The immunogenicity of the intradermal injection of seasonal trivalent influenza vaccine containing influenza A(H1N1)pdm09 in COPD patients soon after a pandemic

Figures & data

Table 1. Demographic and clinical characteristics of COPD patients in the intradermal (ID) group (n = 75) and intramuscular (IM) group (n = 74).

Characteristics	ID group	IM group	P-value
Age, years (mean ± SD, range)	72 ± 8, 60 - 88	73 ± 7, 60 - 94	0.765
Male sex, no. (%)	68 (90.7)	68 (91.9)	0.791
BMI (kg/m^2)^a, no. (%)
< 18.5 (underweight)	15 (20.0)	16 (21.6)	0.253
18.5-24.9 (normal)	44 (58.7)	47 (63.5)	0.273
25-29.9 (overweight)	13 (17.3)	10 (13.5)	0.691
≥ 30 (obese)	3 (4.0)	1 (1.4)	0.558
Severity of COPD^b, no. (%)
Mild	18 (24.0)	18 (24.3)	0.963
Moderate	36 (48.0)	29 (39.2)	0.278
Severe	18 (24.0)	25 (33.8)	0.188
Very severe	3 (4.0)	2 (2.7)	0.660
Co-morbidity, no. (%)
Hypertension	50 (66.7)	38 (51.4)	0 .057
Dyslipidemia	34 (45.3)	32 (43.2)	0.797
Diabetes mellitus	11 (14.7)	9 (12.2)	0.654
Coronary artery disease	13 (17.3)	10 (13.5)	0.519
Cerebrovascular accident	3 (4.0)	7 (9.5)	0.183
Inhaled corticosteroid use, no. (%)	36 (48.0)	41 (55.4)	0.366
Previous TIV, no. (%)	63 (84.0)	57 (77.0)	0.282
Previous TIV, months (mean + SD)	16.2 ± 8.9	14.7 ± 7.0	0.303

BMI = body mass index,

^a WHO BMI Classification³⁰,

^b a spirometric classification of COPD severity¹, TIV = trivalent influenza vaccination

Table 2. Hemagglutination inhibition (HI) antibody titers in the intradermal (ID) group (n = 75) compared with intramuscular (IM) group (n = 74) pre-vaccination and 4 weeks post-vaccination.

		H1N1pdm09		H3N2		B
	CPMP Age > 60 yrs	ID	IM	ID	IM	ID	IM
Pre-vaccination GMT (95% CI)		13.8(10.2 – 18.7)	13.0(10.0-17.0)	30.3(21.9-41.9)	26.0(18.7-36.2)	9.6(7.5-12.4)	8.9(7.1-11.3)
P-value		0.984		0.479		0.812
Post-vaccination GMT(95% CI)		70.3(49.5– 99.8)	97.4(69.8-135.8)	160.0(116.8-219.2)	141.7(102.0-196.7)	23.2(17.2-31.3)	20.2(14.8-27.5)
P-value		0.192		0.601		0.449
Seroconversion factor (95% CI)	> 2.0	13.1(9.0-17.2)	19.9(12.7-27.1)	16.4(10.1-22.7)	17.2(10.7-23.8)	4.6(3.1-6.1)	5.7(3.5-7.8)
P-value		0.113		0.971		0.371
Seroconversion rate %, (95% CI)	> 30	50.7(39.6-61.7)	66.2(54.8-76.0)	60.0(48.7-70.3)	55.4(44.1-66.2)	26.7(18.0-37.7)	24.3(15.9-35.3)
P-value		0.054		0.570		0.743
Pre-vaccination seroprotection rate%, (95% CI)		24.0(15.7-34.9)	28.4(19.3-39.6)	50.7(39.6-61.7)	40.5(30.1-52.0)	17.3(10.3-27.6)	14.9(8.3-24.9)
P-value		0.543		0.215		0.682
Post-vaccination seroprotection rate%, (95% CI)	> 60	64.0(52.7-74.0)	78.4(67.6-86.3)	81.3(71.0-88.7)	79.7(69.1-87.4)	41.3(30.9-52.6)	36.5(26.4-47.9)
P-value		0.053		0.805		0.544

CPMP = Committee for Proprietary Medicinal Products.⁴

GMT = Geometric mean titers.

Seroconversion factor = the ratio of the HI titer after vaccination to the HI titer before vaccination.

Seroconversion rate = the percentage of post-vaccination HI titer ≥ 1:40 in patients with pre-vaccination titer < 1:10 or ≥ 4-fold increase in post-vaccination HI titer in patients with a pre-vaccination titer ≥ 1:10.

