Immunogenicity and safety of a second booster dose of an acellular pertussis vaccine combined with reduced antigen content diphtheria-tetanus toxoids 10 years after a first booster in adolescence: An open, phase III, non-randomized, multi-center study

Figures & data

Figure 1. Participant flowchart. Footnote: Td group, participants receiving Td as first booster dose in the primary study and Tdap as decennial booster dose (second booster dose) in the current study; Tdap group, participants receiving Tdap booster doses 10 years apart; N, number of participants in each group; M, month; ATP, according-to-protocol.

Table 1. Summary of demographic characteristics (total vaccinated cohort).

	Td group	Tdap group	Total
	N = 37	N = 128	N = 165
Mean age ± SD, years	23.3 ± 2.4	23.5 ± 2.1	23.5 ± 2.1
Median age (minimum–maximum), years	23 (20–29)	23 (20–29)	23 (20–29)
Gender
Male, n (%)	19 (51.4)	71 (55.5)	90 (54.5)
Female	18 (48.6)	57 (44.5)	75 (45.5)
Ethnicity, n (%)
American Hispanic or Latino	4 (10.8)	12 (9.4)	16 (9.7)
Not American Hispanic or Latino	33 (89.2)	116 (90.6)	149 (90.3)
Geographic ancestry, n (%)
Black	1 (2.7)	6 (4.7)	7 (4.2)
White/Caucasian	31 (83.8)	114 (89.1)	145 (87.9)
Oriental	0 (0.0)	1 (0.8)	1 (0.6)
Other	5 (13.5)	7 (5.5)	12 (7.3)

Td group, participants receiving Td as first booster dose in the primary study and Tdap as decennial booster dose (second booster dose) in the currentstudy;Tdapgroup, participants receiving Tdap booster doses 10 years apart; N, number of participants; n (%), number (percentage) of participants in each category; SD, standard deviation.

Table 2. Results of co-primary objectives.

Response to diphtheria and tetanus antigens (according-to-protocol cohort for immunogenicity)
	Td group		Tdap group		Difference in seroprotection rates
	N	n (%)	N	n (%)	Tdap minus Td, % (95% CI)
Diphtheria	35	35 (100)	115	115 (100)	0.00 (−3.25–9.95)
Tetanus	35	35 (100)	115	115 (100)	0.00 (−3.25–9.95)
Response to pertussis antigens (total vaccinated cohort)
	Comparator group^a		Tdap group		Tdap/ Comparator
	N	GMC	N	GMC	GMC ratio (95% CI)
Pertussis toxoid	2884	41.7	124	83.5	2.00 (1.69–2.37)
Filamentous hemagglutinin	685	47.2	124	285.5	6.05 (5.14–7.11)
Pertactin	631	113.0	124	442.6	3.92 (3.22–4.76)

Td group, participants receiving Td as first booster dose in the primary study and Tdap as decennial booster dose (second booster dose) in the current study; Tdap group, participants receiving Tdap booster doses 10 years apart; N, number of participants with available results; n (%), number (percentage) of seroprotected participants (with anti-diphteria/tetanus antibody concentrations ≥0.1 IU/ml); 95% CI, 95% standardized asymptotic confidence interval; GMC, geometric mean antibody concentration.

Note:

^a Infants vaccinated with DTaP in a German efficacy study.³⁰ Given the absence of serologic correlates of protection against pertussis, an immuno-bridging approach was used to assess immune responses to pertussis antigens, by extrapolating the efficacy of a vaccine against pertussis as demonstrated in infants to an older age group, as previously described.²⁹

Values above the non-inferiority margin (the lower limit of the 95% CI ≥-10% for the first co-primary objective and ≥0.67 for the second co-primary objective) are bolded.

Table 3. Immune responses to Tdap vaccination (according-to-protocol cohort for immunogenicity).

