• Type: Subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• 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).
• AMA1 from P. falciparum 3D7 gene engineering:
  • 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)
  • Detailed Gene Information: Click Here.
• Immunization Route: Intramuscular injection (i.m.)

• Type: Subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• 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).
• AMA1 from P. falciparum 3D7 gene engineering:
  • 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)
  • Detailed Gene Information: Click Here.
• Immunization Route: Intramuscular injection (i.m.)

• Type: Recombinant vector vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: PvDBPII: region II of P. vivax Duffy-binding protein (Hou et al., 2022)
• PvDBPII gene engineering:
  • Type: Recombinant protein preparation
  • Description: Region II of PvDBP, a 327-amino acid domain. (Hou et al., 2022)
  • Detailed Gene Information: Click Here.
• Vector: ChAd63: Chimpanzee adenovirus: vector for prime vaccination (Hou et al., 2022), MVA: modified vaccinia Ankara: vector for booster vaccination (Hou et al., 2022)
• Immunization Route: Intramuscular injection (i.m.)
• Description: Prime-boosting vaccine that use different vectors: ChAd63 PvDBP is the prime vaccination and MVA PvDBP is the booster. (Hou et al., 2022)

• Type: Recombinant vector vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: AMA1: apical membrane antigen 1 of P. falciparum(Sheehy et al., 2012)
• AMA1 from P. falciparum 3D7 gene engineering:
  • Type: Recombinant protein preparation
  • Detailed Gene Information: Click Here.
• Vector: 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)
• Immunization Route: Intramuscular injection (i.m.)
• 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)

• Type: Recombinant vector vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: ME-TRAP: multiple epitope thrombospondin-related adhesion protein of the pre-erythrocyte stage P.falciparum (Mensah et al., 2016)
• TRAP from P. falciparum gene engineering:
  • Type: Recombinant vector construction
  • Detailed Gene Information: Click Here.
• Vector: ChAd63: Chimpanzee adenovirus: vector for prime vaccination (Mensah et al., 2016), MVA: modified vaccinia Ankara: vector for booster vaccination (Mensah et al., 2016)
• Immunization Route: Intramuscular injection (i.m.)
• Description: Prime-boosting vaccine that use different vectors: ChAd63 ME-TRAP is the prime vaccination and MVA ME-TRAP is the booster.

• Type: Recombinant vector vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: MSP1: merozoite surface protein 1 of P.falciparum(Sheehy et al., 2011)
• MSP-1 from P. falciparum gene engineering:
  • Type: Recombinant protein preparation
  • Description: conserved blocks of P. falciparum MSP1 sequence and the sequence encoding 42-kDa C-terminus (MSP142) (Sheehy et al., 2011)
  • Detailed Gene Information: Click Here.
• Vector: 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)
• Immunization Route: Intramuscular injection (i.m.)
• 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)

• Type: Recombinant vector vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• 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)
• RH5 gene engineering:
  • Type: Recombinant protein preparation
  • Description: reticulocyte–binding protein homolog 5 full length sequence (Payne et al., 2017)
  • Detailed Gene Information: Click Here.
• Vector: ChAd63 (Payne et al., 2017): Chimpanzee adenovirus: vector for prime vaccination (Mensah et al., 2016); MVA (Payne et al., 2017): modified vaccinia Ankara: vector for booster vaccination (Mensah et al., 2016)
• Immunization Route: Intramuscular injection (i.m.)

• Type: Recombinant vector vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: FMP012: Escherichia coli-expressed P. falciparum cell-traversal protein for ookinetes and sporozoites (PfCelTOS) (Bennett et al., 2014)
• pfCelTOS gene engineering:
  • Type: Recombinant protein preparation
  • Detailed Gene Information: Click Here.
• Immunization Route: Intramuscular injection (i.m.)

• 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:
  • 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).

• Type: Subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• 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)
• msp3 gene engineering:
  • Type: Recombinant protein preparation
  • Detailed Gene Information: Click Here.
• Immunization Route: Intramuscular injection (i.m.)
• Description: A protein-protein conjugate malaria and helminth TBV that uses a modified msp3 protein as an antigen and Alhydrogel (R) and CRM197 as adjuvant.

• 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:
  • 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
• Host Species for Licensed Use: Human
• Host Species as Laboratory Animal Model: human
• 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.

