An indirect treatment comparison (ITC) and matching-adjusted indirect comparison (MAIC) between a 15-valent (V114) and a 20-valent (PCV20) pneumococcal conjugate vaccine among healthy infants

Figures & data

Figure 1. Indirect treatment comparison network.

PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.

Table 1. Summary description of demographic variables inserted as potential effect modifiers in the MAIC, before and after matching.

		V114
	PCV20	Before matching	After matching
	N = 1988	N = 1714	ESS = 1049.9^b
Age in days, mean (SD)	65.8 (7.6)	61.8 (8.5)	65.8 (7.6)
Race^a
White	78.8% (1496)	55.5% (952)	78.8%
Black or African American	11.5% (218)	6.1% (105)	11.5%
Multiple	7.4% (141)	10.4% (178)	7.4%
Asian	1.7% (32)	26.2% (449)	1.7%
American Indian or Alaska Native	0.4% (7)	1.1% (19)	0.4%
Native Hawaiian or other Pacific Islander	0.2% (4)	0.6% (10)	0.2%
Missing	90	1	0

^aRace was displayed as percentage (number of infants) in the first two columns (PCV20 and V114 before matching), the denominator of the percentage being all infants with a known race (i.e. N = 1898 for PCV20 and N = 1713 for V114). In the last column (V114 after matching), race was displayed as the weighted percentage, with weights estimated from matching-adjusted indirect comparison moment matching.

^bThe ESS was computed as the square of the summed weights divided by the sum of the squared weights. The group-specific ESS is not included because ESS does not partition additively into the sum of its parts. The number of infants per race category is the same as before matching, but individuals are weighted to match the race distribution in the PCV20 population.

ESS: effective sample size; N: number of infants; MAIC: matching-adjusted indirect comparison; PCV20: 20-valent pneumococcal conjugate vaccine; V114: 15-valent pneumococcal conjugate vaccine.

Figure 2. Matching-adjusted indirect comparison analysis of the IgG response rate difference for V114 vs PCV20 in healthy infants, ~30 days after completing the third dose (administered at ~6 months of age).

Values and data points present serotype-specific IgG response rate differences as calculated in the matching-adjusted indirect comparison analysis with their respective 95% CI between parentheses and drawn as black lines. V114 was considered non-inferior to PCV20 when the lower bound of the 95% CI was above an IgG response rate difference of -10% points (i.e. with 97.5% certainty, infants vaccinated with V114 did not have a response rate that is ≥ 10% points lower than the rate for those vaccinated with PCV20); the red, vertical, dashed line displays this cutoff. V114 was considered superior to PCV20 when the lower bound of the 95% CI was above 0 (i.e. with 97.5% certainty, infants vaccinated with V114 had a higher response rate than those vaccinated with PCV20); the green, vertical, dashed line displays this cutoff.

CI:confidence interval; IgG: immunoglobulin G; PCV20: 20-valent pneumococcal conjugate vaccine; V114: 15-valent pneumococcal conjugate vaccine.

Table 2. Analysis of percentage of infants with a serological response (IgG ≥0.35 µg/mL) 30 days after the third dose (administered at ~6 months of age) – ITC and MAIC of V114 to PCV20.

