A phase 3 randomized, open-label study evaluating the immunogenicity and safety of concomitant and staggered administration of a live, pentavalent rotavirus vaccine and an inactivated poliomyelitis vaccine in healthy infants in China

ABSTRACT

This open-label, randomized, phase 3 study in China (V260-074; NCT04481191) evaluated the immunogenicity and safety of concomitant and staggered administration of three doses of an oral, live, pentavalent rotavirus vaccine (RV5) and three doses of an intramuscular, inactivated poliomyelitis vaccine (IPV) in 400 healthy infants. The primary objective was the non-inferiority of neutralizing antibody (nAb) responses in the concomitant- versus the staggered-use groups. Antibody responses were measured at baseline and 1-month post-dose 3 (PD3). Parents/legal guardians recorded adverse events for 30 or 15 d after study vaccinations in the concomitant-use or staggered-use groups, respectively. At PD3, >98% of participants seroconverted to all three poliovirus types, and the primary objective was met as lower bounds of the two-sided 95% CI for between-group difference in nAb seroconversion percentages ranged from − 4.3% to − 1.6%, for all poliovirus types, p < .001. At PD3, geometric mean titers (GMTs) of nAb responses to poliovirus types 1, 2, and 3 in the concomitant-use group and the staggered-use group were comparable; 100% of participants had nAb titers ≥1:8 and ≥1:64 for all poliovirus types. Anti-rotavirus serotype-specific IgA GMTs and participants with ≥3-fold rise in postvaccination titers from baseline were comparable between groups. Administration of RV5 and IPV was well tolerated with comparable safety profiles in both groups. The immunogenicity of IPV in the concomitant-use group was non-inferior to the staggered-use group and RV5 was immunogenic in both groups. No safety concerns were identified. These data support the concomitant use of RV5 and IPV in healthy Chinese infants.

KEYWORDS:

• Poliomyelitis
• gastroenteritis
• immunogenicity
• safety
• concomitant
• pentavalent rotavirus vaccine
• inactivated polio vaccine

Introduction

Rotavirus (RV) is the most common cause of severe diarrhea in infants and young children globally.^1,2 In China, RV causes over 40% of diarrhea-related hospitalizations and ~ 30% of diarrhea-related outpatient visits in children aged <5 y.^3,4 There is currently no antiviral therapy available to treat rotavirus gastroenteritis (RVGE); the only available therapy is supportive oral or intravenous rehydration for treatment of associated symptoms, such as dehydration.⁵

Safe, effective RV vaccines have been available for nearly 2 decades.¹ There are three RV vaccines approved for marketing in China: Lanzhou Lamb Rotavirus (LLR; Lanzhou Institute of Biological Products, Lanzhou, China; approved on 22 April 2000),^6,7 RotaTeq™ (RV5; Merck & Co., Inc., Rahway, NJ, USA; approved on 12 April 2018),⁸ and a trivalent live human-lamb reassortant rotavirus vaccine (LLR3; Lanzhou Institute of Biological Products, Lanzhou, China; approved on 17 April 2023).⁹ RV5 is an oral, live, pentavalent (G1, G2, G3, G4, and P1A[8]), human-bovine (WC3), reassortant RV vaccine indicated for the prevention of RVGE in infants and children caused by the serotypes G1, G2, G3, G4, and G9.¹⁰ The first dose of RV5 should be administered at 6 to 12 weeks of age and subsequent doses administered at 4-to 10-week intervals so that the 3-dose series is completed no later than 32 weeks of age.⁸ RV5 demonstrated high overall and serotype-specific efficacy against RVGE in Chinese clinical trials.¹¹

The concomitant use of RV5 with licensed pediatric vaccines, including diphtheria, tetanus, and acellular pertussis vaccine (DTaP); inactivated poliovirus vaccine (IPV); Haemophilus influenzae type b conjugate vaccine (Hib); hepatitis B vaccine; hexavalent vaccine (combined vaccine against diphtheria, tetanus, pertussis, poliomyelitis, H. influenzae type b, and hepatitis B); pneumococcal conjugate vaccine; and oral poliomyelitis vaccine (OPV), has been evaluated in phase 3 clinical trials.^12–14 These studies demonstrated that RV5 is well tolerated when given concomitantly with other routine pediatric vaccines and does not interfere with the immunogenicity of these vaccines. RV5 has also been shown to be well tolerated when administered to Chinese infants along with trivalent oral poliomyelitis vaccine (tOPV) and DTaP vaccines (V260-024; NCT02062385).¹⁵ Additionally, prior studies conducted in various sites across the globe including Mexico, Costa Rica, Guatemala, Brazil, Germany, Austria, Belgium, United States of America, and Finland showed that concomitant administration of RV5 with OPV does not interfere with the immunogenicity of poliovirus types 1, 2, and 3.^12–14,16

OPVs containing live attenuated poliovirus Sabin strains (types 1, 2, or 3) have served as the primary tool to eradicate polio worldwide.¹⁷ Prior licensed formulations of OPV include: (1) monovalent OPVs containing types 1, 2, or 3; (2) bivalent OPV (bOPV) containing types 1 and 3; and (3) trivalent (tOPV) containing types 1, 2, and 3.¹⁸ On rare occasions, the use of type 2–containing OPV can result in cases of polio due to vaccine-associated paralytic polio and circulating type 2 vaccine–derived polioviruses.¹⁸ For this reason, the global eradication of polio requires the cessation of all formulations of OPVs in routine immunization as soon as possible after the eradication of wild poliovirus (WPV) transmission.¹⁹ In an important step towards eradication of polio, in 2012, the Strategic Advisory Group of Experts on immunization recommended the withdrawal of the type 2 component of OPV as soon as possible from routine immunization programs in all countries, facilitated by the introduction of at least one dose of IPV.²⁰ Wild polio virus types 2 (WPV2) and 3 (WPV3) were declared eradicated worldwide in 2015 and 2020, respectively.²¹ As of 2022, WPV1 remains endemic in Pakistan and Afghanistan.²¹ As a response to the changing disease burden, a global campaign was initiated to eventually transition to IPV-exclusive essential immunization by 2030.^19,21

