Immunogenicity and safety of Ebola virus vaccines in healthy adults: a systematic review and network meta-analysis

Figures & data

Table 1. Characteristics of included trials investigating the immunogenicity and safety of Ebola virus vaccination

Study	Country	Design	Age (years)	Follow-up	Proportion of men participants		Vaccine type	Dosing Information	Main outcomes at 14 days for Safety and 28 days for Immunogenicity measured by ELISA	Sponsorship
Martin et al.^Citation10	USA	RCT, phase 1, double-blind	18–44	12 months	67%	DNA		EBODNA012-00-VP (2 mg), EBODNA012-00-VP (4 mg), EBODNA012-00-VP (8 mg), placebo	ELISA positive response rate to GP [Z], pain, myalgia, headache, fever, myalgia, malaise, nausea, induration, skin discoloration	NR
Ledgerwood et al.^Citation11	USA	RCT, phase 1, double-blind	18–50	48 weeks	53%	rAd5.ZEBOV-GP		rAd5.ZEBOV.GP (2 × 10^9 VP), rAd5.SBOV.GP (2 × 10^10 VP), placebo	ELISA positive response rate to GP [Z], pain, myalgia, headache, fever, myalgia, malaise, chills, nausea, redness, swelling	NR
Zhu et al. ^Citation12	China	RCT, phase 1, double-blind	18–60	4 weeks	49%	rAd5.ZEBOV-GP		rAd5.ZEBOV.GP high dose (1.6 × 10^11 PV), rAd5.ZEBOV.GP low dose (4 × 10^10 PV), placebo	ELISA EC90 positive response, pain, myalgia, headache, fever, myalgia, fatigue, vomiting, cough, diarrhea, induration, redness, swelling, joint pain	Government and Industry
Huttner et al.^Citation13	Switzerland (Geneva)	RCT, phase 1–2, double-blind	18–65	12 weeks	54%	rVSVΔG-ZEBOV-GP		rVSVΔG-ZEBOV-GP (3 × 10^5 PFU), rVSVΔG -ZEBOV-GP (1 × 10^7 PFU), rVSVΔG -ZEBOV-GP (5 × 10^7 PFU), placebo	ELISA seropositivity rate, local pain, fever, fatigue, headache, myalgia, chills,	Wellcome Trust through WHO
Kibuuka et al.^Citation14	Uganda (Kampala)	RCT, phase 1b, double-blind	18–50	24 months	82%	DNA		EBO vaccine (4 mg), placebo	Proportion of positive response by ELISA titer of 30 or higher, pain, tenderness, swelling, redness, chills, aching joints, fatigue, headache, fever, nausea, muscle aches	Government
Agnandji et al.^a Citation15	Switzerland (Geneva)	RCT, phase 1, double-blind	18–65	6 months	61%	rVSV-ZEBOV-GP		rVSVΔG -ZEBOV-GP (1 × 10^7 PFU), rVSVΔG -ZEBOV-GP (5 × 10^7 PFU), placebo	Seropositivity rate measured by ELISA of 50 or more, erythema, swelling/induration, pain, fever, chills, myalgia, headache, fatigue, gastro-intestinal symptoms, oral vesicle, arthralgia, arthritis	Government
D Tapia et al.^b,d Citation16	USA, Mali (groups 3B and 3 C)	RCT, phase 1, double-blind	18–65	5 months	45% (USA), 80% (Mali)	ChAd3-EBO-Z		ChAd3-EBO-Z (1 × 10^10 VP), ChAd3-EBO-Z (1 × 10^11 VP), ChAd3-EBO-Z (2.5 × 10^10 VP), ChAd3-EBO-Z (5 × 10^10 VP),	Proportion of positive ELISA GP [Z] response or responses of more than reference value, pain and tenderness, fever, fatigue, myalgia, arthralgia, headache, chills, nausea	Government
De Santis et al.^Citation17	Switzerland (Lauzanne)	RCT, phase 1–2a, double-blind	18–65	6 months	49%	ChAd3-EBO-Z		ChAd3-EBO-Z (2.5 × 10^10 VP), ChAd3-EBO-Z (5 × 10^10 VP), placebo	Proportion of positive ELISA GP [Z] response, pain, swelling, erythema, axillary lymphatic-node, chills, fatigue or malaise, headache, fever, nausea, musculo- articular pain, abdominal pain, conjunctivitis, rhinitis, sweating	Government
Milligan et al.^c, d Citation18	UK	RCT, phase 1, observer-blind	18–50	8 months	36%	Ad26.ZEBOV, MVA-BN-Filo		Ad26.ZEBOV (5 × 10^10 VP), MVA-BN-Filo (1 × 10^8 TCID50), placebo	Percentages of vaccine responders assessed by ELISA, pain, erythema, warmth, pruritus, swelling, induration, fatigue, headache, fever, nausea, myalgia, chills, rash, nausea, pyrexia, arthralgia, vomiting	Government and Industry
Heppner et al.^Citation19	USA	RCT, phase 1, double-blind	18–61	12 months	53%	rVSVΔG-ZEBOV-GP		rVSVΔG-ZEBOV-GP (3 × 10^3 PFU), rVSV-ZEBOV-GP (3 × 10^4 PFU), rVSVΔG-ZEBOV-GP (3 × 10^5 PFU), rVSVΔG -ZEBOV-GP (3 × 10^6 PFU), rVSV-ZEBOV-GP (9 × 10^6 PFU), rVSVΔG-ZEBOV-GP (2 × 10^7 PFU), rVSVΔG -ZEBOV-GP (1 × 10^8 PFU), placebo	Seroconversion for IgG ELISA as four times or more than baseline titer, abdominal pain, diarrhea, fatigue, shivering or chills, headache, joint aches and pain, joint swelling or tenderness, vomiting, myalgia, nausea, fever, sweats arm pain, local tenderness	Government