Seroprotection rate = the percentage of patients with post-vaccination HI titer ≥ 1:40.

Table 3. Hemagglutination inhibition (HI) antibody titers in the intradermal (ID) group (n = 64) compared with intramuscular (IM) group (n = 62) pre-vaccination and 4 weeks post-vaccination in patients who had no previous vaccination containing influenza A(H1N1)pdm09 virus or no history of influenza A(H1N1)pdm09 infection.

	H1N1pdm09		H3N2		B
	ID	IM	ID	IM	ID	IM
Pre-vaccination GMT (95% CI)	14.0(10.1-19.4)	12.9(9.6-17.4)	32.6(22.8-46.6)	25.0(17.6-35.5)	9.2(7.1-11.9)	8.5(6.7-10.7)
P-value	0.789		0.307		0.835
Post-vaccination GMT(95% CI)	74.2 (51.6-106.6)	95.7 (66.7-137.2)	165.3 (117.0-233.5)	127.9 (88.9-184.2)	21.3(15.5-29.4)	19.1(13.6 -26.8)
P-value	0.316		0.296		0.517
Seroconversion factor^* (95% CI)	12.4(8.3-16.5)	19.9(12.1-27.7)	17.0(9.6-24.2)	15.6(9.0-22.2)	4.3(2.9-5.7)	5.8(3.4-8.2)
P-value	0.168		0.935		0.490
Seroconversion rate^* %, (95% CI)	53.1(41.1-64.8)	66.1(53.7-76.7)	60.9(48.7-72.0)	56.5(44.1-68.1)	17.2(9.7-28.4)	17.7(10.0-29.2)
P-value	0.137		0.609		0.935
Pre-vaccination seroprotection rate%, (95% CI)	23.4(14.6-35.2)	27.4(17.8-39.7)	54.7(42.6-66.3)	40.3(29.0-52.8)	15.6(8.5-26.6)	12.9(6.4-23.7)
P-value	0.608		0.107		0.662
Post-vaccination seroprotection rate^*%, (95% CI)	67.2(55.0-77.5)	79.0(67.2-87.5)	82.8(71.6-90.3)	77.4(67.2-87.5)	37.5(26.7-49.8)	33.9(23.3-46.3)
P-value	0.134		0.448		0.671

* Committee for Proprietary Medicinal Products (CPMP) criteria⁴: Seroconversion factor > 2.0, Seroconversion rate > 30, seroprotection rate > 60.

Table 4. Hemagglutination inhibition (HI) antibody titers 4 weeks post-vaccination by baseline seronegative and seropositive status in the intradermal (ID) group (total n = 75) compared to intramuscular (IM) group (total n = 74).

		Seronegative (HI titers < 1:10)						Seropositive (HI titers > 1:10)
		H1N1pdm09		H3N2		B		H1N1pdm09		H3N2		B
	CPMPAge> 60 yrs	ID n = 36	IM n = 36	ID n = 14	IM n = 18	ID n = 51	IM n = 51	ID n = 39	IM n = 38	ID n = 61	IM n = 56	ID n = 24	IM n = 23
Pre-vaccination GMT (95% CI)		5	5	5	5	5	5	35.3(23.8-52.5)	32.1(23.7-43.6)	45.8(33.5-62.8)	44.2(31.7-61.6)	38.9(25.6-59.0)	32.4(22.0-47.7)
P-value								0.892		0.881		0.566
Post-vaccination GMT(95% CI)		37.0 (23.0-59.7)	52.4 (31.4-87.4)	97.5 (40.4-235.1)	74.1 (34.5-159.2)	15.9 (11.8-21.3)	14.6 (10.4-20.6)	127.0(80.9-199.2)	175.3(122.8-250.2)	179.3(128.0-251.1)	174.5(122.5-248.6)	51.9(27.9-96.6)	41.2(23.0-73.8)
P-value		0.325		0.604		0.400		0.410		0.900		0.493
Seroconversion factor (95% CI)	> 2.0	17.6(10.3-24.8)	29.2 (15.3-43.1)	44.9 (16.3-73.4)	37.3 (14.4-60.2)	5.7(3.7-7.8)	6.8(3.9-9.6)	9.0(4.9-13.1)	11.0(6.9-15.1)	9.8(6.6-13.1)	10.6 (6.7-14.8)	2.2(1.2-3.1)	3.3(0.3-6.4)
P-value		0.325		0.604		0.400		0.162		0.886		0.630
Seroconversion rate %, (95% CI)	> 30	47.2 (32.0-63.0)	61.1 (44.8-75.2)	71.4 (45.0-88.7)	66.7 (43.5-83.9)	27.5 (17.0-41.0)	27.5 (17.0-41.0)	53.8 (38.6-68.4)	71.1 (55.1-83.1)	57.4 (44.9-69.0)	51.8 (39.0-64.3)	25.0 (11.7-45.2)	17.4 (6.3-37.7)
P-value		0.237		0.773		1.000		0.119		0.544		0.524
Pre-vaccination seroprotection rate%, (95% CI)		0	0	0	0	0	0	46.2 (31.6-61.4)	55.3 (39.7-69.9)	62.3(49.7-73.4)	53.6(40.7-66.0)	54.2(35.1-72.1)	47.8 (29.2-67.0)
P-value								0.424		0.339		0.664
Post-vaccination seroprotection rate%, (95% CI)	> 60	47.2 (32.0-63.0)	61.1 (44.8-75.2)	71.4 (45.0-88.7)	66.7 (43.6-83.9)	27.5 (17.0-41.0)	27.5 (17.0-41.0)	79.5 (64.2-89.5)	94.7 (81.8-99.5)	83.6 (72.2-91.0)	83.9 (72.0-91.5)	70.8 (50.6-85.3)	56.5 (36.8-74.4)
P-value		0.237		0.773		1.000		0.047^*		0.962		0.307