In 2000, China was declared WPV-free by the Regional Commission for the Certification of Poliomyelitis Eradication in the World Health Organization (WHO) Western Pacific Region.²² Two polio vaccines are currently available in China: IPV and bOPV.²³ Poliovirus vaccination is currently administered in a 4-dose schedule (IPV-IPV-bOPV-bOPV).²³ Since 2019, the immunization schedule in China has gradually been transitioned to a 2-dose IPV schedule and is expected to be changed to the WHO-recommended IPV-exclusive schedule in the future.^21,23

The primary objective of this study was to evaluate the immunogenicity and safety of concomitant and staggered administration of RV5 and IPV in healthy infants in China.

Materials and methods

Study design

This study was a randomized, single-site, open-label, phase 3 clinical trial designed to evaluate the immunogenicity and safety of concomitant and staggered administration of RV5 (RotaTeq™; Merck & Co., Inc., Rahway, NJ, USA; approved in China, 2018) and IPV (Sabin strain–based; Beijing Institute of Biological Products Co., Ltd., Beijing, China; approved in China, 2017) in healthy infants in China (V260-074; NCT04481191, registered July 22, 2020).

Participants were randomly assigned in a 1:1 ratio to receive RV5 and IPV in a concomitant (concomitant-use group) or sequential (staggered-use group) schedule (Figure 1). Study vaccines used in the trial were single batch, locally sourced, and managed by local subsidiaries and the study site. The study vaccines were categorized as investigational medicinal products according to local legislation, based on guidance issued by the European Commission. In the concomitant-use group, an oral dose of RV5 (2 mL/dose) was concomitantly administered with an intramuscular injection of IPV (0.5 mL/dose) on the same day, with an interval of at least 30 d between each vaccination visit: Visit 2 (Study Month 0.5; Dose Period 1), Visit 4 (Study Month 1.5; Dose Period 2), and Visit 6 (Study Month 2.5; Dose Period 3). In the staggered-use group, RV5 and IPV were administered separately, with an interval of at least 15 d between vaccinations: an oral dose of RV5 was administered at Visit 1 (Study Day 1; Dose Period 1), Visit 3 (Study Month 1; Dose Period 2), and Visit 5 (Study Month 2, Dose Period 3), and an intramuscular injection of IPV was administered at Visit 2 (Study Month 0.5, Dose Period 1), Visit 4 (Study Month 1.5, Dose Period 2), and Visit 6 (Study Month 2.5, Dose Period 3).

Figure 1. Study design.

Abbreviations: IPV, inactivated poliomyelitis vaccine; RV5, pentavalent rotavirus vaccine; VRC, vaccination report card.

Each participant received 3 doses of RV5 and IPV in a concomitant-use or staggered-use schedule. In the concomitant-use group, an oral dose of RV5 (2mL/dose) was concomitantly administered (same day) with an intramuscular injection of IPV (0.5mL/dose, Sabin strain based) at Visit 2, Visit 4, and Visit 6. In the staggered-use group, an oral dose of RV5 (2mL/dose) was administered at Visit 1, Visit 3, and Visit 5, and an intramuscular injection of IPV (0.5mL/dose, Sabin strain based) was administered at Visit 2, Visit 4, and Visit 6. In the concomitant-use group, serum samples were obtained from each participant at Visit 1 prior to vaccination and at Visit 8 (1 month post Dose 3 of RV5 and IPV). In the staggered use group, serum samples were obtained from each participant at Visit 1 prior to vaccination, Visit 7 (1 month post Dose 3 of RV5), and Visit 8 (1 month post Dose 3 of IPV). Paper VRCs were used by each participant’s legally acceptable representative to record the participant’s daily axillary temperature from Day 1 through Day 7 post each study vaccination; solicited injection site AEs from Day 1 through Day 7 post each vaccination of IPV and solicited systemic AEs from Day 1 through Day 7 post each study vaccination; and any other AEs from Day 1 through Day 15 post each study vaccination in both the concomitant-use and staggered-use groups. In addition, any AEs from Day 16 through Day 30 post each study vaccination in the concomitant-use group were collected on the VRC.

Administration of other routine pediatric vaccines (excluding rotavirus and polio vaccines other than the study vaccines), including those part of the China Expanded Program of Immunization (EPI) or non-EPI vaccines, were permitted during the study. It was recommended that other routine vaccines be administered on the same day as study vaccination. If other routine vaccines were to be administered on a day different from that of study vaccination, the interval between nonstudy and study vaccines had to meet the prerequisites of the vaccination visit as prespecified in the protocol and exclusion criteria, namely, that the participant had not received a nonstudy inactivated or recombinant vaccine within 2 weeks (14 d) before each vaccination visit, and/or that the participant had not received a nonstudy live vaccine within 4 weeks (28 d) before each vaccination visit.

This study was conducted in accordance with local and national regulations (including all applicable data protection laws and regulations), the Conference on Harmonization Good Clinical Practice Guideline, the ethical principles that have their origin in the Declaration of Helsinki regarding Independent Ethics Committee (IEC) review, and in accordance with the protection of human participants in biomedical research (MSD Code of Conduct for Interventional Clinical Trials). Written informed consent was obtained from each participant’s parent or legal guardian before beginning any study-related activity. Participants could be discontinued from the study at any time for any reason or could be discontinued from the study at the discretion of the investigator should any untoward effect occur. Ethical approval was obtained from the appropriate local IEC and/or Institutional Review Board (Ethics Review Committee of Vaccine Clinical Research, Guangdong CDC, Guangzhou Shi, Guangdong, China, approval number 2020V001-F01).

