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Vaccine Comparison

FMP1/AS02A MSP3-LSP with aluminium hydroxide P. falciparum DNA and MVA encoding ME-TRAP P. falciparum recombinant vector vaccine MVA.ME-TRAP P. falciparum vaccine Combination B RTS,S/AS02A
Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information Vaccine Information
  • Vaccine Ontology ID: VO_0000777
  • Type: Subunit vaccine
  • Antigen: 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).
  • AMA1 from P. falciparum 3D7 gene engineering:
    • Type: Recombinant protein preparation
    • Detailed Gene Information: Click Here.
  • Adjuvant: AS02 vaccine adjuvant
    • VO ID: VO_0001264
    • 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)
  • 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).
  • Vaccine Ontology ID: VO_0000773
  • Type: Subunit vaccine
  • Antigen: 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).
  • Adjuvant: aluminum hydroxide vaccine adjuvant
    • VO ID: VO_0000127
    • 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).
  • Virulence: No.
  • Vaccine Ontology ID: VO_0000747
  • Type: DNA vaccine
  • Antigen: Multiple epitope-thrombospondin-related adhesion protein (ME-TRAP)
  • TRAP from P. falciparum gene engineering:
    • 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).
    • Detailed Gene Information: Click Here.
  • Vector: pSG2 and MVA (Dunachie et al., 2006)
  • Preparation: 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).
  • 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.
  • Vaccine Ontology ID: VO_0004399
  • Type: Recombinant vector vaccine
  • Status: Research
  • Host Species as Laboratory Animal Model: Human
  • Vector: Recombinant fowlpox strain FP9 and recombinant MVA (Webster et al., 2005)
  • Immunization Route: Intramuscular injection (i.m.)
  • Tradename: Combination B
  • Vaccine Ontology ID: VO_0000740
  • Type: Subunit vaccine
  • Antigen: 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).
  • RESA gene engineering:
    • Type: Recombinant protein preparation
    • Description: The vaccine Combination B contains peptides from the ring-infected erythrocyte surface antigen (RESA) (Genton et al., 2003).
    • Detailed Gene Information: Click Here.
  • MSP-1 gene engineering:
    • Type: Recombinant protein preparation
    • Description: The vaccine Combination B contains MSP1 peptides (Genton et al., 2003).
    • Detailed Gene Information: Click Here.
  • Adjuvant: Montanide ISA 720
    • VO ID: VO_0001268
    • 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).
  • 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).
  • 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.
  • Vaccine Ontology ID: VO_0000774
  • Type: Subunit vaccine
  • Antigen: RTS,S is the pre-erythrocyte sporozoite-stage Plasmodium falciparum antigen. It is a circumsporozoite surface protein (Alonso et al., 2004).
  • Adjuvant: AS02 vaccine adjuvant
  • Preparation: 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).
Host Response Host Response Host Response Host Response Host Response Host Response

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.

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).

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).

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).

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.

