Predicted serotype-specific effectiveness of pneumococcal conjugate vaccines V114 and PCV20 against invasive pneumococcal disease in children

Figures & data

Figure 1. Schematic depiction of the modeling method.

C_p, protective antibody concentration; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; RCDC, reverse cumulative distribution curve; V114, 15-valent pneumococcal conjugate vaccine; VE, vaccine effectiveness.

The flow chart illustrates the two-step method for predicting the VE of the serotypes that V114 and PCV20 have in common with PCV7 or PCV13. Beginning with the known serotype-specific IgG concentrations after vaccination with PCV7/PCV13 (both placebo and active vaccine), simulated RCDCs are used, along with the known serotype-specific VE of PCV7 and PCV13 (nonPCV7 serotypes) (where VE ≈ 1- (p_v/p_c)), to derive the C_p for each serotype (red arrow in the left panel). Then, based on the known serotype-specific IgG concentrations in recipients of V114 (or PCV20), RCDCs are simulated for the same serotypes, and the previously derived C_p values are used to determine the VE (again in terms of p_v and p_c) for those serotypes in V114 (or PCV20; see arrows in right panel). As described in Siber et al [18], p_v is the percentage of subjects with antibody levels less than C_p in the vaccinated cohort, and p_c is the percentage of subjects with antibody levels less than C_p in the control cohort.

Adapted from Ryman et al. 2022 [17] which is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

Table 1. Summary-level input data and sources.

	Vaccine effectiveness		Normalized geometric mean serotype-specific antibody concentration (µg/mL)
Serotype	PCV7 (95% CI)^A	PCV13 (95% CI)^B	Placebo (95% CI)^C	PCV7 (95% CI)^D	PCV13 (95% CI)^E,F,G	V114 (95% CI)^E	PCV20 (95% CI)^F
PCV7
4	93% (65–99)	–	0.04 (0.03–0.05)	1.36 (1.20–1.56)	–	0.92 (0.88–0.95)	0.72 (0.68–0.77)
6B	94% (77–98)	–	0.09 (0.08–0.09)	3.34 (2.75–4.05)	–	1.57 (1.45–1.70)	0.91 (0.85–0.99)
9 V	100% (88–100)	–	0.08 (0.07–0.08)	1.60 (1.41–1.83)	–	0.90 (0.87–0.94)	0.79 (0.75–0.83)
14	94% (81–98)	–	0.17 (0.15–0.19)	4.68 (4.07–5.40)	–	3.73 (3.51–3.96)	2.07 (1.94–2.22)
18C	97% (85–99)	–	0.06 (0.06–0.07)	1.96 (1.71–2.25)	–	0.91 (0.87–0.95)	1.05 (1.00–1.11)
19F	87% (65–95)	–	0.24 (0.23–0.25)	1.44 (1.26–1.65)	–	2.04 (1.97–2.11)	1.45 (1.37–1.52)
23F	98% (80–100)	–	0.10 (0.10–0.11)	1.44 (1.22–1.70)	–	1.15 (1.09–1.21)	0.74 (0.69–0.80)
PCV13
1	–	87% (77–93)	0.05 (0.04–0.05)	–	1.26 (1.21–1.31)	0.94 (0.90–0.98)	0.80 (0.76–0.85)
3	–	80% (30–95)	0.07 (0.07–0.08)	–	0.48 (0.46–0.50)	0.82 (0.79–0.85)	0.33 (0.31–0.35)
5	–	87% (77–93)	0.09 (0.08–0.10)	–	1.06 (1.02–1.11)	0.83 (0.79–0.87)	0.82 (0.77–0.86)
6A	–	86% (76–92)	0.13 (0.13–0.14)	–	1.98 (1.91–2.06)	1.23 (1.18–1.29)	1.53 (1.44–1.61)
7F	–	97% (83–100)	0.07 (0.06–0.07)	–	2.14 (2.06–2.22)	1.79 (1.71–1.87)	1.50 (1.43–1.58)
19A	–	86% (71–94)	0.33 (0.31–0.34)	–	1.39 (1.35–1.44)	1.28 (1.23–1.32)	1.01 (0.95–1.05)

CI, confidence interval; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.

