Supplementary Table 1: Clinical trials of subunit blood-stage vaccines

The following table includes the primary publications of all clinical trials known to the author, as well as unpublished clinical trials listed on clinicaltrials.gov which began enrolment up to and including January 2016.

# / Phase / Vaccine name / Blood-stage Antigen(s) / Allele(s) / Adjuvant/ platform / Year of publication / Population / Reference
1 / I/IIb / SPf66 / 83, 55, 35 kDa peptides / Alum / 1990-1998 / South America, Africa, Asia / 1
2 / Ia / Ro46-2717/2924 / MSP2 (with CSP) / NF54 / Alum / 1995 / Swiss adults / 2
3 / I/IIa / NYVAC-Pf7 / MSP1, AMA1, SERA / 3D7 / NYVAC / 1998 / US adults / 3
4 / Ia / Combination B / MSP1/MSP2/RESA / 3D7 / Montanide ISA 720 / 1999 / Australian adults / 4
5 / Ia / P30P2 MSP-119 / MSP119 / 3D7 or FVO / Alum / 1999 / US adults / 5
6 / Ib / Combination B / MSP1/MSP2/RESA / 3D7 / Montanide ISA 720 / 2000 / PNG adults / 6
7 / IIa / Combination B / MSP1/MSP2/RESA / 3D7 / Montanide ISA 720 / 2000 / Australian adults / 7
8 / IIb / Combination B / MSP1/MSP2/RESA / 3D7 / Montanide ISA 720 / 2002 / PNG children / 8
9 / Ib / Combination B / MSP1/MSP2/RESA / 3D7 / Montanide ISA 720 / 2003 / PNG children / 9
10 / Ia / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel / 2005 / US adults / 10
11 / Ia / MSP3-LSP / MSP3 / Conserved / Alum/ Montanide ISA 720 / 2005 / Swiss adults / 11
12 / Ia / Pf(3D7)AMA1 / AMA1 / 3D7 / Montanide ISA 720 / 2005 / Australian adults / 12
13 / Ia / FMP1 / MSP142 / 3D7 / AS02A / 2006 / US adults / 13
14 / Ib / FMP1 / MSP142 / 3D7 / AS02A / 2006 / Malian adults / 14
15 / Ib / FMP1 / MSP142 / 3D7 / AS02A / 2006 / Kenyan children / 15
16 / Ia / GLURP LSP / GLURP / F32 / Montanide ISA 720 or alum / 2007 / Dutch adults / 16
17 / Ib / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel / 2007 / Malian adults / 17
18 / Ib / FMP1 / MSP142 / 3D7 / AS02A / 2007 / Kenyan adults / 18
19 / Ia / FMP2.1 / AMA1 / 3D7 / AS02A / 2007 / US adults / 19
20 / Ia / MSP1-C1 / MSP142 / 3D7 or FVO / Alhydrogel / 2007 / US adults / 20
21 / Ib / MSP3-LSP / MSP3 / Conserved / Alum / 2007 / Burkina Faso adults / 21
22 / Ia / PEV301 / PEV302 / AMA1 ± CSP / Virosome / 2007 / Swiss adults / 22
23 / Ia / AMA1 FVO / AMA1 / FVO / Alhydrogel/ Montanide ISA720 /AS02 / 2008 / Dutch adults / 23
24 / Ib / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel / 2008 / Malian children / 24
25 / Ia / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel + CpG7909 / 2008 / US adults / 25
26 / Ib / FMP2.1 / AMA1 / 3D7 / AS02A / 2008 / Malian adults / 26
27 / I/IIa / PEV3A / AMA1 / Conserved / Virosome / 2008 / UK adults / 27
28 / Ia / PfCP2.9 / AMA1/MSP142 / 3D7 + FVO / Montanide ISA 720 / 2008 / Chinese adults / 28
29 / Ia / PfCP2.9 / AMA1/ MSP119 / 3D7 + FVO / Montanide ISA 720 / 2008 / Chinese adults / 29
30 / Ia / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel + CpG7909 / 2009 / US adults / 30
31 / Ib / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel + CpG7909 / 2009 / Malian adults / 31
32 / IIb / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel / 2009 / Malian children / 32
33 / IIb / FMP1 / MSP142 / 3D7 / AS02 / 2009 / Kenyan children / 33
34 / I/IIa / FMP2.1 / AMA1 / 3D7 / AS02A vs AS01B / 2009 / US adults / 34
