Systematic: nausea, malaise, headache, fever, feverish, fatigue, arthralgia, and myalgia Most AEs were mild in severity and all resolved completely. (Sheehy et al., 2012)
11. ChAd63-MVA ME-TRAP
a. Type:
Recombinant vector vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
ME-TRAP: multiple epitope thrombospondin-related adhesion protein of the pre-erythrocyte stage P.falciparum (Mensah et al., 2016)
ChAd63: Chimpanzee adenovirus: vector for prime vaccination (Mensah et al., 2016), MVA: modified vaccinia Ankara: vector for booster vaccination (Mensah et al., 2016)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Prime-boosting vaccine that use different vectors: ChAd63 ME-TRAP is the prime vaccination and MVA ME-TRAP is the booster.
i.
Human Response
Host Strain:
Healthy men aged 18–50 years old in the peri-urban area of Dakar in Senegal, West Africa.
Vaccination Protocol:
Random, controlled, single-blinded phase IIb efficacy trial. Participants radomly receive either 1) ChAd63 ME-TRAP (5x105 vp) as prime vaccination and MVA ME-TRAP (2x108 pfu) as booster eight weeks later or 2) two doses of anti-rabies vaccine (0.5ml) at the same interval. (Mensah et al., 2016)
Immune Response:
Increases in anti-TRAP IgG responses. Cellular immunogenicity: TRAP-specific T cells induced 14 days after prime vaccination: 261 SFC per million PBMC (95% CI 165–412) compared with 48 SFC (95% CI 30–79 SFC) in control group. 7 days after booster: 932 SFC (95% CI 754–1152) compared with 57 SFC per million (95% CI 44–72) in control group. Humoral: TRAP peptide pools 1, 2, 3 and 6 frequently recognized: 66–93% positive response to these pools at the peak time point after MVA in TRAP group, comparing with 19% positive response to pool 3 and 10% positive response to pool 1 in control group. Positive correlation between humoral and cellular immunogenicity. Neutralising antibodies to the ChAd63 vector detected: LGMT of 216 (95% CI 188–247), 56% responses above the clinically relevant threshold of 200.(Mensah et al., 2016)
Side Effects:
ChAd63: Solicited local AEs: Mild or moderate pain, itching, redness, swelling, and warmth. Systematic AEs: fever, myalgia, discomfort, headache, arthralgia, and nausea. MVA: more reactogenic than ChAd63, but still tolerable for the majority. Solicited local AEs: swelling, pain, itching, and warmth (last between a few hours to 2 days). Systematic AEs: arthralgia, fever, headache, myalgia, nausea, and discomfort (Mensah et al., 2016)
Efficacy:
PCR positive cases:12 of 57 in TRAP group, 13 of 58 in controls: 8% efficacy, but not statistically significant. Malaria cases: 11 in TRAP group, 12 in control group: unadjusted efficacy of 9%, non-significant. *protocol-specified metaanalysis after pooling the data of the Kenyan and Senegalese trials showed significant protective efficacy of 50% (95% CI 17%-70%). (Mensah et al., 2016)
ChAd63: replication-deficient chimpanzee adenovirus: vector for prime vaccination (Sheehy et al., 2011), MVA: attenuated orthopoxvirusmodified vaccinia virus Ankara: vector for booster vaccination (Sheehy et al., 2011)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Prime-boosting combination that use the same antigen but different vectors: ChAd63 MSP1 is the prime vaccination and MVA MSP1 is the booster. (Sheehy et al., 2011)
Vaccination Protocol:
Phase Ia, non-randomized study. Participants were separated into two groups: 1) Six volunteers received 5 × 10^9 viral particles ChAd63 MSP1 as primary vaccination, and four of these received 5 × 10^8 pfu MVA MSP1 as booster 56 days later. 2) 10 volunteers received 5 × 10^10 viral particles ChAd63 MSP1 as primary vaccination, and eight of these received 5 × 10^8 pfu MVA MSP1 as booster 56 days later. (Sheehy et al., 2011)
Immune Response:
Cellular: peak of IFN-γ SFC response at day 14, stronger response in higher dose group (2,785 versus 979 SFU/million PBMC). Responses contracted by day 56 and were maintained at day 90. After MVA MSP1: responses were boosted and maintained at high level at day 140 with significantly stronger response in higher dose group (1,640 versus 1,347 SFU/million PBMC). Both CD4+ and CD8+ responses were detectable after peptide restimulation on day 84.
Humoral: peak of antibody responses against MSP119 at day 28, stronger response in higher dose group (53.1 versus 7.8 MSP1 AU). Responses contracted by day 56, and only responses in higher dose group were maintained at day 90. After MVA MSP1: responses were significantly boosted and reached peak at day 84, stronger response in higher dose group (4,266 versus 1,618 MSP1 AU). Response maintained at day 140, and higher dose group had stronger response. (Sheehy et al., 2011)
Side Effects:
Local: swelling, pruritus, warmth, erythema, and pain. Systematic: nausea, malaise, headache, fever, feverish, fatigue, arthralgia, and myalgia Most of the AEs were mild in severity and all resolved completely. (Sheehy et al., 2011)
Challenge Protocol:
Sporozoite malaria challenge 12-28 days post second vaccination. (Hill et al., 2009)
13. ChAd63-MVA RH5
a. Type:
Recombinant vector vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
RH5: reticulocyte–binding protein homolog 5: forms a critical nonredundant interaction with its receptor basigin (CD147) on the RBC surface. (Payne et al., 2017)
e. Gene Engineering of
RH5
Type:
Recombinant protein preparation
Description:
reticulocyte–binding protein homolog 5 full length sequence (Payne et al., 2017)
Vaccination Protocol:
Phase I, non-randomized, dose-escalation study. Participants were assigned to one of the four groups: 1) 4 volunteers received 1 dose of ChAd63 RH5 5 x 10^9 vp, 2) 4 volunteers received 1 dose of ChAd63 RH5 5 x 10^10 vp, 3) 8 volunteers received 1 dose of ChAd63 RH5 at 5 x 10^10 vp and 1 dose MVA RH5 at 1 x 10^8 pfu 8 weeks later, 4) 8volunteers received 1 dose of ChAd63 RH5 at 5 x 10^10 vp and 1 dose MVA RH5 at 2 x 10^8 pfu 8 weeks later (Payne et al., 2017)
Immune Response:
Cellular: peak of the response on day 14 after primary vaccination, no significant difference between lower-dose priming and higher-dose priming group. Responses contracted by day 56. The booster dose boosted the responses in all volunteers as measured on day 63, no significant difference between lower-dose booster and higher-dose booster group. Humoral: induced IgG1 and IgG3 serum antibody response and memory B cells (mBCs). 2 of 4 volunteers in lower-dose priming group and 16 of 20 volunteers in higher-dose priming group showed a detectable response on day 28. Response maintained prior to administration of booster and was boosted as measured on day 84. There was significant difference between high-dose booster group and no booster group. Response in higher-dose booster group tended to be higher than that in lower-dose booster group, but did not reach significance. Response decreased by day 140. (Payne et al., 2017)
Side Effects:
Systematic: nausea, fever, arthralgia, feverish, malaise, myalgia, fatigue, headache; Local: itch, redness, warmth, swelling, pain. Most mild or moderate in severity, all resolved in 24 hours. (Payne et al., 2017)
14. ChAd63/MVA Pfs25-IMX313
a. Type:
Recombinant vector vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Baboon
d. Antigen
Pfs25 is a sexual stage antigen of Plasmodium falciparum that is expressed on the surface of the zygote and ookinete forms of the parasite, where it is involved in ookinete formation (de Graaf et al., 2021)
e. Gene Engineering of
Pfs25 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
Recombinant Pfs25 was used as the vaccine antigen.
Replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoded Pfs25-IMX313. (de Graaf et al., 2021)
g. Preparation
For the Pfs25-IMX313 constructs a 229 bp DNA fragment encoding the IMX313 domain was cloned at the C-terminus of Pfs25. The Pfs25-IMX313 insert was subcloned into the ChAd63 and MVA destination and shuttle vectors. (de Graaf et al., 2021)
h. Immunization Route
Intramuscular injection (i.m.)
i. Description
ChAd63/MVA Pfs25-IMX313 uses Pfs25, the vaccine antigen, fused to IMX313 which functions as the adjuvant, and expressed in recombinant replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and an attenuated orthopoxvirus MVA viral vectors.
j.
Human Response
Host Strain:
Healthy Adults
Vaccination Protocol:
Adults were vaccinated with 5x1010vp of ChAd63 Pfs25-IMX313 followed by 1x108pfu of MVA Pfs25-IMX313 56 days after the first vaccination. (de Graaf et al., 2021)
Immune Response:
Vaccination with ChAd63/MVA Pfs25-IMX313 induced antigen-specific T cell responses in all volunteers; IFN-γ T cell responses were induced and peaked at median levels of greater than 2,000 SFU/million PBMCs following the MVA boost. The kinetics and magnitude of the anti-Pfs25 serum IgG antibody response were assessed over time by ELISA against Pfs25 recombinant protein. Priming vaccination with 5 × 1010 vp ChAd63 Pfs25-IMX313 followed by MVA Pfs25-IMX313 boost induced antigen-specific IgG responses in all volunteers. Median transmission reducing activity was 7.2% (range -5.8% to 37.3%) in Group 2B and 25.3% (range 10.2% to 41.3%) in Group 2C. There was no significant inhibition of oocyst intensity, further progression of research unlikely. (de Graaf et al., 2021)
Side Effects:
There were no serious adverse events (SAEs) or unexpected reactions during the course of the trial and no volunteers withdrew due to vaccine-related adverse events (AEs). The reactogenicity of the vaccines was similar to that seen in previous malaria vaccine trials using the same viral vectors at similar doses in healthy adultswith the higher doses of both vaccines associated with an increased number of reported AEs. (de Graaf et al., 2021)
15. FMP012 with AS01B adjuvant system
a. Type:
Recombinant vector vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
FMP012: Escherichia coli-expressed P. falciparum cell-traversal protein for ookinetes and sporozoites (PfCelTOS) (Bennett et al., 2014)
Vaccination Protocol:
Phase 1, non-randomized study Participants were randomly assigned in 2 groups: 1). 10 µg FMP012 antigen reconstituted with 500 µL AS01B adjuvant to equal 0.5 mL final volume. Doses administered intramuscular at week 0, 4, 8, and 24. and 2). 30 µg FMP012 antigen reconstituted with 500 µL AS01B adjuvant to equal 0.5 mL final volume. Doses administered intramuscular at week 2, 6, 10, and 24. (Bennett et al., 2014)
Apical membrane antigen 1 (AMA-1) is an asexual blood stage antigen. AMA-1 is considered to be an important candidate malaria vaccine antigen (Morais et al., 2006; Polhemus et al., 2007).
d. Gene Engineering of
AMA1 from P. falciparum 3D7
Description:
The Plasmodium falciparum vaccine candidate FMP2.1/AS02A , a recombinant E coli-expressed protein based upon the apical membrane antigen-1 (AMA-1 ) of the 3D7 clone formulated with the AS02A adjuvant(Polhemus et al., 2007)
f. Preparation
FMP2.1 antigen represents amino acids #83-531 of the P. falciparum (clone 3D7) AMA-1 protein. Just prior to immunization, the lyophilized FMP2.1 protein was mixed with AS02A such that approximately 8, 20 or 40 μg of FMP2.1 was delivered in a final volume of 0.5 mL of AS02A (Polhemus et al., 2007).
g.
Human Response
Vaccination Protocol:
An open-label, staggered-start, dose-escalating Phase I trial was conducted in 23 malaria-naïve volunteers who received 8, 20 or 40 μg of FMP2.1 in a fixed volume of 0.5 mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations (Polhemus et al., 2007).
Immune Response:
All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-γ and IL-5 ELISPOT assay responses (Polhemus et al., 2007).
Side Effects:
The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events.
17. MSP3-CRM-Vac4All/ Alhydrogel®
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
MSP3 (Thera et al., 2022): merozoite surface protein 3. Presents on the surface of merozoites, forms a protein complex with MSP1, MSP6 and MSP7.The protein complex is bound to receptors during the invasion of erythrocytic cells. (Coelho et al., 2019)
A protein-protein conjugate malaria and helminth TBV that uses a modified msp3 protein as an antigen and Alhydrogel (R) and CRM197 as adjuvant.
h.
Human Response
Vaccination Protocol:
Phase I, Randomised, Dose-Finding Single Center Study, not started. Participants will be randomly put into three groups and will receive 3 doses of MSP3-CRM-Vac4All/ Alhydrogel®. Each group will receive different dose levels of MSP3-CRM-Vac4All/ Alhydrogel®: 3 µg, 10 µg, or 30 µg total MSP3-CRM197 conjugate protein (corresponding to 1, 3, 10 µg MSP3 protein). Participants will receive vaccination on day 1, day 28, and day 56 of the study. (Thera et al., 2022)
The merozoite surface protein-3 long synthetic peptide (MSP3-LSP) comprises the amino acid sequence 186-276 of the Plasmodium falciparum protein MSP3 (Sirima et al., 2007). The C-terminal conserved region of Plasmodium falciparum merozoite surface protein 3 (MSP3) is the trigger antigen of a protective immune response mediated by cytophilic antibodies (Audran et al., 2005).
Description:
aluminium hydroxide (Sirima et al., 2007). In another phase I clinical trial study using MSP3-LSP, two adjuvants were used, including Montanide ISA 720 and aluminum hydroxide (Audran et al., 2005). However, it showed that it was unacceptably reactogenic when it was combined with Montanide (Audran et al., 2005).
e. Virulence
No.
f.
Human Response
Host Strain:
healthy male adults Africans
Vaccination Protocol:
A Phase 1b single-blind controlled trial was performed in the village of Balonghin in Burkina Faso. Thirty male volunteers aged 18-40 years were randomised to receive either three doses of 30 microg MSP3-LSP or 0.5 ml of tetanus toxoid vaccine . The second and third vaccine doses were given 28 and 112 days after the first dose . Participants for 1 year were followed for one year (Sirima et al., 2007).
Persistence:
Immune response did not wane appreciably up to 365 days post-vaccination (Sirima et al., 2007).