^ASource: Whitney et al. (2006) [20].

^BSource: Moore et al. (2016) [21].

^CSource: Clinical trial NCT01340937 [27].

^DSource: Siber et al. (2007) [18].

^ESources: Clinical trials NCT02987972 [22], NCT03620162 [23], and NCT03893448 [24].

^FSource: Clinical trial NCT04382326 [6].

^GPooled across trials listed in notes E and F to reflect the overall population distribution.

Table 2. Estimated protective antibody concentrations.

Serotype	Protective antibody concentration, Cp (median (95% CI) µg/mL)
PCV7
4	0.31 (0.13–0.98)
6B	0.40 (0.11–1.37)
9 V	0.13 (0.05–0.51)
14	0.95 (0.45–2.02)
18C	0.32 (0.13–0.74)
19F	0.41 (0.17–1.04)
23F	0.11 (0.03–0.55)
PCV13
1	0.50 (0.36–0.72)
3	0.23 (0.10–0.71)
5	0.39 (0.29–0.55)
6A	0.90 (0.67–1.21)
7F	0.53 (0.28–1.10)
19A	0.68 (0.46–1.01)

CI, confidence interval; Cp, protective antibody concentration; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine.

Table 3. Observed and predicted vaccine effectiveness.

		Predicted effectiveness, median % (95% CI)
Serotype	Observed effectiveness, median % (95% CI)^A	V114	PCV20
PCV7
4	93% (65–99)	95% (42–100)	77% (36–94)
6B	94% (77–98)	87% (60–94)	74% (39–94)
9 V	100% (88–100)	99% (84–100)	99% (72–100)
14	94% (81–98)	92% (72–97)	75% (50–91)
18C	97% (85–99)	95% (65–99)	94% (69–100)
19F	87% (65–95)	99% (91–100)	96% (68–100)
23F	98% (80–100)	99% (82–100)	93% (61–98)
PCV13
1	87% (77–93)^B	84% (67–93)	67% (55–78)
3	80% (30–94)	98% (58–100)	64% (15–92)
5	87% (77–93)^B	85% (70–91)	79% (67–87)
6A	86% (76–92)^B	69% (54–83)	74% (63–83)
7F	97% (83–100)	96% (79–99)	92% (67–99)
19A	86% (71–94)	88% (68–96)	72% (52–87)

CI, confidence interval; PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.

^ASources: for PCV7, Whitney et al. (2006) [20], and for PCV13, Moore et al. (2016) [21].

^BEffectiveness estimates were not available in Moore et al. (2016) for PCV13 serotypes 1, 5, and 6A, therefore the pooled estimate for ‘PCV13-nonPCV7 types’ was used for serotypes 1 and 5, and the estimate for ‘PCV13-type’ was used for serotype 6A.

Figure 2. Absolute difference in predicted vaccine effectiveness for V114 and PCV20.

PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.

Values reflect the predicted VE (%) for PCV20 subtracted from the predicted VE for V114%), summarized as median (point) and empirical 95% confidence interval (whiskers) across 5,000 simulations. Values greater than zero favor V114.

Table 4. Predicted effectiveness for serotype 3 using Andrews et al. (2014) PCV13 effectiveness estimates as input.

Serotype	Observed effectiveness, median % (95% CI)^A	Predicted effectiveness, median % (95% CI)
		V114	PCV20
3	26% (−69, 68)	56% (0–95)	11% (0–47)

CI, confidence interval; PCV20, 20-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.

^ASource: Andrews et al. (2014) [25].

