Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa

Figures & data

Table 1. Serious adverse events

	R3R		R3C		C3C
	N	% (95% CI)	N	% (95% CI)	N	% (95% CI)
At least one SAE (M0–SE)
5–17M (children)	2976	24.2% (22.7–25.8)	2972	25.3% (23.7–26.9)	2974	28.4% (26.8–30.1)
6–12W (infants)	2180	26.6% (24.8–28.5)	2178	27.6% (25.8–29.6)	2179	28.4% (26.5–30.4)
At least one SAE (M0–SE), excluding malaria
5–17M (children)	2976	22.6% (21.1–24.2)	2972	23.7% (22.2–25.3)	2974	26.4% (24.8–28.0)
6–12W (infants)	2180	25.8% (24.0–27.7)	2178	26.7% (24.9–28.6)	2179	27.1% (25.3–29.0)
At least one SAE within 30 days post–vaccination
5–17M (children)	2976	6.1% (5.3–7.0)	2972	6.0% (5.1–6.9)	2974	6.7% (5.8–7.6)
6–12W (infants)	2180	4.8% (4.0–5.8)	2178	5.6% (4.7–6.7)	2179	5.2% (4.3–6.2)
At least one SAE before dose 4 (M0–M20)	RTS,S/AS01		Control
5–17M, all children	5949	18.6% (17.6–19.6)	2974	22.7% (21.2–24.3)
5–17M, low weight-for-age	695	25.0% (21.9–28.4)	364	24.5% (20.1–29.2)
5–17M, very low weight-for-age	207	26.6% (20.7–33.1)	97	28.9% (20.1–39.0)
6–12W, all infants	4358	22.0% (20.8–23.3)	2179	23.1% (21.3–24.9)
6–12W, low weight-for-age	221	28.5% (22.7–34.9)	126	30.2% (22.3–39.0)
6–12W, very low weight-for-age	147	32.7% (25.2–40.9)	67	25.4% (15.5–37.5)
6–12W, preterm	244	19.7% (14.9–25.2)	118	11.0% (6.0–18.1)
At least one SAE post-dose 4 (M21–SE)	R3R		R3C		C3C
5–17M, all children	2681	10.3% (9.2–11.5)	2719	11.6% (10.4–12.9)	2702	10.6% (9.5–11.8)
5–17M, low weight-for-age	277	11.6% (8.0–15.9)	304	13.2% (9.6–17.5)	297	12.8% (9.2–17.1)
5–17M, very low weight-for-age	48	10.4% (3.5–22.7)	50	16.0% (7.2–29.1)	60	18.3% (9.5–30.4)
6–12W, all infants	1966	9.2% (7.9–10.5)	1996	9.7% (8.4–11.1)	1976	10.2% (8.9–11.6)
6–12W, low weight-for-age	232	14.7% (10.4–19.9)	211	10.0% (6.3–14.8)	195	12.3% (8.0–17.8)
6–12W, very low weight-for-age	48	12.5% (4.7–25.2)	47	19.1% (9.1–33.3)	68	22.1% (12.9–33.8)
At least one fatal SAE (M0–SE)	R3R		R3C		C3C
5–17M, all children	2976	2.0% (1.6–2.6)	2972	1.7% (1.3–2.3)	2974	1.5% (1.1–2.1)
5–17M, girls	1467	2.4% (1.7–3.3)	1500	2.1% (1.5–3.0)	1503	1.1% (0.7–1.8)
5–17M, boys	1509	1.7% (1.1–2.5)	1472	1.3% (0.8–2.0)	1471	2.0% (1.3–2.8)
6–12W, all infants	2180	2.3% (1.7–3.1)	2178	2.5% (1.9–3.3)	2179	1.9% (1.4–2.6)
6–12W, girls	1064	2.5% (1.7–3.7)	1060	2.7% (1.8–3.9)	1100	1.5% (0.8–2.4)
6–12W, boys	1116	2.2% (1.4–3.2)	1118	2.3% (1.5–3.4)	1079	2.4% (1.6–3.5)
At least one fatal SAE within 30 days post-vaccination	R3R		R3C		C3C
5–17M (children)	2976	0.3% (0.1–0.6)	2972	0.2% (0.1–0.4)	2974	0.2% (0.1–0.4)
6–12W (infants)	2180	0.6% (0.3–1.0)	2178	0.5% (0.3–0.9)	2179	0.3% (0.1–0.6)

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine; N, total number of children/infants in the group; %, percentage of children/infants with at least one SAE; M, months; W, weeks; SE, study end; CI, confidence interval; SAE, serious adverse event. Low weight-for-age defined as z-score ≤-2 but >-3, very low weight-for-age as z-score ≤-3.

