Efficacy of phase 3 trial of RTS, S/AS01 malaria vaccine: The need for an alternative development plan

Figures & data

Table 1. Status of vaccine research and development of vaccines for malaria.

Vaccine	Phase I	Phase II	Pivotal
Pre-erythrocytic stage
RTS,S/AS01	X	X	X
ChAd63/MVA ME-TRAP	X	X
PfSPZ attenuated sporozoite	X	X
Polyepitope DNA EP1300	X
PfCelTOS FMP012	X
CSVAC	X
R21/AS01B	X
Adenovirus (Ad35) and adenovirus 26 (Ad26) vectored CS	X
PfCelTOS FMP012/AS01B	X
PfCelTOS FMP012/GLA-SE	X
RTS,S/AS01B + ChAd63/MVA (ME-TRAP)	X
rCSP/GLA-SE	X
Blood-stage
EBA175 RII/aluminum phosphate	X
FMP2.1/AS01B (AMA-1 3D7 E. coli)	X
ChAd63/AMA MVA/AMA1	X
ChAd63 MSP1/MVA MSP1	X
GMZ2	X
GMZ2 field	X	X
pfAMA1-DiCo	X
P27A	X
MSP3	X
MSP3 field		X
SE36	X
NMRC-M3V-Ad-PfCA	X	X
PfPEBS	X
ChAd63 RH5 +/− MVA RH5	X
PRIMVAC	X
Sexual stage
Pfs25 VLP	X
Pfs25-EPA/Alhydroge	X
Pfs230D1M-EPA/Alhydrogel and/or Pfs25-EPA/Alhydrogel	X
ChAd63 Pfs25-IMX313/MVA Pfs25-IMX313	X
P. vivax Project
ChAd63/MVA PvDBP	X

* This information is derived from “Tables of malaria vaccine projects globally, WHO,” Ref#3, and that the source of references for all these vaccines may be found in that reference.

Table 2. Vaccine efficacy against all episodes of clinical malaria in children aged 5–17 mo at enrollment.

	RTS,S/ASO1 Vaccine		Control Vaccine
Population	No. of Events	Person-Yr	No. of Events	Person-Yr	Risk ratio	Vaccine efficacy	Ref.
Per-protocol	1834	2495	1854	1263	0.50	0.50	^21
Per-protocol	4257	61860	3639	31004	0.59	0.41	^18
Per-protocol	6616	60945	5409	30318	0.61	0.39	^18
Intention-to-treat	2343	4243	2289	2110	0.51	0.49	^21
Intention-to-treat	5106	90591	4305	44844	0.59	0.41	^18
Intention-to-treat	8207	89391	6482	44006	0.62	0.38	^18
Month 0 to study end	6616	9957.6	9585	9994.9	0.69	0.31	^20
Months 0–32	4078	7099.7	6768	7088.5	0.60	0.40	^20
Months 0–20	5106	9059.1	4305	4484.4	0.59	0.41	^20
Months21–32	1592	2601	2442	2609.9	0.65	0.35	^20
Months 33 to study end	2539	2862.2	2817	2912	0.92	0.08	^20
Months 21 to study end	4130	5458.9	5259	5516.3	0.79	0.21	^20

In the per-protocol analysis, participants have received 3 doses of RTS,S/AS01 or control vaccine and 3 doses of co-administered vaccine (DTPwHepB/Hib and OPV) according to protocol procedures.

Case definition for clinical malaria: Documented fever as defined by axillary temperature measurement ≥ 37.5 ° C and parasite density above threshold derived using recent historical data appropriate to age by logistic regression method with sufficiently high specificity for all sites in a multi-site trial (a minimum of 80%).

Table 3. Vaccine efficacy against all episodes of clinical malaria in children aged 6–12 mo at enrollment.

	RTS,S/ASO1 Vaccine		Control Vaccine
Population	No. of Events	Person-Yr	No. of Events	Person-Yr	Risk ratio	Vaccine efficacy	Ref.
Per-protocol	2301	3604	1626	1790	0.70	0.30	^19
Per-protocol	3848	53968	2464	26740	0.77	0.23	^18
Per-protocol	5781	53214	3718	26246	0.77	0.23	^18
Intention-to-treat	2615	4688	1864	2345	0.70	0.30	^19
Intention-to-treat	4252	65836	2751	32736	0.77	0.23	^18
Intention-to-treat	6564	64946	4221	32164	0.77	0.23	^18
Month 0 to study end	4993	6156.4	6170	6147.3	0.81	0.19	^20
Months 0–32	3842	5173.3	4916	5162.4	0.78	0.22	^20
Months 0–20	4252	6583.6	2751	3273.6	0.77	0.23	^20
Months21–32	1671	1888.4	2156	1889.3	0.78	0.22	^20
Months 33 to study end	1154	984.9	1254	986.1	0.92	0.08	^20
Months 21 to study end	2822	2871.5	3410	2874.2	0.83	0.17	^20

In the per-protocol analysis, participants have received 3 doses of RTS,S/AS01 or control vaccine and 3 doses of co-administered vaccine (DTPwHepB/Hib and OPV) according to protocol procedures.

