Comparison of immunogenicity between intradermal and intramuscular injections of repeated annual identical influenza virus strains post-pandemic (2011-2012) in COPD patients

Figures & data

Figure 1. Flow chart demonstrating stratified randomization for intradermal (ID) and intramuscular (IM) injection of the 2011–2012 vaccine in chronic obstructive pulmonary disease (COPD) patients.

Table 1. Baseline characteristics of COPD patients in the intradermal (ID) and intramuscular (IM) groups.

Characteristics	ID (n = 41(	IM (n = 39)	P-value
Age, years (mean ± SD, range)	72.1 ± 5.9 (62–84)	75.3 ± 9.7 (62–95)	0.077
Male sex; n (%)	36 (87.8)	38 (97.4)	0.202
BMI, kg/m^2(mean ± SD)	23.2 ± 3.8	20.4 ± 4.2	0.002
BMI classification^a; kg/m^2; n %))
Underweight (<18.5)	2 (4.9)	15 (38.5)	< 0.001
Normal (18.5–24.9)	28 (68.3)	18 (46.2)	0.153
Overweight (25–29.9)	9 (22.0)	5 (12.8)	0.326
Obese (≥30)	2 (4.9)	1 (2.6)	0.284
Smoking status, n (%)	40 (97.6)	39 (100.0)	0.323
Ex-smoker	36 (90.0)	37 (94.9)	0.265
Current smoker	4 (10.0)	2 (5.1)	0.420
Smoking, pack-year (mean ± SD)	58.0 ± 51.3	60.0 ± 42.1	0.854
Severity of COPD^b
Mild	8 (19.5)	15 (38.5)	0.061
Moderate	20 (48.8)	15 (38.5)	0.352
Severe	13 (31.7)	9 (23.1)	0.388
Co-morbidity, n (%)
Hypertension	21 (51.2)	23 (59.0)	0.509
Dyslipidemia	16 (39.0)	17 (43.6)	0.821
Diabetes mellitus	7 (17.1)	4 (10.3)	0.400
Coronary artery disease	4 (9.8)	8 (20.5)	0.220
Cerebrovascular accident	5 (12.2)	2 (5.1)	0.264
Old pulmonary TB	8 (19.5)	13 (33.3)	0.160
Chronic kidney disease	2 (4.9)	0 (0.0)	0.494

COPD, chronic obstructive pulmonary disease; BMI, body mass index; TB, tuberculosis; SD, standard deviation;^aWHO BMI classification¹⁹; ^bGOLD classification of COPD severity by post-bronchodilator FEV₁% predicted, mild (≥ 80), moderate (50–79), severe (30–49).¹

Table 2. The hemagglutination inhibition (HI) titres^† of pre-vaccination and 4 weeks post-vaccination of COPD patients in the intramuscular (IM) group compared between BMI < 18.5 kg/m²(n = 15) and BMI ≥ 18.5 kg/m²(n = 24).

	H1N1pdm09			H3N2			B
	BMI			BMI			BMI
	< 18.5	≥ 18.5	P-value	< 18.5	≥ 18.5	P-value	< 18.5	≥ 18.5	P-value
Pre-vaccination GMT	33.2 (18.5–59.9)	20.6 (12.5–33.9)	0.209	16.6 (8.0–34.6)	17.8 (11.4–27.8)	0.857	6.9 (5.2–9.2)	7.7 (5.6–10.6)	0.626
Post-vaccination GMT	133.0 (67.9–260.5)	134.5 (83.0–218.0)	0.976	96.2 (43.8–211.5)	103.7 (55.4–194.3)	0.877	9.5 (5.7–15.9)	9.4 (6.8–13.2)	0.967
Seroconversion factor	15.5 (−2.5–33.4)	18.1 (6.4–29.8)	0.790	14.8 (4.8–24.8)	17.6 (5.1–30.2)	0.741	2.0 (0.9–3.2)	1.9 (1.2–2.7)	0.851
Seroconversion rate%	53.3 (30.1–75.2)	66.7 (46.7–82.0)	0.505	66.7 (41.7–84.8)	70.8 (50.8–85.1)	1.000	13.3 (37.3–37.9)	12.5 (43.3–31.0)	1.000
Pre-vaccination seroprotection rate%	60.0 (35.7–80.2)	29.2 (14.9–49.2)	0.057	33.3 (15.2–58.3)	33.3 (18.0–53.3)	1.000	0.0 (0.0–20.4)	8.3 (2.3–25.8)	0.514
Post-vaccination seroprotection rate%	93.3 (70.2–98.8)	91.7 (74.2–97.7)	1.000	86.7 (62.1–96.3)	83.3 (64.1–93.3)	1.000	13.3 (3.7–37.9)	12.5 (4.3–31.0)	1.000

^†Presented as value (95%CI); BMI = body mass index; H1N1 = influenza A(H1N1)pdm09; H3N2 = influenza A(H3N2), B = influenza B; GMT = geometric mean titre; seroconversion factor = the ratio of the HI titre after vaccination to the HI titre before vaccination; seroconversion rate = the percentage of post-vaccination HI titre ≥ 1:40 in patients with pre-vaccination titre < 1:10 or ≥ 4-fold increase in post-vaccination HI titre in patients with a pre-vaccination titre ≥ 1:10; seroprotection rate = the percentage of patients with post-vaccination HI titre ≥ 1:40.