	V114 vs PCV13			Indirect comparison V114 vs PCV20
	Before matching	After matching	PCV20 vs PCV13	Before matching (ITC)			After matching (MAIC)
Pneumococcal Serotype	Risk Difference (95% CI)^a	Risk Difference (95% CI)^a	Risk Difference (95% CI)^a	Risk Difference (95% CI)^b	p-value^c, non-inferiority	p-value^d, superiority	Risk Difference (95% CI)^b	p-value^c, non-inferiority	p-value^d, superiority
1	−3.4 (−5.2, −1.8)	−4.7 (−7.3, −2.4)	−8.6 (−12.1, −5.1)	5.2 (1.3, 9.1)	<0.0001		3.9 (−0.4, 8.2)	<0.0001
3	15.6 (12.1, 19.2)	19.0 (14.4, 23.8)	−15.5 (−20.1, −10.8)	31.1 (25.2, 36.9)	<0.0001	<0.0001	34.5 (27.9, 41.1)	<0.0001	<0.0001
4	−2.2 (−4.0, −0.6)	−2.9 (−5.4, −0.7)	−8.4 (−12.0, −4.9)	6.2 (2.2, 10.1)	<0.0001		5.5 (1.2, 9.7)	<0.0001
5	−2.1 (−4.2, −0.2)	−2.1 (−5.1, 0.8)	−4.3 (−7.8, −0.8)^e	2.2 (−1.9, 6.2)	<0.0001		2.2 (−2.4, 6.8)	<0.0001
6A	−4.9 (−7.1, −3.0)	−5.9 (−8.6, −3.7)	−2.4 (−4.6, −0.2)	−2.5 (−5.5, 0.5)	<0.0001		−3.5 (−6.8, −0.2)	<0.0001
6B	−3.4 (−6.6, −0.3)	−3.5 (−7.7, 0.7)	−4.1 (−7.0, −1.2)^e	0.7 (−3.6, 5.0)	<0.0001		0.6 (−4.5, 5.7)	<0.0001
7F	−0.8 (−1.9, −0.1)	−1.4 (−2.9, −0.4)	−1.0 (−2.7, 0.7)	0.2 (−1.8, 2.1)	<0.0001		−0.4 (−2.5, 1.7)	<0.0001
9 V	−1.0 (−2.8, 0.6)	−0.8 (−3.2, 1.5)	−7.9 (−11.3, −4.6)	6.9 (3.1, 10.6)	<0.0001		7.1 (3.0, 11.2)	<0.0001
14	−0.0 (−1.6, 1.6)	−0.1 (−2.0, 1.9)	−0.8 (−3.1, 1.6)	0.8 (−2.1, 3.6)	<0.0001		0.7 (−2.3, 3.8)	<0.0001
18C	−0.9 (−2.6, 0.7)	−1.7 (−4.0, 0.5)	−0.6 (−3.1, 1.9)	−0.3 (−3.3, 2.7)	<0.0001		−1.1 (−4.5, 2.3)	<0.0001
19A	−1.8 (−3.2, −0.8)	−2.7 (−4.7, −1.3)	−1.0 (−2.6, 0.5)^e	−0.8 (−2.8, 1.1)	<0.0001		−1.7 (−4.0, 0.6)	<0.0001
19F	−1.0 (−2.1, −0.4)	−1.4 (−3.0, −0.6)	0.2 (−1.5, 2.0)	−1.2 (−3.1, 0.7)	<0.0001		−1.6 (−3.7, 0.5)	<0.0001
23F	−0.3 (−3.2, 2.7)	−0.7 (−4.7, 3.3)	−7.6 (−11.4, −3.9)	7.3 (2.5, 12.1)	<0.0001		6.9 (1.4, 12.3)	<0.0001

a. Risk difference and CI calculation are based on the Bucher method [23], using separate study results (estimate and its standard error) with a common control arm (PCV13) to perform an indirect comparison of effect between V114 and PCV20. Results in the ‘After Matching’ column are weighted based on the age and race of included infants.

b. One-sided p-value calculated from the test statistic associated with the ITC and MAIC estimates and their standard error with a non-inferiority margin equal to a difference in the IgG response rate of − 10% points.

c. One-sided p-value calculated from the test statistic associated with the ITC and MAIC estimates and their standard error with a superiority margin equal to a difference in the IgG response rate of 0% points; only calculated for Serotype 3.

d. Predefined thresholds differ for serotype 5 (0.23 µg/mL), 6B (0.10 µg/mL), 19A (0.12 µg/mL).

CI:confidence interval; ITC: indirect treatment comparison; MAIC: matching-adjusted indirect comparison; PCV13: 13-valent pneumococcal conjugate vaccine; PCV20: 20-valent pneumococcal conjugate vaccine; V114: 15-valent pneumococcal conjugate vaccine.

Figure 3. Matching-adjusted indirect comparison analysis of the IgG GMC ratio for V114 vs PCV20 in healthy infants, ~30 days after completing the third (figure A) and fourth (figure B) dose.

Values and data points present serotype-specific IgG GMC ratios as calculated in the matching-adjusted indirect comparison analysis with their respective 95% CI between parentheses and drawn as black lines. V114 was considered non-inferior to PCV20 when the lower bound of the 95% CI was above the IgG GMC ratio of 0.5; the red, vertical, dashed line displays this cutoff. V114 was considered superior to PCV20 when the lower bound of the 95% CI was above the IgG GMC ratio of 1.2; the green, vertical, dashed line displays this cutoff.

CI:confidence interval; GMC: geometric mean concentration; IgG: immunoglobulin G; PCV20: 20-valent pneumococcal conjugate vaccine; V114: 15-valent pneumococcal conjugate vaccine.

Table 3. Analysis of IgG GMC ratio at 30 days after the third dose (administered at ~6 months of age) – ITC and MAIC of V114 vs PCV20.