Study population

Healthy male and female infants aged 48–63 d were eligible for enrollment. Key exclusion criteria included any history of rotavirus disease, congenital gastrointestinal disorders, chronic diarrhea, failure to thrive, abdominal surgery, intussusception, poliomyelitis, known or suspected impairment of immunological function, uncontrolled epilepsy, encephalopathy, seizure, other progressive neurological diseases, prior receipt of systemic corticosteroid treatment, blood transfusion or blood products, and prior administration of any rotavirus vaccines or poliovirus vaccines. Participants with fever (axillary temperature ≥ 37.5°C) at the time of vaccination or within 24 hours prior to vaccination were to be rescheduled after complete resolution of febrile illness.

Immunogenicity assessment

In the concomitant-use group, serum samples were obtained at Visit 1 (baseline sample prior to vaccination) and Visit 8 (1 month post Dose 3 of RV5 and IPV). In the staggered-use group, serum samples were obtained at Visit 1 (baseline sample prior to vaccination), Visit 7 (1 month post Dose 3 of RV5), and Visit 8 (1 month post Dose 3 of IPV).

The primary immunogenicity objective was to demonstrate non-inferior immunogenicity of IPV at 1 month post Dose 3 in the concomitant-use group compared with the staggered-use group by measuring neutralizing antibody (nAb) seroconversion percentages for poliovirus types 1, 2, and 3. Seroconversion was defined as antibody titer ≥1:8 post-vaccination in baseline seronegative participants or ≥4-fold increase in titer post vaccination in baseline seropositive participants, consistent with WHO’s recommendation on the immunogenicity evaluation of IPV vaccines.²⁴ The cutoff value for seropositivity was 1:8 for all three poliovirus types.²⁵

The secondary objective was to evaluate the immune responses to IPV at 1 month post Dose 3 in the concomitant-use and staggered-use groups by measuring the nAb titers (geometric mean titers [GMTs]) against poliovirus types 1, 2, and 3 and the nAb response (the proportions of participants with nAb titer ≥1:8 and ≥1:64) against each poliovirus type. The immunogenicity of IPV was measured using the poliovirus serum nAb assay developed by the National Institutes for Food and Drug Control (NIFDC, Beijing, China).

An exploratory objective was to evaluate the immune responses to RV5 at 1 month post Dose 3 in the concomitant-use and staggered-use groups. The immunogenicity of RV5 was measured using an anti-rotavirus type-specific immunoglobulin A (IgA) against each of human rotavirus serotypes G1, G2, G3, G4, and P1A[8] using the assay developed by NIFDC. The GMTs and seroresponse rates (defined as the proportion of participants with ≥3-fold increase in titer post-vaccination from baseline) were measured using the same methods as described elsewhere^13,26,27 and adopted in the prior efficacy study in China.¹⁵

The immunogenicity assessments were performed on the per-protocol immunogenicity (PPI) populations. Eligible participants were those who received all 3 scheduled doses of study vaccines, adhered to guidelines for administration of study vaccines, provided baseline and post-vaccination blood samples within the acceptable day range, and did not have important deviations from the protocol that may have substantially affected the results of the primary endpoint. Supportive analysis for the primary immunogenicity objective was performed on the full analysis set (FAS) of all participants who provided baseline and post–Dose 3 serum samples, regardless of protocol deviations.

Safety assessments

Safety analyses were based on all-participants-as-treated (APaT) population, which consisted of all randomly assigned participants who received ≥1 dose of study vaccine. Paper vaccine report cards (VRCs) were provided to participants’ parents or legal guardians to record any reportable safety events following each vaccination. For the 7-day period after each vaccination, parents/legal guardians were instructed to record daily axillary temperature. Temperature measurements were additionally recorded on the VRC from Day 8 through Day 30 in the concomitant-use group or Day 8 through Day 15 in the staggered-use group if fever (defined as an axillary temperature of ≥ 37.5°C or equivalent) was suspected. The safety evaluation included any nonserious adverse events (AEs) reported from Day 1 through Day 30 post vaccination in the concomitant-use group or from Day 1 through Day 15 post vaccination in the staggered-use group, and all serious AEs (SAEs) were reported throughout the duration of the study.

A secondary objective of the study was to evaluate the safety of concomitant administration of RV5 and IPV based on the proportions of participants experiencing solicited injection-site AEs (following administration of IPV), solicited systemic AEs, and SAEs. Evaluation of the safety of concomitant administration of RV5 and IPV was based on the proportions of the APaT population experiencing solicited injection site AEs (erythema, swelling, induration, and pain at the injection site of IPV from Day 1 through Day 7 following each dose of IPV vaccine); solicited systemic AEs (diarrhea and/or vomiting) from Day 1 through Day 7 following each study vaccination; and SAEs regardless of causality (including intussusception as an event of clinical interest) collected from randomization throughout the entire study period. Specific terms included for each AE category were based on MedDRA version 25.0. The severity of AEs was assessed by the investigator based on the study sponsor (MSD) criteria (mild, awareness of symptoms, but easily tolerated; moderate, definitely acting like something is wrong; severe, extremely distressed or unable to do usual activities) and the China Regulatory Agency toxicity criteria (China Regulatory Agency, National Medical Products Administration) per the study protocol.

Statistical analyses

For the primary immunogenicity hypothesis, the statistical criterion for non-inferiority required that the lower bound of the two-sided 95% confidence interval (CI) of the difference in nAb seroconversion percentages (concomitant-use group minus staggered-use group) at 1 month post Dose 3 be greater than − 10%.¹³ The CI was calculated using the Miettinen and Nurminen method.²⁸ The planned sample size of 400 participants (200 in each group) provided an overall power of approximately 90% to establish that the concomitant-use group is noninferior to the staggered-use group in the seroconversion percentage to each of poliovirus types 1, 2, and 3 at 1 month post Dose 3, at an overall one-sided 2.5% α-level. The planned sample size was calculated based on the method proposed by Miettinen and Nurminen²⁸ and was performed using PASS 2008 software.