		Td group (N = 35)		Tdap group (N = 115)
	Threshold (IU/ml)	% (95% CI)	GMC (95% CI)	% (95% CI)	GMC (95% CI)
Diphtheria
Pre-booster	≥0.1	100 (90.0–100)	1.6 (1.1–2.3)	100 (96.8–100)	1.6 (1.3–2.1)
	≥1	65.7 (47.8–80.9)		60.9 (51.3–69.8)
Post-booster	≥0.1	100 (90.0–100)	6.8 (5.4–8.6)	100 (96.8–100)	6.0 (5.3–6.9)
	≥1	97.1 (85.1–99.9)		100 (96.8–100)
Tetanus
Pre-booster	≥0.1	100 (90.0–100)	1.8 (1.4–2.4)	100 (96.8–100)	1.8 (1.5–2.2)
	≥1	77.1 (59.9–89.6)		74.8 (65.8–82.4)
Post-booster	≥0.1	100 (90.0–100)	9.9 (7.9–12.5)	100 (96.8–100)	9.7 (8.5–11.0)
	≥1	100 (90.0–100)		100 (96.8–100)
PT
Pre-booster	≥2.693	60.0 (42.1–76.1)	5.3 (3.4–8.2)	87.8 (80.4–93.2)	9.9 (8.1–12.2)
Post-booster		100 (90.0–100)	66.2 (50.8–86.2)	100 (96.8–100)	87.3 (74.5–102.4)
FHA
Pre-booster	≥2.046	97.1 (85.1–99.9)	21.7 (13.4–35.4)	100 (96.8–100)	36.9 (31.5–43.3)
Post-booster		100 (90.0–100)	336.2 (250.0–452.2)	100 (96.8–100)	290.5 (252.5–334.2)
PRN
Pre-booster	≥2.187	94.3 (80.8–99.3)	27.8 (13.7–56.3)	100 (96.8–100)	71.6 (56.7–90.6)
Post-booster		100 (90.0–100)	425.5 (281.9–642.3)	100 (96.8–100)	463.3 (390.8–549.3)

Td group, participants receiving Td as first booster dose in the primary study and Tdap as decennial booster dose (second booster dose) in the current study; Tdap group, participants receiving Tdap booster doses 10 years apart; N, number of participants with available results; IU, international units; %, percentage of participants with antibody concentrations at least the pre-specified thresholds; CI, confidence interval; GMC, geometric mean antibody concentration; Pre-booster, before vaccination in the current study; Post-booster, 1 month post-booster vaccination in the current study; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PRN, pertactin.

Table 4. Booster response and alternative booster response to diphtheria and tetanus and booster response to pertussis components, overall and by initial serostatus (according-to-protocol cohort for immunogenicity).

	Td group		Tdap group
	N	% (95% CI)	N	% (95% CI)
Diphtheria
Booster response	35	40.0 (23.9–57.9)	115	40.9 (31.8–50.4)
Alternative booster response	30	70.0 (50.6–85.3)	98	59.2 (48.8–69.0)
Tetanus
Booster response	35	60.0 (42.1–76.1)	115	55.7 (46.1–64.9)
Alternative booster response	32	84.4 (67.2–94.7)	105	82.9 (74.3–89.5)
Pre-vaccination status
PT
S−	14	100 (76.8–100)	14	85.7 (57.2–98.2)
S+ (<4*2.693 IU/mL)	9	88.9 (51.8–99.7)	47	95.7 (85.5–99.5)
S+ (≥4*2.693 IU/mL)	12	91.7 (61.5–99.8)	54	90.7 (79.7–96.9)
Overall	35	94.3 (80.8–99.3)	115	92.2 (85.7–96.4)
FHA
S−	1	100 (2.5–100)	0	—
S+ (<4*2.046 IU/mL)	8	100 (63.1–100)	4	100 (39.8–100)
S+ (≥4*2.046 IU/mL)	26	96.2 (80.4–99.9)	111	90.1 (83.0–94.9)
Overall	35	97.1 (85.1–99.9)	115	90.4 (83.5–95.1)
PRN
S−	2	100 (15.8–100)	0	—
S+ (<4*2.187 IU/mL)	9	100 (66.4–100)	9	100 (66.4–100)
S+ (≥4*2.187 IU/mL)	24	75.0 (53.3–90.2)	106	66.0 (56.2–75.0)
Overall	35	82.9 (66.4–93.4)	115	68.7 (59.4–77.0)

Td group, participants receiving Td as first booster dose in the primary study and Tdap as decennial booster dose (second booster dose) inthecurrentstudy;Tdapgroup, participants receiving Tdap booster doses 10 years apart; N,numberofparticipants with available results; %, percentage of participants with booster response; CI, confidenceinterval;S-,seronegative;S+, seropositive;Overall,participantseitherseropositive or seronegative at pre-vaccination; N, number of participants with both pre- and post-vaccination results available; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PRN, pertactin; IU, international units.

