Waning rate of immunity and duration of protective immunity against diphtheria toxoid as a function of age and number of doses: Systematic review and quantitative data analysis

Figures & data

Figure 1. A hypothesized schematic image of the data and analysis and measurement of waning rate of immunity and duration of protective immunity.

The peak of the immunity curve shows the peak immunity after vaccination. The slope of the graph is waning of immunity after the respective number of doses previously given. Durations of protective immunity are determined by the peak immunity levels after vaccination and waning rate (slope). Figure was adapted from “WHO immunological basis for immunization series: module 3 tetanus”.⁵¹

Figure 2. Results of literature search and flow diagram.

Table 1. Summary table of 15 countries included in the quantitative analysis.

Authors	Country	Study year	Age	3 doses	4th dose	5th dose	DTP intro	Booster intro*	Sample size	Sampling method	Hoy’s criteria	DTP3 coverage
			(year)	(month)	(year)	(year)						mean (range)
di Giovine et al.	Czech Rep	2001	0-75+	2,3,4	1.5 (D)	5 (D)	1960	1986	3123	Community	10	100% (96–100%)
Edmunds et al.^Citation31	Denmark	1995	0-75+	3,5,12	5 (D)		1930s	1996	2989	Residual sera	8	89% (86–91%)
Edmunds et al.^Citation31	Finland	1995	0-75+	3,4,5	2 (D)	11-13 (d)	1943	1989*	3381	Residual sera	10	95% (90–99%)
Edmunds et al.^Citation31	France	1995	0-75+	2,3,4	1.5 (D)	5 (D)	1938	NA	2462	Residual sera	8	91% (79–96%)
di Giovine et al.^Citation32	Hungary	2003	0-60+	3,4,5	3 (D)	6 (D)	1960	1971	2600	Residual sera	8	99% (99–100%)
di Giovine et al.^Citation32	Ireland	2003	0-60+	2,4,6	4 (D)	12 (d)	1960	1996*	3300	Residual sera	8	66% (36–86%)
di Giovine et al.^Citation32	Israel	2000	0-60+	2,4,6	1 (D)	7 (D)	1951	1999	3300	Residual sera	10	92% (91–96%)
Edmunds et al.^Citation31	Italy	1996	0-75+	3,5,11	5-6 (D)	X (d)	1939	NA	3111	Residual sera	8	93% (83–95%)
di Giovine et al.^Citation32	Latvia	2003	0-60+	3,4.5,6	1.5 (D)	7 (D)	1960	1998*	3300	Community	10	91% (80–98%)
di Giovine et al.^Citation32	Luxembourg	2001	4-70+	2,4,5	1(D)	5 (D)	1960	1999	3200	Community	8	87% (68–98%)
Skogen et al.^Citation30	Norway	1994	1-12	3,5,11	11(d)		1942	NA	400	Residual sera (subnational)	6	88% (80–98%)
Skogen et al.^Citation30	Russia	1994	1-10	3,4.5,6	2 (D)	6 (D)	1958	NA	264	Residual sera (subnational)	6	76% (73–79%)
di Giovine et al.^Citation32	Slovakia	2003	0-60+	2,4,10	2 (D)	5 (D)	1960	1998	3300	Community	10	99% (99–100%)
Edmunds et al.^Citation31	Sweden	1995	0-75+	3,5,11	10 (D)		1951	NA	3633	Community	10	99% (99–99%)
Edmunds et al.^Citation31	UK	1996	0-75+	2,3,4	3.3 (D)	15 (d)	1940	1994*	3224	Residual sera	8	69% (41–94%)

X: Decennial booster dose.

D and d refer to high and low dose of diphtheria toxoid, respectively.

†Final sample size was not reported for some studies (Hungary, Ireland, Israel, Latvia, Luxembourg and Slovakia). For those studies, the target sampling size was used for sample size.

*Multiple booster doses were used in the majority of countries. The introduction years of the booster dose were for the fifth dose.

§Hoy’s criterion score were used to assess the quality of the prevalence study for the systematic review.

