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Vaccine Comparison

P. falciparum DNA Vaccine encoding EBA-175 P. falciparum Hsp90 Protein Subunit Vaccine P. falciparum MSP1 from transgenic mice with Freund's adjuvant P. falciparum MSP3 Protein Subunit Vaccine P. falciparum Subunit SE36 Protein Vaccine P. knowlesi DNA vaccine encoding PkCSP, PkSSP2, PkAMA1, and PkMSP1p42 P. vivax PVS25 with Montanide ISA-720
Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information
  • Vaccine Ontology ID: VO_0004196
  • Type: DNA vaccine
  • Status: Research
  • Antigen: P. falciparum EBA-175 RII
  • eba-175 gene engineering:
    • Type: DNA vaccine construction
    • Detailed Gene Information: Click Here.
  • Vector: expression plasmid vector VR1020
  • Immunization Route: Intradermal injection (i.d.)
  • Vaccine Ontology ID: VO_0011396
  • Type: Subunit vaccine
  • Status: Research
  • Hsp90 gene engineering:
    • Type: Recombinant protein preparation
    • Detailed Gene Information: Click Here.
  • Adjuvant: complete Freunds adjuvant
  • Immunization Route: Subcutaneous injection
  • Vaccine Ontology ID: VO_0000775
  • Type: Subunit vaccine
  • Antigen: the 42-kDa C-terminal portion of Plasmodium falciparum merozoite surface protein 1 (MSP1) (Stowers et al., 2002).
  • MSP-1 gene engineering:
    • Type: Recombinant protein preparation
    • Description: Generated by transgenic mice (Stowers et al., 2002).
    • Detailed Gene Information: Click Here.
  • Adjuvant: complete Freunds adjuvant
    • VO ID: VO_0000139
    • 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).
  • Adjuvant: incomplete Freunds adjuvant
    • VO ID: VO_0000142
    • 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).
  • 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).
  • Virulence: None.
  • Description: It is likely for producing efficacious malarial vaccines in transgenic animals (Stowers et al., 2002).
  • Vaccine Ontology ID: VO_0011440
  • Type: Subunit vaccine
  • Status: Research
  • msp3 gene engineering:
    • Type: Recombinant protein preparation
    • Detailed Gene Information: Click Here.
  • Adjuvant: complete Freunds adjuvant
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0011415
  • Type: Subunit vaccine
  • Status: Clinical trial
  • SERA-5 gene engineering:
    • Type: Recombinant protein preparation
    • Detailed Gene Information: Click Here.
  • Adjuvant: aluminum hydroxide vaccine adjuvant
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0004595
  • Type: DNA vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Rhesus monkeys
  • AMA1 from P. knowlesi gene engineering:
    • Type: DNA vaccine construction
    • Detailed Gene Information: Click Here.
  • CSP from P. knowlesi gene engineering:
    • Type: DNA vaccine construction
    • Detailed Gene Information: Click Here.
  • MSP1 from P. knowlesi gene engineering:
    • Type: DNA vaccine construction
    • Detailed Gene Information: Click Here.
  • SSP2 from P. knowlesi gene engineering:
    • Type: DNA vaccine construction
    • Detailed Gene Information: Click Here.
  • Vector: VR1020 prime, recombinant canarypox viruses boost (Rogers et al., 2001)
  • Immunization Route: Intramuscular injection (i.m.)
  • Vaccine Ontology ID: VO_0000776
  • Type: Subunit vaccine
  • Antigen: 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).
  • cjaA gene engineering:
    • Type: Recombinant protein preparation
    • Description: Pvs25 was cloned and purified from yeast (Arevalo-Herrera et al., 2005).
    • Detailed Gene Information: Click Here.
  • Adjuvant: Montanide ISA 720
    • VO ID: VO_0001268
    • Description: Montanide ISA-720 an adjuvant suitable for human vaccination trials (Arevalo-Herrera et al., 2005).
  • 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).
  • Virulence: Not virulent.
Host Response Host Response Host Response Host Response Host Response Host Response Host Response

Monkey Response

  • Host Strain: Aotus lemurinus lemurinus
  • 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 104 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).

