Immunogenicity of simultaneous versus sequential administration of a 23-valent pneumococcal polysaccharide vaccine and a quadrivalent influenza vaccine in older individuals: A randomized, open-label, non-inferiority trial

Figures & data

Figure 1. CONSORT flowchart

Table 1. Patients' characteristics at allocation

	Simultaneous group	Sequential group
Variable	(N = 81)	(N = 80)
Age, years (± standard deviation)	71.0 (±5.1)	70.2 (±4.1)
Male	48 (59.3)	49 (61.3)
Influenza vaccination in last year^*	20 (25.0)	29 (36.7)
Previous history of pneumonia^†	13 (16.0)	14 (17.7)
Previous history of influenza^†	10 (12.3)	15 (19.0)
Underlying disease
Chronic lung disease	54 (66.7)	55 (68.8)
Chronic heart disease	12 (14.8)	10 (12.5)
Hypertension	36 (44.4)	28 (35.0)
Diabetes	19 (23.5)	16 (20.0)
Dyslipidemia	37 (45.7)	28 (35.0)
Chronic renal disease	3 (3.7)	1 (1.2)
Cerebral vascular disorder	4 (4.9)	5 (6.2)
Neuromuscular disease	0 (0.0)	1 (1.2)
Chronic liver disease	1 (1.2)	2 (2.5)

Note. Data are expressed as number (%) of patients, unless otherwise indicated.

* data from 2 subjects are missing.

^† data from 1 subject are missing.

Figure 2. Differences in the response rates of 23F between the 2 groups (the rate in the simultaneous group minus that in the sequential group)

Table 2. Odds ratios for seroresponses 4–6 weeks post-vaccination with the 23-valent pneumococcal polysaccharide vaccine.

		Crude analysis		Multivariate analysis^*
Category	n/N (%)	OR (95% CI)	P-value	OR (95% CI)	P-value
23F
Sequential group	59/76 (77.6)	1 (reference)	0.982	1 (reference)	0.997
Simultaneous group	63/81 (77.8)	1.01 (0.48–2.14)		1.00 (0.47–2.13)
3
Sequential group	52/76 (68.4)	1 (reference)	0.923	1 (reference)	0.964
Simultaneous group	56/81 (69.1)	1.03 (0.53–2.03)		1.02 (0.51–2.03)
4
Sequential group	66/76 (86.8)	1 (reference)	0.004	1 (reference)	0.003
Simultaneous group	54/81 (66.7)	0.30 (0.14–0.68)		0.30 (0.13–0.67)
6B
Sequential group	63/76 (82.9)	1 (reference)	0.133	1 (reference)	0.134
Simultaneous group	59/81 (72.8)	0.55 (0.26–1.20)		0.55 (0.25–1.20)
14
Sequential group	67/76 (88.2)	1 (reference)	<0.001	1 (reference)	<0.001
Simultaneous group	49/81 (60.5)	0.21 (0.09–0.47)		0.20 (0.09–0.47)
19A
Sequential group	59/76 (77.6)	1 (reference)	0.732	1 (reference)	0.705
Simultaneous group	61/81 (75.3)	0.88 (0.42–1.84)		0.86 (0.40–1.86)

* Adjusted for age (<70 and ≥70 years) and sex (male and female) as explanatory variables.

OR, odds ratio; CI, confidence interval.

Table 3. Antibody titers to pneumococcal capsular polysaccharides.

	Simultaneous group		Sequential group
Variable	N	GMC	N	GMC	P-value^*
23F
Before vaccination (P0)	81	0.40	80	0.20	<0.001
4–6 weeks after vaccination (P1)	81	2.04	76	1.41	0.157
6 months after vaccination (P2)	81	2.12	72	1.70	0.351
3
Before vaccination (P0)	81	0.07	80	0.07	0.277
4–6 weeks after vaccination (P1)	81	0.24	76	0.21	0.482
6 months after vaccination (P2)	81	0.26	72	0.24	0.632
4
Before vaccination (P0)	81	0.08	80	0.05	0.004
4–6 weeks after vaccination (P1)	81	0.24	76	0.28	0.520
6 months after vaccination (P2)	81	0.30	72	0.36	0.403
6B
Before vaccination (P0)	81	0.24	80	0.14	0.007
4–6 weeks after vaccination (P1)	81	0.96	76	0.96	0.993
6 months after vaccination (P2)	80	1.18	72	1.29	0.697
14
Before vaccination (P0)	81	0.68	80	0.42	0.032
4–6 weeks after vaccination (P1)	81	2.78	76	4.72	0.070
6 months after vaccination (P2)	81	3.57	73	6.21	0.046
19A
Before vaccination (P0)	81	0.72	80	0.49	0.051
4–6 weeks after vaccination (P1)	81	3.74	76	2.92	0.332
6 months after vaccination (P2)	81	4.61	73	3.38	0.147

