ABSTRACT
This Phase I study evaluated the safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), via subcutaneous (SC) or intramuscular (IM) administration, in healthy Japanese infants 3 months of age. A total of 133 participants were randomized to receive four doses (3 + 1 regimen) of V114-SC (n = 44), V114-IM (n = 45), or 13-valent PCV (PCV13)-SC (n = 44) at 3, 4, 5, and 12–15 months of age. Diphtheria, tetanus, and pertussis–inactivated poliovirus (DTaP–IPV) vaccine was administered concomitantly at all vaccination visits. The primary objective was to assess the safety and tolerability of V114-SC and V114-IM. Secondary objectives were to assess the immunogenicity of PCV and DTaP–IPV at 1-month post-dose 3 (PD3). On days 1–14 following each vaccination, the proportions of participants with systemic adverse events (AEs) were comparable across interventions, whereas injection-site AEs were higher with V114-SC (100.0%) and PCV13-SC (100.0%) than with V114-IM (88.9%). Most AEs were mild or moderate in severity and no vaccine-related serious AEs or deaths were reported. Serotype-specific immunoglobulin G (IgG) response rates at 1-month PD3 were comparable across groups for most shared serotypes between V114 and PCV13. For additional V114 serotypes 22F and 33F, IgG response rates were higher with V114-SC and V114-IM than with PCV13-SC. DTaP–IPV antibody response rates at 1-month PD3 for V114-SC and V114-IM were comparable with PCV13-SC. Findings suggest that vaccination with V114-SC or V114-IM in healthy Japanese infants is generally well tolerated and immunogenic.
Introduction
Young age is a major risk factor for pneumococcal infection, with children <5 years of age being particularly vulnerable.Citation1 In this age group, there is high disease burden and mortality associated with invasive pneumococcal disease (IPD).Citation2 Despite the significant public health impact of currently available pneumococcal conjugate vaccines (PCVs), IPD remains a leading cause of vaccine-preventable disease globally, including in Japan, representing an unmet medical need.Citation3 In regions where multivalent PCVs have been introduced into infant immunization schedules, the burden of disease attributed to non-vaccine serotypes (NVTs) has increased.Citation4,Citation5
A 13-valent PCV (PCV13; Prevenar 13) was approved for the prevention of IPD caused by serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, and was incorporated into the national immunization program for infants and children (<5 years of age) in Japan in 2013.Citation6,Citation7 In Japan, PCV13 is administered subcutaneously to infants from 2 months of age using a 3 + 1 dosing schedule, with an interval of at least 27 days for primary immunization series and at least 60 days after the last dose of primary immunization for booster immunization.Citation8
V114 (VAXNEUVANCE™, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA) is a 15-valent PCV that contains the 13 serotypes in PCV13 along with two additional serotypes, 22F and 33F. These additional serotypes cause a substantial IPD burden in children <5 years of age.Citation9 Both serotypes have high invasive disease potential,Citation10 and serotype 33F is associated with multidrug resistance.Citation11,Citation12 In Japan, serotypes 22F and 33F are important contributors to IPD.Citation13–15
V114 is licensed and recommended for use in children in the United States, European Union, Canada, and other countries globally.Citation16–18 Similar to other licensed PCVs, V114 can be administered concomitantly with other routine pediatric vaccines in these approved countries, including those containing diphtheria, tetanus, and pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), and hepatitis B (HepB) antigens, rotavirus, and measles, mumps, and rubella vaccine.Citation6,Citation19–22 DTaP–IPV (Quattrovac® and Tetrabik®) is a pediatric combination vaccine manufactured and distributed locally in Japan, and is included in the national immunization program for routine administration to Japanese infants in a 3 + 1 dosing schedule. The primary immunization series is administered from 3 months of age, with an interval of 3–8 weeks, followed by a booster dose at 12–18 months after the third dose. PCV13 can be administered concomitantly with DTaP–IPV in Japan.Citation8
Subcutaneous (SC) injection is the typical administration route used for most pediatric vaccines in Japan.Citation21,Citation23 Using this administration route, a Phase III study in Japanese infants demonstrated that V114 is well tolerated and immunogenic, with non-inferior responses to the 13 serotypes shared with PCV13 and higher responses to the two additional serotypes included in V114.Citation24 However, intramuscular (IM) administration may be beneficial as an alternative route in infants, as it is known to be associated with a lower frequency of injection-site adverse events (AEs) compared with SC administration, while having comparable immunogenicity to the SC route.Citation25,Citation26
This Phase I trial compared the safety, tolerability, and immunogenicity of V114 administered via SC or IM routes with DTaP–IPV co-administration in healthy Japanese infants, using PCV13 administered SC as the active comparator.