For the secondary immunogenicity objective of evaluating the nAb titer against poliovirus types 1, 2, and 3 at 1 month post Dose 3, point estimates for GMTs were calculated by exponentiating the estimates of the mean of the natural log values. The within-group 95% CIs were derived by exponentiating the CIs of the mean of the natural log values based on the t distribution. For the secondary immunogenicity objective, to evaluate the nAb responses to each poliovirus types 1, 2, and 3 at 1 month post Dose 3, the 95% CIs of proportions of participants with nAb titer ≥1:8 and ≥1:64 for poliovirus types 1, 2, and 3 within each group were provided and obtained by using the exact binomial Clopper and Pearson method.

For the exploratory endpoint of IgA Ab responses to RV serotypes, the within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t distribution for the continuous endpoints, and the within-group 95% CIs were based on the exact binomial Clopper and Pearson method for the dichotomous endpoints.

Results

Participant disposition

Out of 430 participants screened for eligibility, 400 healthy infants were evaluated from August 25, 2020, through May 8, 2021, in China, with 200 participants in each group (Figure 2). Most enrolled participants completed the study (93.8%). In the concomitant-use group, 189 participants received ≥1 dose of RV5 or IPV, 186 participants completed all scheduled doses of RV5, and 185 participants completed the study. In the staggered-use group, all 200 participants received ≥1 dose of RV5, 193 participants completed all scheduled doses of RV5 and IPV, and 190 participants completed the study. The most common reason for discontinuing study vaccination in both vaccination groups was withdrawal by parents/legal guardians of participants. No participants discontinued study vaccination due to an AE.

Figure 2. Participant disposition.

Abbreviations: IPV, inactivated poliomyelitis vaccine; OPV, oral poliomyelitis vaccine; RV5, pentavalent rotavirus vaccine.

^aOne participant in the concomitant-use group received one dose of IPV outside of the study, prior to Dose period 1 (Visit 2, ie, the first vaccination of RV5/IPV) and thus only received Dose 1 of RV5 at Dose period 1. This participant continued and completed the entire study.

^bOne participant in the concomitant-use group received a dose of OPV outside of the study, prior to Dose period 3 (Visit 6, ie, the last vaccination of RV5/IPV) and thus only received Dose 3 of RV5 at Dose period 3. This participant continued and completed the entire study.

Participant demographics and baseline characteristics

The baseline demographics were generally comparable across study vaccination groups. All enrolled participants (N = 400) were Chinese with a median age of 52.0 d (range, 48–63 d). The majority (55.3%) of participants were male (Table 1). All participants received bacille Calmette-Guérin (BCG: tuberculosis) and hepatitis B vaccines before receiving the first study vaccination (Table S1). Most participants (97.4%) received DTaP from Dose 1 of study vaccination through the final visit of the study (Table S2).

Table 1. Baseline demographics and patient characteristics (enrolled population).

Characteristic	Concomitant-use group (n = 200)	Staggered-use group (n = 200)	Total (N = 400)
Age, days
Mean (SD)	53.3 (4.8)	53.3 (4.6)	53.3 (4.7)
Median	52.0	52.5	52.0
Min, max	48.0, 63.0	48.0, 63.0	48.0, 63.0
Sex, n (%)
Male	114 (57.0)	107 (53.5)	221 (55.3)
Female	86 (43.0)	93 (46.5)	179 (44.8)
Race, n (%)
Asian	200 (100.0)	200 (100.0)	400 (100.0)
Weight, kg
Participants with data, n (%)	200 (100.0)	200 (100.0)	400 (100.0)
Mean (SD)	5.3 (0.6)	5.3 (0.6)	5.3 (0.6)
Median	5.3	5.3	5.3
Min, max	3.5, 7.6	3.9, 7.0	3.5, 7.6
Height, cm
Participants with data, n (%)	200 (100.0)	200 (100.0)	400 (100.0)
Mean (SD)	57.6 (2.2)	57.5 (2.1)	57.6 (2.1)
Median	57.5	57.5	57.5
Min, max	52.0, 63.0	51.0, 62.5	51.0, 63.0
Feeding status, n (%)
Breastfeeding only	72.0 (36.0)	73.0 (36.5)	145 (36.3)
Formula feeding only	29.0 (14.5)	18.0 (9.0)	47.0 (11.8)
Combination of breast and formula feeding	99.0 (49.5)	109 (54.5)	208 (52.0)

Abbreviation: SD, standard deviation.

Immunogenicity

Neutralizing antibody seroconversion to poliovirus at 1 month post dose 3

The primary immunogenicity endpoint was met, as lower bounds of the two-sided 95% CI for between-group difference (concomitant-use group minus staggered-use group, ranged from −4.3% to −1.6%) were greater than −10% for all poliovirus types (Table 2). The nAb seroconversion percentages for each poliovirus type 1, 2, and 3 at 1 month post Dose 3 in the concomitant-use group were non-inferior to those observed in the staggered-use group (Table 2). The nAb seroconversion percentages for all 3 poliovirus types by study vaccination group in the FAS population were generally consistent with those observed in the PPI population for IPV (Table S3).

Table 2. Summary of neutralizing antibody seroconversion percentages to poliovirus types 1, 2, and 3 at 1 month post dose 3 of IPV (PPI population for IPV).