Agnandji et al.^Citation4	Gabon (Lambaréné)	RCT, phase 1, open-label	18–50	6 months	82%	rVSVΔG-ZEBOV-GP		rVSVΔG -ZEBOV-GP (3 × 10^3 PFU), rVSVΔG -ZEBOV-GP (3 × 10^4 PFU), rVSVΔG -ZEBOV-GP (3 × 10^5 PFU), rVSVΔG -ZEBOV-GP (3 × 10^6 PFU), rVSVΔG -ZEBOV-GP (2 × 10^7 PFU), placebo	Seropositivity rates as percentage of participants having arbitrary ELISA units (AEU) > a cutoff per vaccine, Seroconversion rates as % of converted in each group, pain, swelling, chills, fatigue, headache, fever, nausea, myalgia, arthralgia, mouth ulcer, skin lesion, blister, malaria, rhinitis, cough, gastro-intestinal symptoms	Government
Zhu et al.^Citation20	Sierra Leone	RCT, phase 2, double-blind	18–50	6 months	54%	rAd5.ZEBOV-GP		rAd5.ZEBOV-GP (1.6 × 10^11 VP), rAd5.ZEBOV-GP (8 × 10^10 VP), placebo	Number of responders assessed by neutralizing antibody titer against Ad5 > 1:200, induration, swelling, rash, fever, headache, fatigue, cough, pain, joint pain, muscle pain, throat pain, diarrhea, itch, vomiting	Government and Industry
Kennedy et al.^Citation21	Liberia	RCT, phase 2, double-blind	18 or more	12 months	63%	ChAd3-EBO-Z, rVSV-ZEBOV-GP		ChAd3-EBO-Z (1 × 10^11 VP), rVSV-ZEBOV-GP (2 × 10^7 VP), placebo	Positive antibody response as IgG antibody titer against EBOV-GP of more than 607 EU, headache, muscle pain, feverishness, fatigue, joint pain, rash, nausea, abnormal sweating, mouth ulcer	Government
Elsherif et al.^Citation22	Canada	RCT, phase 1, observer-blind	18–65	6 months	42%	rVSVΔG-ZEBOV-GP		rVSVΔG-ZEBOV-GP (1 × 10^5 PFU), rVSVΔG-ZEBOV-GP (5 × 10^5 PFU), rVSVΔG-ZEBOV-GP (3 × 10^6 PFU), placebo	Seroconversion as at least 4-fold increase from ELISA baseline, pain, abdominal pain, chills, arthralgia, fever, diaphoresis, diarrhea, fatigue, headache, myalgia, nausea	Government
Li et al.^d Citation23	China	RCT, phase 1, double-blind	18–60	6 months	48%	rAd5.ZEBOV-GP		rAd5.ZEBOV-GP (1.6 × 10^11 VP), rAd5.ZEBOV (4 × 10^10 VP), placebo	Number of responders assessed by neutralizing antibody titer against Ad5 > 1:200, induration, swelling, itch, fever, headache, fatigue, cough, pain, joint pain, muscle pain, throat pain, diarrhea, vomiting	Government
Regules et al.^Citation24	USA	RCT, phase 1, observer-blind	18–50	8.5 months	71%	rVSVΔG-ZEBOV-GP		rVSVΔG-ZEBOV-GP (3 × 10^6 PFU), rVSVΔG -ZEBOV-GP (2 × 10^7 PFU), rVSVΔG-ZEBOV-GP (1 × 10^8 PFU), placebo	Positive response for ELISA was a titer of 50 or more, Seroconversion was a quadrupling of the titer over the baseline value, abdominal pain, site pain, headache, myalgia, nausea, fever, fatigue, chills, arthralgia, diaphoresis, diarrhea	Government
Mutua et al.^d Citation25	Kenya (Nairobi)	RCT, phase 1, observer-blind	18–50	12 months	68%	Ad26.ZEBOV, MVA-BN-Filo		Ad26.ZEBOV (5 × 10^10 VP), MVA-BN-Filo (1 × 10^8 TCID50)	ELISA positive response rate to GP [Kikwit], injection site pain, injection site pruritus, injection site warmth, headache, fatigue, fever, myalgia, arthralgia, chills, nausea, vomiting, rash, pyrexia, pruritus (generalized)	Government and Industry
Anywaine et al.^d Citation26	Uganda (Masaka), Tanzania (Mwanza)	RCT, phase 1, observer-blind	18–50	8 months	79%	Ad26.ZEBOV, MVA-BN-Filo		Ad26.ZEBOV (5 × 10^10 VP), MVA-BN-Filo (1 × 10^8 TCID50)	ELISA positive response rate to GP [Kikwit], injection site pain, injection site pruritus, injection site warmth, headache, fatigue, fever, myalgia, arthralgia, chills, nausea, vomiting, rash, pyrexia, pruritus (generalized)	Government and Industry
Samai et al.^Citation27	Sierra Leone	RCT, phase 2/3 unblinded	≥18 year older	6 months	60.6%	rVSVΔG-ZEBOV-GP		rVSVΔG-ZEBOV-GP (single dose 2 × 10^7 PFU)	Vaccine efficacy ≥ 50% or there was a 2-fold infection risk increase; safety outcome	Government
Halperin et al.^Citation28,Citation29	USA, Spain, Canada	RCT, phase 3, double blind, placebo controlled	18–65	24 months	45.9%	rVSVΔG-ZEBOV-GP		rVSVΔG-ZEBOV-GP 2x10^7 PFU, High dose 1 × 10^8 PFU	ELISA positive response rate to GP, PRNT seroresponse rate, injection site adverse events, fever, headache, arthralgia, pain, chills, fatigue	Government and industry
Clark et al.^Citation30	Melbourne, USA	RCT, phase 1, Double blind, placebo controlled	27–60	6 months	46%	rVSVN4CT1-EBOVGP1		rVSVN4CT1-EBOVGP1 2 doses (d0, d28) low dose 2.5 × 10^4 intermediate dose 2.0 × 10^5 High dose 1.8x10^8	ELISA positive response rate to GP, fever, malaise or fatigue, myalgia, headache, nausea, vomiting, chills, arthralgia, diarrhea	Government