Immune Response:
Humoral immune responses (IgG, IgG subclasses, IgM) to MSP3-LSP peptide were similar in the two groups following vaccination. Some cell-mediated immune responses appeared to differ between the two vaccine groups. After the second dose of MSP3-LSP, there appeared to be a marked increase in the lymphocyte proliferation index and IFN-gamma in response to stimulation with MSP3-LSP (Sirima et al., 2007).
Side Effects:
There were no serious adverse events in either vaccine group. In both groups participants reported local reactions at the site of injection when compared to an earlier trial in European volunteers. Only one systemic adverse event ( tachycardia ) was identified which occurred immediately after the first vaccination in one individual receiving MSP3-LSP. No clinically significant biological abnormalities following vaccination were observed (Sirima et al., 2007).
Description:
In summary, this Phase 1b single-blind controlled trial showed that three doses of 30 microg MSP3-LSP when administered subcutaneously on days 0 , 28 and 112 are well-tolerated by adult males previously exposed to natural P falciparum infection. MSP3-LSP is able to stimulate an enhanced cell-mediated immune response in individuals with some degree of preexisting immunity (Sirima et al., 2007).
(Coutant et al., 2012) nonintegrative lentiviral vectors (NILV) encoding Plasmodium yoelii Circumsporozoite Protein (Py CSP), and challenged with sporozoites one month later. 50% (37.5-62.5) of the animals were fully protected. Moreover, protection was long-lasting with 42.8% sterile protection six months after the last immunization.
(Lanar et al., 1996) NYVAC-based vaccinia virus recombinants expressing the circumsporozoite protein (CSP) were evaluated in the Plasmodium berghei rodent malaria model system. Immunization of mice with a NYVAC-based CSP recombinant elicited a high level of protection (60 to 100%).
A tandem repeat of the B cell immunodominant repeat epitope (DPPPPNPN)2D of the malaria parasite Plasmodium berghei circumsporozoite protein (P4c-Mal) (Kaba et al., 2009).
e. Gene Engineering of
CS from P. berghei str. ANKA
Vaccination Protocol:
Mice were randomly divided into groups of 5 or 10 and immunized i.p. three times at 14-day intervals. Where indicated, a positive control group was immunized with irradiated P. berghei sporozoites (Kaba et al., 2009).
Challenge Protocol: P. berghei sporozoites (ANKA strain), maintained by cyclical transmission in mice and Anopheles stephensi, were dissected from mosquitoes 21–23 days after their infectious blood meal and used within 6 h. Fourteen days after the final immunization or at other specific times on long-term memory experiments, mice were challenged with a lethal dose of live P. berghei sporozoites by i.v. inoculation. C57BL/6, MHC KO, and nude mice were injected with 1000 sporozoites and BALB/c mice were injected with 4000 sporozoites per mouse (Kaba et al., 2009).
Efficacy:
More than 95% of mice immunized with P4c-Mal, both with and without Montanide ISA-720, or R-PbCSP in Montanide ISA-720 did not develop any parasitemia and thus showed complete protection against challenge with viable sporozoites (Fig. 2B). This ability to prevent parasitemia and thus prevent malaria following sporozoite challenge is equivalent to what is only achieved with the whole, irradiated sporozoite immunization regime. In contrast, as few as 5% of animals administered saline, saline and Montanide ISA-720, or R-PbCSP in saline did not develop parasites and survived until 11 days post challenge. No animal was observed with blood stage parasites that did not die naturally or was killed according to protocol. These results show that immunization with P4c-Mal had a significant ability to induce a protective immune response in the presence as well as in the absence of adjuvant (Kaba et al., 2009).
Efficacy:
Vaccination with CSP-3p28 resulted in better (100%) protection than CSP alone (60%) against P. berghei sporozoites at the 6-week challenge (p = 0.043) suggesting that the addition of 3 copies of the p28 peptide to CSP results in the generation of a better vaccine (Bergmann-Leitner et al., 2007).
Efficacy:
Protection obtained by gene gun delivery into the liver once (73%) was significantly higher than that by the material into the skin twice (31%) (Yoshida et al., 2000).
Vaccination Protocol:
Lyophilized rPbMSP1 was mixed with alum on the day of injection. Each vaccine formulation, containing 10 ug was administered through IP route to mice .
Challenge Protocol:
For challenge study, mice were intraperitoneally inoculated with parasitized erythrocytes at a density of either 10^6 or 10^5 parasitized erythrocytes per mouse (Wan et al., 2007).
Efficacy:
Eight out of ten mice vaccinated with rMSP1 in alum survived challenge with P. berghei (Wan et al., 2007).
Vaccination Protocol:
Groups of three to five mice were immunized i.p. with 15 µg of rAMA1B emulsified in Montanide ISA720. Four weeks later, a booster immunization was given using the same amount of rAMA1B emulsified with Montanide ISA720. Controls were immunized with PBS emulsified in Montanide ISA720 (Xu et al., 2000).
Challenge Protocol:
Ten days after being given a booster immunization the mice were challenged i.v. with 1 x 10^5 P. chabaudi adami parasitized erythrocytes (Xu et al., 2000).
Efficacy:
Immunized mice demonstrated significantly lower peak parasitemias compared with PBS-immunized mice, showing that rAMA1B immunization confers protection against challenge with P. chabaudi (Xu et al., 2000).
29. P. falciparum CS expressed in irradiated P. berghei as Vaccine
Vaccination Protocol:
In order to induce sterile immunity in all the animals, BALB/cJ mice were immunized with 12,000 rad-irradiated P. berghei sporozoites as follows: one dose of 75,000 sporozoites followed by two booster doses of 25,00 of P. berghei sporozoites on days 15 and 21. In [BALB/c×C57BL/6] F1 mice immunisation was made with 3 injections of 10,000 P. berghei irradiated sporozoites at days 0, 15 and 21 (Grüner et al., 2007).
Challenge Protocol:
Control mice and mice immunized with irradiated sporozoites (transfected with P. falciparum CS) were challenged intravenously with 5,000 P. berghei or P. berghei [PfCS] sporozoites (Grüner et al., 2007).
Efficacy:
Mice immunized with irradiated sporozoites were protected from challenge (Grüner et al., 2007).
Multiple epitope-thrombospondin-related adhesion protein (ME-TRAP)
f. Gene Engineering of
TRAP from P. falciparum
Type:
Epitope construction used for delivery vector
Description:
Multiple epitopes from the thrombospondin-related adhesion protein were prepared. The ME-TRAP were then introduced into three delivery vectors: DNA and modified vaccinia virus Ankara (MVA) (Dunachie et al., 2006).
DNA and modified vaccinia virus Ankara (MVA) prime-boost regimes were assessed by using either thrombospondin-related adhesion protein (TRAP) with a multiple-epitope string ME (ME-TRAP) (Dunachie et al., 2006).
i. Description
The T-cell responses induced by this prime-boost regime , in animals and humans, are substantially greater than the sum of the responses induced by DNA or MVA vaccines used alone, leading to the term introduced here of "synergistic" prime-boost immunisation.
j.
Human Response
Vaccination Protocol:
Sixteen healthy subjects who never had malaria (malaria-naive subjects) received two priming vaccinations with DNA, followed by one boosting immunization with MVA, with ME-TRAP (Dunachie et al., 2006).
Immune Response:
The vaccines were well tolerated and immunogenic, with the DDM-ME TRAP regimen producing strong ex vivo IFN-gamma ELISPOT responses
Challenge Protocol:
Two weeks after the final vaccination, the subjects underwent P. falciparum sporozoite challenge, with six unvaccinated controls.
Efficacy:
One of eight subjects receiving the DDM-ME TRAP regimen was completely protected against malaria challenge, with this group as a whole showing significant delay to parasitemia compared to controls (P = 0.045). The peak ex vivo IFN-gamma ELISPOT response in this group correlated strongly with the number of days to parasitemia (P = 0.033). Therefore, prime-boost vaccination with DNA and MVA encoding ME-TRAP resulted in partial protection against P. falciparum sporozoite challenge in the present study (Dunachie et al., 2006).
Vaccination Protocol:
Intradermal delivery of DNA vaccines was performed under light sedation with Ketamine at 20 mg/kg intramuscularly, using a 1 mL insulin syringe with a fused 29-gauge 0.5-inch needle. Monkeys received a total of 500 μg of plasmid DNA in saline in a series of four immunizations at weeks 0, 3, 6, and 47 on the lower back on six different sites. The maximal volume administered in any one site was 100 μl (Sim et al., 2001).
Challenge Protocol:
Aotus monkeys were challenged with 1 X 10^4 P. falciparum (FVO) infected erythrocytes (Sim et al., 2001).
Efficacy:
One of three monkeys vaccinated with EBA-175 was protected from challenge of parasitized erythrocytes (Sim et al., 2001).
Vaccination Protocol:
Monkeys were immunized on days 0, 21, and 42 with 120/~g of protein in PBS/0.1% SDS. Each dose consisted of 1.5ml emulsified with Freund's complete adjuvant for the first immunization and Freund's incomplete adjuvant for the others, injected subcutaneously on multiple sites in the back. Control monkeys received the same treatment but without parasite proteins (Bonnefoy et al., 1994).
Challenge Protocol:
All monkeys were challenged on day 56 by intravenous injection of 5 x 10^7 FUP/SP-infected monkey erythrocytes (Bonnefoy et al., 1994).
Efficacy:
The three control monkeys showed a rapid rise of parasitaemia with a prepatent period of 2 days and required drug treatment within 7 days to prevent fatal outcome. Three immunized monkeys developed a reduced parasitaemia with a prepatent period of 2 to 6 days with a maximum peak of parasitaemia of 5-11.6% that dropped spontaneously. The two other immunized monkeys developed parasitaemia similar to the controls and were drug-cured at day 7 (Bonnefoy et al., 1994).
Recombinant proteins GST-DG729, GST-NN and GST-PC were designed to cover 95% of the LSA-3 antigen and were used as a mixture (called LSA-3 GST-rec) (Daubersies et al., 2000).
Vaccination Protocol:
50 μg of recombinant LSA-3 peptides were emulsified in Montanide ISA51 and were injected subcutaneously into chimpanzees (Daubersies et al., 2000).
Challenge Protocol:
All chimpanzees were immunized at weeks 0, 4 and 8 and were challenged with 2 x 10^4 sporozoites at week 13 (Daubersies et al., 2000).
Efficacy:
Immunization with LSA-3 induced protection against successive heterologous challenges with large numbers of P. falciparum sporozoites (Daubersies et al., 2000).
Vaccination Protocol:
Sheep were immunized intramuscularly (i.m.) in the left rear leg, with a second immunization in the right rear leg 4 weeks later. A 100 μg antigen dose was delivered in 1.0 ml. Serum was prepared from bleeds taken prior to the first immunization, 3 or 4 weeks later (i.e. prior to the second dose), and a final bleed 2 weeks after the second immunization (Pye et al., 1997).
Immune Response:
Sheep immunized with MSA-2 and SAF-1 had higher antibody response than sheep immunized with MSA-2 and alhydrogel (Pye et al., 1997).
35. P. falciparum MSP1 from transgenic mice with Freund's adjuvant
Description:
The initial vaccinations were emulsified with complete Freund's adjuvant (Sigma), and the next two with incomplete Freund's adjuvant (Sigma) (Stowers et al., 2002).
Description:
The initial vaccinations were emulsified with complete Freund's adjuvant (Sigma), and the next two with incomplete Freund's adjuvant (Sigma) (Stowers et al., 2002).
g. Preparation
Two strains of transgenic mice were generated that secrete into their milk a malaria vaccine candidate, the 42-kDa C-terminal portion of Plasmodium falciparum merozoite surface protein 1 (MSP1-42). One strain secretes an MSP1-42 with an amino acid sequence homologous to that of the FVO parasite line. In the other strain, an MSP1-42 where two putative N-linked glycosylation sites in the FVO sequence have been removed. Both forms of MSP142 were purified from whole milk to greater than 91% homogeneity at high yields (Stowers et al., 2002).
h. Virulence
None.
i. Description
It is likely for producing efficacious malarial vaccines in transgenic animals (Stowers et al., 2002).
j.
Monkey Response
Host Strain:
owl monkey (Aotus nancymai)
Vaccination Protocol:
In total 28 monkeys were randomly assigned to groups of seven. The three vaccine groups received bvMSP1-42, TgMSP1-42 NG, and TgMSP1-42 G, respectively, and the fourth group placebo. Monkeys received three vaccinations of 100 µg of the respective recombinant protein 3 wk apart, following our established protocol. The initial vaccinations were emulsified with complete Freund's adjuvant (Sigma), and the next two with incomplete Freund's adjuvant (Sigma) (Stowers et al., 2002).
Immune Response:
There was a significant difference in the Endpoint ELISA titers to bvMSP142 between those animals vaccinated with bvMSP142 and TgMSP142 G (P = 0.008), and between those vaccinated with TgMSP142 NG and TgMSP142 G (P = 0.05). No differences in titers were observed between the bvMSP142 and TgMSP142 NG groups. No significant differences were seen in ELISA titers to other antigens (TgMSP142 NG, TgMSP142 G, or MSP119), nor were any significant differences seen in IFA titers against P. falciparum FVO parasites. Overall, antibody titers to none of the four antigens used as ELISA capture antigens (bvMSP142, TgMSP142 NG, TgMSP142 G, or MSP119) correlated with the primary outcome of protection as defined above (cumulative parasitemia until first monkey treated for anemia). However, antibody titers to bvMSP142 did correlate with days until treatment (r2 = 0.6241, P = 0.005) and inversely with parasitemia at time of treatment (r2 = -0.4206, P = 0.05) (Stowers et al., 2002).
Side Effects:
During vaccination, three animals died (two in the TgMSP142 NG group and one in the TgMSP142 G group), unfortunately not a rare occurrence with these fragile monkeys. No animals died during the second study. When partially protected from P. falciparum malaria, it is a characteristic of Aotus monkeys that some protected animals will suffer from anemia (Stowers et al., 2002).
Challenge Protocol:
Vaccinated monkeys were challenged 15 days after the third vaccination by i.v. infusion of a freshly passaged preparation of 10^4 infected RBC of the highly virulent P. falciparum FVO strain. Monkeys were treated when parasitemia reached 5%, or their hematocrit fell below 20%. All monkeys not treated previously were treated on day 30. The treatment consisted of mefloquine administered in a single dose of 25 mg/kg of body mass by intubation. The second Aotus challenge trial followed the protocol outlined above, with the exceptions that only two groups (TgMSP142 NG and placebo) and a larger challenge inoculum were used (1 ml of 5 × 104 pRBCs/ml) (Stowers et al., 2002).