Table 2. Age ranges and original sample sizes for the 15 countries population included in the quantitative analysis for waning rate of immunity. ^30–32

Country		After 3 doses	After 4 doses	After 5 doses	After 6 doses
Czech Republic	Age range (year)	1	2-4	7-19	ns
	Sample size	56	283	1289
Denmark	Age range (year)	2-4	6-16	ns	ns
	Sample size	287	783
Finland	Age range (year)	1	2-10	13-17	ns
	Sample size	100	854	470
France	Age range (year)	1	2-5	7-10	12-15
	Sample size	45	200	173	173
Hungary	Age range (year)	ns	3-5	6-10	13-14
	Sample size		300	500	200
Ireland	Age range (year)	ns	4-9	13-19	ns
	Sample size		600	700
Israel	Age range (year)	ns	1-6	ns	ns
	Sample size		600
Italy	Age range (year)	1-4	8-15	ns	ns
	Sample size	359	695
Latvia	Age range (year)	ns	2-6	8-12	14-19
	Sample size		500	500	500
Luxembourg	Age range (year)	ns	4	ns	9-11
	Sample size		100		300
Norway	Age range (year)	1-10	12	ns	ns
	Sample size	336	29
Russia	Age range (year)	1	3-5	6-8	9-10
	Sample size	15	99	79	58
Slovakia	Age range (year)	1	3-4	6-10	ns
	Sample size	100	200	500
Sweden	Age range (year)	1-9	10-19	ns	ns
	Sample size	528	724
UK	Age range (year)	ns	6-13	15-17	ns
	Sample size		763	299

ns: no samples were included in the analysis for respective countries and doses.

The sample size in this table for Ireland, Israel, Hungary, Latvia, Luxembourg, and Slovakia were the number of samples that were planned to be collected as final sample sizes were not available in the cited publications.

Figure 3. Seroprevalence and DTP3 coverage by age and year of birth in data included in the analyses.

These figures are a descriptive aid to show which data were used for the regression analysis. Data from four countries are shown here. Some birth cohorts shaded in gray were removed for various reasons: (1) some birth cohorts were too old to receive booster doses when they were introduced, e.g., ≥10 years old birth cohort in Slovakia, and (2) GMC was lower than the peak at the age of the scheduled booster dose, e.g., the birth cohort aged 5-6 years in the Czech Republic and the birth cohorts aged 11 and 12 years in Finland. The birth cohorts removed from the analysis were expressed as hollow circles and the remaining cohorts included in the analysis were shown as solid circles. Solid circles indicate GMC, and triangles indicate national DTP3 coverage. Arrows indicate the vaccination schedule in each country.

Figure 4. Declining trend of GMC over time after different numbers of DTP doses were given in 15 countries: Czech Republic, Denmark, Finland, France, Hungary, Ireland, Israel, Italy, Latvia, Luxembourg, Norway, Russia, Slovakia, Sweden, and the United Kingdom.

Each observed value of GMC was plotted over time for each country on a log₁₀ scale. Predicted lines were drawn by the simple linear regression of immunity over time but not adjusted for coverage.

Table 3. The peak GMC level, annual percentage decrease of GMC level, and duration of protective immunity after three, four, and five doses: Duration of protective immunity was estimated as the time at which GMC declined to 0.1 IU/ml or 0.01 IU/ml.

	Peak GMC level (intercept)		Annual percent decrease (slope)		Duration of protective immunity (intercept-threshold/slope)
	IU/ml	(95% CI)	%	(95% CI)	Declined to 0.1 IU/ml		Declined to 0.01 IU/ml
					year	(95% CI)	year	(95% CI)
After 3 doses	0.21	(0.13, 0.35)	26%	(20.5, 31.9%)	2.5	(0.9, 4.0)	10.0	(7.4, 12.5)
After 4 doses	0.71	(0.45, 1.12)	17%	(12.2, 21.9%)	10.3	(7.1, 13.6)	22.5	(16.1, 29.0)
After 5 doses	0.58	(0.36, 0.94)	7%	(1.7, 11.5%)	25.1	(7.6, 42.6)	58.0	(16.6, 99.4)

*Peak GMC level (intercept) and annual percentage decrease (slope) after each vaccine dose were estimated assuming at 90% of DTP3 coverage with 95% CI from the model. The mean peak GMC level (IU/ml) was calculated by 10exp(“intercept”). Annual percentage decrease was calculated by (1 − 10exp(“slope”)) x 100%).

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