Penta- and hexavalent vaccination of extremely and very-to-moderate preterm infants born at less than 34 weeks and/or under 1500 g: A systematic literature review

Figures & data

Figure 1. PRISMA flow diagram of study selection.

PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses; N, number of records.

Table 1. Characteristics of studies included in the review.

Ref.	Country	Study design	Study population (case definition), N/Comparator, N	Penta- or hexavalent vaccine (Trade name)	Parameters evaluated
					Immunogenicity	Efficacy	Effectiveness	Safety	Impact	Compliance	Completion
Pentavalent vaccines
Bary-Weisberg, 2021^Citation30	Israel	National cohort study	LBW (<2500 g), N = 13895 2000–2499 g, N = 9661 1500–1999 g, N = 2629 1000–1499 g, N = 1025 <1000 g, N = 580 NBW (≥2500g), N = 167647	DTaP-IPV-Hib (NS)	✕	✕	✕	✕	✕	✔	✕
Klein, 2010^Citation31	US	Open-label prospective study	Preterm (≤33 weeks), N = 33 Full-term (≥37 weeks), N = 50	DTaP-IPV-HBV (Pediarix)	✔	✕	✕	✔	✕	✕	✕
Kulkarni-Munje, 2021^Citation32	India	Prospective observational study	Preterm (28–32 weeks), N = 33 Full-term (>36 weeks), N = 80	DTwP-HBV-Hib (NS)	✔	✕	✕	✕	✕	✕	✕
Lee, 2006^Citation33	Canada	Retrospective cohort study	Preterm (≤32 weeks), vaccinated, N = 124 Preterm (≤32 weeks), not vaccinated, N = 124	DTwP-IPV-Hib (NS, before July 1, 1997), N = 34 or DTaP-IPV-Hib (NS, after July 1, 1997), N = 90	✕	✕	✕	✔	✕	✕	✕
Ochoa, 2015^Citation34	Peru	Prospective cohort study	Preterm (<37 weeks and <1500 g), N =  198 <1000 g, N = 41 1000–<1500 g, N  = 157	DTP-Hib-HBV (NS)	✕	✕	✕	✕	✕	✔	✔
Omeñaca, 2011a^Citation35	Spain	Phase IIIb open, controlled study	Preterm: <31 weeks, N = 56 Full-term: >36 weeks, N = 150	DTaP-HBV-IPV (Infanrix penta)	✔	✕	✕	✔	✕	✕	✕
Hexavalent vaccine
Czajka, 2017^Citation36	Poland	Retrospective observational study	Preterm (<30 weeks and <1500 g), N  = 61 hospitalized, N  =  42 not hospitalized, N = 19	DTaP-HBV-IPV/Hib (Infanrix hexa)	✕	✕	✕	✔	✕	✔	✕
Faldella, 2007^Citation37	Italy	Prospective observational study	Preterm (<31 weeks), N = 45	DTaP-IPV-Hib-HBV (Hexavac)	✕	✕	✕	✔	✕	✔	✕
Omeñaca, 2010^Citation38	Spain	Open-label study	Preterm*: 31–33 weeks, N = 24 28–30 weeks, N = 21 24–27 weeks, N = 20 <1500 g, N= 53 <1000 g, N = 25 Full-term: ≥37 weeks, N = 92	DTaP-HBV-IPV/Hib (Infanrix hexa)	✔	✕	✕	✕	✕	✕	✕
Vázquez, 2008^Citation39	NR	Open-label study	Preterm (24–36 weeks), N = 169 VLBW (<1500 g), N = 84 LBW (1500–<2000 g), N = 85	DTaP-HBV-IPV/Hib (Infanrix hexa)	✔	✕	✕	✔	✕	✕	✕
Penta- and hexavalent vaccines
Flatz-Jequier, 2008^Citation40	Switzerland	Retrospective observational study	Preterm (<32 weeks) and VLBW (NS) hospitalized, N = 135 not hospitalized, N = 308	DTaP-IPV/Hib (Infanrix IPV/Hib) or DTaP-HBV-IPV/Hib (Infanrix hexa)	✕	✕	✕	✔	✕	✕	✕
Furck, 2010^Citation41	Germany	Prospective observational study	Preterm (NS) and VLBW (<1500 g), N  = 473	DTaP-IPV/Hib (Infanrix IPV/Hib), N = 162/DTaP-HBV-IPV/Hib (Infanrix hexa), N = 311	✕	✕	✕	✔	✕	✕	✕
Omeñaca, 2011b^Citation42	Spain, Greece	Prospective observational study	Preterm: 27–<31 weeks, N = 50 Full-term: >36 weeks, N = 149	Primary: DTaP-HBV-IPV/Hib (Infanrix hexa) Booster: DTaP-IPV/Hib (Infanrix IPV/Hib)	✔	✕	✕	✕	✕	✕	✕
Ziegler, 2010^Citation43	Germany	Cross-sectional study	Preterm (NS) and VLBW (<1500 g), N = 318	hexavalent (NS)/pentavalent (NS)	✕	✕	✕	✕	✕	✔	✔

aP, acellular pertussis; D, diphtheria; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; IPV, inactivated poliovirus vaccine; LBW, low birthweight; N, number of infants; NBW, normal birthweight; NR, not reported; NS, not specified; Ref., reference; T, tetanus; US, United States; VLBW, very low birthweight; wP, whole-cell pertussis.

*Groups of preterm infants stratified according to gestational age and birthweight overlap.

✔, data present; ✕, data not present.

Table 2. Seroconversion/Seropositivity rates after penta- or hexavalent vaccination.