Methods
Study design
This was a multicenter, randomized, double-blind trial designed to assess the safety, tolerability, and immunogenicity of two different administration routes of V114 (SC or IM) in healthy Japanese infants (Protocol V114–028). PCV13, administered via SC route, was given as the active comparator. The study was conducted between April 2019 and June 2020 (clinical trials.gov. NCT03848065) in 14 clinical investigator study sites located in Japan.
The trial planned to enroll 120 healthy Japanese infants at approximately 3 months of age, randomized 1:1:1 to receive either V114 via SC injection (V114-SC), V114 via IM injection (V114-IM), or PCV13 via SC injection (PCV13-SC). DTaP–IPV was administered at the same time as PCV but in different limbs, according to the routine schedule. The rationale for initiating the PCV vaccination series at 3 months of age, rather than the recommended 2 months of age, was to align with the currently approved schedule of DTaP–IPV in Japan.
This trial was conducted as a double-blind trial under in-house blinding procedures. The sponsor personnel, except those who are specifically designated to serve as unblinded roles, remained blinded to the treatment assignment of individual participants until the end of the trial. Site personnel, except those who are specifically designated to serve as unblinded roles, as well as participants and their parents/legal guardians, also remained blinded until the end of the trial.
This study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.
Participant selection
Healthy male and female infants 3 months of age (3 months of age to 1 day prior to 4 months of age, inclusive) were eligible for the study. Written informed consent was provided by a legally acceptable representative who understood the study procedures, alternative therapies available, and risks involved with the study. Key exclusion criteria included: history of IPD or known history of other culture-positive pneumococcal disease, known hypersensitivity to vaccines or any component of the PCV or any diphtheria toxoid-containing vaccine, contraindication to the PCV13 and/or DTaP–IPV vaccine being administered in the study, recent febrile illness (axillary temperature ≥37.5°C) occurring within 72 h prior to receipt of study vaccine, known or suspected impairment of immunological function, or history of congenital or acquired immunodeficiency.
Vaccines
V114 (VAXNEUVANCE™, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA) is a 15-valent PCV. Each dose (0.5 mL) contains 2 μg of pneumococcal capsular polysaccharide from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F, 22F, and 33F, and 4 μg from serotype 6B, all conjugated to CRM197 carrier protein and adjuvanted with 125 µg aluminum phosphate.Citation27
PCV13 (Prevenar 13; Wyeth LLC, marketed by Pfizer, New York, NY, USA) is a 13-valent PCV. Each dose (0.5 mL) contains 2.2 μg capsular polysaccharide from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F, and 4.4 μg from serotype 6B, all conjugated to CRM197 carrier protein and adjuvanted with 125 µg aluminum phosphate.Citation6
The concomitant vaccine assessed in this study was DTaP–IPV, which was administered as a 0.5 mL SC dose.
Safety assessment
Safety endpoints and objectives
The primary objective of the trial was to describe the safety and tolerability of V114-SC and V114-IM in healthy infants. Primary endpoints included solicited injection-site AEs during day 1 to day 14 post-vaccination, solicited systemic AEs during day 1 to day 14 post-vaccination, and vaccine-related serious AEs (SAEs) throughout the study (until 1-month post-dose 4 [PD4]).
Statistical power calculations of sample size for safety assessment
With 40 participants per arm, there is an 80% probability that a particular safety event is observed in at least one in 40 patients, if the true incidence of the event is 4%.
Safety analysis
The evaluation of safety included complaints reported directly by the participant’s parent/guardian using a paper Vaccination Report Card (VRC). The complaints were subsequently assessed by the study investigators to determine whether they met protocol-defined AE criteria and to assess the causality relationship to study vaccines. The analyses of AEs included non-serious AEs reported through day 14 post-vaccination and SAEs reported by 1-month PD4.
Participants reported maximum body temperatures from days 1–7 post-vaccination, as well as any solicited injection-site AEs (redness, swelling, hard lump, and pain/tenderness), solicited systemic AEs (irritability, drowsiness, hives/welts, and appetite loss), and any other injection-site or systemic AEs from days 1–14 post-vaccination. Vaccine-related SAEs were recorded from the time the consent form was signed and throughout the study.