Poliovirus type	Concomitant-use group (N = 180)		Staggered-use group (N = 187)		Percentage point difference^a
	Observed seroconversion^b, n (%)	95% CI^c	Observed seroconversion^b, n (%)	95% CI^c	Estimate (95% CI)^d,e	p-value^d,e
1	178 (98.9)	96.0%, 99.9%	187 (100.0)	98.0%, 100.0%	−1.1 (−4.0, 0.9)	<.001
2	177 (98.3)	95.2%, 99.7%	186 (99.5)	97.1%, 100.0%	−1.1 (−4.3, 1.5)	<.001
3	180 (100.0)	98.0%, 100.0%	186 (99.5)	97.1%, 100.0%	0.5 (−1.6, 3.0)	<.001^d,e

Abbreviations: CI, confidence interval; IPV, inactivated poliomyelitis vaccine; N, number of participants in per-protocol immunogenicity population for IPV; n, number of participants with the seroconversion.

^aConcomitant-use group − staggered-use group.

^bThe seroconversion is defined as antibody titer ≥ 1:8 post-vaccination in baseline seronegative participants or ≥ 4-fold increase in titer post-vaccination in baseline seropositive participants.

^cThe within-group 95% CIs are based on the exact binomial method proposed by Clopper and Pearson.

^dEstimated difference, 95% CI, and p-value are based on the unstratified Miettinen and Nurminen method.

^eA conclusion of non-inferiority of concomitant-use group to staggered-use group is based on the lower bound of the two-sided 95% CI for the difference in percentages (Concomitant-use group − Staggered-use group) being > −10% points (one-sided p-value <.025).

Neutralizing antibody titer and response to poliovirus at 1 month post dose 3

The nAb GMTs to each of poliovirus types 1, 2, and 3 at 1 month post Dose 3 of the PPI population for IPV in the concomitant-use and the staggered-use groups were generally comparable (Table 3). Poliovirus nAb GMTs at 1 month post Dose 3 for the concomitant- and staggered-use groups were 5,600.80 and 5,344.24 for type 1; 1,059.83 and 1,122.43 for type 2; and 3,405.56 and 3,261.69 for type 3, respectively (Table 3). For IPV, all participants (100%) had nAb titers ≥1:8 and ≥1:64 for each of poliovirus types 1, 2, and 3 at 1 month post Dose 3 in both concomitant-use and staggered-use groups (Table 3).

Table 3. Summary of neutralizing antibody responses to poliovirus types 1, 2, and 3 (PPI population for IPV).

Poliovirus type	Endpoint	Timepoint	Observed response (95% CI)^a
			Concomitant-use group (n = 180)	Staggered-use group (n = 187)
1	GMT	Pre Dose 1 of IPV	15.22 (12.88–17.98)	15.66 (13.33–18.41)
		1 month post Dose 3 of IPV	5,600.80 (4,898.46–6,403.85)	5,344.24 (4,657.51–6,132.22)
	% ≥ 1:8	Pre Dose 1 of IPV	70.0 (62.7–76.6)	69.0 (61.8–75.5)
		1 month post Dose 3 of IPV	100.0 (98.0–100.0)	100.0 (98.0–100.0)
	% ≥ 1:64	1 month post Dose 3 of IPV	100.0 (98.0–100.0)	100.0 (98.0–100.0)
2	GMT	Pre Dose 1 of IPV	9.76 (8.40–11.33)	8.86 (7.71–10.19)
		1 month post Dose 3 of IPV	1059.83 (951.13–1,180.96)	1122.43 (1,002.74–1,256.41)
	% ≥ 1:8	Pre Dose 1 of IPV	51.1 (43.6–58.6)	48.1 (40.8–55.5)
		1 month post Dose 3 of IPV	100.0 (98.0–100.0)	100.0 (98.0–100.0)
	% ≥ 1:64	1 month post Dose 3 of IPV	100.0 (98.0–100.0)	100.0 (98.0–100.0)
3	GMT	Pre Dose 1 of IPV	5.88 (5.29–6.54)	6.49 (5.67–7.44)
		1 month post Dose 3 of IPV	3405.56 (3,033.93–3,822.71)	3261.69 (2,913.70–3,651.24)
	% ≥ 1:8	Pre Dose 1 of IPV	26.7 (20.4–33.8)	27.8 (21.5–34.8)
		1 month post Dose 3 of IPV	100.0 (98.0–100.0)	100.0 (98.0–100.0)
	% ≥ 1:64	1 month post Dose 3 of IPV	100.0 (98.0–100.0)	100.0 (98.0–100.0)

Abbreviations: CI, confidence interval; GMT, geometric mean titer; IPV, inactivated poliomyelitis vaccine. n, number of participants in per-protocol immunogenicity population for IPV.

^aFor the continuous endpoints, the within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t distribution. For the dichotomous endpoints, the within-group 95% CIs are based on the exact binomial method proposed by Clopper and Pearson.

Anti-rotavirus type-specific IgA antibody responses at 1 month post dose 3

For RV5, the anti-rotavirus type-specific IgA GMTs against rotavirus serotypes G1, G2, G3, G4, and P1A[8] and the proportions of participants with ≥3-fold rise for each serotype at 1 month post Dose 3 in the concomitant-use group were generally comparable with those in the staggered-use group (Table 4).

Table 4. Summary of IgA antibody responses to rotavirus vaccine serotypes (PPI population for RV5).