RCT: randomized controlled trials; rVSVΔG-ZEBOV-GP: recombinant replication competent vesicular stomatitis virus-based vaccine expressing the glycoprotein of a Zaire Ebolavirus; ChAd3-EBO-Z: replication-defective chimpanzee adenovirus 3 vector expressing Zaire-Ebola virus glycoprotein; MVA-BN-Filo: modified vaccinia Ankara (MVA) expressing Zaire Ebola virus glycoprotein and other filovirus antigens; Ad5.ZEBOV: adenovirus type-5 vector-based Ebola vaccine; Ad26.ZEBOV: adenovirus type-26 vector-based Ebola vaccine; EBODNA012-00-VP: Ebola virus glycoprotein DNA vaccine; ELISA: enzyme-linked immunosorbent assay. ^a Studies in Lambaréné, Kilifi, and Hamburg were open-label, uncontrolled phase 1 trials; ^b Group 3A and group 4 from Malian trials were open-label, and Nested randomized Malian trial is a nested booster study, these trials were excluded from the review and network meta-analysis. ^c Additional nonrandomized open-label group received Ad26.ZEBOV (5 × 10⁷ VP) prime and MVA-BN-Filo (1 × 10⁸ TCID₅₀) boost on 15-day were excluded in this study. ^d These studies included both prime and boost on days 29 or 56 or later; only data for the first vaccination (prime) were considered in this study. PFU: plaque-forming unit; TCID₅₀: 50% tissue culture infectious doses; VP: viral particles. NR: not reported.

Figure 1. PRISMA flowchart of studies selected for meta-analysis of RCT Ebola vaccine

Figure 2. Network graph of eligible Ebola vaccines comparisons for immunogenicity