• 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.)
• Description: A prime boost P. falciparum vaccine that utilizes FP9 and MVA as recombinant vectors for priming and boosting, respectively (Webster et al., 2005).

• 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 from P. falciparum gene engineering:
  • Type: Recombinant protein preparation
  • Description: The vaccine Combination B contains MSP1 peptides (Genton et al., 2003).
  • Detailed Gene Information: Click Here.
• Adjuvant:
  • 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.

• Type: Live, attenuated vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: Genetically attenuated NF54 strain P.falciparum sporozoites: p52 and p36 gene deleted
• Immunization Route: mosquito bites

• Type: Live, attenuated vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: Pb(PfCS@UIS4): genetically modified parasite: P. falciparum circumsporozoite (CS)- protein gene integrated in the P. berghei parasite. (Reuling et al., 2020)
• CS from P. falciparum gene engineering:
  • Type: Genetic modification
  • Description: PfCS expressed by P. berghei (Reuling et al., 2020)
  • Detailed Gene Information: Click Here.
• Immunization Route: infectious mosquito bites

• Type: Subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• Antigen: Pfs230 domain 1 (Duffy et al. 2021)
• Pfs230 gene engineering:
  • Type: Recombinant protein preparation
  • 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)
  • Detailed Gene Information: Click Here.
• Immunization Route: Intramuscular injection (i.m.)
• Description: Malaria transmission blocking vaccine: block parasite transmission through mosquitoes (Coelho et al., 2021)

• Type: protein-nanoparticle vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• 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)
• Pfs25 from P. falciparum 3D7 gene engineering:
  • Type: Recombinant protein preparation
  • Description: Pfs25 antigen is genetically fused to the IMX313 oligomerization domain (Mulamba et al., 2022)
  • Detailed Gene Information: Click Here.
• Adjuvant:
  • VO ID: VO_0005206
  • 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)
• Immunization Route: Intramuscular injection (i.m.)
• Description: **Mechanism: Human get vaccinated --> Human produce antibodies --> mosquitoes take up antibodies --> reduce parasite fertilization in mosquitoes (Mulamba et al., 2022)

• Type: Subunit vaccine
• Status: Clinical trial
• Host Species for Licensed Use: Human
• 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)
• CS from P. vivax gene engineering:
  • 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)
  • Detailed Gene Information: Click Here.
• Adjuvant:
  • VO ID: VO_0001270
• Immunization Route: Intramuscular injection (i.m.)

• Tradename: Mosquirix
• Vaccine Ontology ID: VO_0003093
• Type: Subunit vaccine
• Status: Licensed
• Host Species for Licensed Use: Human
• Antigen: RTS,S: fragment of circumsporozoite protein of the pre-erythrocyte sporozoite-stage P.falciparum(Laurens, 2020)
• CS from P. falciparum gene engineering:
  • Type: Recombinant protein preparation
  • Description: Part of CSP from P. falciparum: 18 NANP repeats and C-terminus exclusive of GPI sequence(Laurens, 2020)
  • Detailed Gene Information: Click Here.
• Adjuvant:
  • VO ID: VO_0005358
  • Description: combination of liposome, MPL, and QS-21(Laurens, 2020)
• Immunization Route: Intramuscular injection (i.m.)

• Vaccine Ontology ID: VO_0000774
• Type: Subunit vaccine
• Status: Clinical trial
• Antigen: RTS,S is the pre-erythrocyte sporozoite-stage Plasmodium falciparum antigen. It is a circumsporozoite surface protein (Alonso et al., 2004).
• Adjuvant:
  • VO ID: VO_0001264
• 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).

Human Response

• 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)

Human Response

• 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)

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)

Human Response

• Host Strain: malaria-naive adults from Oxford area(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)

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)

Human Response

• Host Strain: malaria-naive adults from Oxford area (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)

Human Response

• Host Strain: healthy adults in United Kingdom (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)

Human Response

• 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)

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

• 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)

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: 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)

Human Response

• 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)

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)

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)

Human Response

• Host Strain: malaria-naïve or semi-immune adults
• 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)
• Challenge Protocol: sporozoite CHMI at month 9 (Arévalo-Herrera et al., 2022)

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)

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).