Ref.	Study vaccine Co-administration HBV birth dose	Dose/Timing of sampling	Study population (case definition), N	Seroconversion/Seropositivity rate (%)
				Anti-HBs, ≥ 10 mIU/mL	Anti-PRP, ≥ 0.15 µg/mL	Anti-D, ≥ 0.1 IU/mL	Anti-T, ≥ 0.1 IU/mL	Anti-PV1, ≥ 1:8 dilution	Anti-PV2, ≥ 1:8 dilution	Anti-PV3, ≥ 1:8 dilution	Anti-PT, ≥ 5 ELU/mL	Anti-FHA, ≥ 5 ELU/mL	Anti-PRN, ≥ 5 ELU/mL
Pentavalent vaccines
Klein, 2010^Citation31	DTaP-IPV-HBV (Pediarix) Co-administration: pneumococcal (PCV7, Prevnar) and Hib (ActHIB) HBV birth dose: NR	Post-primary, 1 month after 3^rd dose	Preterm (≤33 weeks), N = 22	-	-	-	-	100	100	100	-	-	-
			Full-term (≥37 weeks), N  = 28	-	-	-	-	100	100	100	-	-	-
Kulkarni-Munje, 2021^Citation32	DTwP-HBV-Hib (NS) Co-administration: NR HBV birth dose: infants weighing ≥2000 g (N = 114/193)	Post-primary, 1 month after 3^rd dose	Preterm (28–32 weeks), N = 24	91.7^#	95.8	91.7	100	-	-	-	75.0^¶	-	-
			Full-term (>36 weeks), N  = 54	100^#	98.1	98.1	100	-	-	-	74.1^¶	-	-
Omeñaca, 2011b^Citation42	Booster: DTaP-IPV/Hib (Infanrix IPV/Hib); for data on primary vaccination see hexavalent vaccinations Co-administration: PHiD-CV (Synflorix), 3-dose primary+booster HBV birth dose: NR	Post-booster, 1 month after booster dose	Preterm (27–30 weeks), N  = 3–21^‡	-	100	100	100	100	100	100	100	100	100
			Full-term (>36 weeks), N  = 20–60^‡	-	100	100	100	100	100	100	100	100	100
Omeñaca, 2011a^Citation35	Primary: DTaP-HBV-IPV (Infanrix penta) Co-administration: Hib-MenC-TT (Menitorix) and PCV7 (Prevenar); ORV was permitted at any time HBV birth dose: 2 infants	Post-primary, 1 month after 3^rd dose	Preterm (<31 weeks), N = 40–44^‡	97.5, n.s.	-	-	-	-	-	-	-	-	-
			Full-term (>36 weeks), N = 129–142^‡	100	-	-	-	-	-	-	-	-	-
Hexavalent vaccines
Omeñaca, 2010^Citation38	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	Post-primary, 1 month after 3^rd dose	Full-term (≥37 weeks), N  = 84	95.2	-	-	-	-	-	-	-	-	-
			Preterm (31–33 weeks), N = 24	83.3	-	-	-	-	-	-	-	-	-
			Preterm (28–30 weeks), N = 20	100	-	-	-	-	-	-	-	-	-
			Preterm (24–27 weeks), N = 20	100	-	-	-	-	-	-	-	-	-
			Preterm (≥1000–<1500 g), N  = 26	100	-	-	-	-	-	-	-	-	-
			Preterm (<1000 g), N  = 25	92	-	-	-	-	-	-	-	-	-
		Post-booster, 1 month after booster	Full-term (≥37 weeks), N =  68	98.5	-	-	-	-	-	-	-	-	-
			Preterm (31–33 weeks), N  = 23	78.3	-	-	-	-	-	-	-	-	-
			Preterm (28–30 weeks), N  =  18	100	-	-	-	-	-	-	-	-	-
			Preterm (24–27 weeks), N = 18	100	-	-	-	-	-	-	-	-	-
Omeñaca, 2011b^Citation42	Primary: DTaP-HBV-IPV/Hib (Infanrix hexa); for data on booster vaccination see pentavalent vaccinations Co-administration: PHiD-CV (Synflorix), 3-dose primary+booster HBV birth dose: NR	Post-primary, 1 month after primary vaccination	Preterm (27–30 weeks), N = 8–18^‡	100	100	100	100	100	100	90.9	100	100	100
			Full-term (>36 weeks), N = 12–63^‡	100	100	100	100	100	100	100	100	100	100
Vázquez, 2008^Citation39	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	Post-primary, 1 month after 3^rd dose	Preterm (24–36 weeks) and VLBW (<1500 g), N = 76–79^‡	93.7	98.7	98.7	100	100	100	100	92.4	98.7	100
			Preterm (24–36 weeks) and LBW (1500–2000 g), N = 78–82^‡	94.9	98.7	100	100	100	100	100	96.3	96.3	96.3
		Pre-booster, immediately before booster dose	Preterm (24–36 weeks) and VLBW (<1500 g), N = 42–62^‡	61.0	63.9	61.7^†	61.3	95.3	97.6	93.0	-	-	-
			Preterm (24–36 weeks) and LBW (1500–2000 g), N  = 49–57^‡	69.6	78.9	55.6^†	73.2	98.0	92.0	95.9	-	-	-
		Post-booster, 1 month after booster dose	Preterm (24–36 weeks) and VLBW (<1500 g), N  =  47–62^‡	88.7	100	98.4	100	100	100	100	98.4	96.8	96.8
			Preterm (24–36 weeks) and LBW (1500–2000 g), N = 49–57^‡	96.5	100	100	100	100	100	100	98.2	100	100

aP, acellular pertussis; D, diphtheria; ELU, enzyme-linked immunosorbent assay units; FHA, filamentous hemagglutinin; HBs, hepatitis B surface antigen; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; Hib-MenC-TT, combined Hib-Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine; IPV, inactivated poliovirus vaccine; IU, international units; LBW, low birthweight; N, number of infants; NR, not reported; n.s., not significant; NS, not specified; ORV, oral rotavirus vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; PHiD-CV, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; PRN, pertactin; PRP, polyribosylribitol phosphate; PT, pertussis toxoid; PV, poliovirus; Ref., reference; T, tetanus; VLBW, very low birthweight; wP, whole-cell pertussis.

*/n.s., Statistical significance/no statistical significance between preterm and comparator groups. Where nothing is stated, significance was not reported in the article. If more than two groups are presented, the overall significance level is indicated.