Case definition for clinical malaria: Documented fever as defined by axillary temperature measurement ≥ 37.5 ° C and parasite density above threshold derived using recent historical data appropriate to age by logistic regression method with sufficiently high specificity for all sites in a multi-site trial (a minimum of 80%).

Table 4. Vaccine efficacy against all episodes of severe malaria in children aged 5–17 mo at enrollment.

	RTS,S/ASO1 Vaccine		Control Vaccine
Population	No. of Events	Person-Yr	No. of Events	Person-Yr	Risk ratio	Vaccine efficacy	Ref.
Per-protocol	120	4557	95	2328	0.65	0.35	^18
Per-protocol (primary)	57	2830	56	1466	0.53	0.47	^21
Per-protocol (secondary)	74	2830	72	1466	0.53	0.47	^21
Intention-to-treat	156	5949	118	2974	0.66	0.34	^18
Intention-to-treat (primary)	81	3997	74	2003	0.55	0.45	^21
Intention-to-treat (secondary)	102	3997	92	2003	0.56	0.44	^21
Month 0 to study end	116	2976	171	2974	0.68	0.32	^20
Months 0–32	99	2976	152	2974	0.65	0.35	^20
Months 0–20	156	5949	118	2974	0.66	0.34	^20
Months21–32	43	2679	42	2701	1.03	−0.03	^20
Months 33 to study end	23	2236	20	2309	1.19	−0.19	^20
Months 21 to study end	64	2681	62	2702	1.04	−0.04	^20

In the per-protocol analysis, participants have received 3 doses of RTS,S/AS01 or control vaccine and 3 doses of co-administered vaccine (DTPwHepB/Hib and OPV) according to protocol procedures.

Case definition for severe malaria: a proposed case definition for malaria for malaria vaccine trials P. falciparum parasitaemia and one or more of the following criteria: prostration, respiratory distress, blantyre coma score ≤ 2, seizures; 2 or more hypoglycaemia < 2.2 mmol, a naemia < 5 g/dl and without any of the following pneumonia (clinical assessment and CXR), meningitis (based on CSF examination), bacteraemia (based on blood culture) and astroenteritis (clinical assessment).

Table 5. Vaccine efficacy against all episodes of severe malaria in children aged 6–12 mo at enrollment.

	RTS,S/ASO1 Vaccine		Control Vaccine
Population	No. of Events	Person-Yr	No. of Events	Person-Yr	Risk ratio	Vaccine efficacy	Ref.
Per-protocol	58	3995	46	2008	0.63	0.37	^19
Per-protocol	63	3995	51	2008	0.62	0.38	^19
Per-protocol	100	3996	59	2007	0.85	0.15	^18
Intention-to-treat	77	4358	52	2179	0.74	0.26	^19
Intention-to-treat	83	4358	58	2179	0.72	0.28	^19
Intention-to-treat	121	4358	66	2179	0.92	0.08	^18
Month 0 to study end	96	2180	116	2179	0.83	0.17	^20
Months 0–32	89	2180	101	2179	0.88	0.12	^20
Months 0–20	121	4358	66	2179	0.92	0.08	^20
Months21–32	29	1966	43	1976	0.68	0.32	^20
Months 33 to study end	12	1654	16	1657	0.75	0.25	^20
Months 21 to study end	39	1966	58	1976	0.68	0.32	^20

In the per-protocol analysis, participants have received 3 doses of RTS,S/AS01 or control vaccine and 3 doses of co-administered vaccine (DTPwHepB/Hib and OPV) according to protocol procedures.

Case definition for severe malaria: a proposed case definition for malaria for malaria vaccine trials P. falciparum parasitaemia and one or more of the following criteria: prostration, respiratory distress, blantyre coma score ≤ 2, seizures; 2 or more hypoglycaemia < 2.2 mmol, a naemia < 5 g/dl and without any of the following pneumonia (clinical assessment and CXR), meningitis (based on CSF examination), bacteraemia (based on blood culture) and astroenteritis (clinical assessment).

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