Efficacy:
Vaccination with the glycosylated version of milk-derived MSP1(42) conferred no protection compared with an adjuvant control. Vaccination with the nonglycosylated, milk-derived MSP1(42) successfully protected the monkeys, with 4/5 animals able to control an otherwise lethal infection with P falciparum compared with 1/7 control animals (Stowers et al., 2002).
Description:
Analysis of the different vaccines used suggested that the differing nature of the glycosylation patterns may have played a critical role in determining efficacy (Stowers et al., 2002).
Vaccination Protocol:
Seven monkeys were vaccinated with 100 μg of EcMSP3, seven with 100 μg of control protein Pfs25, a parasite protein expressed during the mosquito stage of the life cycle. Each monkey received 0.125 mL of antigen emulsified in complete Freund's adjuvant at four sites, for a total of 0.5 mL, followed by two booster vaccinations with the same dose of antigen in a Montanide ISA51 (SEPPIC) formulation at 3-week intervals (Tsai et al., 2009).
Challenge Protocol:
Seventeen days after the third vaccination, the monkeys were challenged by intravenous infusion of 5 × 10^4 P. falciparum FVO strain parasitized RBCs collected from a naïve donor monkey (Tsai et al., 2009).
Efficacy:
By day 11 post-challenge, the parasitemia in all but one monkey in the control group had reached the predetermined upper limit and were treated In contrast, no animals in the EcMSP3-vaccinated group required treatment by this time (Tsai et al., 2009).
Vaccination Protocol:
MIce were immunized at 14-day intervals with three doses of 10 μg MSPs (Bracho et al., 2009).
Immune Response:
AFCo1 significantly enhanced the IgG and T-cell response against MSP4, with a potency equivalent to CFA, with the response being characterized by both IgG1 and IgG2a isotypes, increased interferon gamma production and a strong DTH response, consistent with the ability of AFCo1 to induce Th1-like immune responses (Bracho et al., 2009).
Vaccination Protocol:
Mice were immunized subcutaneously in the scruff of the neck three times with 25 or 10 or 1 µg/dose of recombinant PfCelTOS or saline emulsified in Montanide ISA 720 (Bergmann-Leitner et al., 2010).
Challenge Protocol:
Fourteen days after the final immunization, mice were challenged by subcutaneous inoculation (into the inguinal region) with 4,000 P. berghei sporozoites for Balb/c and 15,000 P. berghei sporozoites for CD-1 mice, dissected from infected mosquito salivary glands. The challenge dose was determined by titration studies in each mouse strain and compared to the different challenge routes. Infection was determined by the presence of blood stage parasites in Giemsa stained thin blood smears on day 6 and day 8 after challenge. Animals that were not infected at that time were tested again on day 14. Mice that remained un-infected by day 14 were classified as sterilely protected. We used this evaluation schedule because animals that are infected with P. berghei ANKA strain malaria parasites do not self-cure.
Efficacy Detail
No.
Efficacy method
Result
Description
Group Efficacy Detail
1
CFU
Immunization with PfCelTOS resulted in potent humoral and cellular immune responses and most importantly induced sterile protection against a heterologous challenge with P. berghei sporozoites in a proportion of both inbred and outbred mice (Bergmann-Leitner et al., 2010).
Vaccination Protocol:
Mice were injected intraperitoneally with r-Pfen emulsified in Freund's adjuvant at 21-day intervals (the first injection was 100 μg of r-Pfen in complete Freund's adjuvant, followed by 50 μg for the two boosters in incomplete Freund's adjuvant). In one control group, mice were injected in parallel with a recombinant Drosophila odorant binding protein OSF (as an irrelevant His-tagged protein control) emulsified in complete Freund's adjuvant. The other control group received no injections. After three immunizations, the antibody titers against r-Pfen were monitored (Pal-Bhowmick et al., 2007).
Challenge Protocol:
Mice having anti-r-Pfen antibody titers greater than 1:300,000 were then challenged with the lethal strain of P. yoelii (strain 17XL; 10^6 parasites per mouse), and parasitemia was monitored daily (Pal-Bhowmick et al., 2007).
Efficacy:
All the control mice and the mice immunized with the irrelevant His-tagged protein developed a high degree of parasitemia (>17% on average) by day 4 postchallenge, whereas r-Pfen-immunized mice showed <1% parasitemia at that time point. The highest average parasitemia values were 70% and 40% for nonimmunized mice and mice injected with irrelevant His-tagged protein, respectively. However, among the mice immunized with r-Pfen, there was significant delay in the increase in parasitemia, and the highest average parasitemia was about 20% on day 8 postchallenge. The averages of these groups were compared using one-way analysis of variance, which showed that the mice immunized with enolase were significantly protected (Pal-Bhowmick et al., 2007).
40. P. falciparum recombinant vector vaccine MVA.ME-TRAP
A prime boost P. falciparum vaccine that utilizes FP9 and MVA as recombinant vectors for priming and boosting, respectively (Webster et al., 2005).
g.
Human Response
Vaccination Protocol:
FFM Regime: FP9 priming, either once or twice, followed by MVA boosting (Webster et al., 2005).
Vaccine Immune Response Type:
VO_0000286
Immune Response:
Vaccine regimes with FP9 as the priming agent induced significantly more CD8+ T cells in addition to the CD4+ T cells. This finding suggests that induced CD8+ T cell responses may be of particular value in vaccination against liver-stage malaria (Webster et al., 2005).
Efficacy:
Two of five subjects who went on to a malaria challenge conducted 14 days after their final vaccination were completely protected. These two subjects were entered, without further vaccinations, into a second malaria challenge 6 months later in which one subject (137) remained completely protected. In addition, all 17 subjects immunized with this FFM regime (FP9 priming, once or twice, followed by MVA boosting) who underwent challenge, overall, compared with nonvaccinees, had a significant delay in time to onset of parasitemia (Webster et al., 2005).
Vaccination Protocol:
The monkeys, weighing between 680 and 760 g at the beginning of the experiment, were divided into two groups. Group1 monkeys (R57, R59, and R61) received SE36/AHG and Group2 monkeys (R60 and R62) received PBS as a control by intra-muscular injection in their left thigh 5 and 3 weeks before challenge infection. Monkey R61 received a third injection on the 2 weeks before challenge infection. The dose used was 50 μg SE36 protein with 500 μg aluminum hydroxide gel (50/500) in 0.5 ml of PBS. Group2 monkeys (R60 and R62) received the same volume of PBS (Horii et al., 2010).
Challenge Protocol:
Two weeks after the last immunization, all monkeys were challenged with P. falciparum-infected red blood cells. Each of the five squirrel monkeys received 1 × 10^9 parasitized red blood cells. Parasitemia was monitored daily by counting 5000 RBCs in Giemsa-stained thin blood smears (Horii et al., 2010).
Efficacy:
Whereas two control monkeys developed 10–20% peak parasitemia, the parasitemia in the two immunized monkeys with higher antibody titers stayed at low values below 3% (Fig. 3B). One vaccinated monkey (Monkey R61), with the lowest antibody titer, developed 5% peak parasitemia but was able to control parasitemia by Day 7 onwards. Importantly, control monkeys did not raise anti-SE36 IgG titer even after the onset of parasitemia which parallels the less immunogenicity of SERA5 N-terminal domain observed in endemic areas. Thus, although the observed protection was not able to prevent infection, vaccinated monkeys had lower parasitemia and booster effects on antibody titers were observed after infection for all vaccinated monkeys (Horii et al., 2010).
h.
Chimpanzee Response
Vaccination Protocol:
Three chimpanzees, named Satoru (7 years old male, 45 kg), Arare (10 years old female, 51 kg) and Mizuo (11 years old male, 60 kg) were born in Japan, and thus have no prior exposure to P. falciparum. Satoru, Arare and Mizuo received 10/100, 50/500 and 450/4500 SE36/AHG, respectively by subcutaneous injection on their backs after anesthetization with Ketamine hydrochloride (5 mg/kg) at Weeks 0, 4 and 8 (Horii et al., 2010).
Immune Response:
Chimpanzee immunization experiment, likewise, indicated the immunogenicity of SE36/AHG and a long duration of antibody production over 1-year with only a gradual decrease. Three chimpanzees were immunized with GMP-grade SE36/AHG of either 10/100, 50/500 or 450/4500 dose. Throughout the study, all blood biochemistry results were normal according to human standards and no signs of systemic aberrations were observed, except for the commonly observed swelling at the administration sites (Horii et al., 2010).
The vaccine Combination B contains three recombinant asexual blood-stage Plasmodium falciparum proteins: merozoite surface protein (MSP) 1, MSP2 and ring-infected erythrocyte surface antigen (RESA) (Genton et al., 2003).
e. Gene Engineering of
RESA
Type:
Recombinant protein preparation
Description:
The vaccine Combination B contains peptides from the ring-infected erythrocyte surface antigen (RESA) (Genton et al., 2003).
Description:
Montanide ISA 720. It is an oil composition containing a natural metabolizable oil and a highly refined emulsifier from the mannide mono-oleate family (Genton et al., 2003).
h. Preparation
Combination B is a malaria vaccine that comprises recombinant P falciparum blood-stage proteins MSP1, MSP2 and RESA, formulated with the adjuvant Montanide ISA 720 (Genton et al., 2003a). The three vaccine candidate antigens were produced by recombinant DNA technology. All three antigens were expressed in Escherichia coli with histidine tags to facilitate purification by nickel chelate chromatography. Two of the antigens, 190LCS.T3 (Ro 45-2067) and Ag1624 (Ro 46-2924), corresponded to parts of the well-characterized merozoite surface proteins MSP1 and MSP2, respectively. The MSP1 antigen was the 190L fragment from the K1 parasite line, comprising the relatively conserved blocks 3 & 4 of MSP1 fused with a universal T cell epitope derived from the circumsporozoite protein of P. falciparum. The MSP2 antigen corresponded to the near full-length MSP2 sequence of the 3D7 cloned line. Ag1505H (Ro 45-2164) consisted of the C-terminal 70% of RESA of the FCQ-27/PNG parasite line. All three antigens were supplied in separate vials at a concentration of 160 μg/ml of saline-Montanide ISA720 emulsion. Prior to use the three formulations were mixed and diluted with additional emulsion to give a dose of 15 μg of each antigen in a total volume of 0.55 ml (Genton et al., 2003).
i. Description
The "Combination B" vaccine resulted from a collaborative effort by the Papua New Guinea Institute for Medical Research along with the Australian Cooperative Research Center for Vaccine Technology in Queensland, The Walter and Eliza Hall Research Institute and the Swiss Tropical Institute (Girard et al., 2007). This vaccine has led to a considerable reduction of parasite density in the immunized children.
j.
Human Response
Host Strain:
Papua New Guinean children
Vaccination Protocol:
To insure safety, the enrolment and immunisations were done sequentially, with 10 days observation between each sub-cohort. It was started with one block (3 No SP+vaccine, 3 No SP+placebo, 3 SP+vaccine, 3 SP+placebo) of the older age group, then the remaining four blocks (12 No SP+vaccine, 12 No SP+placebo, 12 SP+vaccine, 12 SP+placebo) of this stratum, then one block of the younger age group, and then the remaining four blocks of this stratum. Children were given either SP or a sugar tablet (indistinguishable tablets provided by Hoffman La-Roche). During Week 0 they were injected i.m. in the left lateral thigh with the vaccine or placebo. Four weeks after the first injection, they received a second injection i.m. in the right lateral thigh (Genton et al., 2003).
Immune Response:
The vaccine induced significant antibody responses to all three antigens but triggered an IFN-γ response to MSP1 only. At Week 12, the IFN-γ response to MSP1 was substantially higher in the vaccine group where No SP had been given (Genton et al., 2003)
Side Effects:
No serious or severe AEs occurred. Moderate AEs were seen in 3% of the vaccine and 3% of the placebo recipients after first injection and in 12 and 10% after second injection (Genton et al., 2003).
Description:
This is a phase I-IIb double-blind randomised placebo-controlled trial was undertaken in 120 children aged 5-9 years.
43. P. knowlesi DNA vaccine encoding PkCSP, PkSSP2, PkAMA1, and PkMSP1p42
Challenge Protocol:
100 sporozoites were injected into the saphenous vein. Beginning on day 6 after challenge peripheral thick and thin blood films were examined to determine parasitemia. (Rogers et al., 2001)
Efficacy:
Following challenge with 100 P. knowlesi sporozoites, 1 of 12 experimental monkeys was completely protected and the mean parasitemia in the remaining monkeys was significantly lower than that in 4 control monkeys (Rogers et al., 2001).
P. vivax protein Pvs25 is the vaccine antigen. It is a protein composed of four cysteine-rich epidermal growth factor–like domains expressed on the surface of zygotes and ookinetes of P. vivax (Arevalo-Herrera et al., 2005).
Description:
Montanide ISA-720 an adjuvant suitable for human vaccination trials (Arevalo-Herrera et al., 2005).
f. Preparation
To produce a recombinant protein, Pvs25 was expressed in S. cerevisiae in a secreted form. Briefly, P. vivax genomic DNA from the Salvador I strain was used to amplify the gene fragment encoding the Pvs25 regions (Ala23-Leu195), which was inserted into the yeast episomal plasmid YEpRPEU-3 that encodes a secretory {alpha} factor containing a 6-His tail.12 Supernatants of fermentation were recovered by tangential microfiltration, concentrated by ultrafiltration, and extensively dialyzed. The retentate was incubated overnight at 4°C with Ni-nitrilotriacetic acid agarose. Proteins were purified by chromatography (Arevalo-Herrera et al., 2005).
Vaccination Protocol:
Male and female adult, malaria-naive Aotus monkeys were randomly allocated into two groups. An experimental group of six animals (group A) were immunized with the recombinant Pvs25 vaccine. A control group of three animals (group B) were immunized with adjuvant alone. Both groups were immunized on days 0, 60, and 120. Group A was inoculated with a total volume of 500 µL of vaccine formulated as 100 µg of the Pvs25 recombinant protein in Montanide ISA-720 in a 7:3 antigen:adjuvant ratio. Group B was injected with distilled water containing no protein and mixed in the same adjuvant following the same procedure. The immunization was performed by the subcutaneous route distributed in five different sites of the thorax and abdomen of each animal (Arevalo-Herrera et al., 2005).