Note:Booster responsesweredefined onemonthpost-vaccinationwithTdapas follows: (i) for diphtheria and tetanus, antibody concentrations ≥0.4 IU/ml in initiallyseronegativeparticipants(i.e.,withpre-vaccinationantibodyconcentrations <0.1 IU/ml) or as a ≥4-fold increaseofantibodyconcentrations ininitially seropositive participants (i.e., with pre-vaccination antibody concentrations ≥ 0.1 IU/ml);(ii)foreachpertussiscomponent,as anincreaseof antibody concentrations of ≥4*assay cut-off in initially seronegative participants (i.e., with pre-vaccinationantibodyconcentrationsbelowtheassaycut-off),asa≥4-foldincreasefrom pre-boosterlevelsininitiallyseropositiveparticipants with concentrations <4*assaycut-off,andasa≥2-foldincreasefrompre-booster levels in initially seropositive participants with concentrations ≥ 4*assay cut-off.

Alternative booster response for diphtheria and tetanus excluded participants with pre-vaccination antibody concentration ≥ 6.0 IU/ml and was defined one month post-vaccinationwithTdapas:(i)antibodyconcentrations ≥0.4 IU/ml in participantswithpre-vaccinationconcentrations<0.1IU/ml;(ii) a≥4-fold increase from pre-booster levels of antibody concentrations in participants with pre-vaccinationconcentrations<1.0 IU/ml;(iii) ≥2-fold increase from pre-booster levels ofantibodyconcentrationsinparticipantswithpre-vaccinationconcentrations between ≥1.0 and < 6.0 IU/ml.

Table 5. Summary of reactogenicity and safety following administration of a Tdap dose (total vaccinated cohort).

	Td group		Tdap group
	n	% (95% CI)	n	% (95% CI)
	N = 36		N = 125
Solicited adverse events
Solicited local adverse events
Pain	21	58.3 (40.8–74.5)	97	77.6 (69.3–84.6)
Grade 3	2	5.6 (0.7–18.7)	6	4.8 (1.8–10.2)
Redness	15	41.7 (25.5–59.2)	47	37.6 (29.1–46.7)
Grade 3	0	0.0 (0.0–9.7)	1	0.8 (0.0–4.4)
Swelling	7	19.4 (8.2–36.0)	30	24.0 (16.8–32.5)
Grade 3	0	0.0 (0.0–9.7)	0	0.0 (0.0–2.9)
Solicited general adverse events
Fatigue	8	22.2 (10.1–39.2)	38	30.4 (22.5–39.3)
Grade 3	0	0.0 (0.0–9.7)	3	2.4 (0.5–6.9)
Gastrointestinal symptoms	1	2.8 (0.1–14.5)	11	8.8 (4.5–15.2)
Grade 3	0	0.0 (0.0–9.7)	2	1.6 (0.2–5.7)
Headache	8	22.2 (10.1–39.2)	40	32.0 (23.9–40.9)
Grade 3	0	0.0 (0.0–9.7)	3	2.4 (0.5–6.9)
Fever (≥37.5°C)	1	2.8 (0.1–14.5)	3	2.4 (0.5–6.9)
Grade 3	0	0.0 (0.0–9.7)	0	0.0 (0.0–2.9)
	N = 37		N = 128
Unsolicited adverse events
Any adverse event	10	27.0 (13.8–44.1)	33	25.8 (18.5–34.3)
Related to vaccination	1	2.7 (0.1–14.2)	5	3.9 (1.3–8.9)
Grade 3	2	5.4 (0.7–18.2)	3	2.3 (0.5–6.7)
Large swelling reactions	0	0.0 (0.0–9.5)	0	0.0 (0.0–2.8)
Serious adverse events	0	0.0 (0.0–9.5)	0	0.0 (0.0–2.8)

Td group, participants receiving Td as first booster dose in the primary study and Tdap asdecennialboosterdose(secondboosterdose) in the current study; Tdap group, participants receiving Tdap booster doses 10 years apart; n (%), number (percentage) of participantsreportingtheadverseeventatleast once; CI, confidence interval; N,numberofparticipantswithdocumenteddoses (for solicited adverse events) or administered doses (for unsolicited adverse events).

Note:Grade3 wasdefinedasdiameter > 50 mm (for redness and swelling), temperature >39.0°C (for fever) and as preventing normal activity for all other adverse events.

Gastrointestinal symptoms include nausea, vomiting, diarrhea and/or abdominal pain.

Large swelling reactions were defined as swelling with a diameter >100 mm, noticeable diffuse swelling or noticeable increase of limb circumference.

Figure 2. Focus on Patient section.