Line width is proportional to the number of trials comparing every pair of vaccine. The size of the circle is proportional to the number of participants assigned to receive the vaccine. rVSVZGP (10e5 or lower), (10e6), (10e7), (2dose10e7), (5dose10e7), and (10e8) were the recombinant replication competent vesicular stomatitis virus-based vaccine expressing the glycoprotein of a Zaire Ebolavirus (rVSVΔG-ZEBOV-GP) at doses of ≤ 10⁵ plaque-forming unit (PFU), 10⁶ PFU, 10⁷ PFU, 2 × 10⁷ PFU, 5 × 10⁷ PFU, and 10⁸ PFU; ChAd3 (10e10) and (10e11) were the replication-defective chimpanzee adenovirus 3 vector expressing Zaire-Ebola virus glycoprotein (ChAd3-EBO-Z) at doses of 10¹⁰ viral particles (VP) and 10¹¹ VP; MVA (10e8) was the modified vaccinia Ankara (MVA) expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo) at doses of 1 × 10⁸ 50% tissue culture infectious doses (TCID₅₀); Ad5 (8dose10e10 or lower) and (1.6dose10e11) were the adenovirus type-5 vector-based Ebola vaccine (Ad5-ZEBOV) at doses of ≤ 5 × 10¹⁰ VP and 1.6 × 10¹¹ VP; Ad26 (5dose10e10) was the adenovirus type-26 vector-based Ebola vaccine (Ad26-ZEBOV) at doses of 5 × 10¹⁰ VP; and DNAEBO (4 mg or lower) and 8 mg were the Ebola virus glycoprotein DNA vaccine (EBODNA012-00-VP) at doses of ≤ 4 mg/ml and 8 mg/ml; rVSVN4CT1 (10e5 or lower), and (10e6) were the recombinant replication competent vesicular stomatitis virus-based vaccine expressing HIV-1 gag and glycoprotein of Ebolavirus (rVSVN4CT1-EBOVGP1) at doses of 2.5 × 10⁴ PFU, 2.5 × 10⁵ PFU, and 2 × 10⁶ PFU.

Figure 3. Summary of risk bias assessment for RCTs Ebola vaccines comparisons

Number in parentheses are references.

Figure 4. Pairwise comparisons in network meta-analysis for immunogenicity

Figure 5. Pairwise comparisons in network meta-analysis for safety outcomes (injection site-pain, fatigue, headache, myalgia, and fever)

OR: odds ratio; CI: 95% confidence interval; rVSVZGP (10e5 or lower), (10e6), (10e7), (2dose10e7), (5dose10e7), and (10e8) were the recombinant replication competent vesicular stomatitis virus-based vaccine expressing the glycoprotein of a Zaire Ebolavirus (rVSVΔG-ZEBOV-GP) at doses of ≤ 10⁵ plaque-forming unit (PFU), 10⁶ PFU, 10⁷ PFU, 2 × 10⁷ PFU, 5 × 10⁷ PFU, and 10⁸ PFU; ChAd3 (10e10) and (10e11) were the replication-defective chimpanzee adenovirus 3 vector expressing Zaire-Ebola virus glycoprotein (ChAd3-EBO-Z) at doses of 10¹⁰ viral particles (VP) and 10¹¹ VP; MVA (10e8) was the modified vaccinia Ankara (MVA) expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo) at doses of 1 × 10⁸ 50% tissue culture infectious doses (TCID₅₀); Ad5 (8dose10e10 or lower) and (1.6dose10e11) were the adenovirus type-5 vector-based Ebola vaccine (Ad5-ZEBOV) at doses of ≤ 5 × 10¹⁰ VP and 1.6 × 10¹¹ VP; Ad26 (5dose10e10) was the adenovirus type-26 vector-based Ebola vaccine (Ad26-ZEBOV) at doses of 5 × 10¹⁰ VP; and DNAEBO (4 mg or lower) and 8 mg were the Ebola virus glycoprotein DNA vaccine (EBODNA012-00-VP) at doses of ≤ 4 mg/ml and 8 mg/ml; rVSVN4CT1 (10e5 or lower), and (10e6) were the recombinant replication competent vesicular stomatitis virus-based vaccine expressing HIV-1 gag and glycoprotein of Ebolavirus (rVSVN4CT1-EBOVGP1) at doses of 2.5 × 10⁴ PFU, 2.5 × 10⁵ PFU, and 2 × 10⁶ PFU.

Table

RCT	randomized controlled trials
rVSVΔG-ZEBOV-GP	recombinant replication competent vesicular stomatitis virus-based vaccine expressing the glycoprotein of a Zaire Ebolavirus
ChAd3-EBO-Z	replication-defective chimpanzee adenovirus 3 vector expressing Zaire-Ebola virus glycoprotein
MVA-BN-Filo	modified vaccinia Ankara (MVA) expressing Zaire Ebola virus glycoprotein and other filovirus antigens
Ad5.ZEBOV	adenovirus type-5 vector-based Ebola vaccine
Ad26.ZEBOV	adenovirus type-26 vector-based Ebola vaccine
EBODNA012-00-VP	Ebola virus glycoprotein DNA vaccine
ELISA	enzyme-linked immunosorbent assay
PFU	plaque-forming unit
TCID50	50% tissue culture infectious doses
VP	viral particles
NR	not reported.

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Availability of data and materials

The data are available upon request ([email protected]).