Immune Response:
Antigen-specific antibody responses to the Pvs25 protein as determined by ELISA were evident by day 30 after the first immunization at low levels (61–478 units of anti-Pvs25). By day 60, at the time of the first boosting dose, responses of most animals were similar and by day 90, antibodies were boosted in all but two animals. Only one monkey had an apparent boost with the third antigen injection given on day 120. All animals had maximum antibody levels by day 150. These levels started to decrease by day 180, but were still detectable 10 months after the first immunization (Arevalo-Herrera et al., 2005).
Challenge Protocol:
Approximately 10 months after the last immunization (day 440) when specific antibodies to Pvs25 are no longer detected by ELISA, all monkeys were challenged with the P. vivax Salvador I strain by intravenous injection of 105 parasitized red blood cells. Total parasitemia and gametocytemia were followed every other day using thick and thin blood smears stained with Giemsa. Parasite concentrations were expressed as the number of gametocytes per microliter and the percentage of red blood cells parasitized by asexual parasite forms.19 Monkeys were bled post-challenge (days 447–503) to evaluate the presence of antibodies to Pvs25 by ELISA. In addition, the infectivity of circulating gametocytes was tested by feeding of An. albimanus mosquitoes with parasitized monkey red blood cells mixed with normal AB human sera using the MFA on days 460 (Arevalo-Herrera et al., 2005).
Efficacy:
All monkeys developed patent parasitemia by day 453, approximately two weeks after intravenous challenge. The peak of parasitemia for most of the monkeys was observed between days 462 and 464 with parasitemias and ranged from 0.1% to 1.3% as determined by thin blood smear. Gametocytes were first evident between days 458 and 460 and remained at detectable levels in all animals until day 468. Plasma samples obtained on days 447, 462, 482, and 503 after parasite challenge were negative for antibodies directed to the Pvs25 recombinant protein by ELISA. Gametocytes that developed in both groups were infectious to mosquitoes as determined in an MFA conducted with monkey blood drawn on day 460 in which plasma from AB human control sera was replaced by sera from infected monkeys. This result supports the viability and functionality of the circulating gametocytes from both the Pvs25-immunized and the control animals.
Mosquitoes fed with P. vivax gametocyte-carrying human blood in the presence of either normal monkey plasma or normal AB human sera (negative controls) produced positive infections with an arithmetic mean of oocysts per midgut ranging between 0.3 and 3.8 and 0.2 and 1.0 oocysts, respectively. However, plasma from the Pvs25-immunized Aotus tested individually were highly inhibitory and completely blocked the development of oocysts, in all assays (reduction of the oocysts number > 98%) using three different P. vivax human isolates. Plasma from monkeys in the Montanide ISA-720 control group showed similar inhibition to the normal monkey plasma (negative control). Therefore, boosting of antibodies to Pvs25 is not caused by the parasite infection, this Pvs25 vaccine can be used as a malaria transmission-blocking vaccine (Arevalo-Herrera et al., 2005).
Challenge Protocol:
Two weeks after the final immunization, the mice were challenged i.p. with 10^5 P. yoelii pRBC. The course of infection was monitored by microscopic examination of tail-blood smears stained with Gimsa. (Sakai et al., 2003)
Efficacy:
MSP1 vaccine alone conferred partial protection. Vaccination with MSP1 + IL-12 conferred the strongest protective immunity against the infection. Only two of the six mice immunized with MSP1 alone survived, while five of the six mice immunized with MSP1 + IL-12 survived (Sakai et al., 2003).
46. P. yoelii DNA vaccine encoding PyHEP17 Protein
Host Strain:
BALB/cByJ, A/J, B10.BR, B10.Q and C57BL/6
Vaccination Protocol:
Female 6- to 8-wk-old mice were immunized three times at 3-wk intervals intramuscularly in each tibialis anterior muscle with 50 μg of PyHEP17 DNA in 50 μl of saline or unmodified nkCMVintpolyli plasmid. 2 wk after the third immunization, mice were challenged by tail-vein injection with 100 infectious sporozoites or 200 infected erythrocytes (Doolan et al., 1996).
Challenge Detail
No.
Pathogen Name
Dose
Route
Age
Interval
1
Plasmodium yoelii
100 CFU in volume ml
Tail vein injection
day
14 day
Efficacy Detail
No.
Efficacy method
Result
Description
Group Efficacy Detail
1
In vivo protection study
CFU
Immunization with PyHEP17 DNA partially protected three of the five strains >20% against challenge with 100 infectious sporozoites. A 2 to 6 day delay in the onset of parasitemia in some nonprotected mice was consistent with partial immunity, which eliminated up to 90% of infected hepatocytes (Doolan et al., 1996).
Efficacy:
The full-length gene of PySSP2 in the nkCMVint vector induced specific antibodies and protected 50% of immunized mice. Subsequently, outbred CD-l mice were immunized with nkCMVint and VR1012 vector based PySSP2 DNA vaccines and as many as 33% were protected (Hoffman et al., 1997).
Efficacy:
Mice immunized with three doses of pDIP/PyCSP.1 and challenged with 5 × 105 P. yoelii sporozoites had a significant reduction in liver stage infection compared with mice immunized with the empty plasmid. Most importantly, 9 of 16 mice were protected against challenge (Hoffman et al., 1994).
Efficacy:
In experiment 1, 40% of mice immunized with the combination of pPyHsp60-VR1012 and pmurGM-CSF did not develop parasitemia during the 14 days postchallenge. Only this group had statistically significant protection on day 14 as compared with the pooled controls (two-tailed Fisher's exact test: P = 0.031 , group 1.B versus group 1.H + group 1.I). However, in experiment 2 (identical immunization schedule), immunized mice only experienced delayed parasitemia, rather than protection from parasitemia (Sanchez et al., 2001).
50. P. yoelii MSP1 and MSP4/5 Proteins Subunit Vaccine
Vaccination Protocol:
One group of mice was treated by gavage with 25 μg of EcMSP4/5, and the other group was treated by gavage with 25 μg of EcMSP4/5 plus an amount of GST-PyMSP119 equivalent to 25 μg of PyMSP119 (Wang et al., 2004).
Challenge Protocol:
In order to examine the protective efficacy of the induced antibodies, the immunized mice were challenged at 2 weeks after the sixth immunization with a lethal dose of 10^5 P. yoelii YM parasites (Wang et al., 2004).
Efficacy:
Oral immunization of mice with Escherichia coli-expressed Plasmodium yoelii merozoite surface protein 4/5 or the C-terminal 19-kDa fragment of merozoite surface protein 1 induced systemic antibody responses and protected mice against lethal malaria infection. All of the eight immunized mice survived the challenge, with peak parasitemia levels between 0.2 and 55.2% (Wang et al., 2004).
Vaccination Protocol:
All the immunizations with TyCS-VLP carrying the CTL epitope of the P. yoelii circumsporozoite protein (SYVPSAEQI), except the dose response and the route of immunization experiments, consisted of 50 mg per mouse injected intramuscularly (i.m.) in the leg quadriceps (Oliveira-Ferreira et al., 2000).
Challenge Protocol:
Mice were challenged with 75 sporozoites per mice administered i.v. (Oliveira-Ferreira et al., 2000).
Efficacy:
2/8 mice immunized with the TyCs-VLP vaccine were protected from challenge with P. yoelii sporozoites (Oliveira-Ferreira et al., 2000).
Host Strain:
Four volunteers identifying as Caucasian and two as African American. (Spring et al., 2013)
Vaccination Protocol:
Single group, non-randomized, phase I/IIa Trial. 6 volunteers received five infectious bites from GAP-infected Anopheles mosquito at first exposure, and then received around 200 bites as second exposure one month later. (Spring et al., 2009)
Immune Response:
Humoral: Post 5 bites: below the threshold. Post 200 bites: Pre-erythrocytic stage antigens: LSA-1 still not detectable, 2.9 μg/ml (0.7–12.3 μg/ml) CSP. Blood stage antigens: Only the volunteer with a peripheral blood stage parasitemia has humoral response to MSP-1 (3D7) and MSP-1 (FVO).
Cellular: IFN-γ, IL-2 and TNF responses significantly increased in the CD4 T cell compartment after 5 bites exposure, and amongst CD8 T cells after 200 bites exposure. IFN-γ production was primarily produced by CD8 T cells, and TNF production was primarily produced by CD4 T cells. No significant responses to CSP overlapping peptides or CSP recombinant protein observed.
Memory responses: CSP peptide 2, CelTOS and MSP-1 recalled the highest responses, followed by CSP and LSA-1 protein and then AMA-1, the CSP peptide pool and CSP peptide 4. LSA-1 peptide pools #1 and #2 failed to recall any responses. (Spring et al., 2013)
Side Effects:
First exposure: erythema and pruritus Second exposure: local: erythema, pruritus, edema; systematic: fever, nausea/vomiting, headache and malaise in the first 24 hours of exposure. **One volunteer developed peripheral P. falciparum parasitemia on day 12 post-second, high dose exposure:24 parasites/μL, experienced fever, headache, fatigue, malaise, and myalgia. The Stopping Rule was activated and therefore the efficacy test was not executed as originally planned. (Spring et al., 2013)
55. Pb(PfCS@UIS4)
a. Type:
Live, attenuated vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
Pb(PfCS@UIS4): genetically modified parasite: P. falciparum circumsporozoite (CS)- protein gene integrated in the P. berghei parasite. (Reuling et al., 2020)
Vaccination Protocol:
Non-randomized phase I/IIa study. Volunteers in the experiment groups were first exposed to 1) 5, 2) 25, or 3) 75 Pb(PfCS@UIS4)-infected mosquitoes for first dose of vaccination, and were then exposed to ~75 Pb(PfCS@UIS4)-infected mosquitoes on week 4, 8, and 16 for the second, third, and fourth doses of vaccination. Group 3 were challenged by 5 Pf-infected mosquitoes together with the control group that did not receive vaccination. (Reuling et al., 2020)
Side Effects:
Mild or moderate headache, nausea, and malaise. (Reuling et al., 2020)
Challenge Protocol:
CHMI: volunteers were exposed to 5 NF54 Pf-infected mosquitoes 3 weeks after the last dose of vaccination (Reuling et al., 2020)
Efficacy:
Sterile protection against an NF54 P. falciparum challenge was not observed, but there was a significant delay in time to parasitemia in PbVac-immunized subjects (9.9 ± 2.0 days) compared to controls (7.7 ± 1.6 days) (P=0.026) There was also a significantly 12.8-fold lower parasite peak density on the day of first positive PCR in immunized volunteers compared to the control group (P = 0.04) Collectively, this corresponds to an estimated 95% average reduction in parasite liver load. (Reuling et al., 2020)
56. PbVac P. Berghei Whole-Sporozoite Vaccine
a. Type:
Inactivated or "killed" vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Baboon
d. Antigen
PbVac has been engineered to express the immunodominant Pf antigen, the circumsporozoite protein (PfCS), flanked by the Pb pre-erythrocytic stage-specific promoter, UIS4 (upregulated in infective sporozoites 4). PbVac infects and develops in human hepatocytes but not in human red blood cells. (Mendes et al., 2018)
e. Immunization Route
Intramuscular injection (i.m.)
f. Description
PbVac is a transgenic line of the rodent malaria parasite P. berghei (Pb) that expresses the P. falciparum (Pf) circumsporozoite protein (PfCS). It is capable of infecting and developing in human hepatocytes but not in human erythrocytes, and inducing neutralizing antibodies against the human Pf parasite.
g.
Rabbit Response
Host Strain:
NZW rabbits
Vaccination Protocol:
This study performed an extensive evaluation of potential toxicity resulting from 5 consecutive administrations of PbVac delivered to rabbits by 97 infective mosquito bites each, ensuring 75 effective bites per administration. (Mendes et al., 2018)
Immune Response:
After vaccination, the parasite is completely eliminated from rabbits’ livers and all other organs analyzed up to 10 days after its administration. Pre-clinical results has shown that PbVac is unable to lead to a patent blood stage infection in rabbits and is incapable of developing in human erythrocytes. (Mendes et al., 2018)
Description:
This study revealed the absence of toxicity as a result of vaccine administration, indicating the safety of its use in non-permissive human hosts.
57. PfAMA1-FVO/ Alhydrogel
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
None
d. Antigen
Recombinant protein Pichia pastoris-expressed AMA-1, surface protein expressed during the asexual blood stage of Plasmodium falciparum. PfAMA1-FVO is a lyophilized preparation of the ectodomain of the FVO clone of P. falciparum AMA1 (Thera et al., 2016)
e. Gene Engineering of
AMA1 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
A lyophilized preparation of the ectodomain of the FVO clone of P. falciparum AMA1 (Thera et al., 2016)
The vaccine was prepared in single dose vials containing 62.5 µg AMA1 protein, 23.3 µg EDTA, 25 mg saccharose, 187 µg NaH2PO4·2H2O, 226 µg Na2HPO4. Vials were reconstituted by adding 625 µL 0.2 % Alhydrogel® suspension. he reconstituted vaccine was then incubated for 60 min at room temperature to facilitate adsorption to the Alhydrogel® and a dose of 0.5 mL containing 50 µg AMA1 and approximately 0.5 mg aluminium was used for injection. (Thera et al., 2016)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The PfAMA1-FVO vaccine uses the FVO clone of the AMA1 surface protein as the vaccine antigen and Alhydrogel as the adjuvant.
i.