Note. Data are presented as the geometric mean concentrations (GMC) of immunoglobulin G to each pneumococcal capsular polysaccharide, in micrograms per milliliter. All changes within each group from P0 to P1 and P2 were statistically significant (P < 0.001) based on paired t-tests.

* P-values were calculated using Student's t-tests.

Table 4. Odds ratios for seroprotection 4–6 weeks post-vaccination with the quadrivalent influenza vaccine.

		Crude analysis		Multivariate analysis^*
Category	n/N (%)	OR (95% CI)	P-value	OR (95% CI)	P-value
H1N1
Sequential group	60/77 (77.9)	1 (reference)	0.336	1 (reference)	0.156
Simultaneous group	68/81 (84.0)	1.48 (0.67–3.30)		1.90 (0.78–4.59)
H3N2
Sequential group	68/77 (88.3)	1 (reference)	0.235	1 (reference)	0.259
Simultaneous group	66/81 (81.5)	0.58 (0.24–1.42)		0.56 (0.21–1.52)
B Texas
Sequential group	45/77 (58.4)	1 (reference)	0.027	1 (reference)	0.021
Simultaneous group	33/81 (40.7)	0.49 (0.26–0.92)		0.46 (0.24–0.89)
B Phuket
Sequential group	48/77 (62.3)	1 (reference)	0.812	1 (reference)	0.842
Simultaneous group	49/81 (60.5)	0.93 (0.49–1.76)		0.93 (0.47–1.86)

* Adjusted for age at vaccination (<70 and ≥70), sex and pre-vaccination titer (<1:10 and ≥1:10, in H1N1, B texas and B Phuket; and ≤1:10 and >1:10 in H3N2) as explanatory variables.

OR, odds ratio; CI, confidence interval.

Table 5. Adverse events in patients of the simultaneous and sequential groups.

	Simultaneous group	Sequential group
	%, (n/N)	%, (n/N)	P-value^†
Systemic events
Total	24.7 (20/81)	39.2 (31/79)	0.062
Fever	2.5 (2/79)	3.9 (3/76)	0.677
Fatigue	11.1 (9/81)	24.1 (19/79)	0.038
Headache	4.9 (4/81)	6.3 (5/79)	0.744
Joint pain	13.6 (11/81)	13.9 (11/79)	1.000
Pain of axilla	4.9 (4/81)	5.2 (4/77)	1.000
Rash	1.2 (1/81)	2.5 (2/79)	0.618
Local reactions
Pneumococcal vaccination
Total	49.4 (40/81)	59.7 (46/77)	0.205
Induration	24.7 (20/81)	19.5 (15/77)	0.450
Itch	19.8 (16/81)	15.6 (12/77)	0.537
Pain	34.6 (28/81)	48.1 (37/77)	0.106
Redness	28.4 (23/81)	26.0 (20/77)	0.858
Swelling	29.6 (24/81)	18.2 (14/77)	0.098
Influenza vaccination
Total	46.9 (38/81)	36.7 (29/79)	0.204
Induration	23.5 (19/81)	15.2 (12/79)	0.231
Itch	22.2 (18/81)	17.7 (14/79)	0.555
Pain	28.4 (23/81)	19.0 (15/79)	0.195
Redness	23.5 (19/81)	22.8 (18/79)	1.000
Swelling	23.5 (19/81)	19.0 (15/79)	0.564

Note. The population in which safety was assessed comprised study participants who received a minimum of 1 dose of the study vaccine.

^† P-values were calculated using Fisher's exact test.