35 / Ia / GMZ2 / GLURP + MSP3 / Conserved / Alum / 2009 / German adults / 35
36 / Ib / MSP3-LSP / MSP3 / Conserved / Alum / 2009 / Tanzanian children / 36
37 / Ib / MSP3-LSP / MSP3 / Conserved / Alum / 2009 / Burkina Faso adults / 37
38 / (IIb) / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel / 2010 / Malian children / 38
39 / Ia / AMA1-C1 / AMA1 / 3D7 + FVO / Montanide ISA 720 / 2010 / Australian adults / 39
40 / Ia / EBA175_RII NG / EBA175_RII / 3D7 / Adjuphos / 2010 / US adults / 40
41 / Ib / FMP2.1 / AMA1 / 3D7 / AS02A / 2010 / Malian children / 41
42 / Ia / MSP1-C1 / MSP1 / 3D7 + FVO / Alhydrogel plus CpG7909 / 2010 / US adults / 42
43 / Ia / SE36 / SERA5 / Honduras-1 / Alhydrogel / 2010 / Japanese male adults / 43
44 / Ib / GMZ2 / GLURP + MSP3 / Conserved / Alum (AlOH) / 2010 / Gabonese adults / 44
45 / IIa / AMA1-C1 / AMA1 / 3D7 + FVO / Alhydrogel + CpG7909 / 2011 / UK adults / 45
46 / IIb / FMP2.1 / AMA1 / 3D7 / AS02A / 2011 / Malian children / 46
47 / (IIb) / MSP3-LSP / MSP3 / Conserved / Alum / 2011 / Burkina Faso adults / 47
48 / Ib / PEV3B / AMA1 + CSP / Virosome / 2011 / Tanzanian adults & children / 48
49 / Ia / PfM128 / MSP1 / 3D7+Wellcome / ChAd63-MVA / 2011 / UK adults / 49
50 / Ia / NMRC-M3V-Ad-PfCA / AMA1 + CSP / 3D7 / AdHu5 / 2011 / US adults / 50
51 / Ia / MSP2-C1 / MSP2 / 3D7 + FC27 / Montanide ISA 720 / 2011 / Australian adults / 51
52 / Ib / GMZ2 / GLURP + MSP3 / Conserved / Alum / 2011 / Gabonese children / 52
53 / Ia / AMA1 (bi-allelic) / AMA1 / 3D7 + FVO / ChAd63-MVA / 2012 / UK adults / 53
54 / I/IIa / PfM128 and AMA1 (bi-allelic) / MSP1 ± AMA1 / 3D7 + FVO (AMA1) or 3D7 + Wellcome (MSP1) / ChAd63-MVA / 2012 / UK adults / 54
55 / Ia / BSAM2 / MSP1 + AMA1 / 3D7 + FVO (AMA1) or 3D7 + Wellcome (MSP1) / Alhydrogel + CpG7909 / 2012 / US adults / 55
56 / Ia/b / FMP10 / MSP142 / FVO / AS01 / 2013 / US adults & Kenyan adults / 56
57 / Ib / BK-SE36 / SERA5 / Honduras-1 / Alhydrogel / 2013 / Ugandan adults and children / 57
58 / IIa / NMRC-M3V-Ad-PfCA / AMA1 + CSP / 3D7 / AdHu5 / 2013 / US adults / 58
59 / IIa / NMRC-M3V-D/AdPfCA / AMA1 / 3D7 / DNA-AdHu5 / 2013 / US adults / 59
60 / Ia / AMA1 bi-allelic / AMA1-C1 / AMA1 / 3D7 + FVO / ChAd63-MVA & Alhydrogel/ CpG 7909 / 2014 / UK adults / 60
61 / Ia / JAIVAC-1 (MSP119 + EBA175 F2) / MSP1 + EBA175 / FVO(MSP1) + Camp(EBA) / ISA720 / 2015 / Indian adults / 61
62 / Ia/Ib / AMA1 DiCo / AMA1 / DiCo / GLA-SE or Alhydrogel / Unpublished / European & African adults / NCT02014727
63 / Ia / P27a / Tex1/ PFF0165c / GLA-SE or Alhydrogel / Unpublished (completed) / Swiss adults / NCT01949909
64 / Ia / RH5 / RH5 / 3D7 / ChAd63-MVA / Unpublished (completed) / UK adults / NCT02181088
65 / Ia / PvDBP_RII / DBP / Salvador I / ChAd63-MVA / Unpublished (completed) / UK adults / NCT01816113

Supplementary References

1 Graves, P. & Gelband, H. Vaccines for preventing malaria (SPf66). Cochrane Database Syst Rev, CD005966, (2006).

2 Sturchler, D., Berger, R., Rudin, C., Just, M., Saul, A., Rzepczyk, C., Brown, G., Anders, R., Coppel, R., Woodrow, G. et al. Safety, immunogenicity, and pilot efficacy of Plasmodium falciparum sporozoite and asexual blood-stage combination vaccine in Swiss adults. Am J Trop Med Hyg 53, 423-431, (1995).