Human Response
Host Strain:
Adults in Bandiagara aged 18–55 years old
Vaccination Protocol:
The study vaccines were given on study days 0, 28 and 56. (Thera et al., 2016)
Immune Response:
The PfAMA1 vaccine induced a significant increase in AMA1-specific IgG following vaccination (p < 0.05); after vaccination, titres increased gradually in the PfAMA1 recipients until day 84 when a maximum level was observed with a geometric mean of 17,584 arbitrary units 95 % CI (9889 to 31,267). Antibody titres peaked 1 month after the third dose reaching a 3.5 fold rise. (Thera et al., 2016)
Side Effects:
The 40 participants experienced a total of 257 adverse events, 136 were solicited AEs and 121 were unsolicited AEs. Additional vaccine doses did not globally increase the number of AEs. injection site pain was reported at least by 60 % of the participants after any dose compared to 40 % in the control group. Overall, the results showed a good biological safety profile. (Thera et al., 2016)
Description:
PfAMA1-FVO malaria vaccine candidate clinical development was stopped after the present trial was completed, partly because of the potential limits imposed by strain specificity of protection to polymorphic AMA1 confirmed in human (Thera et al., 2016)
58. PfP0 P-BSA
a. Type:
Subunit vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Human
d. Antigen
PfP0 P peptide: 16-amino-acid C-terminal peptide sequence of ribosomal phosphoprotein P0 of P. falciparum (Rajeshwari et al., 2004)
e. Gene Engineering of
PfP0
Type:
Recombinant protein preparation
Description:
PfP0 P peptide was coupled to BSA (PfP0 P-BSA) using glutaraldehyde (Rajeshwari et al., 2004)
Vaccination Protocol:
Mice were injected intraperitoneally with PfP0 P-BSA conjugate in Freund's adjuvant at 21-day intervals. In one control group, mice were injected in parallel with PBS emulsified in Freund's adjuvant. The other control group received no injections. The titers of the anti-PfP0 antibodies were measured after five immunizations. (Rajeshwari et al., 2004)
Challenge Protocol:
The mice were challenged with P. yoelii (106 parasites per mouse) after 5 immunizations. (Rajeshwari et al., 2004)
Efficacy:
Two of the six mice immunized with PfP0 P peptide developed parasitemia, compared with all 14 mice developed parasitemia in the control. One immunized mouse showed parasitemia on day 7 and died on day 8, and the other mouse showed parasitemia on day 14 but recovered by day 31, while all controls developed parasitemia by the sixth day postchallenge. The mean parasitemia levels of the three groups were statistically significantly different on day 9 (P < 0.0001), day 11 (P = 0.0014), day 13 (P = 0.0007), day 15 (P = 0.003), and day 17(P = 0.023). (Rajeshwari et al., 2004)
59. PfRH5 DNA Vaccine
a. Type:
DNA vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Antigen
PfRH5: reticulocyte-binding protein homolog 5, a leading blood-stage antigen to APCs. The vaccine uses PfRH5ΔNL, the crystal structure and key functional antibody epitopes for the trunacated version of PfRH5. (Bjerkan et al., 2021)
e. Gene Engineering of
RH5
Type:
Recombinant protein preparation
Description:
The crystal structure and key functional antibody epitopes for the truncated version of PfRH5 were characterized to create PfRH5ΔNL, used as the vaccine antigen. (Bjerkan et al., 2021)
DNA vaccines were encoded in a pUMVC4a plasmid vector (Aldevron) under a CMV-IE promoter and containing a tPA signal peptide. The targeted constructs were cloned into pUMVC4a using PmlI and BamHI.(Bjerkan et al., 2021)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The PfRH5 DNA Vaccine vaccine is designed as bivalent homodimers where each chain is composed of an amino-terminal single chain fragment variable (scFv) targeting unit specific for major histocompatibility complex class II (MHCII) expressed on APCs, and a carboxyl-terminal antigenic unit genetically linked by the dimerization units. This vaccine uses PfRH5ΔNL as the antigen, with the APC-targeted vaccine construct, termed a “Vaccibody”. (Bjerkan et al., 2021)
i.
Mouse Response
Host Strain:
Female BALB/c mice
Vaccination Protocol:
For intramuscular (i.m.) delivery of DNA vaccines, mice were shaved on each leg, and 25 µg of PfRH5ΔNL-containing DNA or 2.5 µg of PvDBP-containing DNA was injected in a 50 µl volume into each quadriceps femoris muscle (50 µg or 5 µg total DNA/mouse, respectively). Immediately after injection, electrical pulses were applied at the injection site. BALB/c mice were immunized three times at three weeks intervals, with 50 µg plasmids that encoded either MHCII-targeted or non-targeted Vaccibodies, or antigen alone. (Bjerkan et al., 2021)
Immune Response:
Vaccination with the MHCII-targeted vaccine showed significantly increased levels of total PfRH5FL-specific IgG compared to vaccination with the antigen alone at days 41 and 62 post-prime vaccination. The results showed that vaccination with the MHCII-targeted-PfRH5ΔNL vaccine induced significantly higher levels of IFN-γ producing cells in response to PfRH5FL protein in both spleens and dLNs as compared to vaccination with the non-targeted control vaccine and PfRH5ΔNL antigen alone. Strong and comparable levels of GIA were detected for IgG raised following DNA vaccination with PfRH5ΔNL-containing vaccines and the PfRH5ΔNL control vaccine. (Bjerkan et al., 2021)
60. PfRipr5/ Alhydrogel
a. Type:
Protein Subunit Vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Antigen
PfRipr5: a protein fragment of PfRipr complex considered to play one of the central roles in the sequential molecular events leading to P. falciparum merozoite invasion. PfRipr5 is a protein fragment inducing the most potent growth inhibitory antibodies as comparable level to the antibodies against full-length PfRip. (Takashima et al., 2022)
e. Preparation
PfRipr5 recombinant protein was produced in a 50 L stirred-tank bioreactor by infecting insect High Five cells at 2 ×106 cell/mL with a recombinant baculovirus encoding pfripr5 nucleotide sequence and His6-tag for purification, using a multiplicity of infection of 0.1 virus per cell. cell culture bulk was clarified using a Sartopore 2 30’’ 0.45 µm + 0.2 µm filter, loaded on a Histrap HP column, and protein was eluted with a linear Imidazole gradient. The eluate was concentrated using a Vivaflow 200 Hydrosart 10 kDa and loaded into a Superdex 75 prep grade XK50/100 gel size-exclusion chromatography column, from which fractions corresponding to monomeric PfRipr5 were collected. The collected fractions were loaded in a HiPrep desalting 26/10 column, the eluate was concentrated as mentioned above, and then sterile-filtered (0.2 μm). The final sample was formulated in 16 mM sodium phosphate buffer, 250 mM NaCl, at pH 8.0, aliquoted and stored at -80°C. (Takashima et al., 2022)
f. Immunization Route
Intramuscular injection (i.m.)
g. Description
PfRipr5/ Alhydrogel is a asexual-blood stage malaria vaccine that uses the PfRipr5 protien segment as the vaccine antigen and an Alhydrogel adjuvant. (Takashima et al., 2022)
h.
Rabbit Response
Host Strain:
Japanese white rabbits
Vaccination Protocol:
Japanese white rabbits (n=6 per group) were subcutaneously immunized with the PfRipr5 protein alone (50 µg/shot) or with PfRipr5 antigen (0, 50, and 200 µg/shot) formulated with the aforementioned adjuvants at the specific concentrations in 500 µL injection, twice at three-week intervals (Day 0 and Day 21). Antisera were collected two weeks after the last immunization (Day 35). (Takashima et al., 2022)
Immune Response:
Formulation of PfRipr5 with Alhydrogel® induced statistically significant higher levels of antibodies in most low dose (50 µg) (Mean ELISA titers: Alum = 1.0 ×105 (P<0.01)); and in all high dose groups (200µg) (Mean ELISA titers: Alum = 8.8 ×104 (P<0.05)). The GIA activity of IgG induced by PfRipr5 Alhydrogel® formulation was higher in the low dose (50 µg) (Mean %GIA = 37%) than in the high dose (200 µg) (Mean %GIA = 19.9%) groups. (Takashima et al., 2022)
Description:
The current study shows that PfRipr5 antigen alone was immunogenic to rabbits without any adjuvant, although the generated antibodies could not induce significant GIA activities.(Takashima et al., 2022)
61. PfRipr5/ CAF01
a. Type:
Protein Subunit Vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Baboon
d. Antigen
PfRipr5: a protein fragment of PfRipr complex considered to play one of the central roles in the sequential molecular events leading to P. falciparum merozoite invasion. PfRipr5 is a protein fragment inducing the most potent growth inhibitory antibodies as comparable level to the antibodies against full-length PfRip. (Takashima et al., 2022)
e. Preparation
PfRipr5 recombinant protein was produced in a 50 L stirred-tank bioreactor by infecting insect High Five cells at 2 ×106 cell/mL with a recombinant baculovirus encoding pfripr5 nucleotide sequence and His6-tag for purification, using a multiplicity of infection of 0.1 virus per cell. cell culture bulk was clarified using a Sartopore 2 30’’ 0.45 µm + 0.2 µm filter, loaded on a Histrap HP column, and protein was eluted with a linear Imidazole gradient. The eluate was concentrated using a Vivaflow 200 Hydrosart 10 kDa and loaded into a Superdex 75 prep grade XK50/100 gel size-exclusion chromatography column, from which fractions corresponding to monomeric PfRipr5 were collected. The collected fractions were loaded in a HiPrep desalting 26/10 column, the eluate was concentrated as mentioned above, and then sterile-filtered (0.2 μm). The final sample was formulated in 16 mM sodium phosphate buffer, 250 mM NaCl, at pH 8.0, aliquoted and stored at -80°C. The PfRipr5 was diluted in 10 mM Tris buffer with 2% glycerol (pH=7.0) to the target concentration in each vaccine formulation. CAF01 vaccine formulations containing CAF®01 (1250 µg/mL DDA and 250 µg/mL TDB), and either 100 µg/mL (low dose) or 400 µg/mL (high dose) of PfRipr5.
f. Immunization Route
Intramuscular injection (i.m.)
g. Description
PfRipr5/ CAF01 is a asexual-blood stage malaria vaccine that uses the PfRipr5 protien segment as the vaccine antigen and a CAF01 adjuvant.
h.
Rabbit Response
Host Strain:
Japanese white rabbits
Vaccination Protocol:
apanese white rabbits (n=6 per group) were subcutaneously immunized with the PfRipr5 protein alone (50 µg/shot) or with PfRipr5 antigen (0, 50, and 200 µg/shot) formulated with the aforementioned adjuvants at the specific concentrations in 500 µL injection, twice at three-week intervals (Day 0 and Day 21). Antisera were collected two weeks after the last immunization (Day 35). (Takashima et al., 2022)
Immune Response:
Formulation of PfRipr5 with CAF®01 induced statistically significant higher levels of antibodies in most low dose (50 µg) (Mean ELISA titers: CAF = 1.0 ×105 (P<0.01)) and in all high dose groups (200 µg) (Mean ELISA titers: CAF = 1.1 ×105 (P<0.001)). The GIA activities of IgG induced by PfRipr5 CAF®01 formulations were higher in the high dose (200 µg) (Mean %GIA: CAF = 49.4%) than in the low dose (50 µg) (Mean %GIA: CAF = 38%) groups. (Takashima et al., 2022)
Description:
The PfRipr5/CAF®01 formulation was identified as the most promising vaccine candidate for further development because of its higher immunogenicity. (Takashima et al., 2022)
62. PfRipr5/GLA-SE
a. Type:
Protein Subunit Vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Baboon
d. Antigen
PfRipr5: a protein fragment of PfRipr complex considered to play one of the central roles in the sequential molecular events leading to P. falciparum merozoite invasion. PfRipr5 is a protein fragment inducing the most potent growth inhibitory antibodies as comparable level to the antibodies against full-length PfRip. (Takashima et al., 2022)
e. Preparation
PfRipr5 recombinant protein was produced in a 50 L stirred-tank bioreactor by infecting insect High Five cells at 2 ×106 cell/mL with a recombinant baculovirus encoding pfripr5 nucleotide sequence and His6-tag for purification, using a multiplicity of infection of 0.1 virus per cell. cell culture bulk was clarified using a Sartopore 2 30’’ 0.45 µm + 0.2 µm filter, loaded on a Histrap HP column, and protein was eluted with a linear Imidazole gradient. The eluate was concentrated using a Vivaflow 200 Hydrosart 10 kDa and loaded into a Superdex 75 prep grade XK50/100 gel size-exclusion chromatography column, from which fractions corresponding to monomeric PfRipr5 were collected. The collected fractions were loaded in a HiPrep desalting 26/10 column, the eluate was concentrated as mentioned above, and then sterile-filtered (0.2 μm). The final sample was formulated in 16 mM sodium phosphate buffer, 250 mM NaCl, at pH 8.0, aliquoted and stored at -80°C. GLA-SE vaccine formulation contains GLA-SE (50 µg/mL) and 400 µg/mL (high dose) of PfRipr5. (Takashima et al., 2022)
f. Immunization Route
Intramuscular injection (i.m.)
g. Description
PfRipr5/ GLA-SE is a asexual-blood stage malaria vaccine that uses the PfRipr5 protien segment as the vaccine antigen and a GLA-SE adjuvant.
h.
Rabbit Response
Host Strain:
Japanese white rabbits
Vaccination Protocol:
Japanese white rabbits (n=6 per group) were subcutaneously immunized with the PfRipr5 protein alone (50 µg/shot) or with PfRipr5 antigen (0, 50, and 200 µg/shot) formulated with the aforementioned adjuvants at the specific concentrations in 500 µL injection, twice at three-week intervals (Day 0 and Day 21). Antisera were collected two weeks after the last immunization (Day 35).
Immune Response:
Formulation of PfRipr5 with GLA-SE in in the high dose group (200 µg) produced Mean ELISA titers: GLA = 1.2 ×105 (P<0.001)and the low dose (50 µg) formulation Mean ELISA titer = 8.0 ×104. The GIA activities of IgG induced by PfRipr5 GLA-SE were higher in the high dose (200 µg) (Mean %GIA: GLA = 36.2%)
63. Pfs230D1-EPA/ AS01
a. Type:
Subunit vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Antigen
Pfs230 domain 1: Pre-fertilization antigens, expressed during gametocyte development in human (Duffy et al. 2021)
e. Immunization Route
Intramuscular injection (i.m.)
f. Description
The Pfs230D1-EPA/AS01 uses the Pfs230D1 pre-fertilization antigen conjugated with EPA nanoparticles with GSK platform AS01 as the vaccine adjuvant tested on mice.
g.