	V114 vs PCV13			Indirect comparison V114 vs PCV20
	Before matching	After matching	PCV20 vs PCV13	Before matching (ITC)			After matching (MAIC)
Pneumococcal Serotype	IgG GMC ratio (95% CI)^a	IgG GMC ratio (95% CI)^a	IgG GMC ratio (95% CI)^a	IgG GMC ratio (95% CI)^b	p-value^c, non-inferiority	p-value^d, superiority	IgG GMC ratio (95% CI)^b	p-value^c, non-inferiority	p-value^d, superiority
1	0.64 (0.59, 0.69)	0.65 (0.61, 0.70)	0.65 (0.59, 0.72)	0.98 (0.87, 1.12)	<0.0001		1.00 (0.89, 1.13)	<0.0001
3	1.73 (1.61, 1.87)	1.67 (1.55, 1.81)	0.70 (0.64, 0.76)	2.47 (2.21, 2.77)	<0.0001	<0.0001	2.39 (2.12, 2.68)	<0.0001	<0.0001
4	0.95 (0.88, 1.03)	0.95 (0.88, 1.02)	0.70 (0.63, 0.78)	1.36 (1.19, 1.55)	<0.0001		1.36 (1.19, 1.55)	<0.0001
5	0.72 (0.66, 0.80)	0.73 (0.67, 0.80)	0.69 (0.61, 0.77)	1.04 (0.90, 1.21)	<0.0001		1.06 (0.91, 1.22)	<0.0001
6A	0.52 (0.48, 0.58)	0.52 (0.47, 0.56)	0.72 (0.65, 0.81)	0.72 (0.62, 0.84)	<0.0001		0.72 (0.63, 0.83)	<0.0001
6B	0.81 (0.71, 0.93)	0.83 (0.73, 0.95)	0.60 (0.51, 0.70)	1.35 (1.10, 1.66)	<0.0001		1.38 (1.13, 1.70)	<0.0001
7F	0.77 (0.71, 0.83)	0.75 (0.70, 0.81)	0.75 (0.69, 0.81)	1.03 (0.92, 1.15)	<0.0001		1.00 (0.90, 1.11)	<0.0001
9 V	0.91 (0.84, 1.00)	0.97 (0.89, 1.05)	0.72 (0.65, 0.80)	1.26 (1.10, 1.45)	<0.0001		1.35 (1.18, 1.54)	<0.0001
14	0.70 (0.63, 0.78)	0.72 (0.65, 0.80)	0.79 (0.71, 0.89)	0.89 (0.76, 1.04)	<0.0001		0.91 (0.78, 1.06)	<0.0001
18C	0.76 (0.70, 0.83)	0.79 (0.73, 0.85)	0.77 (0.70, 0.84)	0.99 (0.87, 1.12)	<0.0001		1.03 (0.91, 1.16)	<0.0001
19A	0.71 (0.65, 0.77)	0.71 (0.66, 0.77)	0.79 (0.72, 0.86)	0.90 (0.79, 1.02)	<0.0001		0.90 (0.80, 1.01)	<0.0001
19F	0.74 (0.69, 0.79)	0.75 (0.70, 0.80)	0.79 (0.73, 0.86)	0.94 (0.84, 1.04)	<0.0001		0.95 (0.85, 1.06)	<0.0001
23F	0.89 (0.80, 0.99)	0.90 (0.81, 0.99)	0.66 (0.58, 0.75)	1.35 (1.14, 1.59)	<0.0001		1.36 (1.16, 1.61)	<0.0001

a. GMC ratio and CI are calculated using the t-distribution with the variance estimate from a serotype-specific linear model utilizing the natural log-transformed antibody concentrations as the response and a single term for vaccination group.

b. GMC ratio and 95% CI are based on the Bucher method [23], using separate study results (estimate and its standard error) with a common control arm (PCV13) to perform an indirect comparison of effect between V114 and PCV20. Results in the ‘After matching’ column are weighted based on the age and race of included infants.

c. One-sided p-value calculated from the test statistic associated with the ITC and MAIC estimates and their standard error with a non-inferiority margin equal to an IgG GMC ratio of 0.5.

d. One-sided p-value calculated from the test statistic associated with the ITC and MAIC estimates and their standard error with a superiority margin equal to an IgG GMC ratio of 1.2; only calculated for Serotype 3.

CI:confidence interval; GMC: geometric mean concentration; IgG: immunoglobulin G; ITC: indirect treatment comparison; MAIC: matching-adjusted indirect comparison; PCV13: 13-valent pneumococcal conjugate vaccine; PCV20: 20-valent pneumococcal conjugate vaccine; V114: 15-valent pneumococcal conjugate vaccine.

Table 4. Analysis of IgG GMC ratio at 30 days after the fourth dose (administered at ~ 12 to 15 months of age) – ITC and MAIC of V114 vs PCV20.