3 Ockenhouse, C. F., Sun, P. F., Lanar, D. E., Wellde, B. T., Hall, B. T., Kester, K., Stoute, J. A., Magill, A., Krzych, U., Farley, L. et al. Phase I/IIa safety, immunogenicity, and efficacy trial of NYVAC-Pf7, a pox-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria. J Infect Dis 177, 1664-1673, (1998).

4 Saul, A., Lawrence, G., Smillie, A., Rzepczyk, C. M., Reed, C., Taylor, D., Anderson, K., Stowers, A., Kemp, R., Allworth, A. et al. Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant. Vaccine 17, 3145-3159, (1999).

5 Keitel, W. A., Kester, K. E., Atmar, R. L., White, A. C., Bond, N. H., Holland, C. A., Krzych, U., Palmer, D. R., Egan, A., Diggs, C. et al. Phase I trial of two recombinant vaccines containing the 19kd carboxy terminal fragment of Plasmodium falciparum merozoite surface protein 1 (msp-1(19)) and T helper epitopes of tetanus toxoid. Vaccine 18, 531-539, (1999).

6 Genton, B., Al-Yaman, F., Anders, R., Saul, A., Brown, G., Pye, D., Irving, D. O., Briggs, W. R., Mai, A., Ginny, M. et al. Safety and immunogenicity of a three-component blood-stage malaria vaccine in adults living in an endemic area of Papua New Guinea. Vaccine 18, 2504-2511, (2000).

7 Lawrence, G., Cheng, Q. Q., Reed, C., Taylor, D., Stowers, A., Cloonan, N., Rzepczyk, C., Smillie, A., Anderson, K., Pombo, D. et al. Effect of vaccination with 3 recombinant asexual-stage malaria antigens on initial growth rates of Plasmodium falciparum in non-immune volunteers. Vaccine 18, 1925-1931, (2000).

8 Genton, B., Betuela, I., Felger, I., Al-Yaman, F., Anders, R. F., Saul, A., Rare, L., Baisor, M., Lorry, K., Brown, G. V. et al. A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis 185, 820-827, (2002).

9 Genton, B., Al-Yaman, F., Betuela, I., Anders, R. F., Saul, A., Baea, K., Mellombo, M., Taraika, J., Brown, G. V., Pye, D. et al. Safety and immunogenicity of a three-component blood-stage malaria vaccine (MSP1, MSP2, RESA) against Plasmodium falciparum in Papua New Guinean children. Vaccine 22, 30-41, (2003).

10 Malkin, E. M., Diemert, D. J., McArthur, J. H., Perreault, J. R., Miles, A. P., Giersing, B. K., Mullen, G. E., Orcutt, A., Muratova, O., Awkal, M. et al. Phase 1 clinical trial of apical membrane antigen 1: an asexual blood-stage vaccine for Plasmodium falciparum malaria. Infect Immun 73, 3677-3685, (2005).

11 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. Infect Immun 73, 8017-8026, (2005).

12 Saul, A., Lawrence, G., Allworth, A., Elliott, S., Anderson, K., Rzepczyk, C., Martin, L. B., Taylor, D., Eisen, D. P., Irving, D. O. et al. A human phase 1 vaccine clinical trial of the Plasmodium falciparum malaria vaccine candidate apical membrane antigen 1 in Montanide ISA720 adjuvant. Vaccine 23, 3076-3083, (2005).

13 Ockenhouse, C. F., Angov, E., Kester, K. E., Diggs, C., Soisson, L., Cummings, J. F., Stewart, A. V., Palmer, D. R., Mahajan, B., Krzych, U. et al. Phase I safety and immunogenicity trial of FMP1/AS02A, a Plasmodium falciparum MSP-1 asexual blood stage vaccine. Vaccine 24, 3009-3017, (2006).