Mouse Response
Host Strain:
CD-1 Mice
Immune Response:
Pfs230D1-EPA induces higher titers and IgG levels in AS01 vs. alum adjuvants in mice (Rausch et al., 2023)
Description:
Expressed by gametocytes in the human stage of P. falciparum. Also a surface antigen of gametes and zygotes in the mosquito stage. Mediates binding of exflagellating microgametes to red blood cells. (Coelho et al., 2021)
Malaria transmission blocking vaccine: block parasite transmission through mosquitoes (Coelho et al., 2021)
h.
Human Response
Host Strain:
Adults in Mali
Vaccination Protocol:
Phase I, Dose-Escalating, Double-Blind, Randomized, Comparator-Controlled Trial. Ongoing. Participants are randomly assigned to different groups, getting 3 doses of 1) 160 µg/mL conjugated Pfs230D1M and 124 µg/mL conjugated EPA or 2) 160 µg/mL conjugated Pfs230D1M and 143 µg/mL conjugated EPA or 3)Verorab Rabies, each dose injected at 0, 1, and 2 months. Outcome Measures: Primary: Number of local and systemic adverse events (AEs) and serious adverse events (SAEs) to assess the safety of the study drug Secondary: 1) Level of humoral immune response as measured by ELISA titer response to Pfs230D1M after third immunization. 2) Duration of humoral immune response as measured by ELISA titer response to Pfs230D1M after third immunization. 3) Level of functional antibody response to Pfs230D1M as measured by standard membrane feeding assay (Duffy et al. 2021)
65. Pfs25 VLP-FhCMB
a. Type:
Subunit vaccine
b. Status:
Licensed
c. Host Species for Licensed Use:
None
d. Antigen
Pfs25: is a member of a Plasmodium protein family characterized by the presence of epidermal growth factor (EGF)-like repeat motifs, numerous cysteine residues and a complex tertiary structure. (Chichester et al., 2018)
e. Gene Engineering of
Pfs25 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
Pfs25 is used as the malaria vaccine antigen.
Pfs25 VLP-FhCMB, a chimeric non-enveloped VLP comprising Pfs25 fused to the Alfalfa mosaic virus coat protein (CP), produced in hydroponically grown Nicotiana benthamiana plants using a Tobacco mosaic virus (TMV)-based hybrid vector, then purified and characterized. 400 µg of total protein per mL in an aqueous formulation containing 50 mM sodium phosphate. Four total protein dose levels of the vaccine (2, 10, 30 and 100 μg per 0.5 mL) were formulated in the clinic on the day of administration with 0.3% Alhydrogel (Chichester et al., 2018)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Pfs25 VLP-FhCMB is a plant-produced Pfs25 virus-like particle usedas a transmission blocking vaccine against malaria
66. Pfs25-EPA / AS01
a. Type:
Protein-nanoparticle vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Baboon
d. Antigen
Pfs25, a post-fertilization antigen that is involved in ookinete formation and survives in the mosquito midgut (Mulamba et al., 2022)
e. Gene Engineering of
Pfs25 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
Pfs25 (or P25) from P. falciparum was used as the vaccine antigen
Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa (Talaat et al., 2016). In addition, AS01 is used as the vaccine adjuvant.
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
Pfs25-EPA/ AS01 vaccine is made by using the Pfs25 as the vaccine antigen, which is conjugated to EPA nanoparticles, and the GSK platform AS01 serves as the vaccine adjuvant (Talaat et al., 2016).
i.
Mouse Response
Host Strain:
CD-1 Mice
Efficacy:
Pfs25-EPA formulated in AS01 induced significantly higher antibody levels than unconjugated Pfs25 formulated in AS01 (Rausch et al., 2023) Pfs25-EPA/AS01 showed significant oocyst reduction compared to Pfs25-EPA/Alhydrogel, but the difference between these groups was not statistically significant at end of study (Rausch et al., 2023)
67. Pfs25-EPA/Alhydrogel
a. Manufacturer:
Walter Reed Army Institute of Research Bioproduction Facility
b. Type:
Subunit vaccine
c. Status:
Licensed
d. Host Species for Licensed Use:
None
e. Antigen
Pfs25H is a Pichia pastoris-expressed hexa-His tagged recombinant Pfs25, a post-fertilization surface antigen of ookinetes in the mosquito stage of P. falciparum. (Talaat et al., 2016)
f. Gene Engineering of
Pfs25 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
Pfs25H is a Pichia pastoris-expressed hexa-His tagged recombinant Pfs25 used as the vaccine antigen.
The Pfs25-EPA conjugate was produced by reaction between thiolated Pfs25H and maleimide-activated rEPA, followed by purification using size-exclusion chromatography. Pfs25-EPA was subsequently formulated with Alhydrogel®. 78 μg/mL Pfs25H and 93 μg/mL rEPA, bound to 1600 μg/mL Alhydrogel® in a volume of 0.8 mL. (Talaat et al., 2016)
h. Immunization Route
Intramuscular injection (i.m.)
i. Description
The Pfs25-EPA/ Alhydrogel uses a recombinant Pfs25 antigen with a recombinant EPA (rEPA) formulated with an Alhydrogel adjuvant.
j.
Human Response
Host Strain:
Healthy adults age 18–50 were recruited from the Baltimore, MD region without significant medical conditions.
Vaccination Protocol:
Participants were divided into three groups: Group 1a received two injections of a low vaccine dose (8 μg Pfs25H), Group 1b received two injections of a medium dose (16 μg Pfs25H) at 0 and 2 months, and Group 2 received four injections of a high dose (47 μg Pfs25H) at 0, 2, 4, and 10 months. Additionally, one high responder in Group 1a received a third injection of the low vaccine dose (8 μg Pfs25H) at 10 months. (Talaat et al., 2016)
Immune Response:
Proportion of antibody levels in responders increased after second, third vaccinations, and the final booster, demonstrating immunogenicity. However, antibody levels declined rapidly weeks after the final dose.
68. Pfs25-IMX313/Matrix-M
a. Type:
protein-nanoparticle vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
Pfs25: post-fertilization antigen, three potential N-linked glycosylation sites (112, 165 and 187) mutated. Involved in ookinete formation, survival in the mosquito midgut, and a possible role in parasite traversal of the mid-gut epithelium. (Mulamba et al., 2022)
e. Gene Engineering of
Pfs25 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
Pfs25 antigen is genetically fused to the IMX313 oligomerization domain (Mulamba et al., 2022)
Description:
A potent saponinbased adjuvant, comprising partially purifed extracts of the bark of the Quillaja saponaria Molina tree, phosphatidylcholine and cholesterol. Enhance immune responses (Mulamba et al., 2022)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
**Mechanism: Human get vaccinated --> Human produce antibodies --> mosquitoes take up antibodies --> reduce parasite fertilization in mosquitoes (Mulamba et al., 2022)
i.
Human Response
Host Strain:
Semi-immune healthy adults from Bagamoyo district in Tanzania
Vaccination Protocol:
Phase I trial, not started. A two-years enrollment schedule has been designed, with one group of volunteers receiving immunization at months; zero, one and three, while another group shall receive immunization at months; zero, one and seven. Enrollment of volunteers will follow a strict staggered approach, with one of group of adults receiving a low dose of the vaccine followed by another adults’ group receiving a high dose of the vaccine in six-weeks interval.(Mulamba et al., 2022)
69. Pfs25/ Montanide ISA 51
a. Type:
Live, attenuated vaccine
b. Status:
Licensed
c. Host Species for Licensed Use:
None
d. Antigen
Pfs25, a protein expressed on the surface of ookinetes of P. falciparum (Wu et al., 2008)
e. Gene Engineering of
Pfs25 from P. falciparum 3D7
Type:
Recombinant protein preparation
Description:
Recombinant Pfs25 was used as the vaccine adjuvant. (Wu et al., 2008)
Recombinant proteins Pfs25 were produced in the yeast expression system utilizing Pichia pastoris. A hexa-His tag was added to the C-terminus of the recombinant protein to facilitate purification and characterization. the Pfs25 at a concentration of 320 µg/mL in phosphate-buffered saline (PBS, 155 mM NaCl, 1 mMKH2PO4, 3 mM Na2HPO3) was aseptically emulsified with an equal volume of Montanide ISA 51 to give a final vaccine concentration of 160 µg/mL. The emulsion was achieved by homogenizing the mixture in a volume of 200 mL in a 400-mL vessel at room temperature for 6 min at 6000 rpm using an Omni Mixer-ES homogenizer. (Wu et al., 2008)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The Pfs25/ Montanide ISA 51 uses Pfs25, a P. falciparum ookinete surface protein, as the vaccine antigen emulsified in Montanide ISA 51 as the vaccine adjuvant.
i.
Human Response
Host Strain:
healthy US volunteers
Vaccination Protocol:
Vaccines were administered at three dose levels (5, 20, and 80 µg per dose in 0.5 mL) (Wu et al., 2008)
Immune Response:
Four of 10 volunteers, including the one that developed a leukemoid reaction (Volunteer “C”), had no detectable antibodies against Pfs25 (i.e. <25 ELISA units) by day 120 following the first vaccination. Of the 2 volunteers that developed grade 3 induration, one (Volunteer “H”) had a minimal antibody level of 30 ELISA units on day 90, 30 days after the induration resolved. The other (Volunteer “G”) had 132 ELISA units on day 60. All 5 volunteers (Volunteers “A” through “E”) receiving a second dose of 5 µg Pfs25/ISA 51 developed substantial antibody levels against Pfs25 following the second vaccination (Table 4). The antibody levels reached a peak 30–60 days after the second vaccination and the geometric mean of the peak of this group was 1295 ELISA units. (Wu et al., 2008)
Side Effects:
Local adverse events included erythema, induration, swelling, and tenderness at the site of injection. Solicited systemic adverse events included fever (oral temperature≥37.5°C), headache, nausea, malaise, myalgia, and arthralgia. In the groups receiving antigen with ISA 51, 6 volunteers experienced severe local reaction, 4 experienced moderate local reaction, and 14 experienced mild reaction (maximum severity for each). Four of six volunteers who received the control vaccine (PBS/ISA 51) complained of mild injection site pain lasting up to 4 days and two recipients reported mild erythema for one day. (Wu et al., 2008)
Efficacy:
In ex vivo membrane feeding assays, one antiserum that contained 7322 ELISA units resulted in reduction of the parasite in mosquitoes by >90%. The severity and duration of the local reactions seen in this study, combined with the observed systemic reactions, make further progression of the Montanide ISA 51 formulations unlikely.
70. Pfs48/45 in Matrix-M
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
Pfs48/45 (Minassian et al., 2022): plays an important role in the fertilization of plasmodium: males lacking Pfs48/45 show severely reduced fertility and are incapable of adhering to and penetrating female gametes. (Theisen et al., 2017)
e. Gene Engineering of
Pfs48/45
Type:
Recombinant protein preparation
Description:
Pfs48/45 and the 10 C and 6 C fusion proteins. The secondary structure prediction of Pfs48/45 have assigned 2 loops in domain II between amino acid residues 190–210 and 239–259, and in domain III between the residues 302–327 and 357–397. Epitope I is located between residues 295 and 418. (Theisen et al., 2017)
Transmission Blocking Vaccine: induce antibodies that taken up by the mosquito and subsequently prevent development of parasites in the mosquito midgut (Theisen et al., 2017)
Vaccination Protocol:
Non-randomized, phase Ia trial, not strated. Participants will be separated into three different groups with 8-10 participants in each group: 1) low dose: three doses of 10 µg Pfs48/45 in 50 µg Matrix-M on days 0, 28 and 56; 2) standard dose: three doses of 50 µg Pfs48/45 in 50 µg Matrix-M on days 0, 28 and 56; and 3) two doses of 50 µg Pfs48/45 in 50 µg Matrix-M on days 0 and 28, followed by one dose of 10 µg Pfs48/45 in 50 µg Matrix-M on day 56. (Minassian et al., 2022)
71. PfSPZ
a. Type:
Live, attenuated vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
live (metabolically active), nonreplicating, radiation-attenuated P. falciparum sporozoites (SPZ)(Oneko et al., 2021)
Vaccination Protocol:
Double-blind, randomized, placebo-controlled Phase2 trial. Participants were randomly assigned in 4 groups, each receiving 1) 4.5 × 105, 2) 9.0 × 105 and 3) 1.8 × 106 PfSPZ or 4) normal saline placebo. (Oneko et al., 2021)
Immune Response:
Dose-dependent increase in IgG and IgM antibody responses and a significantly greater rate of seroconversion and net increase in IgG and IgM antibodies: 94.0% and 89.5% of vaccinees and 12.7% and 12.7% of controls had increased IgG and IgM antibodies two weeks after third vaccination. Dose-dependent increase in the PfCSP-specific memory B cell response. ** There were low-to-undetectable PfSPZ-specific CD4 and CD8 T cell responses, which might because of the limited magnitude and functional capacity of γδ T cells in infants. (Oneko et al., 2021)
Side Effects:
Mild to moderate fever (more common in participants in the highest-dose group); febrile seizures. (Oneko et al., 2021)
Efficacy:
No statistically significant (P < 0.05) VE against the presence of parasitemia at the primary 6-month end point by either proportional or time-to-event analyses. (Oneko et al., 2021)
g.
Human Response
Vaccination Protocol:
Phase I trial. 57 adults participated in the trial. 40 of them were vaccine recipients (36 completed the vaccination), 12 were CHMI controls, and 5 were backup controls. For volunteers in the vaccination group: 1) 2 of the volunteers were given 2 × 10^3 PfSPZ per dose without CHMI to access safety, while the rest of the vaccination group were given 1.35 × 10^5 PfSPZ per dose and given CHMI later. (Seder et al., 2013)
Challenge Protocol:
CHMI ~3 weeks after last immunization (Seder et al., 2013)
Efficacy:
16 of 17 subjects who received 7.5 × 10^3 and 3×10^4 PfSPZ Vaccine per dose developed parasitemia. Among the nine subjects who had received four doses of 3 × 10^4 PfSPZ Vaccine, one did not develop parasitemia, whereas the other eight had a 1.4 day prolongation of time to parasitemia compared with the six nonvaccinated controls (P = 0.007, LogRank). The prepatent periods in the 7.5 × 10^3 PfSPZ Vaccine-per-dose group were not significantly different than those of controls. 12 of 15 subjects immunized with 1.35 × 10^5 PfSPZ Vaccine per dose were protected (P = 0.028). Three of nine subjects in the four-dose group and none of six in the five-dose group developed parasitemia (P = 0.015 for the fivedose group versus controls, Fisher’s exact test). All subjects who did not develop parasitemia were negative as determined by means of quantitative PCR at 28 days after CHMI. In the three vaccinated subjects that became infected, there was a modest delay in the time to positive PCR. (Seder et al., 2013)
Persistence:
A FabB/FabF genetically attenuated parasite is attenuated in mice (Butler et al., 2011).