Statistical methods for key safety analysis
The analysis of safety results followed a tiered approach, with tiers differing with respect to the analyses performed. Tier 1 safety endpoints included solicited injection-site and systemic AEs during day 1 to day 14 post-vaccination that were specifically prompted for on the VRC. Endpoints not defined as Tier 1 were classified as belonging to ‘Tier 2’ or ‘Tier 3.’ Tier 2 endpoints included AE summary measures (any AE, any vaccine-related AE, any SAE, any vaccine-related SAE, and discontinuation of study vaccine due to an AE), AEs (specific terms as well as system organ classes [SOCs]) that occurred in at least four subjects in any vaccination group, and body temperatures (≥37.5°C, ≥38.0°C, ≥39.0°C, and ≥40.0°C) collected from day 1 through day 7. P values (for Tier 1 endpoints) and 95% confidence intervals (CIs) (for Tier 1 and Tier 2 endpoints) were analyzed for between-group differences in the percentage of participants with events. These analyses were performed using the Miettinen and Nurminen method.Citation28
Immunogenicity assessment
Immunogenicity endpoints and objectives
Secondary objectives of the trial included pneumococcal immunoglobulin G (IgG) response rates for each of the 15 serotypes at 1-month post-dose 3 (PD3), pneumococcal serotype-specific IgG geometric mean concentrations (GMCs) at 1-month PD3, and antigen-specific response rates to the antigens included in DTaP–IPV at 1-month PD3, for each vaccination group; the immunogenicity of co-administration with V114 was compared with the co-administration with PCV13, the standard of care in Japan. Pneumococcal serotype-specific IgG response rates and GMCs were also assessed pre-dose 4 and 1-month PD4 as exploratory objectives.
Statistical power calculations of sample size for immunogenicity assessment
It was expected that 36 participants per arm would be included in the per-protocol population at 1-month PD3. The between-group differences and corresponding 95% CIs for the proportion of participants achieving the threshold values for the IgG in response to a particular pneumococcal serotype or a component of DTaP–IPV would depend on the number of participants achieving the threshold value in the two groups being compared (Supplemental Information, Table S1).
Statistical analysis for key immunogenicity analysis
The proportion of responders at 1-month PD3 for each of the 15 serotypes contained in V114 were analyzed by vaccination group. IgG response rates were defined as the proportion of participants meeting the serotype-specific IgG threshold concentration of ≥0.35 μg/mL, which was measured via the validated pneumococcal electrochemiluminescence (PnECL) assay, bridged to the World Health Organization (WHO) reference enzyme-linked immunosorbent assay (ELISA).Citation29 Within-group 95% CIs were calculated based on the method of Clopper and Pearson.Citation30 The proportions of participants meeting threshold values at 1-month PD3 for diphtheria toxin (≥0.1 IU/mL), tetanus toxin (≥0.01 IU/mL), pertussis toxin (≥10 EU/mL), pertussis filamentous hemagglutinin (FHA; ≥10 EU/mL), as well as poliovirus type 1 [neutralizing antibody titers (NA) ≥1:8], type 2 (NA ≥ 1:8), and type 3 (NA ≥ 1:8), were analyzed using the same method.
The IgG concentrations at 1-month PD3 were natural log-transformed and assessed using an analysis of variance model, with a single factor for vaccination group. The within-group means and the corresponding 95% CIs were estimated using this model. The point estimates, as well as the lower and upper limits of the 95% CIs, were exponentiated to obtain the estimates on the original scale for IgG GMCs by vaccination group.
Results
Participants
A total of 133 infant participants were screened and randomized to receive V114-SC (n = 44), V114-IM (n = 45), or PCV13-SC (n = 44) in Japan. Of those randomized, 132 participants received at least one dose of a study vaccine and 130 participants completed the study (Supplemental Information, Table S2).
The demographic characteristics were comparable across all study intervention groups. The median age of participants was 14 weeks (12–16 weeks) and there was a slightly larger proportion of male participants than female participants across vaccination groups ().
Table 1. Patient demographic and baseline characteristics (all randomized).
Safety
Overall, the proportions of participants with systemic AEs and vaccine-related AEs were comparable across intervention groups. The proportions of participants with SAEs were comparable across groups, with percentages of 2.3% (n = 1), 6.7% (n = 3), and 4.7% (n = 2) in the V114-SC, V114-IM, and PCV13-SC groups, respectively. No vaccine-related SAEs were reported. One death due to an unknown cause was reported in the V114-IM group (201 days PD3); the primary diagnosis of sudden infant death syndrome was suspected but could not be established, as the infant was >1 year of age. This death was assessed by investigators as not related to the study vaccine ().
Table 2. Summary of AEs.
All the participants (100%) in the V114-SC and PCV13-SC groups and 89% in the V114-IM group reported injection-site AEs (). Most of the injection-site AEs across all study interventions were the solicited events of erythema, induration, swelling, and pain. All injection-site AEs were of mild or moderate intensity. The proportions of participants with DTaP–IPV-related injection-site AEs following any vaccination were generally comparable across the vaccination groups (data not shown).