* The level of critical significance was assigned at p < 0.05.

Table 5. Side effects of influenza vaccination in the intradermal (ID) group (n = 67) and the intramuscular (IM) group (n = 67).

Side effects		ID n (%)	IM n (%)	P-value
Local	Erythema	67 (100.0)	34 (50.7)	< 0.001^*
	Itching	18 (26.9)	1 (1.5)	< 0.001^*
	Swelling	66 (98.5)	11 (16.4)	< 0.001^*
	Ecchymosis	16 (23.9)	2 (3.0)	0.001^*
Systemic	Fever	0 (0)	2 (3.0)	< 0.001^*
	Myalgia	1 (1.5)	4 (6.0)	0.43
	Headache	0 (0)	3 (4.5)	< 0.001^*

* Statistically significant at P < 0.05

Figure 1. Numbers and types of acute respiratory illness (ARI) in the intradermal injection (ID, total events = 70) and intramuscular injection (IM, total events = 76) groups. The numbers of patients in each ARI type was not significantly different between the ID and IM groups.

Table 6. Influenza-related acute respiratory illness diagnosed by hemagglutination inhibition (HI) titers or RT-PCR in the intradermal (ID) injection and intramuscular (IM) injection.

	Influenza-related ARI diagnosed by			HI titers at baseline and 4 wks post-vaccination						HI titers of influenza-related ARI
				H1N1		H3N2		B		H1N1		H3N2		B
Case	HI titers	RT-PCR	ARI after vaccination (days)	0 wk	4 wks	0 wk	4 wks	0 wk	4 wks	1^st serum	2^nd serum	1^st serum	2^nd serum	1^st serum	2^nd serum
IM1	Flu A undefined subtype	NA	34	5	5	5	10	5	5	5	640	10	320	5	5
IM2	Flu Undefined type	NA	182	40	640	10	320	5	80	20	160	20	80	10	40
IM3	H1N1	NA	173	5	10	80	640	5	10	40	160	160	40	5	5
IM4	H1N1	NA	189	20	40	80	640	20	80	5	80	640	320	5	5
IM5	H1N1	Neg.	329	5	10	5	80	5	80	80	640	40	80	10	40
IM6	H1N1	H1N1	337	5	40	40	640	5	10	20	640	5	5	10	5
ID1	FluUndefined type	Neg.	334	10	20	10	320	5	160	5	80	5	80	5	40
ID2	H1N1	NA	171	40	640	40	80	5	10	10	320	20	5	20	10
ID3	H3N2	Neg.	362	20	640	40	640	5	40	80	80	40	640	5	5
ID4	Neg.	H3N2	345	640	640	10	20	5	5	20	40	5	5	5	5

IM = intramuscular group, ID = intradermal group, ARI = acute respiratory illness, RT-PCR = reverse transcription-polymerase chain reaction

NA = not available, Neg. = negative, H1N1 = influenza A(H1N1)pdm09, H3N2 = influenza A(H3N2), B = influenza B