^#None of the preterm infants received an HBV birth dose; 75 out of 80 full-term infants received an HBV birth dose.

^‡Number of infants with available data differed per immunogenicity outcome. Therefore, a range was provided as denominator.

^¶>22 units (U)/mL (%); discordance in the article: text states >22 U/mL twice, vs. 20 U/mL in the table.

^†Percentage of infants with anti-D antibody concentration ≥0.1 IU/mL by enzyme-linked immunosorbent assay (ELISA) or ≥0.016 IU/mL for pre-booster samples.

Table 3. Antibody GMCs/GMTs after penta- or hexavalent vaccination and overall immunogenicity conclusion by the authors.

Ref.	Study vaccine Co-administration HBV birth dose	Dose/Timing	Study population (case definition), N	Parameter										Overall immunogenicity conclusions/interpretation/summary by the authors^#
				Anti-HBs, mIU/mL	Anti-PRP, µg/mL	Anti-D, IU/mL	Anti-T, IU/mL	Anti-PV1	Anti-PV2	Anti-PV3	Anti-PT, ≥5 ELU/mL	Anti-FHA, ≥5 ELU/mL	Anti-PRN, ≥5 ELU/mL
Pentavalent vaccines
Klein, 2010^Citation31	DTaP-IPV-HBV (Pediarix) Co-administration: pneumococcal (PCV7, Prevnar) and Hib (ActHIB) HBV birth dose: NR	Post-primary, 1 month after 3^rd dose	Preterm (≤33 weeks), N = 22	-	-	-	-	1338, *	1172, n.s.	1350, n.s.	-	-	-	Although preterm infants developed seroprotective** titers to all three PV serotypes, the GMT to PV type 1 was significantly lower in preterm infants (no significant differences in GMTs to poliovirus types 2 and 3 between the two groups).
			Full-term (≥37 weeks), N =  28	-	-	-	-	2609	1728	1666	-	-	-
Kulkarni-Munje, 2021^Citation32	DTwP-HBV-Hib (NS) Co-administration: NR HBV birth dose: Infants weighing ≥2000 g (N = 114/193)	Post-primary, 1 month after 3^rd dose	Preterm (28–32 weeks), N = 24	253.8*	1.6*	0.5, n.s.	1.4, n.s.	-	-	-	29.2^¶, n.s.	-	-	Irrespective of gestational age, all preterm infants developed adequate antibody response against T and D and protective** but lower antibody levels for Hib and HBV as compared to their full-term counterparts. Suboptimal response to PT in all the infant groups emerged as a major concern.
			Full-term (>36 weeks), N = 54	306.8	7.7	0.7	1.8	-	-	-	30.3^¶	-	-
Omeñaca, 2011b^Citation42	Booster: DTaP-IPV/Hib (Infanrix IPV/Hib); for data on primary vaccination see hexavalent vaccinations Co-administration: PHiD-CV (Synflorix), 3-dose primary+booster HBV birth dose: NR	Post-booster, 1 month after booster dose	Preterm (27–30 weeks), N = 3–21^‡	-	33.731	6.252	12.374	512.0	1290.1	574.7	38.4	250.3	259.7	One month after booster vaccination, all subjects were seroprotected**/seropositive for antibodies against the antigens. Antibody GMCs/GMTs were within the same ranges across groups and in line with previous experience with these DTaP-based combination vaccines when administered separately.
			Full-term (>36 weeks), N =  20–60^‡	-	38.713	6.730	13.026	1327.9	1116.9	1692.5	45.1	229.0	264.5
Omeñaca, 2011a^Citation35	Primary: DTaP-HBV-IPV (Infanrix penta) Co-administration: Hib-MenC-TT (Menitorix) and PCV7 (Prevenar); ORV was permitted at any time HBV birth dose: 2 infants	Post-primary, 1 month after 3^rd dose	Preterm (<31 weeks), N =  40–44‡	264.3*	-	-	-	-	-	-	-	-	-	No difference between groups in the percentage of subjects reaching either the 10 mIU/mL or 100 mIU/mL cut-offs was observed. The post-dose 3 anti-HBs GMC was significantly lower in the preterm group than in the full-term group.
			Full-term (>36 weeks), N = 129–-142‡	586.6	-	-	-	-	-	-	-	-	-
Hexavalent vaccines
Omeñaca, 2010^Citation38	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	Post-primary, 1 month after 3^rd dose	Full-term (≥37 weeks), N = 84	867.1	-	-	-	-	-	-	-	-	-	Preterm babies responded well immunologically and similarly to children born at full term. The response in terms of seroprotection** rates was not influenced by gestational age or birthweight.
			Preterm (31–33 weeks), N = 24	418.0	-	-	-	-	-	-	-	-	-
			Preterm (28–30 weeks), N = 20	1044.5	-	-	-	-	-	-	-	-	-
			Preterm (24–27 weeks), N = 20	364.8	-	-	-	-	-	-	-	-	-
			Preterm (≥1000–<1500 g), N = 26	1294.5	-	-	-	-	-	-	-	-	-
			Preterm (<1000g), N = 25	250.7	-	-	-	-	-	-	-	-	-
		Post-booster, 1 month after booster	Full-term (≥37 weeks), N = 68	1965.0	-	-	-	-	-	-	-	-	-
			Preterm (31–33 weeks), N = 23	1127.2	-	-	-	-	-	-	-	-	-
			Preterm (28–30 weeks), N = 18	3555.9	-	-	-	-	-	-	-	-	-
			Preterm (24–27 weeks), N = 18	1054.0	-	-	-	-	-	-	-	-	-
Omeñaca, 2011b^Citation42	Primary: DTaP-HBV-IPV/Hib (Infanrix hexa); for data on booster vaccination see pentavalent vaccinations Co-administration: PHiD-CV (Synflorix), 3-dose primary+booster HBV birth dose: NR	Post-primary, 1 month after primary vaccination	Preterm (27–30 weeks), N = 8–18^‡	431.9	4.031	2.495	7.745	271.3	341.7	248.4	41.9	188.6	127.6	One month after primary vaccination, all subjects were seroprotected**/seropositive for antibodies against the antigens, except one subject in preterm group I (group not included in this review) after primary vaccination who was not seroprotected** against PV type 3. Antibody GMCs/GMTs were within the same ranges across groups and in line with previous experience with these DTaP-based combination vaccines when administered separately.
			Full-term (>36 weeks), N = 12–63^‡	462.9	7.952	3.077	7.695	230.1	194.4	384.8	47.3	163.1	119.1
Vázquez, 2008^Citation39	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	Post-primary, 1 month after 3^rd dose	Preterm (24–36 weeks) and VLBW (<1500 g), N = 76–79^‡	444.1, n.s.	2.104, n.s.	1.072, n.s.	2.722, n.s.	695.0, n.s.	563.5, n.s.	757.9 *	25.5 *	84.9, n.s.	110.1, n.s.	No significant differences were noted between the VLBW and LBW groups (birthweight below or above 1.5 kg) in terms of seroprotection** or vaccine response rates except for anti-PRP antibody concentrations ≥ 1.0 µg/mL observed in 65.4% of VLBW infants and 80.8% of LBW infants after primary vaccination.
			Preterm (24–36 weeks) and LBW (1500–2000 g), N = 78–82^‡	576.4	2.503	1.048	2.688	903.1	658.3	1322.1	36.6	95.5	115.7
		Pre-booster, immediately before booster dose	Preterm (24–36 weeks) and VLBW (<1500 g), N = 42–62^‡	23.5, n.s.	0.331, n.s.	0.083, n.s.	0.153, n.s.	67.8, n.s.	50.8, n.s.	45.2, n.s.	3.3, n.s.	23.1, n.s.	8.2, n.s.
			Preterm (24–36 weeks) and LBW (1500–2000 g), N = 49–57^‡	32.7	0.405	0.070	0.142	86.3	69.6	88.7	3.6	25.8	11.5
		Post-booster, 1 month after booster dose	Preterm (24–36 weeks) and VLBW (<1500 g), N = 47–62^‡	1026.5 n.s.	60.515 n.s.	2.522, n.s.	8.481, n.s.	1240.3 n.s.	1395.5 n.s.	1894.4 n.s.	44.4, n.s.	504.2, n.s.	312.5, n.s.
			Preterm (24–36 weeks) and LBW (1500–2000 g), N = 49–57^‡	1785.6	51.120	3.762	9.837	1868.0	1560.5	2385.3	56.1	616.3	418.3