	V114 vs PCV13			Indirect comparison V114 vs PCV20
	Before matching	After matching	PCV20 vs PCV13	Before matching (ITC)			After matching (MAIC)
Pneumococcal Serotype	IgG GMC ratio (95% CI)^a	IgG GMC ratio (95% CI)^a	IgG GMC ratio (95% CI)^a	IgG GMC ratio (95% CI)^b	p-value^c, non-inferiority	p-value^d, superiority	IgG GMC ratio (95% CI)^b	p-value^c, non-inferiority	p-value^d, superiority
1	0.66 (0.62, 0.72)	0.66 (0.61, 0.71)	0.69 (0.63, 0.76)	0.96 (0.85, 1.08)	<0.0001		0.96 (0.85, 1.08)	<0.0001
3	1.35 (1.25, 1.46)	1.41 (1.31, 1.53)	0.66 (0.61, 0.73)	2.05 (1.82, 2.30)	<0.0001	<0.0001	2.14 (1.90, 2.41)	<0.0001	<0.0001
4	0.77 (0.71, 0.84)	0.75 (0.69, 0.82)	0.78 (0.70, 0.86)	0.99 (0.86, 1.13)	<0.0001		0.96 (0.84, 1.10)	<0.0001
5	0.63 (0.58, 0.69)	0.63 (0.57, 0.68)	0.74 (0.67, 0.82)	0.85 (0.75, 0.97)	<0.0001		0.85 (0.74, 0.97)	<0.0001
6A	0.60 (0.54, 0.65)	0.59 (0.54, 0.64)	0.77 (0.70, 0.85)	0.78 (0.68, 0.89)	<0.0001		0.77 (0.67, 0.87)	<0.0001
6B	0.74 (0.67, 0.81)	0.76 (0.69, 0.84)	0.70 (0.62, 0.79)	1.06 (0.91, 1.23)	<0.0001		1.09 (0.93, 1.27)	<0.0001
7F	0.70 (0.65, 0.77)	0.69 (0.63, 0.75)	0.76 (0.70, 0.82)	0.92 (0.82, 1.03)	<0.0001		0.91 (0.81, 1.02)	<0.0001
9 V	0.73 (0.67, 0.80)	0.74 (0.68, 0.81)	0.80 (0.73, 0.88)	0.91 (0.80, 1.04)	<0.0001		0.93 (0.81, 1.05)	<0.0001
14	0.81 (0.73, 0.89)	0.80 (0.72, 0.89)	0.90 (0.81, 1.00)	0.90 (0.78, 1.04)	<0.0001		0.89 (0.77, 1.03)	<0.0001
18C	0.85 (0.78, 0.93)	0.88 (0.80, 0.96)	0.74 (0.67, 0.82)	1.15 (1.00, 1.31)	<0.0001		1.19 (1.04, 1.36)	<0.0001
19A	0.74 (0.68, 0.80)	0.77 (0.71, 0.83)	0.85 (0.77, 0.94)	0.87 (0.77, 0.99)	<0.0001		0.91 (0.80, 1.03)	<0.0001
19F	0.79 (0.74, 0.86)	0.80 (0.74, 0.87)	0.86 (0.78, 0.96)	0.92 (0.81, 1.04)	<0.0001		0.93 (0.82, 1.06)	<0.0001
23F	0.61 (0.56, 0.68)	0.65 (0.58, 0.71)	0.64 (0.57, 0.72)	0.95 (0.82, 1.11)	<0.0001		1.02 (0.87, 1.19)	<0.0001

a. GMC ratio and CI are calculated using the t-distribution with the variance estimate from a serotype-specific linear model utilizing the natural log-transformed antibody concentrations as the response and a single term for vaccination group.

b. GMC ratio and 95% CI are based on the Bucher method [23], using separate study results (estimate and its standard error) with a common control arm (PCV13) to perform an indirect comparison of effect between V114 and PCV20. Results in the ‘After matching’ column are weighted based on the age and race of included infants.

c. One-sided p-value calculated from the test statistic associated with the ITC and MAIC estimates and their standard error with a non-inferiority margin equal to an IgG GMC ratio of 0.5.

d. One-sided p-value calculated from the test statistic associated with the ITC and MAIC estimates and their standard error with a superiority margin equal to an IgG GMC ratio of 1.2.

CI:confidence interval; GMC: geometric mean concentration; IgG: immunoglobulin G; ITC: indirect treatment comparison; MAIC: matching-adjusted indirect comparison; PCV13: 13-valent pneumococcal conjugate vaccine; PCV20: 20-valent pneumococcal conjugate vaccine; V114: 15-valent pneumococcal conjugate vaccine.

Bucher HC, Guyatt GH, Griffith LE, et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997 Jun;50(6):683–691. doi: 10.1016/S0895-4356(97)00049-8

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Data availability statement

Summary/aggregate data from the PCV20 study were used for this analysis and are publicly available online [18, 21-22]; the authors of this study do not own these data. Data from the V114 phase 3 study used in this analysis may be made available to qualified researchers upon reasonable request from the corresponding author and/or Merck & Co., Inc., Rahway, NJ, U.S.A. (Data Access mailbox).