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).
  • Challenge Protocol: Children were not challenged (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).
References References References References References References
Morais et al., 2006: Morais CG, Soares IS, Carvalho LH, Fontes CJ, Krettli AU, Braga EM. Antibodies to Plasmodium vivax apical membrane antigen 1: persistence and correlation with malaria transmission intensity. The American journal of tropical medicine and hygiene. 2006 Oct; 75(4); 582-7. [PubMed: 17038677].
Polhemus et al., 2007: Polhemus ME, Magill AJ, Cummings JF, Kester KE, Ockenhouse CF, Lanar DE, Dutta S, Barbosa A, Soisson L, Diggs CL, Robinson SA, Haynes JD, Stewart VA, Ware LA, Brando C, Krzych U, Bowden RA, Cohen JD, Dubois MC, Ofori-Anyinam O, De-Kock E, Ballou WR, Heppner DG Jr. Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naive adults at the Walter Reed Army Institute of Research. Vaccine. 2007 May 22; 25(21); 4203-12. [PubMed: 17442466].
Audran et al., 2005: Audran R, Cachat M, Lurati F, Soe S, Leroy O, Corradin G, Druilhe P, Spertini F. Phase I malaria vaccine trial with a long synthetic peptide derived from the merozoite surface protein 3 antigen. Infection and immunity. 2005 Dec; 73(12); 8017-26. [PubMed: 16299295].
Sirima et al., 2007: Sirima SB, Nebie I, Ouedraogo A, Tiono AB, Konate AT, Gansane A, Derme AI, Diarra A, Ouedraogo A, Soulama I, Cuzzin-Ouattara N, Cousens S, Leroy O. Safety and immunogenicity of the Plasmodium falciparum merozoite surface protein-3 long synthetic peptide (MSP3-LSP) malaria vaccine in healthy, semi-immune adult males in Burkina Faso, West Africa. Vaccine. 2007 Mar 30; 25(14); 2723-32. [PubMed: 17280744].
Dunachie et al., 2006: Dunachie SJ, Walther M, Epstein JE, Keating S, Berthoud T, Andrews L, Andersen RF, Bejon P, Goonetilleke N, Poulton I, Webster DP, Butcher G, Watkins K, Sinden RE, Levine GL, Richie TL, Schneider J, Kaslow D, Gilbert SC, Carucci DJ, Hill AV. A DNA prime-modified vaccinia virus ankara boost vaccine encoding thrombospondin-related adhesion protein but not circumsporozoite protein partially protects healthy malaria-naive adults against Plasmodium falciparum sporozoite challenge. Infection and immunity. 2006; 74(10); 5933-5942. [PubMed: 16988273].
Webster et al., 2005: Webster DP, Dunachie S, Vuola JM, Berthoud T, Keating S, Laidlaw SM, McConkey SJ, Poulton I, Andrews L, Andersen RF, Bejon P, Butcher G, Sinden R, Skinner MA, Gilbert SC, Hill AV. Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(13); 4836-4841. [PubMed: 15781866].
Genton et al., 2003: Genton B, Al-Yaman F, Betuela I, Anders RF, Saul A, Baea K, Mellombo M, Taraika J, Brown GV, Pye D, Irving DO, Felger I, Beck HP, Smith TA, Alpers MP. Safety and immunogenicity of a three-component blood-stage malaria vaccine (MSP1, MSP2, RESA) against Plasmodium falciparum in Papua New Guinean children. Vaccine. 2003 Dec 8; 22(1); 30-41. [PubMed: 14604568].
Genton et al., 2003a: Genton B, Anders RF, Alpers MP, Reeder JC. The malaria vaccine development program in Papua New Guinea. Trends in parasitology. 2003 Jun; 19(6); 264-70. [PubMed: 12798084].
Girard et al., 2007: Girard MP, Reed ZH, Friede M, Kieny MP. A review of human vaccine research and development: malaria. Vaccine. 2007 Feb 19; 25(9); 1567-80. [PubMed: 17045367].
Alonso et al., 2004: Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, Mandomando I, Spiessens B, Guinovart C, Espasa M, Bassat Q, Aide P, Ofori-Anyinam O, Navia MM, Corachan S, Ceuppens M, Dubois MC, Demoitie MA, Dubovsky F, Menendez C, Tornieporth N, Ballou WR, Thompson R, Cohen J. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet. 2004 Oct 16-22; 364(9443); 1411-20. [PubMed: 15488216].
Bojang et al., 2001: Bojang KA, Milligan PJ, Pinder M, Vigneron L, Alloueche A, Kester KE, Ballou WR, Conway DJ, Reece WH, Gothard P, Yamuah L, Delchambre M, Voss G, Greenwood BM, Hill A, McAdam KP, Tornieporth N, Cohen JD, Doherty T. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet. 2001 Dec 8; 358(9297); 1927-34. [PubMed: 11747915].