aP, acellular pertussis; D, diphtheria; ELU, enzyme-linked immunosorbent assay units; FHA, filamentous hemagglutinin; GMC/T, geometric mean antibody concentration/titer; HBs, hepatitis B surface antigen; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; Hib-MenC-TT, combined Hib-Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine; IPV, inactivated poliovirus vaccine; IU, international units; LBW, low birthweight; N, number of infants; NR, not reported; n.s., not significant; NS, not specified; ORV, oral rotavirus vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; PHiD-CV, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; PRN, pertactin; PRP, polyribosylribitol phosphate; PT, pertussis toxoid; PV, poliovirus; Ref., reference; T, tetanus; VLBW, very low birthweight; wP, whole-cell pertussis.

^#Overall conclusion/interpretation/summary by the authors is also based on data presented in Table 2.

*/n.s. Statistical significance/no statistical significance between preterm and comparator groups. Where nothing is stated, significance was not reported in the article. If more than two groups are presented, the overall significance level is indicated.

**Seroprotection thresholds represent antibody levels that have been demonstrated to confer protection in the full-term infant population; their protective effect was however not assessed in preterm infants.

^¶unit (U)/mL.

^‡Number of infants with available data differed per immunogenicity outcome. Therefore, a range was provided as denominator.

Table 4. Overall, serious, and cardiorespiratory adverse events after penta- and hexavalent vaccines.

Ref.	Follow-up	Definitions	Study vaccine Co-administration HBV birth dose	Dose	Study population (case definition), N/ Comparator, N	Parameter (%)				Conclusions/interpretation/summary by the authors
						Overall, ≥1 AEs (^asolicited, ^bunsolicited)	Overall SAEs (^avaccine-related, ^bnot related)	Fatal AEs (^avaccine-related, ^bnot related, ^cpossibly related)	Cardiorespiratory AEs (^aapnea, ^bbradycardia, ^cincrease in cardiorespiratory AEs)
Pentavalent vaccines
Klein, 2010^Citation31	Medically attended events Emergency department visits Hospitalizations within 30 days post-vaccination	Medically attended events: fever, seizures, rash, swelling, and irritability (from electronic records)	DTaP-IPV-HBV (Pediarix) Co-administration: pneumococcal (PCV7, Prevnar) and Hib (ActHIB) HBV birth dose: NR	Overall primary	Preterm (≤33 weeks), N = 33	-	-	-	-	No medically attended events for fever, seizure, or swelling for either preterm or term infants after any vaccine dose. No hospitalizations within 30 days for either group.
					Full-term (≥37 weeks), N = 50	-	-	-	-
Lee, 2006^Citation33	Frequency of cardiorespiratory AEs (recorded 72 h pre-immunization and 72 h post-immunization)	Apnea: ≥20 s cessation of respiration Bradycardia: heart rate <100/min for ≥20 s Desaturation: oxygen saturation ≤85% Increase in cardiorespiratory AE: 1) resurgence of ABD (>1 ABD within 72 h post-immunization, with no ABD 72 h pre-immunization), or 2) increased ABD (a 25% increase in the number of ABD events within 72 h post-immunization vs. 72 h pre-immunization)	DTwP-IPV-Hib (NS, until July 1, 1997, N = 34) or DTaP-IPV-Hib (NS, after July 1, 1997, N = 90) Co-administration: NR HBV birth dose: NR	1^st	Preterm (≤32 weeks), received 1^st dose prior to discharge from NICU N = 124^†	-	-	-	45.2	There is an increase in cardiorespiratory AEs in the 72 h following the first dose of DTP-IPV-Hib in preterm infants discharged from NICU.
Omeñaca, 2011a^Citation35	Specific local and general solicited AEs (recorded on diary cards for 4 days after each vaccination) Unsolicited AEs (recorded on diary cards for 31 days after each vaccination) SAEs (recorded from enrollment to 1 month after the booster dose)	-	Primary: DTaP-HBV-IPV (Infanrix penta) Co-administration: Hib-MenC-TT (Menitorix) and PCV7 (Prevenar); ORV was permitted at any time HBV birth dose: 2 infants	Overall primary	Preterm (<31 weeks), N = 56	5.4^b	-^‡	0.0	1.8^a	NR (primary objective was on immunogenicity and safety of Hib-MenC-TT, when co-administered with other vaccines)
					Full-term (>36 weeks), N = 150	32.0^b	-^‡	0.7^b	-
Hexavalent vaccines
Czajka, 2017^Citation36	Monitoring in the hospital for 2 days after vaccination	Cardiorespiratory AEs: any adverse symptoms such as bradycardia, apnea, or drops in saturation	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	Overall primary	Preterm (<1500 g and <30 weeks), hospitalized (vaccination at neonatal ward), N = 42	-	0.0^a	-	0.0	The children vaccinated in the hospital setting did not develop any adverse symptoms such as bradycardia, apnea, or drops in saturation. Neither of the subgroups experienced any SAEs related to vaccination.
	Reported by parents/legal guardians	-		Overall primary	Preterm (<1500 g and <30 weeks), not hospitalized (vaccination at clinic), N = 19	-	0.0^a	-	NR
Faldella, 2007^Citation37	Continuous monitoring (for 3 days before and 3 days after vaccination)	Cardiorespiratory AEs: apnea, bradycardia and desaturation Apnea: cessation of respiration for ≥20 s, associated with bradycardia and/or desaturation or cyanosis Desaturation: O2 saturation ≤88% Bradycardia: ≤100/min for ≥20 s, and associated with apnea and/or desaturation or cyanosis	DTaP-IPV-Hib-HBV (Hexavac) Co-administration: None HBV birth dose: No	1^st	Preterm (<31 weeks), vaccinated at NICU N = 45	-	-	-	11.1	DTaP-IPV-Hib-HBV vaccine can cause AEs as apnea, bradycardia and desaturation in very preterm infants. These mainly affect babies with chronic disease still in therapy. Hospitalized healthy preterm infants without chronic disease and therapy seem to be less vulnerable to cardiorespiratory AEs.
Vázquez, 2008^Citation39	SAEs: throughout the entire primary vaccination and booster vaccination phases	-	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	Overall primary	Preterm (24–36 weeks, <2000 g), N = 169	-	≥1 SAE: 20.1	0.6^b 0.6^c	-	The vaccine was well tolerated in preterm infants of low birthweight.
				Booster	Preterm (24–36 weeks, <1500 g), N = 63	-	3.2^b	-	-
					Preterm (24–36 weeks, 1500–2000 g), N = 61	-	4.9^b	-	-
Penta- and hexavalent vaccines
Flatz-Jequier, 2008^Citation40	Data was retrieved from medical records and nurses’ charts for 24 h before and 48 h after vaccination	Cardiorespiratory AEs: apnea, bradycardia or desaturation Apnea: cessation of respiration for ≥20 s Bradycardia: drop in heart rate to <100/min Desaturation: O2 saturation ≤90%	DTaP-IPV/Hib (Infanrix IPV/Hib)/DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: alone, with a pneumococcal vaccine (PCV7, Prevenar), or with respiratory syncytial virus monoclonal antibodies, according to Swiss recommendations HBV birth dose: NR	1^st	Preterm (<32 weeks), VLBW (NS), hospitalized (at the time of vaccination), N = 135	-	-	-	25.2	The third dose was tolerated well by all infants.
					Preterm (<32 weeks), VLBW (NS), not hospitalized (at the time of vaccination), N = 308	-	-	-	0.0
				2^nd	Preterm (<32 weeks), VLBW (NS), hospitalized (at the time of vaccination), N = 135	-	-	-	4.4
Furck, 2010^Citation41	Up to 48 h (recorded by the nurse)	Cardiorespiratory AEs: apnea and bradycardia Apnea: cessation of respiration for ≥20 s Bradycardia: decrease in heart rate to ≤90/min for ≥20 s, requiring intervention In infants already suffering from single apnea/bradycardia events before immunization, only an increase in frequency was considered as an AE	DTaP-IPV/Hib (Infanrix IPV/Hib, N = 162)/DTaP-HBV-IPV/Hib (Infanrix hexa, N = 311) Co-administration: HBV (Gen H-B-Vax K pro infantibus, N = 162), pneumococcal (PCV7, Prevenar, N = 260) HBV birth dose: NR	1^st	Preterm (NS) and VLBW (<1500 g), 1^st dose during primary hospital stay N = 473	-	-	-	10.8^a 10.8^b	Between the vaccine groups there were no significant differences for local reactions or fever. Apnea and bradycardia appeared significantly more often in group C (Infanrix + Prevenar) than in the other two groups.
			DTaP-IPV/Hib (Infanrix IPV/Hib) Co-administration: HBV (Gen H-B-Vax K pro infantibus) HBV birth dose: NR		Preterm (NS) and VLBW (<1500 g), N = 162	-	-	-	6.2^a 5.7^b
			DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: none HBV birth dose: NR		Preterm (NS) and VLBW (<1500 g), N = 51	-	-	-	3.9^a 9.8^b
			DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: pneumococcal (PCV7, Prevenar) HBV birth dose: NR		Preterm (NS) and VLBW (<1500 g), N = 260	-	-	-	15.0^a 14.2^b
			DTaP-IPV/Hib (Infanrix IPV/Hib, N = 162)/DTaP-HBV-IPV/Hib (Infanrix hexa, N = 311) Co-administration: HBV (Gen H-B-Vax K pro infantibus, N = 162), pneumococcal (PCV7, Prevenar, N = 260) HBV birth dose: NR	2^nd	Preterm (NS), VLBW (<1500 g), 2^nd dose during hospital stay N = 47	-	-	-	4.3^a,b

ABD, apnea, bradycardia, desaturation; AE, adverse event; aP, acellular pertussis; D, diphtheria; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; Hib-MenC-TT, combined Hib-Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine; IPV, inactivated poliovirus vaccine; N, number of infants; NICU, neonatal intensive care unit; NS, not specified; NR, not reported; ORV, oral rotavirus vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; Ref., reference; SAE, serious adverse event; T, tetanus; VLBW, very low birthweight; wP, whole-cell pertussis.

^†All identified infants had a previous history of typical apnea or bradycardia of prematurity.

^‡SAEs are reported for different follow-up periods. For those periods, the denominator for preterm/full-term infants included in the safety analysis is not specified, and only counts (no proportions) are reported. Therefore, these results have not been included in this table.

Table 5. Compliance with penta- and hexavalent vaccine schedules.

Ref.	Study population (case definition), N	Study vaccine	Dose	Recommendations for timely vaccination	Age at immunization (mean ± SD)	Vaccinated according to recommendations, %	Vaccinated earlier than recommended, %	Vaccinated later than recommended, %	Author conclusions
Pentavalent vaccines
Bary-Weisberg, 2021^Citation30	NBW (≥2500 g), N = 167,647	DTaP-IPV-Hib (NS)	1^st	2 (4, 6, 12) months	-	90.0^†	-	10.0^†	LBW infants were significantly more likely to receive the first dose of DTaP-Hib-IPV in delay, compared to 90% of NBW infants who received the first dose on time. Besides this initial delay in providing protection, all future doses in the series were subsequently delayed.
	LBW (1000 g–1499 g), N = 1025		1^st	2 (4, 6, 12) months	-	81.0^†	-	19.0^†
	LBW (<1000 g), N = 580		1^st	2 (4, 6, 12) months	-	52.0^†	-	48.0^†
Ochoa, 2015^Citation34	Preterm (<37 weeks and <1500 g), N = 198	DTP-Hib-HBV (NS)	1^st	2 months	3.4 ± 1.2 months	-	-	-	VLBW infants are vaccinated with a delay.
			2^nd	4 months	5.5 ± 1.3 months	-	-	-
			3^rd	6 months	7.7 ± 1.3 months	-	-	-
Hexavalent vaccines
Czajka, 2017^Citation36	Preterm (<30 weeks and <1500 g), N = 61	DTaP-HBV-IPV/Hib (Infanrix hexa)	1^st	6–8 weeks (42–56 days)	88.2 ± 37.2 days	-	-	-	The majority received their first DTaP vaccinations after the recommended period. The mean age at first DTaP vaccination expressed in days differed significantly between the two subgroups (higher in not hospitalized infants)^.‡
			2^nd	ND; recommendations of the Polish Neonatal Society: 3–4 months^¶	150.2 ± 40.7 days	-	-	-
			3^rd	ND; recommendations of the Polish Neonatal Society: 5–6 months^¶	248.1 ± 162.3 days	-	-	-
	Preterm (<30 weeks and <1500 g), hospitalized (vaccinated at neonatal wards), N = 42		1^st	6–8 weeks (42–56 days)	74.1 ± 21.5 days	-	-	-
			2^nd	ND; recommendations of the Polish Neonatal Society: 3–4 months^¶	139.6 ± 29.3 days	-	-	-
			3^rd	ND; recommendations of the Polish Neonatal Society: 5–6 months^¶	214.0 ± 73.9 days	-	-	-
	Preterm (<30 weeks and <1500 g), not hospitalized (vaccinations at clinic), N = 19		1^st	6–8 weeks (42–56 days)	119.4 ± 45.5 days	-	-	-
			2^nd	ND; recommendations of the Polish Neonatal Society: 3–4 months^¶	173.5 ± 52.4 days	-	-	-
			3^rd	ND; recommendations of the Polish Neonatal Society: 5–6 months^¶	323.7 ± 258.2 days	-	-	-
Faldella, 2007^Citation37	Preterm (<31 weeks), N = 45	DTaP-IPV-Hib-HBV (Hexavac)	1^st	Between 60–90 days	-	48.8	37.7	13.3	-
Penta- and hexavalent vaccines
Ziegler, 2010^Citation43	Preterm (<1500 g), N = 318	pentavalent (NS, N = 16) or hexavalent (NS, N = 302)	1^st	ND; STIKO recommendations: 2 months^§	3.1 months	36.2	6.9	56.9	Vaccination was clearly delayed (according to STIKO recommendations) in the studied population.
			2^nd	ND; STIKO recommendations: 3 months^§	4.5 months	26.4	-	-
			3^rd	ND; STIKO recommendations: 4 months^§	6.0 months	21.7	-	-
			4^th	ND; STIKO recommendations: 11–14 months^§	15.7 months	47.3	-	-

aP, acellular pertussis; D, diphtheria; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; IPV, inactivated poliovirus vaccine; LBW, low birthweight; N, number of infants; NBW, normal birthweight; ND, not described; NS, not specified; Ref., reference; SD, standard deviation; STIKO, Ständige Impfkommission des Robert Koch-Institutes Berlin; T, tetanus; VLBW, very low birthweight.

^†Compliance data were extracted from a graph (Figure 3) in the article and therefore represent approximate percentages. The percentage for delayed vaccination includes mild delay (>1 month and ≤3 months), moderate delay (>3 months and ≤6 months), severe delay (>6 months) and unvaccinated (at 24 months).

^‡Conclusion included 61 infants who received DTaP-HBV-IPV/Hib (Infanrix hexa) and 48 who received DTaP (Infanrix/Tripacel).

^¶Data on Polish immunization schedule was retrieved from https://immunizationdata.who.int/pages/schedule-by-country/pol.html?DISEASECODE=&TARGETPOP_GENERAL= (date: 24/02/2022); https://www.sabin.org/sites/sabin.org/files/documents/poland_ip.pdf (date: 24/02/2022)..

^§Children included in the study were born in 2004–2007, the STIKO recommendations for those years were retrieved from.

https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2004/Ausgabenlinks/30_04.pdf?__blob=publicationFile (date: 24/02/2022), https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2005/Ausgabenlinks/30_05.pdf?__blob=publicationFile (date: 24/02/2022), https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2006/Ausgabenlinks/30_06.pdf?__blob=publicationFile (date: 24/02/2022), https://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2007/Ausgabenlinks/30_07.pdf?__blob=publicationFile (date: 24/02/2022).

Table

Ref.	Follow-up	Definitions	Study vaccine Co-administration HBV birth dose	Dose	Study population (case definition), N/Comparator, N	Pain, any (%)	Pain, Grade 3%)	Redness, any (%)	Redness, Grade 3/>20 mm (%)	Swelling, any (%)	Swelling, Grade 3/>30 mm^a (%)
Pentavalent vaccines
Omeñaca, 2011a^35	Recorded on diary cards for 4 days after each dose	Grade 3 pain: cried when limb was moved/spontaneously painful Grade 3 redness and swelling: diameter > 30 mm	Primary: DTaP-HBV-IPV (Infanrix penta) Co-administration: Hib-MenC-TT (Menitorix) and pneumococcal (PCV7, Prevenar); ORV was permitted at any time HBV birth dose: 2 infants	Overall primary	Preterm (<31 weeks), N = 56	69.6	7.1	50.0	0.0	60.7	1.8
					Full-term (>36 weeks), N = 150	60.0	5.3	78.7	9.3	69.3	6.0
Hexavalent vaccines
Vázquez, 2008^39	Reported by parents via diary cards on the day of each vaccination and for 3 subsequent days	Grade 3 pain: crying when limb was moved Grade 3 redness and swelling: diameter > 20 mm	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	1^st	Preterm (24–36 weeks, 1500–2000 g), N = 85	51.8	11.8	25.0	1.2	30.6	2.4
					Preterm (24–36 weeks, <1500 g), N = 84	29.8	2.4	19.0	1.2	26.2	4.8
				2^nd	Preterm (24–36 weeks, 1500–2000 g), N = 84	46.4	4.8	32.1	2.4	34.5	1.2
					Preterm (24–36 weeks, <1500 g), N = 81	42.9	10.7	33.3	6.0	27.4	3.6
				3^rd†	Preterm (24–36 weeks, 1500–2000 g), N = 84	36.9	7.1	31.0	2.4	35.7	4.8
					Preterm (24–36 weeks, <1500 g), N = 63	34.6	2.5	30.9	3.7	27.2	4.9
				Booster^†	Preterm (24–36 weeks, 1500–2000 g), N = 61	41.0	1.6	26.2	9.8	21.3	6.6
					Preterm (24–36 weeks, <1500 g), N = 63	44.4	6.3	31.7	3.2	25.4	3.2

aP, acellular pertussis; D, diphtheria; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; Hib-MenC-TT, combined Hib-Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine; IPV, inactivated poliovirus vaccine; N, number of infants; NR, not reported; ORV, oral rotavirus vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; Ref., reference; T, tetanus.

^aOmeñaca (2011b)⁴² reports data on >50 mm and/or any noticeable diffuse injection-site swelling or increased circumference of the injected limb; not presented in table.

Table

Ref.	Follow-up	Definitions	Study vaccine Co-administration HBV birth dose	Dose	Study population (case definition), N/Comparator, N	Irritability, any (%)	Irritability, Grade 3%)	Loss of appetite, any (%)	Loss of appetite, Grade 3%)	Fever, any (%)	Drowsiness, any (%)	Drowsiness, Grade 3%)
Pentavalent vaccines
Omeñaca, 2011a^3	Recorded on diary cards for 4 days after each dose	Fever: “any”^‡ Grade 3 drowsiness: preventing normal activity Grade 3 irritability/fussiness: crying that could not be comforted/prevented normal activity Grade 3 loss of appetite: not eating at all	Primary: DTaP-HBV-IPV (Infanrix penta) Co-administration: Hib-MenC-TT (Menitorix) and pneumococcal (PCV7, Prevenar); ORV was permitted at any time HBV birth dose: 2 infants	Overall primary	Preterm (<31 weeks), N = 56	73.2	8.9	55.4	0.0	55.4	67.9	1.8
					Full-term (>36 weeks), N = 150	70.0	9.3	66.7	2.0	56.7	68.0	3.3
Hexavalent vaccines
Vázquez, 2008^39	Reported by parents via diary cards on the day of each vaccination and for 3 subsequent days	Fever: axillary temperature>37.5ºC^‡ Grade 3 irritability: inconsolable or persistent crying Other grade 3 systemic symptoms: preventing normal daily activities	DTaP-HBV-IPV/Hib (Infanrix hexa) Co-administration: NR HBV birth dose: NR	1^st	Preterm (24–36 weeks, 1500–2000 g), N = 85	51.8	2.4	25.9	0.0	18.8	38.8	0.0
					Preterm (24–36 weeks, <1500 g), N = 84	26.2	2.4	14.3	0.0	8.3	25.0	0.0
				2^nd	Preterm (24–36 weeks, 1500–2000 g), N = 84	46.4	1.2	15.5	0.0	21.4	39.3	0.0
					Preterm (24–36 weeks, <1500 g), N = 81	38.1	2.4	17.9	0.0	26.2	31.0	0.0
				3^rd	Preterm (24–36 weeks, 1500–2000 g), N = 84	44.0	3.6	15.5	2.4	14.3	21.4	2.4
					Preterm (24–36 weeks, <1500 g), N = 63	39.5	2.5	18.5	0.0	16.0	24.7	0.0
				Booster	Preterm (24–36 weeks, 1500–2000 g), N = 61	41.0	3.3	14.8	1.6	26.2	29.5	4.9
					Preterm (24–36 weeks, <1500 g), N = 63	34.9	0.0	12.7	0.0	11.1	22.2	3.2
Penta- and hexavalent vaccines
Furck, 2010^41	Up to 48 h (recorded by the nurse, fever measured every 3 h)	Fever^‡: rectal, >38.5ºC	DTaP-IPV/Hib (Infanrix IPV/Hib, N = 162)/DTaP-HBV-IPV/Hib (Infanrix hexa, N = 311) Co-administration: HBV (Gen H-B-Vax K pro infantibus, N = 162), pneumococcal (PCV7, Prevenar, N = 260) HBV birth dose: NR	1^st	Preterm (NS) and VLBW (<1500 g), 1^st dose during primary hospital stay N = 473	-	-	-	-	2.8	-	-

aP, acellular pertussis; D, diphtheria; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; Hib-MenC-TT, combined Hib-Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine; IPV, inactivated poliovirus vaccine; N, number of infants; NR, not reported; NS, not specified; ORV, oral rotavirus vaccine; PCV7, 7-valent pneumococcal conjugate vaccine; Ref., reference; T, tetanus; VLBW, very low birthweight.

^‡Proportions for other thresholds of fever were also reported in the article.

Bary-Weisberg D, Stein-Zamir C. Vaccination timeliness and completeness among preterm and low birthweight infants: a national cohort study. Hum Vaccin Immunother. 2021;17(6):1666–74. doi:10.1080/21645515.2020.1840255.

 PubMed Web of Science ®Google Scholar

Klein NP, Gans HA, Sung P, Yasukawa LL, Johnson J, Sarafanov A, Chumakov K, Hansen J, Black S, Dekker CL. Preterm infants’ T cell responses to inactivated poliovirus vaccine. J Infect Dis. 2010;201(2):214–22. doi:10.1086/649590.

 PubMed Web of Science ®Google Scholar

Kulkarni-Munje A, Malshe N, Palkar S, Amlekar A, Lalwani S, Mishra AC, Arankalle V. Immune response of Indian preterm infants to pentavalent vaccine varies with component antigens and gestational age. Front Immunol. 2021;12:592731. doi:10.3389/fimmu.2021.592731.

 PubMed Web of Science ®Google Scholar

Lee J, Robinson JL, Spady DW. Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants. BMC Pediatr. 2006;6():20. doi:10.1186/1471-2431-6-20.

 PubMedGoogle Scholar

Ochoa TJ, Zea-Vera A, Bautista R, Davila C, Salazar JA, Bazán C, López L, Ecker L. Vaccine schedule compliance among very low birth weight infants in Lima, Peru. Vaccine. 2015;33(2):354–8. doi:10.1016/j.vaccine.2014.11.014.

 PubMed Web of Science ®Google Scholar

Omeñaca F, Arístegui J, Tejedor JC, Moreno-Perez D, Ruiz-Contreras J, Merino JM, Muro Brussi M, Sánchez-Tamayo T, Castro Fernandez J, Cabanillas L, et al. Combined Haemophilus Influenzae type B-Neisseria meningitidis serogroup C vaccine is immunogenic and well tolerated in preterm infants when coadministered with other routinely recommended vaccines. Pediatr Infect Dis J. 2011;30(11):e216–24. doi:10.1097/INF.0b013e3182293a82.

 PubMed Web of Science ®Google Scholar

Czajka H, Lauterbach R, Pawlik D, Radziszewska R. Implementation of mandatory vaccinations against diphtheria, tetanus and pertussis in preterm infants as part of the Polish Immunization Programme. Pediatr Pol. 2017;92(5):485–93. doi:10.1016/j.pepo.2017.05.008.

 Google Scholar

Faldella G, Galletti S, Corvaglia L, Ancora G, Alessandroni R. Safety of DTaP–IPV–Hib–HBV hexavalent vaccine in very premature infants. Vaccine. 2007;25(6):1036–42. doi:10.1016/j.vaccine.2006.09.065.

 PubMed Web of Science ®Google Scholar

Omeñaca F, Garcia-Sicilia J, Boceta R, García-Corbeira P. Hepatitis B response of premature infants after primary and booster immunisation with a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenzae type B vaccine. Infect Dis Obstet Gynecol. 2010;2010:802503. doi:10.1155/2010/802503.

 PubMedGoogle Scholar

Vázquez L, Garcia F, Rüttimann R, Coconier G, Jacquet JM, Schuerman L. Immunogenicity and reactogenicity of DTPa-HBV-IPV/Hib vaccine as primary and booster vaccination in low-birth-weight premature infants. Acta Paediatr. 2008;97(9):1243–9. doi:10.1111/j.1651-2227.2008.00884.x.

 PubMed Web of Science ®Google Scholar

Flatz-Jequier A, Posfay-Barbe KM, Pfister RE, Siegrist CA. Recurrence of cardiorespiratory events following repeat DTaP-based combined immunization in very low birth weight premature infants. J Pediatr. 2008;153(3):429–31. doi:10.1016/j.jpeds.2008.03.043.

 PubMed Web of Science ®Google Scholar

Furck AK, Richter JW, Kattner E. Very low birth weight infants have only few adverse events after timely immunization. J Perinatol. 2010;30(2):118–21. doi:10.1038/jp.2009.112.

 PubMed Web of Science ®Google Scholar

Omeñaca F, Merino JM, Tejedor JC, Constantopoulos A, Papaevangelou V, Kafetzis D, Tsirka A, Athanassiadou F, Anagnostakou M, François N, et al. Immunization of preterm infants with 10-valent pneumococcal conjugate vaccine. Pediatrics. 2011;128(2):e290–8. doi:10.1542/peds.2010-1184.

 PubMed Web of Science ®Google Scholar

Ziegler B, Strassburg HM. Impfstatus bei Frühgeborenen mit einem Geburtsgewicht unter 1500 g im Alter von 2 Jahren – eine deutschlandweite Piloterhebung. Klin Padiatr. 2010;222(4):243–7. doi:10.1055/s-0030-1247586.

 PubMedGoogle Scholar