Monkey Response

  • Host Strain: S. sciureus
  • 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 107 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).

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 104 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).

Monkey Response

  • Host Strain: Aotus nancymai
  • 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 × 104 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).

Monkey Response

  • Host Strain: squirrel monkey (Saimiri sciureus)
  • 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 × 109 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).

Monkey Response

  • Vaccine Immune Response Type: VO_0003057
  • 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).

Monkey Response

  • Host Strain: owl monkey (Aotus lemurinus griseimembra)
  • 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).
  • Side Effects: No adverse side effects were encountered here (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).

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).
References References References References References References References
Sim et al., 2001: Sim BK, Narum DL, Liang H, Fuhrmann SR, Obaldia N 3rd, Gramzinski R, Aguiar J, Haynes JD, Moch JK, Hoffman SL. Induction of biologically active antibodies in mice, rabbits, and monkeys by Plasmodium falciparum EBA-175 region II DNA vaccine. Molecular medicine (Cambridge, Mass.). 2001; 7(4); 247-254. [PubMed: 11471569].
Bonnefoy et al., 1994: Bonnefoy S, Gysin J, Blisnick T, Guillotte M, Carcy B, Pereira da Silva L, Mercereau-Puijalon O. Immunogenicity and antigenicity of a Plasmodium falciparum protein fraction (90-110 kDa) able to protect squirrel monkeys against asexual blood stages. Vaccine. 1994; 12(1); 32-40. [PubMed: 8303938].
Stowers et al., 2002: Stowers AW, Chen Lh LH, Zhang Y, Kennedy MC, Zou L, Lambert L, Rice TJ, Kaslow DC, Saul A, Long CA, Meade H, Miller LH. A recombinant vaccine expressed in the milk of transgenic mice protects Aotus monkeys from a lethal challenge with Plasmodium falciparum. Proceedings of the National Academy of Sciences of the United States of America. 2002 Jan 8; 99(1); 339-44. [PubMed: 11752405].
Tsai et al., 2009: Tsai CW, Duggan PF, Jin AJ, Macdonald NJ, Kotova S, Lebowitz J, Hurt DE, Shimp RL Jr, Lambert L, Miller LH, Long CA, Saul A, Narum DL. Characterization of a protective Escherichia coli-expressed Plasmodium falciparum merozoite surface protein 3 indicates a non-linear, multi-domain structure. Molecular and biochemical parasitology. 2009; 164(1); 45-56. [PubMed: 19073223].
Horii et al., 2010: Horii T, Shirai H, Jie L, Ishii KJ, Palacpac NQ, Tougan T, Hato M, Ohta N, Bobogare A, Arakaki N, Matsumoto Y, Namazue J, Ishikawa T, Ueda S, Takahashi M. Evidences of Protection Against Blood-stage Infection of Plasmodium falciparum by the Novel Protein Vaccine SE36. Parasitology international. 2010; ; . [PubMed: 20493274].
Rogers et al., 2001: Rogers WO, Baird JK, Kumar A, Tine JA, Weiss W, Aguiar JC, Gowda K, Gwadz R, Kumar S, Gold M, Hoffman SL. Multistage multiantigen heterologous prime boost vaccine for Plasmodium knowlesi malaria provides partial protection in rhesus macaques. Infection and immunity. 2001; 69(9); 5565-5572. [PubMed: 11500430].
Arevalo-Herrera et al., 2005: Arevalo-Herrera M, Solarte Y, Yasnot MF, Castellanos A, Rincon A, Saul A, Mu J, Long C, Miller L, Herrera S. Induction of transmission-blocking immunity in Aotus monkeys by vaccination with a Plasmodium vivax clinical grade PVS25 recombinant protein. The American journal of tropical medicine and hygiene. 2005 Nov; 73(5 Suppl); 32-7. [PubMed: 16291764].