Efficacy:
A FabB/FabF genetically attenuated parasite induces complete protection in mice from challenge with wild type Plasmodium (Butler et al., 2011).
73. PvCS/Montanide ISA-51
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
PvCS: circumsporozoite protein of P. vivax. N+C: Two long synthetic peptides (LSP): the N-terminal (N) and C-terminal (C) regions; N+C+R: Three LSP: N-terminal, C-terminal, and the central repeats (R) regions. (Arévalo-Herrera et al., 2022)
e. Gene Engineering of
CS from P. vivax
Type:
Recombinant protein preparation
Description:
N: N-term aa 20–96, C: C-term aa 301–372. R: VK210 (type I): first central repeat (aa 96–104) in tandem three times, collinearly linked to a universal T-cell epitope (ptt-30) derived from tetanus toxin. (Arévalo-Herrera et al., 2022)
Vaccination Protocol:
Randomized, double-blind, controlled Phase II trial. Participants were divided into malaria naïve and semi-immune groups, each of which included experimental and control groups, and received vaccination or placebo at months 0, 2, and 6. Experimental group received PvCS N+C formulated in Montanide ISA-51 as the first dose, and PvCS N+C formulated in Montanide ISA-51 adjuvant as the second and third dose, while control group received three doses of Montanide ISA-51. (Arévalo-Herrera et al., 2022)
Side Effects:
Local: local pain, headache and malaise, mild or moderate cases, all resolved the next day after vaccination. Systematic: low frequency of fever, nausea, chills, diarrhea, and abdominal pain (Arévalo-Herrera et al., 2022)
Vaccination Protocol:
Phase I/IIa, blood-stage trial Volunteers received vaccination based on the time they participated in the experiment: group 1 received three doses of the PvDBPII 50ug/Matrix M1 50ug vaccine at 0, 1 and 14 months, and group 2 received three doses of the PvDBPII 50ug/Matrix M1 50ug vaccine at 0, 1 and 2 months. (Hou et al., 2022)
Immune Response:
Humoral: Anti-PvDBPII (SalI) total IgG serum antibody responses peaked around 2 weeks following the final vaccination. PvDBPII/M-M given at 0, 1 and 14 months induced higher response (geometric mean 198 μg/mL, range 153–335). Cellular: PvDBPII-specific CD4+ CD45RA− CCR7− effector memory T cells producing IFN-γ were detectable following final vaccinations in a delayed dosing regimen. IFN-γ producing CD8+ effector memory T cells were not detectable. (Hou et al., 2022)
Side Effects:
Mild or moderate cases of warmth, itch, injection site pain, redness, malaise, nausea, fatigue, headache, feverishness, myalgia, arthralgia, and temperature, all resolved within 48 hours. (Hou et al., 2022)
Challenge Protocol:
Blood stage CHMI 2–4 weeks after the third dose of vaccination (Hou et al., 2022)
Efficacy:
All volunteers developed parasitemia, but the PMR and LCP is significant lower in the delayed dosing group compared to unvaccinated controls, due to the delayed dosing (PMR: 3.2-fold growth per 48 hours (range 2.3 to 4.3) compared to 6.8-fold growth per 48 hours [range 4.0 to 11.1], p <0.001), resulted in a 7-day delay in median time to reach malaria diagnosis (15.5 days in controls compared to 22.5 days in delayed dosing group). (Hou et al., 2022)
75. PvRII/ AS02A
a. Type:
Subunit vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Macaque
d. Antigen
PvRII, receptor-binding domain of Plasmodium vivax Duffy binding protein, region II, with a C-terminal 6-histidine tag expressed in E. coli. (Moreno et al., 2008)
e. Gene Engineering of
PvDBPII
Type:
Recombinant protein preparation
Description:
The designed gene encoding PvRII was synthesized using overlapping oligomers (Midland Certified Reagent Company) and cloned in plasmid pET28a(+) (Novagen) at NcoI and SalI sites. Expression of recombinant PvRII using synthetic gene was higher compared with native gene. (Yazdani et al., 2006)
PvRII from P. vivax Salvador I strain was cloned as a NcoI-SalI fragment in the E. coli expression vector pET28a(+). Protein expression of the recombinant 6-His tag PvRII was induced with 1 mM IPTG for 4 hours and purified. 50 μg and 10 μg of PvRII formulated in AS02A. (Moreno et al., 2008)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The PvRII/ AS02A vaccine uses recombinant PvRII (region II), the receptor-binding domain of the Plasmodium vivax Duffy binding protein. Antibodies raised against the P.vivax Duffy binding protein, which belong to a family of erythrocyte binding protiens residing in region II, block erythrocyte invasion in the malaria infection process. Formulations emulsified with the AS02A adjuvant elicted higher titer binding inhibitory antibodies compared to other adjuvants such as Alhydrogel and MF59. (Moreno et al., 2008)
76. PvRII/ Montanide ISA 720
a. Type:
Subunit vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Macaque
d. Antigen
PvRII, receptor-binding domain of Plasmodium vivax Duffy binding protein, region II, with a C-terminal 6-histidine tag expressed in E. coli. (Moreno et al., 2008)
e. Gene Engineering of
PvDBPII
Type:
Recombinant protein preparation
Description:
The designed gene encoding PvRII was synthesized using overlapping oligomers (Midland Certified Reagent Company) and cloned in plasmid pET28a(+) (Novagen) at NcoI and SalI sites. Expression of recombinant PvRII using synthetic gene was higher compared with native gene. (Yazdani et al., 2006)
PvRII from P. vivax Salvador I strain was cloned as a NcoI-SalI fragment in the E. coli expression vector pET28a(+). Protein expression of the recombinant 6-His tag PvRII was induced with 1 mM IPTG for 4 hours and purified. 50 μg and 10 μg of PvRII emulsified in Montanide ISA 720. (Moreno et al., 2008)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The PvRII/ Montanide ISA 720 vaccine uses recombinant PvRII (region II), the receptor-binding domain of the Plasmodium vivax Duffy binding protein. Antibodies raised against the P.vivax Duffy binding protein, which belong to a family of erythrocyte binding protiens residing in region II, block erythrocyte invasion in the malaria infection process. Formulations emulsified with the Montanide ISA 720 adjuvant elicted higher titer binding inhibitory antibodies compared to other adjuvants such as Alhydrogel and MF59. (Moreno et al., 2008)
i.
Macaque Response
Host Strain:
Healthy rhesus macaques of Chinese origin from the Yerkes National Primate Research Center facility
Vaccination Protocol:
Selected animals were matched by age, sex and weight, housed in social settings and randomly assigned to six experimental groups of 5 individuals each that received different vaccine formulations (Groups 1-6) and three control groups of two individuals each that received adjuvant alone (Groups 7-9). Groups 3 and 4 received 50 μg and 10 μg of PvRII emulsified in Montanide ISA 720. (Moreno et al., 2008) Intramuscularly, priming into the right quadriceps femoris on day 0, first boost into the right musculus deltoideus on day 60 and the last boost into the left musculus deltoideus on day 150.
Immune Response:
Increase in antibody titers
77. PvRII/ Alhydrogel
a. Type:
Subunit vaccine
b. Status:
Research
c. Host Species for Licensed Use:
Macaque
d. Antigen
PvRII, receptor-binding domain of Plasmodium vivax Duffy binding protein, region II, with a C-terminal 6-histidine tag expressed in E. coli. (Moreno et al., 2008)
e. Gene Engineering of
PvDBPII
Type:
Recombinant protein preparation
Description:
The designed gene encoding PvRII was synthesized using overlapping oligomers (Midland Certified Reagent Company) and cloned in plasmid pET28a(+) (Novagen) at NcoI and SalI sites. Expression of recombinant PvRII using synthetic gene was higher compared with native gene. (Yazdani et al., 2006)
PvRII from P. vivax Salvador I strain was cloned as a NcoI-SalI fragment in the E. coli expression vector pET28a(+). Protein expression of the recombinant 6-His tag PvRII was induced with 1 mM IPTG for 4 hours and purified. 50 μg and 10 μg of PvRII were adsorbed to Alhydrogel. (Moreno et al., 2008)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The PvRII/ Alhydrogel vaccine uses recombinant PvRII (region II), the receptor-binding domain of the Plasmodium vivax Duffy binding protein. Antibodies raised against the P.vivax Duffy binding protein, which belong to a family of erythrocyte binding protiens residing in region II, block erythrocyte invasion in the malaria infection process. Recombinant PvRII formulated with Alhydrogel yielded antibodies with significant binding inhibitory activity.. (Moreno et al., 2008)
i.
Macaque Response
Host Strain:
Healthy rhesus macaques of Chinese origin from the Yerkes National Primate Research Center facility
Vaccination Protocol:
Selected animals were matched by age, sex and weight, housed in social settings and randomly assigned to six experimental groups of 5 individuals each that received different vaccine formulations (Groups 1-6) and three control groups of two individuals each that received adjuvant alone (Groups 7-9). Groups 1 and 2 were immunized with 50 μg and 10 μg of PvRII adsorbed to Alhydrogel, respectively. Intramuscularly, priming into the right quadriceps femoris on day 0, first boost into the right musculus deltoideus on day 60 and the last boost into the left musculus deltoideus on day 150. (Moreno et al., 2008)
Immune Response:
Antibody titers, determined by ELISA, increased in PvRII formulated with Alhydrogel, refolded PvRII induced functional antibodies with the potential to inhibit parasite invasion. (Moreno et al., 2008)
78. Pvs25 mRNA–LNP
a. Type:
Protein Subunit Vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Antigen
Pvs25, the P. vivax ookinete surface protein expressed on the surface of zygotes/ookinetes and essential for the survival of ookinetes in the mosquito midgut (Kunkeaw et al., 2023)
e. Gene Engineering of
Pvs25
Type:
Recombinant protein preparation
Description:
Pvs25A constructs were designed with wildtype signal peptide without the C-terminal GPI anchor, which is essential for parasite cell surface localization. Pvs25A has the wildtype sequence, and Pvs25A I130T contains the I130T substitution predominant in the Asian P. vivax isolates. Pvs25F encodes the full-length sequence of the Pvs25 gene from Sal I with wild-type signal peptide. Pvs25F I130T construct contains the full-length sequence of Pvs25 with the I130T mutation. (Kunkeaw et al., 2023)
Four nucleoside-modified Pvs25 mRNAs were designed based on the sequence of the Pvs25 gene from the reference P. vivax strain Sal I. Two constructs (Pvs25A and Pvs25A I130T) express Pvs25 with wildtype signal peptide without the C-terminal glycosylphosphatidylinositol (GPI) anchor. The other two constructs (Pvs25F and Pvs25F I130T) encode the full-length Pvs25 with its C-terminal GPI anchor. mRNAs were in vitro transcribed using T7 RNA polymerase (Megascript; Ambion) on linearized plasmids encoding mammalian codon-optimized Pvs25. mRNAs were generated to contain 101 nucleotide-long poly(A) tails and modified by replacing uridine-5′-triphosphate with m1Ψ-5′-triphosphate (TriLink BioTechnologies). mRNA capping was performed alongside transcription through the addition of a trinucleotide cap1 analog, CleanCap (TriLink), and mRNA was purified with cellulose-based purification. Purified mRNAs and poly(C) RNA (Sigma) were LNP-encapsulated using a self-assembly process where a mixture of an ionizable cationic lipid, phosphatidylcholine, cholesterol, and polyethylene glycol-lipid in ethanol was rapidly combined with an aqueous solution containing mRNA at acidic pH. (Kunkeaw et al., 2023)
g. Immunization Route
Intramuscular injection (i.m.)
h. Description
The Pvs25 mRNA-LNP uses nucleoside-modified Pvs25 mRNA, the P.vivax surface protein, as the vaccine antigen encapsulated in liquid nanoparticles (LNP).
i.
Human Response
Host Strain:
Human embryonic kidney (HEK) 293 cells
Vaccination Protocol:
Pvs25 mRNA–LNPs were produced and transfected into human embryonic kidney 293 cells. (Kunkeaw et al., 2023)
Immune Response:
Western blot analysis revealed protein production from each Pvs25 mRNA. The levels of Pvs25 protein production from the two full-length constructs (Pvs25F and Pvs25F I130T) were higher than those from the truncated constructs (Pvs25A and Pvs25A I130T).
j.
Mouse Response
Host Strain:
BALB/c mice
Vaccination Protocol:
Vaccination followed a prime-boost schedule (week 0 and 4) via intramuscular injection using three different doses (3, 10, or 30 µg). Serum from each animal was collected 4 weeks after each immunization to determine the level of anti-Pvs25 antibody by ELISA. (Kunkeaw et al., 2023)
Immune Response:
At 4 weeks after the first (prime) vaccination, the Pvs25-specific IgG induced by mRNA–LNPs was detectable with a geometric mean of reciprocal titer (GMT) value between 630–5300. After the booster dose, the antibody levels rose significantly reaching a GMT between 42,000–169,000. At each dose, the Pvs25F mRNA–LNP outperformed other formulations. The mRNA/mRNA homologous vaccination elicited the strongest memory B cell response and induced the most robust Pvs25-specific CD4+ T cell responses as measured by IFN-γ and IL-2 production of CD4+ T cells whereas this was almost absent in the protein/protein homologous (Pvs25 protein/ISA-51) vaccination group.
Efficacy:
All samples from Pvs25 mRNA–LNP-immunized mice exhibited complete (100%) transmission-blocking activity at 1:2 dilution. The percent reduction in the average oocyst number per mosquito by each serum sample (transmission-reducing activity) of these sera remained nearly complete at 1:10 dilution and were ~80% at 1:50 dilution.
79. Pvs25-IMX313/Matrix-M1
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
Pvs25 (Minassian et al., 2022): P.vivax surface protein 25, composed of four cysteine-rich epidermal growth factor–like domains expressed on the surface of zygotes and ookinetes of P. vivax (Arevalo-Herrera et al., 2005).