Rotavirus serotype	Endpoint	Timepoint	Observed response (95% CI)^a
			Concomitant-use group (n = 180)	Staggered-use group (n = 189)
G1	GMT	Pre Dose 1 of RV5	14.55 (12.94–16.35)	14.33 (12.82–16.01)
		1 month post Dose 3 of RV5	254.77 (198.01–327.81)	235.22 (181.49–304.86)
	% ≥3-fold increase in titer	1 month post Dose 3 of RV5	76.1 (69.2–82.1)	72.5 (65.5–78.7)
G2	GMT	Pre Dose 1 of RV5	13.06 (11.91–14.33)	12.60 (11.55–13.74)
		1 month post Dose 3 of RV5	342.65 (265.75–441.80)	312.19 (238.17–409.22)
	% ≥3-fold increase in titer	1 month post Dose 3 of RV5	80.0 (73.4–85.6)	77.8 (71.2–83.5)
G3	GMT	Pre Dose 1 of RV5	14.15 (12.72–15.75)	13.65 (12.33–15.11)
		1 month post Dose 3 of RV5	69.48 (57.23–84.35)	71.34 (58.70–86.70)
	% ≥3-fold increase in titer	1 month post Dose 3 of RV5	47.8 (40.3–55.3)	52.9 (45.5–60.2)
G4	GMT	Pre Dose 1 of RV5	14.72 (13.14–16.49)	14.34 (12.90–15.95)
		1 month post Dose 3 of RV5	159.88 (126.27–202.44)	156.12 (122.63–198.75)
	% ≥3-fold increase in titer	1 month post Dose 3 of RV5	68.9 (61.6–75.6)	65.6 (58.4–72.4)
P1A[8]	GMT	Pre Dose 1 of RV5	14.24 (12.79–15.85)	13.79 (12.47–15.24)
		1 month post Dose 3 of RV5	62.84 (51.82–76.20)	66.51 (54.68–80.89)
	% ≥3-fold increase in titer	1 month post Dose 3 of RV5	46.7 (39.2–54.2)	51.9 (44.5–59.2)

Abbreviations: CI, confidence interval; GMT, geometric mean titer; IgA, immunoglobulin A; RV5, pentavalent rotavirus vaccine.

n, number of participants in per-protocol immunogenicity population for RV5.

^aFor the continuous endpoints, the within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. For the dichotomous endpoints, the within-group 95% CIs are based on the exact binomial method proposed by Clopper and Pearson.

Safety

In both groups, >70% of participants reported ≥ 1 AE across all dose periods (Table 5). A summary of AEs per each dose period is provided in Table S4. The proportions of participants in the concomitant-use group with injection site AEs and systemic AEs across all dose periods were generally comparable to those in the staggered-use group (25.4% vs. 23.0% for injection site AEs, 66.7% vs. 70.0% for systemic AEs). AEs related to the study vaccines were reported by 48.1% of participants in the concomitant-use group and 57.5% of participants in the staggered-use group across all dose periods (Table 5). SAEs were reported in 18 participants (7 from the concomitant-use group and 11 from the staggered-use group) throughout the study (Tables 5 and S5). One participant from the staggered-use group experienced an SAE of enteritis (moderate, grade 3, resolved) that was considered to be related to RV5 by the study investigator (occurred on Day 6 post Dose 1 of RV5; Tables 5 and S5). As of Day 106, the participant had discontinued from the study because of withdrawal by the parent/legal guardian. No participant discontinued the study due to an AE and no deaths occurred (Table 5).

Table 5. Adverse event summary (all-participants-as-treated population across all dose periods^a).

Adverse event, n (%)	Concomitant-use group (n = 189)	Staggered-use group (n = 200)	Total (N = 389)
Participants with one or more adverse event	134 (70.9)	151 (75.5)	285 (73.3)
Injection site	48 (25.4)	46 (23.0)	94 (24.2)
Systemic	126 (66.7)	140 (70.0)	266 (68. 4)
Discontinued vaccine due to an adverse event	0	0	0
Serious adverse events^a	7 (3.7)	11 (5.5)	18 (4.6)
Discontinued vaccine due to a serious adverse event	0	0	0
Vaccine-related^b adverse event	91 (48.1)	115 (57.5)	206 (53.0)
Injection site	48 (25.4)	46 (23.0)	94 (24.2)
Systemic	62 (32.8)	97 (48.5)	159 (40.9)
Discontinued vaccine due to a vaccine-related adverse event	0	0	0
Serious vaccine-related adverse events^a	0	1 (0.5)^c	1 (0.3)
Leading to death	0	0	0
Discontinued vaccine due to a serious vaccine-related adverse event	0	0	0

Abbreviations: IPV, inactivated poliomyelitis vaccine; RV5, pentavalent rotavirus vaccine.

^aSerious adverse events as reported throughout the entire study.

^bAssessed by the investigator to be related to the vaccine (RV5 or IPV).

^cOne participant in the staggered-use group experienced a serious vaccine-related adverse event of enteritis (moderate/grade 3, resolved) on Day 6 post Dose 1 of RV5 that was considered related to RV5 by the investigator.

For the concomitant-use group, systemic adverse events from Day 1 through Day 30 post any vaccination visit and injection site adverse events from Day 1 through Day 15 post any vaccination of IPV are included.

For the staggered-use group, systemic adverse events from Day 1 through Day 15 post any vaccination of RV5 or IPV and injection site adverse events from Day 1 through Day 15 post any vaccination of IPV are included.

Vaccination site adverse events following nonstudy vaccination were included in the category of systemic adverse events.

The most frequently reported systemic AEs (incidence ≥10% in any study vaccination group) following vaccination across all dose periods in both study vaccination groups were diarrhea, upper respiratory tract infection, pyrexia, and vomiting (Table 6). The most commonly reported injection site AE following IPV vaccination (incidence ≥10% in any study vaccination group) across all dose periods in both study vaccination groups was injection site erythema (Table 6). Most injection site AEs (Table 7) and systemic AEs (Table 8) were grade 1 or grade 2 in toxicity (China Regulatory Agency criteria) and were mild to moderate in intensity (MSD criteria; Tables S6 and S7) for both the concomitant-use and staggered-use groups.

Table 6. Most frequently reported adverse events reported in ≥ 5% in one or more vaccination groups (all-participants-as-treated population across all dose periods).