Table 3. Hemagglutination inhibition (HI) antibody titres pre- and 4 weeks post-vaccination of repeated identical influenza virus strains (vaccine 2011–2012) in the intradermal (ID, n = 41) and intramuscular (IM, n = 39) groups.

		H1N1		H3N2		B
	CPMP	ID	IM	ID	IM	ID	IM
Pre-vaccination GMT		19.3 (14.0–26.6)	24.8 (17.1–35.9)	22.5 (15.7–32.2)	17.3 (12.0–25.2)	6.4 (5.5–7.5)	7.4 (5.9–9.2)
P-value		0.311		0.311		0.295
Post-vaccination GMT		196.0 (145.4–264.2)	133.9 (92.1–194.8)	177.1 (120.6–259.9)	100.8 (63.1–160.9)	9.8 (7.6–12.7)	9.5 (7.2–12.4)
P-value		0.110		0.062		0.844
Seroconversion factor	> 2.0	22.9 (13.2–32.6)	17.1 (7.6–26.5)	19.7 (10.4–28.9)	16.6 (8.3–24.8)	2.5 (1.4–3.5)	1.9 (1.3–2.6)
P-value		0.386		0.613		0.390
Seroconversion rate %,	> 30	82.9* (68.7–91.5)	61.5 (45.9–75.1)	65.9 (50.6–78.4)	69.2 (53.6–81.4)	7.3 (2.5–19.4)	12.8 (5.6–26.7)
P-value		0.032		0.747		0.476
Pre-vaccination seroprotection rate %,		41.5 (27.8–56.6)	41.0 (27.1–56.6)	48.8 (34.3–63.5)	33.3 (20.6–49.0)	0.0	5.1 (1.4–16.9)
P-value		0.968		0.161		0.234
Post-vaccination seroprotection rate %,	> 60	95.1 (83.9–98.7)	92.3 (79.7–97.3)	92.7 (80.6–97.5)	84.6 (70.3.-92.8)	9.8 (3.9–22.6)	12.8 (5.6–26.7)
P-value		0.671		0.306		0.734

^†Presented as value (95%CI); *P-value < 0.05; CPMP = Committee for Proprietary Medicinal Products¹⁷; GMT = geometric mean titres; seroconversion factor = the ratio of the HI titre after vaccination to the HI titre before vaccination; seroconversion rate = the percentage of post-vaccination HI titre ≥ 1:40 in patients with pre-vaccination titre < 1:10 or ≥ 4-fold increase in post-vaccination HI titre in patients with a pre-vaccination titre ≥ 1:10; seroprotection rate = the percentage of patients with post-vaccination HI titre ≥ 1:40.

Table 4. Hemagglutination inhibition (HI) antibody titres^† pre- and 4 weeks post-vaccination of annual repeated identical influenza virus strains (2011–2012 vaccine) and previous study (vaccine 2010–2011 vaccine)⁹ in the intradermal (ID) and intramuscular (IM) groups.

		H1N1pdm09					H3N2
		ID		IM		ID		IM
	CPMP	1^st year n = 75	2^nd year n = 41	1^st year n = 74	2^nd year n = 39	1^st year n = 75	2^nd year n = 41	1^st year n = 74	2^nd year n = 39
Pre-vaccination GMT^¶		13.8 (10.2–18.7)	19.3 (14.0–26.6)	13.0 (10.0–17.0)	24.8 (17.1–35.9)	30.3 (21.9–41.9)	22.5 (15.7–32.2)	26.0 (18.7–36.2)	17.3 (12.0–25.2)
P-value		0.159		0.005		0.247		0.130
Post-vaccination GMT^‡		70.3 (49.5–99.8)	196.0 (145.4–264.2)	97.4 (69.8–135.8)	133.9 (92.1–194.8)	160.0 (116.8–219.2)	177.1 (120.6–259.9)	141.7 (102.0–196.7)	100.8 (63.1–160.9)
P-value		< 0.001		0.567		0.481		0.449
Seroconversion factor^‡	> 2	13.1 (9.0–17.2)	22.9 (13.2–32.6)	19.9 (12.7–27.1)	17.1 (7.6–26.5)	16.4 (10.1–22.7)	19.7 (10.4–28.9)	17.2 (10.7–23.8)	16.6 (8.3–24.8)
P-value		0.003		0.495		0.963		0.368
Seroconversion rate %^‡,	> 30	50.7 (39.6–61.7)	82.9 (68.7–91.5)	66.2 (54.8–76.0)	61.5 (45.9–75.1)	60.0 (48.7–70.3)	65.9 (50.6–78.4)	55.4 (44.1–66.2)	69.2 (53.6–81.4)
P-value		0.001		0.897		0.820		0.270
Pre-vaccination seroprotection rate %^¶,		24.0 (15.7–34.9)	41.5 (27.8–56.6)	28.4 (19.3–39.6)	41.0 (27.1–56.6)	50.7 (39.6–61.7)	48.8 (34.3–63.5)	40.5 (30.1–52.0)	33.3 (20.6–49.0)
P-value		0.050		0.173		0.846		0.453
Post-vaccination seroprotection rate %^‡,	> 60	64.0 (52.7–74.0)	95.1 (83.9–98.7)	78.4 (67.6–86.3)	92.3 (79.7–97.3)	81.3 (71.0–88.7)	92.7 (80.6–97.5)	79.7 (69.1–87.4)	84.6 (70.3.-92.8)
P-value		< 0.001		0.115		0.099		0.458