14 Thera, M. A., Doumbo, O. K., Coulibaly, D., Diallo, D. A., Sagara, I., Dicko, A., Diemert, D. J., Heppner, D. G., Jr., Stewart, V. A., Angov, E. et al. Safety and allele-specific immunogenicity of a malaria vaccine in Malian adults: results of a phase I randomized trial. PLoS Clin Trials 1, e34, (2006).

15 Withers, M. R., McKinney, D., Ogutu, B. R., Waitumbi, J. N., Milman, J. B., Apollo, O. J., Allen, O. G., Tucker, K., Soisson, L. A., Diggs, C. et al. Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children. PLoS Clin Trials 1, e32, (2006).

16 Hermsen, C. C., Verhage, D. F., Telgt, D. S., Teelen, K., Bousema, J. T., Roestenberg, M., Bolad, A., Berzins, K., Corradin, G., Leroy, O. et al. Glutamate-rich protein (GLURP) induces antibodies that inhibit in vitro growth of Plasmodium falciparum in a phase 1 malaria vaccine trial. Vaccine 25, 2930-2940, (2007).

17 Dicko, A., Diemert, D. J., Sagara, I., Sogoba, M., Niambele, M. B., Assadou, M. H., Guindo, O., Kamate, B., Baby, M., Sissoko, M. et al. Impact of a Plasmodium falciparum AMA1 vaccine on antibody responses in adult Malians. PLoS ONE 2, e1045, (2007).

18 Stoute, J. A., Gombe, J., Withers, M. R., Siangla, J., McKinney, D., Onyango, M., Cummings, J. F., Milman, J., Tucker, K., Soisson, L. et al. Phase 1 randomized double-blind safety and immunogenicity trial of Plasmodium falciparum malaria merozoite surface protein FMP1 vaccine, adjuvanted with AS02A, in adults in western Kenya. Vaccine 25, 176-184, (2007).

19 Polhemus, M. E., Magill, A. J., Cummings, J. F., Kester, K. E., Ockenhouse, C. F., Lanar, D. E., Dutta, S., Barbosa, A., Soisson, L., Diggs, C. L. et al. 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 25, 4203-4212, (2007).

20 Malkin, E., Long, C. A., Stowers, A. W., Zou, L., Singh, S., Macdonald, N. J., Narum, D. L., Miles, A. P., Orcutt, A. C., Muratova, O. et al. Phase 1 Study of Two Merozoite Surface Protein 1 (MSP1(42)) Vaccines for Plasmodium falciparum Malaria. PLoS Clin Trials 2, e12, (2007).

21 Sirima, S. B., Nebie, I., Ouedraogo, A., Tiono, A. B., Konate, A. T., Gansane, A., Derme, A. I., Diarra, A., Soulama, I., Cuzzin-Ouattara, N. et al. 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 25, 2723-2732, (2007).

22 Genton, B., Pluschke, G., Degen, L., Kammer, A. R., Westerfeld, N., Okitsu, S. L., Schroller, S., Vounatsou, P., Mueller, M. M., Tanner, M. et al. A randomized placebo-controlled phase Ia malaria vaccine trial of two virosome-formulated synthetic peptides in healthy adult volunteers. PLoS One 2, e1018, (2007).

23 Roestenberg, M., Remarque, E., de Jonge, E., Hermsen, R., Blythman, H., Leroy, O., Imoukhuede, E., Jepsen, S., Ofori-Anyinam, O., Faber, B. et al. Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02. PLoS ONE 3, e3960, (2008).

24 Dicko, A., Sagara, I., Ellis, R. D., Miura, K., Guindo, O., Kamate, B., Sogoba, M., Niambele, M. B., Sissoko, M., Baby, M. et al. Phase 1 study of a combination AMA1 blood stage malaria vaccine in Malian children. PLoS ONE 3, e1563, (2008).

25 Mullen, G. E., Ellis, R. D., Miura, K., Malkin, E., Nolan, C., Hay, M., Fay, M. P., Saul, A., Zhu, D., Rausch, K. et al. Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria. PLoS ONE 3, e2940, (2008).

26 Thera, M. A., Doumbo, O. K., Coulibaly, D., Diallo, D. A., Kone, A. K., Guindo, A. B., Traore, K., Dicko, A., Sagara, I., Sissoko, M. S. et al. Safety and immunogenicity of an AMA-1 malaria vaccine in Malian adults: results of a phase 1 randomized controlled trial. PLoS One 3, e1465, (2008).