Table 2. Febrile convulsions incidence and self-controlled case-series analysis

Incidence per 1,000 vaccine doses of febrile convulsions with diagnostic certainty level 1–3 (Brighton collaboration), within 7 days after each dose
	5–17months age category (children)			6–12 weeks age category (infants)
	N	n	Incidence (95% CI)	N	n	Incidence (95% CI)
First 3 doses
RTS,S/AS01	17,306	18	1.0 (0.6–1.6)	12,739	2	0.2 (0.0–0.6)
Control	8728	5	0.6 (0.2–1.3)	6403	3	0.5 (0.1–1.4)
Dose 4
R3R	2447	6	2.5 (0.9–5.3)	1825	4	2.2 (0.6–5.6)
R3C	2472	3	1.2 (0.3–3.5)	1837	0	0.0 (0.0–2.0)
C3C	2473	1	0.4 (0.0–2.3)	1827	1	0.5 (0.0–3.0)
SCCS Risk Ratio (95% CI) of febrile convulsions after each of the first 3 doses (5–17 months age category)
Risk period	R3R	R3C		R3R+R3C	C3C
3 days (days 0–2)	3.8 (1.7–8.7)	2.3 (0.8–6.0)		3.0 (1.6–5.6)	0.8 (0.2–3.5)
7 days (days 0–6)	1.9 (0.9–4.2)	2.2 (1.0–4.9)		2.1 (1.2–3.6)	1.1 (0.4–2.8)
SCCS Risk Ratio (95% CI) of febrile convulsions post-dose 4 (5–17 months age category)
Risk period	R3R	R3C			C3C
3 days (days 0–2)	6.0 (2.1–16.9)	4.5 (0.4–49.6)			0.0
7 days (days 0–6)	2.9 (1.0–7.9)	6.6 (0.6–72.5)			0.4 (0.1–2.9)

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine; N, total number of vaccine doses administered in the group; n, number of vaccine doses followed by febrile convulsions; CI, confidence interval. Risk ratio is the risk ratio of the self-controlled case-series (SCCS) analysis, comparing the incidence in a given risk period (3 and 7 days post-vaccination) to the incidence in the corresponding control period (day 4–30 and day 8–30 post-vaccination, respectively).

Table 3. Meningitis cases

Meningitis cases based on clinical diagnosis by treating physician, n
	5–17 months age category (children)			6–12 weeks age category (infants)
Before dose 4 (M0–M20)
	R3R	R3C	C3C	R3R	R3C	C3C
	N = 2976	N = 2972	N = 2974	N = 2180	N = 2178	N = 2179
Meningitis (no pathogen identified)	4	5	1	2	2	2
Meningitis haemophilus	1	0	0	0	0	0
Meningitis meningococcal	3	1	0	0	0	0
Meningitis pneumococcal	0	1	0	1	2	1
Meningitis tuberculous	0	0	0	0	0	0
Meningitis viral	1	0	0	0	0	0
Meningitis salmonella	0	0	0	2	1	0
Meningitis total	9	7	1	5	5	3
Post-dose 4 (M21–SE)
	R3R	R3C	C3C	R3R	R3C	C3C
	N = 2681	N = 2719	N = 2702	N = 1996	N = 1996	N = 1976
Meningitis (no pathogen identified)	1^a	0	0	0	1	1
Meningitis haemophilus	0	2	0	0	1	1
Meningitis meningococcal	0	1	0	0	0	0
Meningitis pneumococcal	0	0	0	0	0	1
Meningitis tuberculous	1	0	0	0	0	0
Meningitis viral	0	0	0	0	0	0
Meningitis salmonella	0	0	0	0	0	0
Meningitis total	2	3	0	0	2	3
Relative risk for meningitis
	5–17 months age category (children)			6–12 weeks age category (infants)
Before dose 4 (M0–M20)	R3R+R3C vs C3C:			R3R+R3C vs C3C:
	8.0 (95% CI: 1.1–60.3)^b			1.5 (95% CI: 0.4–5.6)^b
Entire study (M0–SE)	R3R vs C3C: 11.0 (95% CI: 1.4–85.1)			R3R vs C3C: 0.8 (95% CI: 0.3–2.7)
	R3C vs C3C: 10.0 (95% CI: 1.3–78.1)			R3C vs C3C: 1.2 (95% CI: 0.4–3.5)
Meningitis and other central nervous system infections assessed by external experts, n
	5–17 months age category (children)			6–12 weeks age category (infants)
Before dose 4 (M0–M20)
	R3R	R3C	C3C	R3R	R3C	C3C
Confirmed meningitis	5	4	0	3	4	1
No meningitis	3	2	2	3	2	3
Undetermined	4	2	3	2	0	0
Post-dose 4 (M21–SE)
	R3R	R3C	C3C	R3R	R3C	C3C
Confirmed meningitis	1	2	0	0	1	2
No meningitis	1	2	0	0	0	1
Undetermined	1	0	0	0	1	0

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine; N, total number of children/infants per group; n, number of cases within the specified category; CI, confidence interval; M, month; SE, study end.

^a This case occurred more than 20 months after dose 1, however, dose 4 was not given.

^b RTS,S Clinical Trials Partnership PLoS Med 2014; 11: e1001685.

Confirmed meningitis, if the clinical pictures and the lab results were consistent with diagnosis of meningitis; undetermined, if the clinical pictures and/or the lab results were not consistent with diagnosis of meningitis and not consistent with another diagnosis, or were missing; no meningitis, if the clinical pictures and the lab results were consistent with another diagnosis.

