Clinically- versus serologically-identified varicella: A hidden infection burden. A ten-year follow-up from a randomized study in varicella-endemic countries

Figures & data

Figure 1. Plain language summary

Figure 2. Study design

D0, day of the first vaccine dose; D42, day of the second vaccine dose (Day 42, administered six weeks after the first vaccine dose); D84, follow-up timepoint at six weeks after the second vaccine dose – Day 84; Y, year; Y1-Y10, regular blood sampling and follow-up timepoints after the second vaccine dose (after one, two, four, six, eight, and ten years); Active Control, participants receiving two doses of trivalent measles-mumps-rubella vaccine (MMR); MMRV, participants receiving two doses of the tetravalent MMR-varicella vaccine; MMR+V, participants receiving one dose of MMR and one dose of monovalent varicella vaccine; 1:3:3, randomization format of participants in the treatment groups (Active control: MMRV: MMR+V); VZV, varicella-zoster virus; Ab, antibodies.

Figure 3. Occurrence of varicella cases in the Active Control group (per-protocol cohort for efficacy)

IDMC, Independent Data Monitoring Committee; PCR, laboratory PCR test for varicella-zoster virus DNA; EPI, established epidemiological link; +, positive; ─, negative; Cases estimated not to meet clinical case criteria by the IDMC (IDMC neg): “IDMC neg PCR ─”, suspected varicella case or no case, “IDMC neg PCR +”, PCR-confirmed, IDMC overruled case; Cases found to meet the clinical case criteria by the IDMC (IDMC pos): “IDMC pos PCR +”, confirmed varicella case, “IDMC pos PCR ─ EPI +”, epidemiologically confirmed varicella case, “IDMC pos PCR ─ EPI ─”, probable varicella case.

Figure 4. Flow of the participants included in the Active Control group

MMR, participants receiving two doses of trivalent measles-mumps-rubella vaccine (Active Control group); MMRV, participants receiving two doses of the tetravalent MMR-varicella vaccine; MMR+V, participants receiving one dose of MMR and one dose of monovalent varicella vaccine; Day 84, follow-up timepoint at six weeks after the second vaccine dose.

Supplementary Table S1: Demographic characteristics (total vaccinated cohort) and 10-year varicella person-year rate (per-protocol efficacy cohort) of study participants per country in the Active Control group

Characteristic		Czech Republic	Greece	Italy	Lithuania	Norway	Poland	Romania	Russia	Slovakia	Sweden
Age in months, mean ± SD		15.3 ± 3.1	15.1 ± 2.8	13.9 ± 2.1	14.4 ± 2.2	14.1 ± 1.0	12.9 ± 1.2	15.3 ± 2.9	12.6 ± 1.2	15.4 ± 2.4	15.5 ± 2.0
Gender, % female		48.1	48.8	57.5	46.2	55.2	53.3	42.6	48.3	46.4	37.2
Ethnicity, n (%)European Arabic or North African Other		184 (99.5)	41 (95.3)	38 (95.0)	93 (100.0)	27 (93.1)	135 (100.0)	46 (97.9)	143 (100.0)	68 (98.6)	43 (100.0)
		0 (0.0)	2 (4.7)	1 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
		1 (0.5)	0 (0.0)	1 (2.5)	0 (0.0)	2 (6.9)	0 (0.0)	1 (2.1)	0 (0.0)	1 (1.4)	0 (0.0)
Care type, n (%)At least one sibling at homeAttending a day care centerAttending a childminderAt least once a week contact		53 (28.6)	12 (27.9)	7 (17.5)	10 (10.8)	10 (34.5)	35 (25.9)	6 (12.8)	32 (22.4)	31 (44.9)	13 (30.2)
		3 (1.6)	1 (2.3)	9 (22.5)	26 (28.0)	13 (44.8)	7 (5.2)	0 (0.0)	125 (87.4)	1 (1.4)	24 (55.8)
		13 (7.0)	9 (20.9)	7 (17.5)	1 (1.1)	8 (27.6)	4 (3.0)	0 (0.0)	12 (8.4)	4 (5.8)	4 (9.3)
		176 (95.1)	40 (93.0)	35 (87.5)	78 (83.9)	19 (65.5)	127 (94.1)	47 (100.0)	131 (91.6)	67 (97.1)	32 (74.4)
10-year person-year rate of varicella, n/T (95% CI)*		0.20 (0.17─0.23)	0.00 (undefined)	0.08 (0.04─0.15)	0.05 (0.03─0.07)	0.16 (0.10─0.26)	0.06 (0.04─0.08)	0.00 (undefined)	0.07 (0.05─0.10)	0.15 (0.11─0.19)	0.21 (0.15─0.30)