Adverse event, n (%)	Concomitant-use group (n = 189)	Staggered-use group (n = 200)	Total (N = 389)
Gastrointestinal disorders	63 (33.3)	83 (41.5)	146 (37.5)
Vomiting	20 (10.6)	39 (19.5)	59 (15.2)
Diarrhea	33 (17.5)	50 (25.0)	83 (21.3)
Dyspepsia	10 (5.3)	13 (6.5)	23 (5.9)
General disorders and administration site conditions	72 (38.1)	74 (37.0)	146 (37.5)
Injection site erythema	45 (23.8)	41 (20.5)	86 (22.1)
Injection site pain	12 (6.3)	7 (3.5)	19 (4.9)
Pyrexia	30 (15.9)	37 (18.5)	67 (17.2)
Infections and infestations	55 (29.1)	64 (32.0)	119 (30.6)
Bronchitis	11 (5.8)	13 (6.5)	24 (6.2)
Nasopharyngitis	14 (7.4)	14 (7.0)	28 (7.2)
Upper respiratory tract infection	31 (16.4)	37 (18.5)	68 (17.5)
Respiratory, thoracic, and mediastinal disorders	33 (17.5)	35 (17.5)	68 (17.5)
Cough	19 (10.1)	14 (7.0)	33 (8.5)
Rhinorrhea	17 (9.0)	18 (9.0)	35 (9.0)
Skin and subcutaneous tissue disorders	22 (11.6)	21 (10.5)	43 (11.1)
Eczema	14 (7.4)	12 (6.0)	26 (6.7)

Abbreviations: IPV, inactivated poliomyelitis vaccine; RV5, pentavalent rotavirus vaccine.

Every participant was counted a single time for each applicable event and vaccination group.

A system organ class or specific adverse event is shown only if the incidence in one or more vaccination group meets the incidence criterion, after rounding.

For the concomitant-use group, systemic adverse events from Day 1 through Day 30 post any vaccination visit and injection site adverse events from Day 1 through Day 15 post any vaccination of IPV are included.

For the staggered-use group, systemic adverse events from Day 1 through Day 15 post any vaccination of RV5 or IPV and injection site adverse events from Day 1 through Day 15 post any vaccination of IPV are included.

Injection site adverse events refer to adverse events that occurred at the vaccination site of nonstudy vaccination.

Table 7. Injection site adverse events by maximum toxicity grade based on Chinese criteria (incidence >0% in one or more vaccination groups, all-participants-as-treated population, across all dose periods).

Adverse event, n (%)	Concomitant-use group (n = 189)				Staggered-use group (n = 200)
	Grade 1	Grade 2	Grade 3	Total	Grade 1	Grade 2	Grade 3	Total
All injection site AEs	40 (21.2)	5 (2.6)	3 (1.6)	48 (25.4)	39 (19.5)	7 (3.5)	0	46 (23.0)
Injection site erythema	40 (21.2)	4 (2.1)	1 (0.5)	45 (23.8)	39 (19.5)	2 (1.0)	0	41 (20.5)
Injection site induration	1 (0.5)	1 (0.5)	0	2 (1.1)	1 (0.5)	1 (0.5)	0	2 (1.0)
Injection site pain	5 (2.6)	5 (2.6)	2 (1.1)	12 (6.3)	2 (1.0)	5 (2.5)	0	7 (3.5)
Injection site swelling	1 (0.5)	3 (1.6)	0	4 (2.1)	1 (0.5)	1 (0.5)	0	2 (1.0)

Abbreviations: AE, adverse event; IPV, inactivated poliomyelitis vaccine.

Every participant was counted a single time for each applicable specific injection site adverse event and is classified according to the highest nonmissing intensity grading.

Injection site adverse events from Day 1 through Day 15 post any vaccination of IPV in both vaccination groups are included.

Only the highest reported grade of a given adverse event is counted for the individual participant.

Grades are based on China Regulatory Agency′ s criteria.

Table 8. Participants with systemic adverse events by maximum toxicity grade based on Chinese criteria (incidence ≥2% in one or more vaccination groups, all-participants-as-treated population, across all dose periods).

Adverse event, n (%)	Concomitant-use group (n = 189)				Staggered-use group (n = 200)
	Grade 1	Grade 2	Grade 3	Total	Grade 1	Grade 2	Grade 3	Total
All systemic AEs	17 (9.0)	101 (53.4)	8 (4.2)	126 (66.7)	11 (5.5)	108 (54.0)	21 (10.5)	140 (70.0)
Bronchitis	0	8 (4.2)	3 (1.6)	11 (5.8)	0	13 (6.5)	0	13 (6.5)
Constipation	0	4 (2.1)	0	4 (2.1)	0	9 (4.5)	0	9 (4.5)
Cough	0	19 (10.1)	0	19 (10.1)	1 (0.5)	13 (6.5)	0	14 (7.0)
Crying	1 (0.5)	3 (1.6)	0	4 (2.1)	0	6 (3.0)	0	6 (3.0)
Diarrhea	19 (10.1)	13 (6.9)	1 (0.5)	33 (17.5)	20 (10.0)	21 (10.5)	9 (4.5)	50 (25.0)
Dyspepsia	0	10 (5.3)	0	10 (5.3)	0	13 (6.5)	0	13 (6.5)
Eczema	0	14 (7.4)	0	14 (7.4)	0	12 (6.0)	0	12 (6.0)
Eye discharge	0	3 (1.6)	0	3 (1.6)	0	4 (2.0)	0	4 (2.0)
Nasal congestion	0	6 (3.2)	0	6 (3.2)	0	8 (4.0)	0	8 (4.0)
Nasopharyngitis	0	14 (7.4)	0	14 (7.4)	0	14 (7.0)	0	14 (7.0)
Pneumonia	0	1 (0.5)	2 (1.1)	3 (1.6)	0	1 (0.5)	6 (3.0)	7 (3.5)
Pyrexia	13 (6.9)	15 (7.9)	2 (1.1)	30 (15.9)	20 (10.0)	16 (8.0)	1 (0.5)	37 (18.5)
Rash	0	4 (2.1)	0	4 (2.1)	1 (0.5)	3 (1.5)	0	4 (2.0)
Rhinorrhea	0	17 (9.0)	0	17 (9.0)	0	18 (9.0)	0	18 (9.0)
Upper respiratory tract infection	0	31 (16.4)	0	31 (16.4)	0	36 (18.0)	1 (0.5)	37 (18.5)
Vomiting	13 (6.9)	7 (3.7)	0	20 (10.6)	23 (11.5)	14 (7.0)	2 (1.0)	39 (19.5)

Abbreviations: AE, adverse event; IPV, inactivated poliomyelitis vaccine.

Every participant was counted a single time for each applicable specific adverse event and is classified according to the highest nonmissing intensity grading.

For the concomitant-use group, systemic adverse events from Day 1 through Day 30 post any vaccination visit are included. For the staggered-use group, systemic adverse events from Day 1 through Day 15 post any vaccination of RV5 or IPV are included.

Grades are based on China Regulatory Agency′ s criteria.

Discussion

The concomitant administration of RV5 with licensed pediatric vaccines has been evaluated in studies worldwide, and the antibody responses to these vaccines were generally acceptable.^12–14 IPV evaluated in these studies included Salk-IPV (wIPV)¹² and Sabin-IPV (sIPV).^13,14 This study in healthy Chinese infants demonstrated that the immunogenicity of IPV in the concomitant-use group was non-inferior to that in the staggered-use group based on nAb seroconversion at 1 month post Dose 3 for each of poliovirus types 1, 2, and 3. The nAb GMT and the proportions of participants with neutralizing antibody titer ≥1:8 and ≥1:64 against each of the poliovirus types were comparable between the vaccination groups, which further demonstrates the robust immunogenicity of IPV when concomitantly administered with RV5. Both anti-rotavirus type-specific IgA GMTs and the proportions of participants with ≥ 3-fold increase in post-vaccination titers from baseline were comparable between the concomitant-use and staggered-use groups. These results are similar to those from the previous efficacy registration study conducted in China (V260-024), where the tOPV was concomitantly administered in subgroup with RV5 (n = 400) and the seroprotection rates of anti-poliovirus types 1, 2 and, 3 in the participants who received RV5 were non-inferior to those who received placebo.^11,15

Concomitant administration of RV5 and IPV was well tolerated, with a safety profile generally comparable to the staggered-use group. Overall, the safety profile for RV5 was consistent with its known safety profile and the current product labeling.^8,10 No new safety concerns were identified for either concomitant or staggered administration of RV5 and IPV. No participants died during the entire study period and no intussusception was reported in any participant during the entire study period. No participants discontinued the study due to an AE.

Strengths of the current study include the robust design of the trial with comparative concomitant- and staggered-use vaccination groups, the strict safety monitoring via VRCs following each vaccination, and the high rate of study vaccination compliance observed in both study vaccination groups. The results of this study are subject to the limitations of the single-site, open-label nature of the study design, which has a potential bias in reporting safety outcomes. Additionally, distinguishing which AE was related to a specific vaccine was difficult to determine due to coadministration of the study vaccines.

This study demonstrated that concomitant use of RV5 and IPV did not interfere with the safety and immunogenicity profiles of either vaccine. No new safety signals were observed. These findings support the concomitant administration of RV5 with IPV to facilitate the vaccination schedule of infants in China.

Author contributions

Shaomin Chen, Zhifang Ying, Yan Liu, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, Yong Zhang, Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, Xueyan Liao, Changgui Li, and Jikai Zhang contributed to the concept and design of the work. Shaomin Chen, Zhifang Ying, Yan Liu, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, Yong Zhang, Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, Xueyan Liao, Changgui Li, and Jikai Zhang contributed to the data acquisition. Shaomin Chen, Zhifang Ying, Yan Liu, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, Yong Zhang, Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, Xueyan Liao, and Jikai Zhang contributed to data analysis. Shaomin Chen, Zhifang Ying, Yan Liu, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, Yong Zhang, Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, Xueyan Liao, Yingmei Tu, Jon Stek, Jonathan Hartzel, Changgui Li, and Jikai Zhang contributed to interpretation of data for the manuscript. Shaomin Chen, Zhifang Ying, Yan Liu, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, Yong Zhang, Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, Xueyan Liao, Yingmei Tu, Jon Stek, Jonathan Hartzel, Changgui Li, and Jikai Zhang drafted the manuscript. Shaomin Chen, Zhifang Ying, Yan Liu, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, Yong Zhang, Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, Xueyan Liao, Yingmei Tu, Jon Stek, Jonathan Hartzel, Changgui Li, and Jikai Zhang revisited the manuscript critically for important intellectual content. All authors approved the final version of the manuscript and are accountable for all aspects of the work.

Acknowledgments

The authors thank all principal investigators for their contributions to the study. Medical writing and editorial support was provided by Toinette Labuschagné, MSc, and Andrea Humphries, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure statement

Zhifang Ying, Yan Liu, Yong Zhang, and Changgui Li are all current employees of the National Institutes for Food and Drug Control (NIFDC), which is responsible for the immunogenicity sample testing. Guixiu Liu, Weiwei Zhao, Rong Fu, Qiong Shou, Minghuan Zheng, and Xueyan Liao are current or former employees of MSD Research and Development (China) Co., Ltd., Beijing, China, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may own stock and/or options in Merck & Co., Inc., Rahway, NJ, USA. Yingmei Tu, Jon Stek, and Jonathan Hartzel are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may own stock and/or options in Merck & Co., Inc., Rahway, NJ, USA. Shaomin Chen, Yuan Li, Yebin Yu, Meilian Huang, Zhuhang Huang, Zhiqiang Ou, Yuyi Liao, and Jikai Zhang have no conflicts to disclose.

Data availability statement

The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the Engage Zone site or via e-mail to Data Access mailbox.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2324538.

Additional information

Funding

This study was sponsored by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.