Figure 1. Meningitis cases by time-to-onset after dose 1 and by treatment group.

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine

Figure 2. Distribution of meningitis cases by site and etiology in both age categories.

One case with viral etiology is included in the “No pathogen identified” category (R3R group)

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine.

Table 4. Distribution of severe malaria manifestations

Hospitalized severe malaria* classified by specific markers of severe disease, n (%)
	5–17 months age category (children)			6–12 weeks age category (infants)
Before dose 4 (M0–M20)
	R3R	R3C	C3C	R3R	R3C	C3C
	N = 86	N = 119	N = 158	N = 82	N = 66	N = 86
BCS ≤2 (compatible with CM)	7 (8.1)	15 (12.6)	6 (3.8)	2 (2.4)	3 (4.5)	4 (4.7)
Hb ≥5 g/dL	6 (7.0)	10 (8.4)	5 (3.2)	0 (0.0)	2 (3.0)	3 (3.5)
Hb <5 g/dL	1 (1.2)	5 (4.2)	1 (0.6)	2 (2.4)	1 (1.5)	1 (1.2)
Hb <5 g/dL (and BCS >2)	11 (12.8)	14 (11.8)	29 (18.4)	13 (15.9)	17 (25.8)	17 (19.8)
Other	67 (77.9)	90 (75.6)	123 (77.9)	65 (79.3)	46 (69.7)	65 (75.6)
Missing	1 (1.2)	0 (0.0)	0 (0.0)	2 (2.4)	0 (0.0)	0 (0.0)
Post-dose 4 (M21–SE)
	R3R	R3C	C3C	R3R	R3C	C3C
	N = 76	N = 103	N = 76	N = 53	N = 63	N = 68
BCS ≤2 (compatible with CM)	12 (15.8)	9 (8.7)	4 (5.3)	4 (7.6)	4 (6.4)	3 (4.5)
Hb ≥5 g/dL	11 (14.5)	9 (8.7)	2 (2.6)	4 (7.6)	4 (6.4)	2 (3.0)
Hb <5 g/dL	1 (1.3)	0 (0.0)	2 (2.6)	0 (0.0)	0 (0.0)	1 (1.5)
Hb <5 g/dL (and BCS >2)	11 (14.5)	18 (17.5)	17 (22.4)	15 (28.3)	15 (23.8)	19 (27.9)
Other	53 (69.7)	75 (72.8)	54 (71.1)	34 (64.2)	42 (66.7)	45 (66.2)
Missing	0 (0.0)	1 (1.0)	1 (1.3)	0 (0.0)	2 (3.2)	1 (1.5)
Cerebral malaria following external expert adjudication (5–17 months age category), n
	Before dose 4 (M0–M20)			Post-dose 4 (M21–SE)
	R3R	R3C	C3C	R3R	R3C	C3C
	N’ = 52	N’ = 69	N’ = 75	N’ = 40	N’ = 60	N’ = 44
Possible CM	3	10	7	7	8	2
Confirmed (by both experts)	2	4	3	2	6	1
Confirmed (by 1 expert)	0	2	1	1	0	1
Uncertain (by 1 or both experts)	1	4	3	4	2	0
No CM	49	59	68	33	52	42

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine; N, number of children/infants hospitalized with severe malaria, *secondary case definition 1 (>5,000 parasites/µL and at least one marker of severe disease, without exclusion of comorbidities); N’, number of children hospitalized with severe malaria with >0 parasites/µL and at least one neurological marker of severe disease, i.e., BCS ≤2, prostration or 2 or more seizures; n (%), number (percentage) of cases within the specified category; M, month; SE, study end; CM, cerebral malaria; BCS, Blantyre coma score; Hb, hemoglobin; other, BCS >2 and Hb ≥5.0 g/dL and at least one of the following: prostration, respiratory distress, 2 or more seizures, hypoglycemia <2.2 mmol/L, acidosis base excess ≤-10.0 mmol/L, or lactate ≥5.0 mmol/L; missing, Hb or BCS unavailable so syndrome classification could not be determined; possible CM, at least one expert could not exclude a diagnosis of CM, i.e., classified the case as “Confirmed CM” or as “Uncertain CM”; no CM, both experts classified the case as “Not CM”; uncertain, both experts classified the case as “Uncertain CM” or one expert classified the case as “Uncertain and one as “Not CM”.

Figure 3. Cerebral malaria cases (identified per computer algorithm) by time-to-onset after dose 1 and by treatment group (5–17 months age category)

R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of control vaccine; C3C, group receiving 4 doses of control vaccine.

Figure 4. Focus on the patient summary of the findings

Table

AE	adverse event
AS	adjuvant system
BCS	Blantyre coma score
BCWG	Brighton Collaboration Working Group
CI	confidence interval
CM	cerebral malaria
CNS	central nervous system
EMA	European Medicines Agency
HIV	human immunodeficiency virus
M	month
MedDRA	Medical Dictionary for Regulatory Activities
PCR	polymerase chain reaction
pIMD	potential immune-mediated disorder
SAE	serious adverse event
SE	study end
SSA	sub-Saharan Africa
VE	vaccine efficacy
WHO	World Health Organization