Table

	V114 Phase 3 Study		PCV20 Phase 3 Study		Whitney et al. 2006	Moore et al. 2016
	V114	PCV13	PCV20	PCV13	Cases	Cases
Number of Children	858	856	1001	987	782	722
Sex, n (%)
Male	461 (53.7)	429 (50.1)	518 (51.7)	505 (51.2)	462 (59.1)	393 (54.4)
Female	397 (46.3)	427 (49.9)	483 (48.3)	482 (48.8)	320 (40.9)	329 (45.6)
Age, weeks (mean±SD)	8.4 ± 1.2	8.4 ± 1.3	NR	NR	-	-
Age, days (arithmetic mean±SD)	NR	NR	65.9 ± 8.0	65.6 ± 7.1	-	-
Age, months (median, range*)	-	-	-	-	21.0 (2–60)	21 (11–37)
Gestational Age (n(%))
≥37 weeks	784 (91.4)	780 (91.1)	NR	NR	NR	NR
<37 weeks	74 (8.6)	76 (8.9)	NR	NR	NR	NR
Race, n (%)
White	472 (55.0)	480 (56.1)	754 (75.3)	742 (75.2)	455 (58.2)	371 (51.4)
Asian	223 (26.0)	226 (26.4)	16 (1.6)	16 (1.6)	NR	NR
Multiple	98 (11.4)	80 (9.3)	68 (6.8)	73 (7.4)	NR	NR
Black or African American	52 (6.1)	53 (6.2)	110 (11.0)	108 (10.9)	198 (25.3)	204 (28.3)
American Indian or Alaska Native	6 (0.7)	13 (1.5)	4 (0.4)	3 (0.3)	NR	NR
Native Hawaiian or Other Pacific Islander	6 (0.7)	4 (0.5)	2 (0.2)	2 (0.2)	NR	NR
Other/unknown	-	-	-	-	129 (16.5)	147 (20.4)
Missing	1 (0.1)	0 (0.0)	47 (4.7)	43 (4.4)	-	-

NR, not reported; PCV13, 13-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; V114, 15-valent pneumococcal conjugate vaccine.

*Range is interquartile for Moore et al. (2016) [21].

Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007 May 10;25(19):3816–3826. doi: 10.1016/j.vaccine.2007.01.119

 PubMed Web of Science ®Google Scholar

Ryman J, Weaver J, Hu T, et al. Predicting vaccine effectiveness against invasive pneumococcal disease in children using immunogenicity data. NPJ Vaccines. 2022 Nov 7;7(1):140. doi: 10.1038/s41541-022-00538-1

 PubMed Web of Science ®Google Scholar

Whitney CG, Pilishvili T, Farley MM, et al. Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: A matched case-control study. Lancet. 2006 Oct 28;368(9546):1495–1502. doi: 10.1016/S0140-6736(06)69637-2

 PubMed Web of Science ®Google Scholar

Moore MR, Link-Gelles R, Schaffner W, et al. Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease in children in the USA: a matched case-control study. Lancet Respir Med. 2016 May;4(5):399–406. doi: 10.1016/S2213-2600(16)00052-7

 PubMed Web of Science ®Google Scholar

A study of v419 given concomitantly with Prevnar 13™ and rotateq™ (p. v419–006). Clinicaltrials.Gov id: Nct01340937. [cited 2022 Feb 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT01340937

 Google Scholar

A study to evaluate the safety, tolerability, and immunogenicity of two lots of v114 in healthy infants (v114-008). Clinicaltrials.Gov id: Nct02987972]. [cited 2022 Feb 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02987972

 Google Scholar

A study to evaluate the interchangeability of v114 and Prevnar 13™ in healthy infants (v114-027/pneu-direction). [Clinicaltrials.Gov id: Nct03620162]. [cited 2022 Feb 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03620162

 Google Scholar

A phase 3, randomized, double-blind trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in healthy infant. Eudract no. 2019-003305-10 [cited 2023 Jun 26]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003305-10/results

 Google Scholar

Andrews NJ, Waight PA, Burbidge P, et al. Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study. Lancet Infect Dis. 2014 Sep;14(9):839–846. doi: 10.1016/S1473-3099(14)70822-9

 PubMed Web of Science ®Google Scholar

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials.