Immunogenicity of H5N1 influenza vaccines in elderly adults: a systematic review and meta-analysis

Figures & data

Figure 1. Selection process for articles used in the meta-analysis

Table 1. Characteristics of included trials

Study	Country	Design	Age (Years)	No.	Vaccine type (Ag)	Dose (μg) + Adjuvant	Outcomes
Czajka 2012^Citation30	Poland, Turkey	RCT	18–60	245	Inactivated (HA+NA)	3.75/7.5 + MF59	HI, AES
			≥61	306
Vesikari 2012^Citation31	Finland, Germany	RCT	18–60	196	Inactivated (HA+NA)	7.5 + MF59	HI
			≥61	201
Bihari 2012^Citation33	Hungary	CBA	18–60	193	Inactivated (HA)	7.5 + MF59	HI, AES
			≥61	148
Banzhoff 2009^Citation32	Italy	RCT	18–60	298	Subunit (HA)	7.5/15 + MF59	HI, AES
			>60	155
Frey 2019^Citation37	Australia, New Zealand, USA, Thailand	RCT	18–64	981	Subunit (HA)	3.75/7.5 + MF59	HI
			≥65	1337
Heijmans 2011^Citation35	Belgian	RCT	≥61	395	Split-virion (HA)	3.75/7.5	HI
						3.75/7.5 + AS03	HI
Brady 2009^Citation25	USA	RCT	≥65	597	Subunit (HA)	3.75/7.5/15/45	HI
						3.75/7.5/15/45 + Alum	HI
Vajo 2010^3Citation6	Hungary	RCT	18–60	190	Inactivated (HA)	3.5/6/12 + Alum	HI
			>60	240			HI
Leroux 2009^Citation29	Belgium, UK	RCT	18–60	300	Split-virion (HA)	7.5	HI
			>60	300		30 + Alum
van der Velden 2012^Citation34	Austria, Finland, Germany	RCT	18–59	270	Inactivated (HA)	7.5	MN, AES
			≥60	272

Abbreviations: RCT, randomized controlled trial; CBA, controlled before-after study; Ag, antigen; HA, hemagglutinin; NA, neuraminidase; Alum, aluminum; HI, hemagglutination inhibition; MN, microneutralization; AES, adverse events.

Figure 2. Summary of risk of bias. Plus signs, yes (low risk of bias); minus signs, no (high risk of bias); question marks, results unclear (unclear risk of bias)

Table 2. Differences in the SCR and SPR resulting from a single dose and two doses

	SCR		SPR
Group	Studies (n)	RR (95% CI)	Studies (n)	RR (95% CI)
Adjuvant
3.75 µg	3^Citation25,Citation30,Citation35	1.87(1.32,2.67)	2^Citation30,Citation35	2.16(1.05,4.42)
7.5 µg	6^Citation25,Citation30–33,Citation35	1.94(1.62,2.23)	5^Citation30–33,Citation35	1.97(1.63,2.39)
15 µg	2^Citation25,Citation32	1.55(1.17,2.0)	1^Citation32	1.55(1.13,2.12)
45 µg	1^Citation25	1.60(1.03,2.48)
No Adjuvant
3.75 µg	2^Citation25,Citation35	1.42 (0.69, 2.91)	1^Citation35	1.71(0.73,4.02)
7.5 µg	3^Citation25,Citation34,Citation35	1.52 (1.27, 1.82)	2^Citation34,Citation35	1.19(1.04,1.35)
15 µg	1^Citation25	3.11 (1.07, 9.06)
45 µg	1^Citation25	1.63 (1.05, 2.53)

Abbreviations: SCR, seroconversion rate; SPR, seroprotection rate; RR, risk ratio; CI, confidence interval.

Figure 3. The differences in the SCR and SPR between different doses of the two-dose vaccines. The differences in the SCR (a) and SPR (b) of antibodies were analyzed between adjacent dosages of the two-dose adjuvanted H5N1 vaccines

Table 3. Pooled SCR and SPR of antibodies to two-dose vaccines with different adjuvants

	SCR		SPR
Group	Studies (n)	Rate (95% CI)	Studies (n)	Rate (95% CI)	CHMP	CBER
3.75 µg
No adjuvant	2^Citation25,Citation35	0.13(−0.03,0.29)	2^Citation25,Citation35	0.13(−0.13,0.29)	NO	NO
MF59	2^Citation30,Citation37	0.59(0.50,0.68)	2^Citation30,Citation37	0.53(0.49,0.56)	SCR	SCR
AS03	1^Citation35	0.72(0.65,0.79)	1^Citation35	0.65(0.58,0.73)	SCR/SPR	SCR/SPR
Alum	1^Citation25	0.08(0.00,0.15)	1^Citation25	0.16(0.06,0.26)	NO	NO
7.5 µg
No adjuvant	4^Citation25,Citation29,Citation34,Citation35	0.33(0.13,0.53)	4^Citation25,Citation29,Citation34,Citation35	0.42(0.20,0.64)	SCR	SCR
MF59	5^Citation30–33,Citation37	0.64(0.50,0.78)	5^Citation30–33,Citation37	0.62(0.56,0.68)	SCR/SPR	SCR/SPR
AS03	1^Citation35	0.88(0.83.0.94)	1^Citation35	0.79(0.73,0.86)	SCR/SPR	SCR/SPR
Alum	1^Citation25	0.12(0.04,0.20)	1^Citation25	0.19(0.09,0.29)	NO	NO
15 µg
No adjuvant	1^Citation25	0.21(0.11,0.32)	1^Citation25	0.29(0.17,0.40)	NO	NO
MF59	1^Citation32	0.70(0.60,0.81)	1^Citation32	0.65(0.54,0.76)	SCR/SPR	SCR/SPR
Alum	1^Citation25	0.13(0.04,0.32)	1^Citation25	0.15(0.06,0.25)	NO	NO

Abbreviations: Alum, aluminum; SCR, seroconversion rate; SPR, seroprotection rate; CI, confidence interval; CHMP, European Committee for Medicinal Products for Human Use; CBER, Center for Biologics Evaluation and Research.

Figure 4. Differences in the SCR and SPR between younger and elderly adults. The differences in SCR (a) and SPR (b) for antibody responses to two doses of OE-adjuvanted H5N1 vaccines were analyzed between younger and elderly adults

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