Adverse events following immunization of co- and separate administration of DTaP-IPV/Hib vaccines: A real-world comparative study

ABSTRACT

To fully understand the safety of DTaP-IPV/Hib vaccination, we evaluated the differences between DTaP-IPV/Hib co-administration and separate administration of the DTaP, IPV and Hib vaccines (DTaP+IPV+Hib) based on adverse events following immunization (AEFI). All AEFI reported in Hebei Province, China, between 2020 and 2022 were included in this study. The risk difference (RD%), relative risk (RR), and Chi-square value were used to compare the differences in reported rates of AEFI between the DTaP-IPV/Hib and DTaP+IPV+Hib groups. From 2020 to 2022, 130 AEFI cases were reported in Hebei Province after DTaP-IPV/Hib vaccination, corresponding to an AEFI reported rate of 66.9/million doses, which was significantly lower than that for DTaP+IPV+Hib (9836 AEFI with a reported rate of 637.8/million doses). The overall reported rate of non-severe AEFI for DTaP+IPV+Hib vaccines was 9.5 times that of DTaP-IPV/Hib vaccination [95% confidence interval (CI): 8.0, 11.3]. Meanwhile, the reported rate of AEFI among infants aged 0–1 y was 9.8 times higher for DTaP+IPV+Hib than for DTaP-IPV/Hib (95% CI: 8.2, 11.7). DTaP+IPV+Hib vaccination also resulted in higher risks of high fever, localized redness and swelling, localized induration, and allergic rash compared with DTaP-IPV/Hib vaccination. The risk of AEFI, which were mostly mild reaction, was higher after vaccination with DTaP+IPV+Hib than after DTaP-IPV/Hib vaccination.

KEYWORDS:

• DTaP-IPV/Hib
• combination vaccine
• vaccine safety
• AEFI
• separate administration
• co-administration

Introduction

Vaccination is the most economical and effective means to control and eliminate infectious diseases.¹ Since the implementation of the Expanded Programme on Immunization of the World Health Organization (WHO) in 1974 and the National Immunization Programme (NIP) in China, along with the continuous development of non-NIP vaccines, many vaccines had been added to pediatric immunization schedules. Children in China can receive up to 36 doses of vaccines before the age of three,² of which 16 doses are concentrated before the age of 1 y.³

The increased in the variety of vaccines can prevent more infectious diseases and establish a more comprehensive immune barrier for children; however, it also increases the cost of vaccination for health departments, the number of visits to vaccination clinics, and the risk of suspected adverse effects, which affects vaccination compliance and may cause children to fail to complete immunization at the optimal time.³ For this reason, the WHO advocates for combination vaccination to reduce the number of shots.⁴ The Vaccine Administration Law of the People’s Republic of China also explicitly supports the development of new vaccines such as multivalent vaccines.⁵

Combination vaccines can reduce the number of shots, simplify the immunization process, the vaccine management, storage and delivery, and reduce the amount of work missed by parents due to vaccination appointments.⁶ Loiacono et al. reported that combination vaccine recipients were nearly three times as likely to complete a four-dose series than stand-alone vaccines.⁷ In addition, combination vaccines reduce the total amount of adjuvants, preservative, and stabilizer compared to monovalent vaccines given multiple times, which might reduce the risk of adverse reactions.⁸

The diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV/Hib) have the active immunogenic components with three vaccines: diphtheria and tetanus toxoids and acellular pertussis adsorbed vaccine (DTaP), inactivated poliovirus vaccine (IPV) and Haemophilus influenzae type b vaccine (Hib). Thus, it reduces the number of vaccination shots from 12 to 4, saves time, and thus improves the timely vaccination rate. However, parental concerns about the safety of the combination vaccine can contribute to vaccine hesitancy.^9,10 Uncertainty about the safety remains a common factor influencing the practical use,^11,12 indicating the need to assess the safety of combination vaccines.

Clinical trials involving Asian infants have revealed that the DTaP-IPV/Hib vaccine was non-inferior compared with separate vaccinated with DTaP-IPV and Hib vaccines (referred to as DTaP/IPV+Hib hereafter) in terms of safety. Nakayama, et al. enrolled 414 healthy infants in Japan,¹³ Lin, et al. enrolled 60 healthy infants in China,¹⁴ and Kang, et al. enrolled 418 healthy Korean infants¹⁵ to compare the safety of the DTaP-IPV/Hib and DTaP-IPV+Hib vaccines: all concluded that DTaP-IPV/Hib was safe and effective when administered to healthy infants. However, these clinical trials involved small sample size and enrolled only healthy infants. Thus, the rare adverse reactions were difficult to detect, and the conclusions were not strong enough to provide generalized recommendations. Studies involving large sample sizes and with real-world data remain lacking.

In this study, we retrospectively evaluated all adverse events following immunization (AEFI) reported after administration of DTaP, IPV, Hib, or DTaP-IPV/Hib vaccines from 2020 to 2022 in Hebei Province, and compared the differences between two groups: those administered with the DTaP-IPV/Hib vaccine and those administered separately with the DTaP, IPV, and Hib vaccines (referred to as DTaP+IPV+Hib hereafter). Hebei Province has a population of approximately 74 million and is located in northern China.¹⁶ This study compared the reported rates of AEFI after combination (DTaP-IPV/Hib) and separate (DTaP+IPV+Hib) vaccine administrations in a large, diverse sample over a 2-y period. Thus, the results provide solid evidence for the safety of the DTaP-IPV/Hib vaccine.

Methods

Definition and classification of AEFI

According to the definition of the National Surveillance Program for Suspected Abnormal Vaccination Reactions (2022 edition),¹⁷ issued by the Ministry of Health of China, the AEFI are defined as reactions or events that occur after immunization and are suspected to be associated with vaccination. AEFI do not necessarily have a causal relationship with the vaccine.¹⁸

According to the severity of the events, AEFI are classified into severe AEFI and non-severe AEFI. Severe AEFI cases refer to events that are fatal or life-threatening, cause permanent or significant disability or impair of organ function. According to the causes of the events, AEFI are divided into adverse reactions, vaccine quality accidents, vaccination accidents, coincidences, and psychogenic reactions. Adverse reactions refer to harmful or unexpected reactions unrelated to the purpose or the administration of qualified vaccines, which are divided into general reactions and abnormal reactions.¹⁷

Immunization schedule of related vaccines

According to the Recommendations: Childhood Immunization Schedule for National Immunization Program Vaccines – China (Version 2021),¹⁹ children are recommended to receive four doses of the DTaP vaccines at 3, 4, 5 and 18 month-age, and two doses of the IPV at two and 3 months along with two doses of the bivalent polio vaccine (bOPV) at 4 months and 4 y for Polio immunization. Like other provinces in China, DTaP and IPV vaccines are freely provided to all children living in Hebei. Meanwhile, the inoculators may recommend, and parents can choose to give the Hib or DTaP-IPV/Hib vaccine to their children at their own expense. The recommendations for the DTaP-IPV/Hib vaccine indicate four doses at 2, 3, 4 and 18 months. Most Hib vaccines used in Hebei are appropriate for infants older than 2 months, and one dose is recommended when the child is one to 5 y old.

AEFI reporting process

According to the National Surveillance Program for Suspected Abnormal Vaccination Reactions (2022 edition)¹⁷ of China, AEFI can be reported by any interested party, including medical personnel, inoculation units, vaccine recipients or their guardians, adverse drug reaction monitoring agencies and vaccine-related entities. After being reported to a local health administration department, the suspected AEFI are then verified and reported through the China National Adverse Events Following Immunization surveillance system (CNAEFIS). The events are then rechecked and monitored by higher-level administrative departments. With the exception of normal reactions such as fever, redness, swelling and induration, all AEFI should be investigated by a group of AEFI investigation and diagnosis experts composed of at least five professional clinicians and epidemiologists. If the AEFI are confirmed, they will be classified into one of the following five categories based on their cause: adverse reactions, vaccine quality accidents, vaccination accidents, coincidences, and psychogenic reactions.

Research design

This study used a cross-sectional research design. All AEFI reported after vaccination with the DTaP-IPV/Hib, DTaP, IPV, or Hib vaccines in Hebei Province from 2020 to 2022 were considered. The gender and age of the vaccine recipients, the inoculation sites, season, and occurrence interval were recorded, counted and compared. To understand the safety of the DTaP-IPV/Hib vaccine, the collected AEFI were classified with DTaP-IPV/Hib and DTaP+IPV+Hib groups, and the reported rates of different AEFI were compared with the two groups.

Data collection

The AEFI was collected from CNAEFIS, a nationwide passive surveillance system for post-marketing vaccine safety.²⁰ All AEFI reported in Hebei Province with reporting times between January 1, 2020, and December 31, 2022, were included in our study. The vaccination data were collected from the Hebei Provincial Immunization Program Information Management System, on June 18, 2023.

The population data for this study were obtained from the Seventh National Population Census Bulletin released by the National Bureau of Statistics of China in 2021.²¹ All data used in our study were in count form and did not include personal information (e.g., name, phone number, address or biospecimens). This study received ethical approval from the Institutional Review Board of Hebei Provincial Center for Disease Control and Prevention (Date: 2023.12.21, No. IRBS2023–016).

Study subjects

All children vaccinated with the DTaP-IPV/Hib, DTaP, IPV, and Hib vaccines were monitored for AEFI. All AEFI reported after vaccination with DTaP-IPV/Hib, DTaP, IPV, or Hib vaccines in Hebei Province from 2020 to 2022 were recorded and classified into the following two groups. No cases were excluded.

DTaP-IPV/Hib vaccine group: This group included AEFI after vaccination with DTaP-IPV/Hib. The reported rate of AEFI was calculated based on the number of DTaP-IPV/Hib vaccine doses administered.

DTaP+IPV+Hib vaccine group: In our study, the DTaP, IPV and Hib vaccines were considered to be fungible with the DTaP-IPV/Hib vaccine. This group included AEFI after separate vaccination with DTaP, IPV, or Hib vaccines. The reported rates of AEFI were calculated based on the sum of those three administered vaccine doses.

Statistical methods

STATA 14.0 software was used to organize and analyze the data. The AEFI reported rate (AEFI number/million doses) was calculated as the number of reported AEFI ÷ the number of doses × 1,000,000 doses. Due to the difference in demographics and dose numbers between two groups, chi-square test, adjusted for gender and age, was used to compare the differences between the two groups, and P-values were calculated. For theoretical frequency <1, Fisher’s exact probability test was used to calculate the P-values. The α value of the test was 0.05.

The risk difference (RD%) was calculated to estimate the difference in AEFI reported rate between the DTaP-IPV/Hib and DTaP+IPV+Hib group, and the 95% confidence interval (95% CI) was calculated using the normal approximation.

The relative risk (RR) was estimated from the AEFI reported rates, and the 95% CI was calculated using the Woolf method. When the number of cases was zero, the RR and 95% CI could not be calculated.

Results

According to the Seventh National Population Census Bulletin (2020),¹⁶ the population of children under 6 y old in Hebei Province was 6,247,535. The gender ratio was approximately 110.2 males:100.0 females.

From 2020 to 2022, 15420,909 doses of the DTaP, IPV, and Hib vaccines and 9,486,224 doses of the DTaP-IPV/Hib vaccine were administered in Hebei Province. A total of 9836 AEFI following DTaP, IPV, or Hib vaccination and 130 AEFI following DTaP-IPV/Hib vaccination were reported.

Differences in age and gender among children between the DTaP-IPV/Hib and DTaP+IPV+Hib groups

The ratio of males to females receiving DTaP-IPV/Hib vaccination doses was 108.0:100.0, lower than the ratio of DTaP+IPV+Hib (108.6:100.0; $x^2$ = 12.2, p < 0.001). The age of DTaP-IPV/Hib vaccination was primarily 0–1-y old (99.3%); in contrast, only 81.5% of DTaP+IPV+Hib vaccine recipients were under 1-y old. The age difference between the groups was significant ($x^2$ = 3.9 × 10⁵, p < 0.001; Table 1). Thus, chi-square test values were adjusted based on the difference on gender and age between two groups.

Table 1. Comparison of genders and ages among recipients of the DTaP+IPV+Hib and DTaP-IPV/Hib vaccinations.

	DTaP+IPV+Hib		DTaP-Hib/IPV		$x^2$	P
	Number of doses	Proportion (%)^a	Number of doses	Proportion (%)
Gender ratio	108.6		108.0		12.2	<.001
Male	8028807	52.1	1009918	51.9
Female	7392102	47.9	934778	48.1
Age					3.9 × 10^5	<.001
0–1 y	12571006	81.5	1930126	99.3
2–6 y	2832476	18.4	14534	0.8
>7 y	17427	0.1	36	0.0
Total	15420909	100.0	1944696	100.0

^aProportion (%) = number of doses of this classification÷number of doses of this group × 100%.

Comparison of the AEFI reported rates between the DTaP-IPV/Hib and DTaP+IPV+Hib groups

From 2020 to 2022, 130 AEFI were reported after DTaP-IPV/Hib vaccination in Hebei Province, corresponding to an AEFI reported rate of approximately 66.9/million doses. In the DTaP+IPV+Hib group, 9836 AEFI were reported, corresponding to a reported rate of 637.8/million doses, significantly higher than the reported rate for DTaP-IPV/Hib ($x^2$ = 979.5, p < 0.001). The overall reported rate of AEFI for DTaP+IPV+Hib was 9.5 times that of DTaP-IPV/Hib vaccination (95% CI: 8.0, 11.3; Table 3).

The inoculation sites for the DTaP-IPV/Hib vaccine were mainly the upper arms (56.2%) and the thighs (43.9%), while the primary sites for DTaP+IPV+Hib administration were the upper arms (88.2%). A total of 636 AEFI occurred after DTaP+IPV+Hib was administered in the buttocks. The inoculation sites differed significantly between the two groups ($x^2$ = 349.2, p < 0.001). Most AEFI reported were in the spring (March, April, and May) and summer (June, July, and August); while the proportions of AEFI reported in the winter (January, February and December) were low in both groups. No significant differences were found between the two groups in terms of the season of AEFI reporting ($x^2$ = 5.7, p = .13).

Most AEFI occurred within 1 d after vaccination for the DTaP-IPV/Hib (70.0%) and the DTaP+IPV+Hib groups (67.9%). No significant differences were found between the two groups (Fisher’s exact probability test, p = .46).

Most AEFI occurred after the fourth dose for both the DTaP-IPV/Hib (35.4%) and DTaP+IPV+Hib groups (32.8%). More AEFI occured after the first dose than after the second or third dosed in both the DTaP-IPV/Hib (31.5%) and DTaP+IPV+Hib (31.0%) groups. No significant differences between the two groups were observed ($x^2$ = 1.7, p = .8; Table 2).

Table 2. Comparison of the characteristics of reported AEFI after DTaP+IPV+Hib and DTaP-IPV/Hib vaccinations.

	DTaP+IPV+Hib		DTaP-Hib/IPV		Rectified by gender and age
	Number of cases	Proportion (%)^a	Number of cases	Proportion (%)	$x^2$	P
Inoculation site					349.2	<.001
Upper arms	8675	88.2	73	56.2
Thighs	525	5.3	57	43.9
Buttocks	636	6.5	0	0.0
Inoculation season					5.7	.1
Spring	3293	33.5	53	40.8
Summer	2909	29.6	40	30.8
Autumn	2018	20.5	17	13.1
Winter	1616	16.4	20	15.4
Occurrence interval					-^b	.5
0 d	6674	67.9	91	70.0
1 d	2301	23.4	28	21.5
2–7 d	789	8.0	9	6.9
8–14 d	39	0.4	1	0.8
15–42 d	25	0.3	1	0.8
>42 d	8	0.1	0	0.00
Doses					1.7	.8
1	3052	31.0	41	31.5
2	1761	17.9	18	13.9
3	1789	18.2	25	19.2
4	3225	32.8	46	35.4
5	9	0.1	0	0.0
Total	9836	100.0	130	100.0

^aProportion(%) = number of doses for this classification ÷ number of doses in this group × 100%.

^bWhen the theoretical frequency was less than 1, Fisher’s exact probability test was used to calculate the P-value.

The gender ratio of AEFI reported after vaccination with DTaP-IPV/Hib was about 120.3 males:100.0 females, which was not significantly different from that in the DTaP+IPV+Hib group (males:females = 126.1:100.0; $x^2$ = 0.07, p = .8). The risk of AEFI reported rate was 9.7 times higher after DTaP+IPV+Hib vaccination compared with DTaP-IPV/Hib vaccine for male (95% CI: 7.7,12.3), and 9.3 times higher for females (95% CI: 7.2, 12.0).

The reported rates of AEFI in infants aged 0–1 y differed between the two groups ($x^2$ = 978.4, p < 0.001). For those infants, DTaP+IPV+Hib vaccines was associated with a 9.8-fold greater risk of AEFI than DTaP-IPV/Hib vaccination (95% CI: 8.2, 11.7). No significant difference in AEFI reported rates was found in children aged two to 6 y and above 7 y.

Regarding AEFI severity, 39 cases of severe AEFI occurred after DTaP+IPV+Hib vaccination, with a reported rate of 2.5/million doses. Only one case of severe AEFI was reported after DTaP-IPV/Hib vaccination, with a reported rate of 0.5/million doses. The reported rates of severe AEFI were not significantly different ($x^2$ = 3.0, p = 0.08). Meanwhile, the risk of non-severe AEFI was 9.6 times higher in the DTaP+IPV+Hib group than in the DTaP-IPV/Hib group (95% CI: 8.0, 11.4).

Regarding AEFI types, the risk of general reactions after DTaP+IPV+Hib vaccination was 9.9 times that of DTaP-IPV/Hib vaccination (95% CI: 8.3, 11.8). No significant difference in the reported rates of abnormal reactions was observed between the two groups ($x^2$ = 2.2, p = .14; Table 3).

Table 3. Comparison of the reported rates of AEFI after DTaP+IPV+Hib and DTaP-IPV/Hib vaccinations.

	DTaP+IPV+Hib		DTaP-Hib/IPV		Rectified by gender and age		RD%		RR
	Number of cases	Reported rate (/million)^a	Number of cases	Reported rate (/million)	$x^2$	P	RD%	95%CI (lower,upper)	RR	95%CI (lower,upper)
Total number of AEFI	9836	637.8	130	66.9	979.5	<0.001	0.06	0.06,0.06	9.5	8.0,11.3
Gender ratio	126.1		120.3		0.07	0.8
Male	5486	683.3	71	70.3	547.5	<0.001	0.06	0.06,0.06	9.7	7.7,12.3
Female	4350	588.5	59	63.1	431.8	<0.001	0.05	0.05,0.05	9.3	7.2,12.0
Age
0–1 y	8038	639.4	126	65.3	978.4	<0.001	0.05	0.05,0.05	9.8	8.2,11.7
2–6 y	1797	634.4	4	275.2	2.9	0.09	0.4	0.009,0.06	2.3	0.9,6.1
>7 y	1	57.4	0	0.0	-	>0.9	0.006	0.006,0.02	/	/
Severity
Sever AEFI	39	2.5	1	0.5	3.0	0.08	2.0 × 10^4	7.3 × 10^5, 3.3 × 10^4	4.9	0.7,35.8
Non-sever AEFI	9797	635.3	129	66.3	976.5	<0.001	0.06	0.06,0.06	9.6	8.0,11.4
Types
General reactions	9752	632.4	124	63.8	980.3	<0.001	0.06	0.06,0.06	9.9	8.3,11.8
Abnormal reactions	67	4.3	4	2.1	2.2	0.1	2.3 × 10^4	2.0 × 10^6,4.6 × 10^4	2.1	0.8,5.8
General reactions
High fever (axillary temperature ≥ 38.6℃)	1213	78.7	40	20.6	80.5	<0.001	0.006	0.006,0.006	3.8	2.8,5.2
Localized redness and swelling (diameter>2.5 cm)	2767	179.4	43	22.1	263.6	<0.001	0.02	0.02,0.02	8.1	6.0,11.0
Localized induration (diameter>2.5 cm)	1081	70.1	22	11.3	94.0	<0.001	0.006	0.006,0.006	6.2	4.1,9.5
Anaphylaxis reactions in total	47	3.1	2	1.0	2.5	0.1	2.0 × 10^4	1.9 × 10^4,2.2 × 10^4	3.0	0.7,12.2
Allergic rash	37	2.4	0	0.0	4.7	0.03	2.4 × 10^4	2.3 × 10^4,2.5 × 10^4	/	/
Angioedema	4	0.3	0	0.0	-	>0.9	2.6 × 10^5	2.3 × 10^5,2.9 × 10^5	/	/
Urticaria	6	0.4	2	1.0	-	0.2	6.4 × 10^5	4.9 × 10^5,7.9 × 10^5	0.4	0.08,1.9
Sterile abscess	6	0.4	1	0.5	-	0.6	1.3 × 10^5	2.0 × 10^6,2.3 × 10^5	0.8	0.09,6.3
Meningitis	1	0.1	0	0.0	-	>0.9	6.5 × 10^6	5.2 × 10^6,7.8 × 10^6	/	/
Febrile convulsion	5	0.3	0	0.0	-	>0.9	3.2 × 10^5	3.0 × 10^5,3.5 × 10^5	/	/
TP	17	1.1	1	0.5	0.6	0.5	5.9 × 10^5	4.8 × 10^5,7.0 × 10^5	2.1	0.3,16.1
Epilepsy	4	0.3	1	0.5	-	0.5	2.6 × 10^5	1.5 × 10^5,3.6 × 10^5	0.5	0.06,4.5
HSP	1	0.1	0	0.0	-	>0.9	6.5 × 10^6	5.2 × 10^6,7.8 × 10^6	/	/
Other diseases	51	3.3	2	1.0	2.9	0.09	2.3 × 10^4	2.1 × 10^4,2.4 × 10^4	3.2	0.8,13.2

^aReported rate (/million) = number of AEFI cases÷number of vaccine doses in this group × 1000,000.

^bWhen the theoretical frequency was less than 1, Fisher’s exact probability test was used to calculate the P-value.

Comparison of the reported rates of general reactions between the DTaP-IPV/Hib and DTaP+IPV+Hib groups

Among the AEFI reported in Hebei Province from 2020 to 2022, the reported rate of fever above 38.6°C was 3.8 times higher in the DTaP+IPV+Hib group than in the DTaP-IPV/Hib group (95% CI: 2.8, 5.2; $x^2$ = 80.5, p < 0.001).

The reported rate of localized redness and swelling (diameter >2.5 cm) was 8.1 times higher in the DTaP+IPV+Hib group than in the DTaP-IPV/Hib group (95% CI: 6.0, 11.0; $x^2$ = 263.6, p < 0.001).

The reported rate of localized induration (diameter >2.5 cm) was 6.2 times higher in the DTaP+IPV+Hib group than in the DTaP-IPV/Hib vaccine (95% CI: 4.1, 9.5; $x^2$ = 94.0, p < 0.001; Table 3).

Comparison of the reported rates of anaphylaxis between DTaP-IPV/Hib and DTaP+IPV+Hib groups

Among the AEFI cases reported in Hebei Province from 2020 to 2022, 47 cases of anaphylaxis reactions were reported after vaccination with DTaP+IPV+Hib, with a reported rate of 3.1/million doses. Two anaphylaxis reactions were reported after DTaP-IPV/Hib vaccination, with a reported rate of 1.0/million doses. There reported rates of anaphylaxis were not significantly different between the two groups ($x^2$ = 2.5, p = .1).

The reported rate of allergic rash was significantly higher after vaccination with DTaP+IPV+Hib than DTaP-IPV/Hib ($x^2$ = 4.7, p = .03). In contrast, the reported rates of angioedema (Fisher’s exact probability test, p > .9) and urticaria (Fisher’s exact probability test, p = .22) were not significantly different between the two groups (Table 3).

Comparison of the reported rates of other diseases between DTaP-IPV/Hib and DTaP+IPV+Hib groups

The reported rates of sterile abscesses (Fisher’s exact probability test, p = .57), meningitis (Fisher’s exact probability test, p > .9), febrile convulsion (Fisher’s exact probability test, p > .9), thrombocytopenic purpura (TP; $x^2$ = 0.6, p = .45), epilepsy (Fisher’s exact probability test, p = .45), Henoch-Schonlein purpura (HSP; Fisher’s exact probability test, p > .9), and other diseases ($x^2$ = 2.9, p = .09) were not significantly different between the two groups (Table 3).

Discussion

Many scientific research organizations have conducted studies to understand the safety of combination vaccines. The Advisory Committee on Immunization Practices,²² reported that the DTaP, inactivated hepatitis b poliomyelitis, IPV, and Hib combined vaccine (DTaP-HBV-IPV/Hib) have good safety, comparing with separate administration. An Indian study²³on the hexavalent vaccine (DTwP-IPV-HB-PRP~T) administered in infants demonstrated no safety concerns. Hansen, et al. retrospectively observed 14,042 infants vaccinated with either DTaP-IPV/Hib or another DTaP-containing vaccine and found no safety concerns following DTaP-IPV/Hib detection.²⁴ In contrast, other studies have found that combination vaccines increase the risk of some diseases compared with monovalent vaccines. A large cohort study conducted in Denmark found that the DTaP-IPV/Hib vaccine increased the risk of febrile seizures than separate administered with DTaP-IPV and Hib vaccines in young children.²⁵ A case series study of children under 2 y of age in Italy found a higher risk of sudden unexpected deaths after DTaP-HBV-IPV/Hib vaccination than separate administration in infants before seven month-old.²⁶ The safety of combination vaccines was inconclusive.

On the other hand, most studies on the safety of combination vaccines were based on short-term clinical trials with small sample sizes and generally include only healthy vaccine recipients.²⁷ Due to the low reported rates of severe AEFI, it is difficult to detect rare adverse effects in studies with small sample sizes. Even in retrospective analyses of deaths, young children receive few vaccines and older children or adults face too many risk factors to guarantee an objective analysis. Moreover, most studies are focused on Europe and the USA,²⁷ because this is where the most clinical trials take place. Few such studies have been conducted in Asia, and those studies lacked a control group who received the same antigens as separate vaccines. In conclusion, based on currently available evidence, it is challenging to understand the differences in AEFI following separate and combination vaccine administration.

Based on all AEFI reported in Hebei Province, China, from 2020 to 2022, we compared the differences in the reported rates of various AEFI types after the administration of the DTaP-IPV/Hib vaccine and the separate administration of the related monovalent vaccines (DTaP+IPV+Hib). The results provide real-world data for the safety study of the DTaP-IPV/Hib vaccine.

The results show that associated reports of AEFI after DTaP-IPV/Hib and DTaP+IPV+Hib vaccinations primarily occurred among the infants under 1 y in age. Compared to the DTaP-IPV/Hib vaccine, more children aged two to 6 y received the DTaP+IPV+Hib vaccinations. The recommended ages for vaccination with DTaP-IPV/Hib, DTaP, and IPV are all before 6 months, with a booster around 18 months (bOPV replaces IPV at the age of 4 y). The schedule is different for the Hib vaccine, with some guidelines suggesting one dose of Hib between 1 and 5 y of age. This was responsible for the higher ages of vaccination observed in the DTaP+IPV+Hib group.

The reported rate of AEFI was higher for DTaP+IPV+Hib than for DTaP-IPV/Hib with non-severe AEFI (high fever, localized redness and swelling, localized induration and allergic rash) accounting for most of the difference. This may be because the combination vaccine can reduce the number of shots and the amount of adjuvants.²⁸ Similarly, prospective studies involving Chinese infants had found that the DTaP-IPV//PRP~T combined vaccine was non-inferior with respect to the separately administered DTaP, IPV, and Hib vaccines in terms of safety.^29,30

No differences were detected in the reported rates of angioedema, urticaria, sterile abscess, meningitis, febrile convulsion, epilepsy, HSP, TP, and other diseases between the DTaP+IPV+Hib and DTaP-IPV/Hib groups. No anaphylactic shock, laryngeal edema, Arthus reaction, convulsions, Guillain-Barre syndrome, acute disseminated encephalomyelitis, encephalitis, and polyneuritis were reported after the DTaP+IPV+Hib or DTaP-IPV/Hib vaccination in Hebei Province from 2020 to 2022.

For most reported AEFI associated with the DTaP+IPV+Hib vaccines, the vaccines were administered in the upper arms. This difference might be attributed to the official guidance on the inoculation sites for the different vaccines. According to the DTaP-IPV/Hib Vaccine Application Technology Guide, issued by the Chinese Preventive Medicine Association in 2011, the best inoculation site for the DTaP-IPV/Hib vaccine is the middle third of the anterolateral side of the baby’s thigh.³¹ The Hib vaccine specification recommends both the upper arm and the thigh as the best inoculation site.

Among the AEFI reported after DTaP+IPV+Hib vaccination, 6.5% occured after inoculated on the buttocks; no such cases were reported for the DTaP-IPV/Hib vaccine. Innoculation on the buttocks is not recommended by the Chinese Code of Practice for Vaccination (2023 edition),³² although it is not explicitly forbidden. To complete the vaccination schedule as soon as possible, inoculation staff may choose to administer multiple vaccines in one visit. For infants at little months with small arms, the thighs and buttocks provide better sites for simultaneous injections. Since combination vaccines require fewer injections, this situation was not observed for the DTaP-IPV/Hib vaccine.

The inoculation seasons in which AEFI reported did not differ between the two groups. Spring and summer were the most common seasons for reported AEFI in both groups. Previous research suggests a seasonal trend in reported AEFI in China, with more AEFI being reported in the summer; this may be related to the seasonality of some diseases.³³ Moreover, redness and swelling or induration symptoms are most easily to observed by caregivers in the summer. Most AEFI occurred on the day of vaccination, and no significant difference in the occurrence interval was found between the groups, consistent with other studies conducted in China from 2017 to 2020.^34–37

Most AEFI were reported after the fourth and first doses in both groups, with no significant difference between the groups. Gender did not affect the reported rates of AEFI in both groups.

It is worth noting that AEFI in China are reported via passive surveillance, with the vaccine recipients or their guardians reporting events to the vaccination management unit. Thus, some AEFI, particularly minor adverse reactions, may fail to be reported. In addition, due to the impact of the COVID-19 pandemic and the large-scale administration of the COVID-19 vaccine in early 2020 in China, the sensitivity of AEFI reporting was lower in 2020 than in 2019.³⁸ The AEFI information was collected based on reporting time, so the associated vaccination date may be earlier. The subjects of AEFI and vaccination doses may be slightly different. For AEFI with low reported rates and a near-zero number of cases, individual cases may have undue influence, leading to large bias.

In conclusion, the risk of AEFI is higher after separate vaccination with DTaP+IPV+Hib vaccines compared with the DTaP-IPV/Hib vaccine, and the difference mainly stems from the occurrence of relatively mild reactions. Both types of vaccination have extremely low reported rates of severe reactions.

Ethical approval statement

This research received ethical approval from the Institutional Review Board of Hebei Provincial Center for Disease Control and Prevention (Date: 2023.12.21, No. IRBS2023–016).

Acknowledgments

The authors thank AiMi Academic Services (www.aimieditor.com) for English language editing and review services.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Hebei Provincial Health and Family Planning Commission provided research funds to author Yiqing Zhu for the Current situation of simultaneous and combination vaccination in some areas of Hebei Province project [No: 20240545]. The Chinese Preventive Medicine Association provided academic advising to author Yiqing Zhu through the “Vaccine and immunization youth talent lift program” for the Investigation on the usage of simultaneous vaccination of immunization programme vaccines and non-immunization programme vaccines in Hebei Province project [No: CPMAQT_YM0303].