Vaccination Protocol:
Non-randomised, Phase Ia study, not started Volunteers will receive 1) three doses of 10 µg Pvs25-IMX313 in 50 µg Matrix-M1 on days 0, 28 and 56, 2) three doses of 50 µg Pvs25-IMX313 in 50 µg Matrix-M1 on days 0, 28 and 56, or 3) two doses of 50 µg Pvs25-IMX313 in 50 µg Matrix-M1 on days 0 and 28, followed by one dose of 10 µg Pvs25-IMX313 in 50 µg Matrix-M1 on day 56 (Minassian et al., 2022)
MSP1-15 as a fusion protein with the α antigen of Mycobacterium kansasii (α-k), which is secreted from the rBCG vaccine vector (Matsumoto et al., 1998).
f. Gene Engineering of
MSP1 from P. yoelii str. 17XNL
Type:
Recombinant vector construction
Description:
A 2.4-kbp fragment containing an α-k–MSP1-15 hybrid gene was subcloned into pSO246. The final construct (designated pSOMSP1-15) was transformed into BCG Tokyo by electroporation (Matsumoto et al., 1998).
Vaccination Protocol:
C3H/He mice were immunized intravenously with 10^6 CFU of rBCGMSP1-15 in 200 μl of PBS containing 0.1% PBS-T80. A control group of mice was injected with 106 CFU of BCG in 200 μl of PBS-T80 or PBS-T80 only. 30 days later, the same amount of each sample was injected intraperitoneally to boost the immune response (Matsumoto et al., 1998).
Vaccine Immune Response Type:
VO_0003057
Challenge Protocol:
Mice were challenged with 10^4 P. yoelii 17XL-parasitized erythrocytes intravenously or intraperitoneally 1 month after the final immunization (Matsumoto et al., 1998).
Efficacy:
3 out of 7 mice immunized with GST-MSP1-15 in RAS and 2 out of 8 mice immunized with GST-MSP1-15 in IFA survived the infection. 6 out of 7 mice immunized with rBCGMSP1-15 survived the infection. Data showed the three adjuvants examined are effective for vaccination with MSP1-15, while their efficacy levels differ. The rBCG system was the most effective for vaccination (Matsumoto et al., 1998).
Description:
Complete Freund's adjuvant (CFA) was used as the first adjuvant. Boosters of the same amount of protein were given in incomplete Freund's adjuvant (IFA) (Kushwaha et al., 2001).
g. Preparation
The four fragments of ABRA, including N-terminal [ABRA (N); aa 24–369], middle [ABRA (M); aa 370–507], N-terminal + middle [ABRA (P); aa 24–507] and the C-terminal [ABRA (C); aa 508–743], were expressed as fusions with either maltose binding protein (MBP) or 6X histidine tag at their amino terminii using pMALc-2 vector from NEB (New England Biolabs, Beverly, MA, USA) or pQE30 vector (Qiagen GmbH, Germany), respectively. These recombinant proteins were purified to near homogeneity by affinity chromatography of the soluble fraction, concentrated, and the purity of the protein judged by SDS-PAGE.
h.
Mouse Response
Host Strain:
BALB/c
Vaccination Protocol:
Groups of BALB/c mice were immunized by i.p. injection with ABRA protein/MBP emulsified in complete Freund's adjuvant (CFA). Control mice received only PBS in the adjuvant. Boosters of the same amount of protein were given in incomplete Freund's adjuvant (IFA). Sera were collected from each group and treated as described earlier (Kushwaha et al., 2001).
Persistence:
Humoral and cell-mediated response was still robust up to 70 days post-immunization (Kushwaha et al., 2001).
Immune Response:
Results showed that ABRA (M), ABRA (C) and ABRA (P) were highly immunogenic in these animals; end point titres greater than 10^5 were observed in these constructs. Mice were immunized using standard methods. Relative concentrations of the antibodies elicited by them in mice at different intervals of immunization were measured at a dilution of 1 : 3000. ABRA (N) and ABRA (C) did not show a boostable antibody response; two secondary immunizations did not result in any increase in the antibody titre. Immunogenicity studies with these constructs in rabbits and mice indicated that the N-terminal region is the least immunogenic part of ABRA. T-cell proliferation experiments in mice immunized with these constructs revealed that the T-cell epitopes were localized in the middle portion of the protein (Kushwaha et al., 2001).
Efficacy:
The purified immunoglobulin G specific to middle and C-terminal fragments prevented parasite growth at levels approaching 80-90% (Kushwaha et al., 2001).
Description:
This antibody response was the focus of intense interest when it was found that mice could be rendered resistant to sporozoite challenge by passive immunisation with monoclonal antibodies against circumsporozoite protein (Kwiatkowski et al., 1997).
Description:
combination of liposome, MPL, and QS-21(Laurens, 2020)
i. Immunization Route
Intramuscular injection (i.m.)
j.
Human Response
Host Strain:
children aged 5-17 months and infants aged 6-12 weeks from sub-Saharan African countries
Vaccination Protocol:
Double-blinded, phaseIII, randomised controlled trial. Participants were randomly assigned in a 1:1:1 ration to receive 1) three doses of RTS,S/AS01 at month 0, 1, and 2 and a booster dose at month 20; 2) three doses of RTS,S/AS01 at month 0, 1, and 2 and a dose of control at month 20; or 3) four doses of control at month 0, 1, 2, and 20. (Laurens, 2020)
Immune Response:
The vaccine induces and increases anti-CSP antibody levels and CD4+ T cell responses. Older children have greater protective immune response than infants, and children received booster have greater protective immune response than children who did not. Children aged 5-17 months received booster dose had 318.3 EU/mL anti-CSP antibody after a month and 52.4 EU/mL after a year, and children did not receive the booster had 34.2 EU/mL after a month and 19.3 EU/mL after a year. Infants aged 6-12 weeks received booster dose had 169.9 EU/mL after a month and 15.9 EU/mL after a year, and infants did not receive the booster had 6.2 EU/mL after a month and 3.7 EU/mL after a year. (Laurens, 2020)
Side Effects:
Increased risk of febrile seizures: children aged 5-17 months more likely to have febrile seizures within 7 days after vaccination than controls. All affected children recovered after 7 days.(Laurens, 2020)
Efficacy:
Efficacy against clinical malaria in 12 months after dose 3: 31.3% (97.5%CI 23.6-38.3%, p< .0001) for 6-12 weeks age and 55.8% (97.5%CI 50.6-60.4%, p< .0001) for 5-17 months age Additional efficacy against clinical malaria at the end of follow-up: booster dose group: 25.9% for 6-12 weeks age and 36.3% for 5-17 months age; 3 doses group: 18.3% for 6-12 weeks age and 28.3% for 5-17 months age. Additional efficacy against severe malaria at the end of follow-up: booster dose group: 17.3% for 6-12 weeks age and 32.2% for 5-17 months age; 3 doses group: 10.3% for 6-12 weeks age and 1.1% for 5-17 months age. (Laurens, 2020)
83. RTS,S/AS01E
a. Type:
Subunit vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
RTS,S is the pre-erythrocyte sporozoite-stage Plasmodium falciparum antigen. It is a circumsporozoite surface protein (Alonso et al., 2004)
e. Immunization Route
Intramuscular injection (i.m.)
f. Description
Developed for immunization of infants in Africa, the RTS,S/ AS01E vaccine uses RTS,S, the P. falciparum circumsporite surface protein with AS01E as the vaccine adjuvant. AS01E contains 50% less liposome-based formulation of MPL and QS-21 compared to AS01B. (Asante et al., 2011)
g.
Human Response
Host Strain:
Children 6-10 weeks of age at first vaccination
Vaccination Protocol:
Children receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo.(Asante et al., 2011)
Immune Response:
At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. (Asante et al., 2011)
Efficacy:
For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003).(Asante et al., 2011)
RTS,S/AS02 is a pre-erythrocyte sporozoite-stage malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum RTS,S fused to HBsAg , incorporating a new adjuvant (AS02) (Bojang et al., 2001; Alonso et al., 2004).
g.
Human Response
Host Strain:
Mozambique children
Vaccination Protocol:
A double-blind, phase IIb, randomised controlled trial was performed in Mozambique in 2022 children aged 1–4 years. The study included two cohorts of children living in two separate areas which underwent different follow-up schemes. Participants were randomly allocated three doses of either RTS,S/AS02A candidate malaria vaccine or control vaccines. The primary endpoint, determined in cohort 1 (n=1605), was time to first clinical episode of P falciparum malaria (axillary temperature ≥37·5°C and P falciparum asexual parasitaemia >2500 per μL) over a 6-month surveillance period. Efficacy for prevention of new infections was determined in cohort 2 (n=417) (Alonso et al., 2004).
Persistence:
Vaccine efficacy in extending time to first infection was determined in cohort 2. 323 children had first episodes of asexual P falciparum parasitaemia (157 in the RTS,S/AS02A group and 166 in the control group), yielding a vaccine efficacy estimate of 45.0% (95% CI 31.4–55.9; p<0.0001). The mean density of asexual-stage parasites at the time of first infection was similar for the control and RTS,S/AS02A groups (3950 vs 3016 per μL, p=0.354). With the same methods as those used to assess persistence of efficacy for cohort 1, the model with the best fit suggested waning efficacy of the vaccine over time, which stabilised at about 40%. The prevalence of asexual P falciparum parasitaemia at the end of follow-up was lower in the RTS,S/AS02A group than in the control group (52.3% vs 65.8%; p=0.019), and prevalence of anaemia at month 8·5 was 2.7% in the control group and 0% in the RTS,S/AS02A group (p=0.056) (Alonso et al., 2004).
Immune Response:
Prevaccination anti-circumsporozoite antibody titres were low in the study children. The vaccine was immunogenic, inducing specific antibody levels after dose three, decaying over 6 months to about a quarter of the initial level, but remaining well above baseline values. Antibody levels in the control group remained low over the follow-up period. The vaccine also induced high levels of antibodies against HBsAg (>97% seroprotection). For both circumsporozoite and HBsAg, immunogenicity of the vaccine was greater in children younger than 24 months of age (Alonso et al., 2004).
Side Effects:
RTS,S/AS02A and control vaccines were safe and well tolerated. More than 92% of children in both groups received all three doses. Local and general solicited adverse events were of short duration and were mostly mild or moderate in intensity. Grade 3 local or general adverse events were uncommon and of short duration. Local injection-site pain that limited arm motion arose after seven (0.2%) doses in the RTS,S/AS02A group and after one (0.03%) dose in the control vaccine group, and injection-site swelling of more than 20 mm happened after 224 (7.7%) and 14 (0.5%) doses, respectively. General solicited adverse events (fever, irritability, drowsiness, anorexia) that prevented normal activities arose after 55 (1.9%) doses in the RTS,S/AS02A group and 23 (0.8%) doses in the control group. At least one unsolicited adverse event was reported by 653 (64.5%) children in the RTS,S/AS02A group and 597 (59.1%) in the control group. 429 serious adverse events were reported: 180 (17.8%) in the RTS,S/AS02A group and 249 (24.7%) in the control group. 15 children died during the study, five (0.6%) in the RTS,S/AS02A group and ten (1.2%) in the control group. Four of those who died had malaria as a significant contributing factor and all four were in the control group. No serious adverse event or death was judged to be related to vaccination (Alonso et al., 2004).
Efficacy:
Vaccine efficacy for the first clinical episodes was 29.9% (95% CI 11.0-44.8; p=0.004). At the end of the 6-month observation period, prevalence of P falciparum infection was 37% lower in the RTS,S/AS02A group compared with the control group (11.9% vs 18.9%; p=0.0003). Vaccine efficacy for severe malaria was 57.7% (95% CI 16.2-80.6; p=0.019). In cohort 2, vaccine efficacy for extending time to first infection was 45.0% (31.4-55.9; p<0.0001) (Alonso et al., 2004).
Description:
Development of an effective malaria vaccine could greatly contribute to disease control. RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on Plasmodium falciparum circumsporozoite surface antigen. The RTS,S/AS02A vaccine was safe, well tolerated, and immunogenic (Alonso et al., 2004).
(Reyes-Sandoval et al., 2008) AdC7 and AdC9 elicited strong immunogenicity ( approximately 20% of CD8(+) T cells in spleen), equivalent to or outperforming AdH5 and inducing sterile protection in 92% (C9), 83% (H5 and C7) and 67% (C6) of the mice, providing the first evidence of single-dose protection to Plasmodium berghei.
f. Immunization Route
Intramuscular injection (i.m.)
86. UK39
a. Type:
Virosome-formulated synthetic peptide vaccine
b. Status:
Clinical trial
c. Host Species for Licensed Use:
Human
d. Antigen
UK39: a circumsporozoite protein (CSP) derived synthetic PE-peptide conjugate (Genton et al., 2007)
e. Gene Engineering of
CSP from P. falciparum
Type:
Conjugate vaccine preparation
Description:
UK39 is a circumsporozoite protein (CSP) derived synthetic PE-peptide conjugate (Genton et al., 2007)
UK39 is a virosome-formulated P. falciparum circumsporozoit protien (CSP) derived synthetic peptide antigen that serves as a malaria vaccine (Genton et al., 2003)
h.
Baboon Response
Host Strain:
healthy Caucasian volunteers aged 18-45 years
Immune Response:
Mean titer and seroconversion rate were higher with the 10ug dose than the 50 ug dose. (Genton et al., 2003)
87. VAR2CSA
a. Type:
Subunit vaccine
b. Status:
Research
c. Host Species for Licensed Use:
None
d. Antigen
PfEMP1: mediate IE adhesion and facilitate parasite immunoevasion through antigenic variation. It is a large cysteine-rich transmembrane multidomain protein (~350 kDa) typically formed by six Duffy-binding-like domains with several interdomain regions. (Renn et al., 2021)
e. Immunization Route
Intramuscular injection (i.m.)
f. Description
VAR2CSA is the leading vaccine candidate to prevent placental malaria by using the VAR2CSA protein as the vaccine antigen and prevens sequesteration of P. falciparum-infected erythrocytes in placenal intervillous spaces.(Renn et al., 2021)
IV. References
1. Adams et al., 2002: Adams S, Brown H, Turner G. Breaking down the blood-brain barrier: signaling a path to cerebral malaria?. Trends in parasitology. 2002 Aug; 18(8); 360-6. [PubMed: 12377286].
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