SD, standard deviation; n (%), number (percentage) of participants in a given category; n/T (95% CI), person-year rate (95% confidence interval). *data for Czech Republic, Lithuania, Poland, Romania and Slovakia have been published³¹

Table 1. Demographic characteristics of participants in the Active Control group (per-protocol cohort for efficacy; N = 744)

Characteristic		Participant features
Age in months, mean ± SD		14 ± 3
Gender, % female		48
Ethnicity, n (%)	European	737 (99)
	Arabic or North African	2 (<1)
	Other	5 (1)
Country, n (%)	Czech Republic	171 (23)
	Greece	32 (4)
	Italy	35 (5)
	Lithuania	86 (12)
	Norway	25 (3)
	Poland	116 (16)
	Romania	42 (6)
	Russian Federation	130 (17)
	Slovakia	68 (9)
	Sweden	39 (5)
Care type, n (%)	At least one sibling at home	192 (26)
	Attending a day care center	187 (25)
	Attending a childminder	57 (8)
	At least once a week contact	680 (91)

N, number of participants included in the cohort; n (%), number of participants in the defined category and their percentage relative to the corresponding cohort size; SD, standard deviation.

Table 2. Anti-VZV antibody levels in the Active Control group participants without a varicella case, or with a case detected since previous visit or before previous visit until each timepoint (per-protocol cohort for efficacy)

			Anti-VZV ≥25 mIU/mL
Varicella case	Timepoint	N	n	% (95% CI)
No case	Y1	626	50	8 (6–10)
	Y2	529	71	13 (11–17)
	Y4	291	90	31 (26–37)
	Y6	190	105	55 (48–63)
	Y8	151	104	69 (61–76)
	Y10	128	96	75 (67–82)
Case since previous visit	Y1	38	35	92 (79–98)
	Y2	56	55	98 (90–100)
	Y4	134	133	99 (96–100)
	Y6	58	58	100 (94–100)
	Y8	24	24	100 (86–100)
	Y10	11	11	100 (71–100)
Case before previous visit	Y2	38	37	97 (86–100)
	Y4	87	86	99 (94–100)
	Y6	181	181	100 (98–100)
	Y8	267	267	100 (99–100)
	Y10	280	279	100 (98–100)

Figure 5. Evolution of anti-VZV antibody GMCs (lines) and the number of participants (table) in the Active Control group (per-protocol cohort for efficacy)

Case before previous visit, varicella case confirmed before blood sampling preceding the reference point; Case since previous visit, varicella case confirmed between previous and reference blood sampling; No case, no varicella case detected until the reference point (data for all of these participants and for a subset excluding the seronegative participants is shown); VZV, varicella-zoster virus; GMC, geometric mean concentration in milli-international units per mL (mIU/mL); 95% CI, 95% confidence interval; Follow-up timepoints, blood samples collected at indicated study visits after the second vaccine dose; Y1–Y10, post-vaccination blood samples obtained at year one, two, four, six, eight, and ten of follow-up.

Figure 6. Reverse cumulative distribution curves of anti-VZV antibody concentrations in Active Control group participants without a varicella case (per-protocol cohort for efficacy)

Participants without a varicella case during the ten-year follow-up period; VZV, varicella-zoster virus; mIU/mL, milli-international units per mL; ELISA, enzyme-linked immunosorbent assay; ELISA cutoff value of 25 mIU/mL of anti-VZV antibody level is indicated by the dotted line in the left panel; MMR, participants receiving the measles-mumps-rubella vaccine; Y1–Y10, post-vaccination blood samples obtained at year one, two, four, six, eight, and ten of follow-up.

Figure 7. Reverse cumulative distribution curves of anti-VZV antibody concentration fold increases in Active Control group participants with a confirmed varicella case since the previous visit (per-protocol cohort for efficacy)

Participants with a confirmed varicella case since the previous visit during the ten-year follow-up period; VZV, varicella-zoster virus; 8-fold increase in anti-VZV antibody concentration indicated by the dotted line in the right panel; MMR, participants receiving the measles-mumps-rubella vaccine; Y1–Y10, post-accination blood samples obtained at year one, two, four, six, eight, and ten of follow-up

Prymula R, Povey M, Brzostek J, Cabrnochova H, Chlibek R, Czajka H, Leviniene G, Man S, Neamtu M, Pazdiora P, et al. Ten-year follow-up on efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: Results from five East European countries. Vaccine. 2021;39(19):2643–51. doi:10.1016/j.vaccine.2021.03.085.

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