^†Presented as value (95% CI); ^¶Unpaired t-test compared between vaccine 2010 – 2011and vaccine 2011–2012; ^‡ Compared between vaccine 2010 – 2011and vaccine 2011 – 2012adjusted pre-vaccination GMTs;1^st year = vaccine 2010–2011; 2^nd year = vaccine 2011–2012; CPMP = Committee for Proprietary Medicinal Products.¹⁷

Table 5. Geometric mean titres (GMTs) and seroprotection rates for influenza A(H1N1)pdm09 and influenza A(H3N2) at baseline and 4 weeks, 3 months, 6 months, and 12 months post-vaccination in the ID and IM groups.

	H1N1pdm09		H3N2
	ID	IM	ID	IM
GMT (95% CI)
Baseline	19.3 (14.0–26.6)	24.8 (17.1–35.9)	22.5 (15.7–32.2)	17.3 (12.0–25.2)
4 weeks	196.0 (145.4–264.2)	133.9 (92.1–194.8)	177.1 (120.6–259.9)	100.8 (63.1–160.9)
3 months	62.7 (46.5–84.6)	81.6 (58.5–114.0)	151.3 (104.8–218.3)	133.2 (89.2–198.8)
6 months	47.3 (33.2–67.5)	77.0 (53.1–111.6)	125.4 (89.2–176.4)	124.6 (85.8–180.8)
12 months	28.6 (20.6–39.7)	33.6 (24.6–45.9)	78.4 (58.3–105.6)	60.4 (44.9–81.2)
P-value	<0.001	0.002	0.060	0.046
Seroprotection rate (%), 95% CI
Baseline	41.5 (27.8–56.6)	41.0 (27.1–56.6)	48.8 (34.3–63.5)	33.3 (20.6–49.0)
4 weeks	95.1 (83.9–98.6)	92.3 (79.7–97.3)	92.7 (80.6–97.5)	84.6 (70.3–92.8)
3 months	73.2 (58.1–84.3)	79.5 (64.5–89.2)	82.9 (68.7–91.5)	82.1 (67.3–91.0)
6 months	53.7 (38.7–67.9)	79.5 (64.5–89.2)	82.9 (68.7–91.5)	84.6 (70.3–92.8)
12 months	41.5 (27.7–56.6)	43.6 (29.3–59.0)	70.7 (55.5–82.4)	66.7 (51.0–79.4)
P-value	<0.001	<0.001	0.190	0.704

Numbers in ID group: at baseline = 41, 4 weeks = 41, 3 months = 37, 6 months = 37, and 12 months = 35; Numbers in IM group: at baseline = 39, 4 weeks = 39, 3 months = 34, 6 months = 36, and 12 months = 32; GMT = geometric mean titre.

Figure 2. (a)Geometric mean titres (GMTs) with SD and (b) seroprotection rates (HI titre ≥ 1:40) at pre-vaccination,4 weeks,3 months, 6 months, and12^tmonths post-vaccination in the ID and IM groups of COPD patients aged >60 years. Numbers inthe ID group: at pre-vaccination = 41,4weeks = 41,3 months = 37, 6months = 37,12months = 35. Numbers in the IM group: at baseline = 39, 4weeks = 39, 3 months = 34, 6months = 36, and 12months = 32.(a) Reference line is the seroprotective HI titre ≥ 40; (b) reference line is the CPMP criterion of seroprotection rate >60% for patients aged >60 years¹⁷.

Table 6. Local and systemic side effects of the intradermal (ID, n = 36) and intramuscular (IM, n = 35) injection.

Side effects		ID, n %))	IM, n (%)	P-value
Local	Erythema	36 (100.0)	19 (54.3)	< 0.001
	Itching	17 (47.2)	5 (15.2)	0.004
	Swelling	36 (100.0)	10 (28.6)	< 0.001
	Ecchymosis	16 (44.4)	6 (18.2)	0.005
Systemic	Fever	5 (13.9)	1 (2.9)	0.097
	Myalgia	11 (30.6)	9 (25.7)	0.653
	Headache	7 (19.4)	6 (17.1)	0.803

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