The distributions of maximum body temperature reported from day 1 to day 7 post-vaccination were comparable across the study vaccination groups ().
Table 3. Analysis of maximum temperatures on days 1–7 following any vaccination.
Immunogenicity
Most participants across all three intervention groups met the serotype-specific IgG threshold concentration of ≥0.35 μg/mL for each of the 13 shared serotypes, and IgG response rates were generally comparable across intervention groups for all shared serotypes at 1-month PD3 (). For the two serotypes unique to V114 (22F and 33F), serotype-specific IgG response rates were higher among recipients of either V114-SC or V114-IM than recipients of PCV13-SC ().
Table 4. Analysis of IgG antibody response rates (% ≥0.35 μg/mL) at 1-month PD3 (PP population).
Both V114-IM and V114-SC were immunogenic, as assessed by IgG GMCs, to all 15 serotypes included in the vaccine. For the two serotypes unique to V114, 22F and 33F, serotype-specific IgG GMCs (μg/mL) at 1-month PD3 were higher among recipients of either V114-IM or V114-SC than PCV13-SC ().
Table 5. Analysis of IgG GMCs (μg/mL) at 1-month PD3 (PP population).
IgG response rates and IgG GMCs at 1-month PD4 increased from levels observed at pre-dose 4 for all 13 shared serotypes (data not shown) and were comparable across intervention groups for most shared serotypes. For the two serotypes unique to V114 (22F and 33F), IgG response rates and IgG GMCs at 1-month PD4 for both V114-SC and V114-IM were greater than PCV13-SC (Supplemental Information, Tables S3 and S4).
DTaP–IPV antibody response rates at 1-month PD3 in both the V114-SC and V114-IM groups were comparable with the PCV13-SC group for all antigens included in DTaP–IPV (Supplemental information, Table S5) and at 1-month PD4 (data not shown).
Discussion
Administration of V114 via SC or IM routes is well tolerated and immunogenic for all 15 serotypes included in the vaccine in healthy Japanese infants. Results demonstrate that V114 vaccination via the SC or IM route at approximately 3, 4, 5, and 12–15 months of age has a safety profile comparable to that of PCV13 administered via the SC route. The overall proportions of participants with solicited AEs were comparable across vaccination groups, with the exception of fewer injection-site AEs associated with IM administration of V114 in comparison with V114-SC and PCV13-SC. These results observed in both vaccines with SC administration are consistent with another Japanese study that assessed V114 in healthy infants.Citation21 The differences observed in injection-site AEs between IM and SC routes have been commonly observed with the administration of other pediatric vaccines.Citation25,Citation26 Historically, in Japan, SC administration has been the preferred route for vaccines, due to reports of serious muscle contracture following IM administration.Citation31 However, increasing evidence suggesting that IM administration has a better safety profile than SC administration has led to the Japanese Pediatric society recommending that IM administration is implemented into childhood vaccinations.Citation32,Citation33 If this implementation is agreed, it would benefit individuals not only from a clinical perspective but also a logistical one, whereby less visits would be required for inoculation against multiple diseases. IM administration would provide increasing opportunity for co-administration of V114 alongside other pediatric vaccines, including DTaP–IPV, with which co-administration was directly assessed in this study.
Results of this Phase I study demonstrate that V114 generates robust immune responses to all 15 serotypes included in the vaccine in infants and toddlers when administered via the SC or IM routes. IgG response rates and GMCs for V114-SC and V114-IM at 1-month PD3 were generally comparable with PCV13-SC for all shared serotypes. For the two additional serotypes (22F and 33F) included in V114, IgG response rates and GMCs were greater among recipients of V114-SC or V114-IM compared with PCV13-SC. The immunogenicity of V114-SC and V114-IM was generally comparable at 1-month PD3. These results are consistent with the findings from a global study in addition to a local Japanese study in healthy infants.Citation21 In addition, co-administration of V114-SC and V114-IM with DTaP–IPV was comparable with the co-administration of PCV13-SC with DTaP–IPV in terms of the safety profile and immune responses to each of the antigens in DTaP–IPV. These results provide further evidence to support the introduction of V114 with both SC and IM routes into Japanese routine immunization schedules.
One limitation of this study is the small sample size assessed. This should be considered when interpreting immunogenicity results. In addition, this study was limited in scope to safety and immunogenicity. Real-world evidence will be required to demonstrate vaccine effectiveness.
In Japan, the burden of IPD is high in infants.Citation34,Citation35 Therefore, robust vaccine-induced immune responses following the infant vaccination series are important to protect infants <1 year of age, when they are most vulnerable to infection and are at the highest risk of developing meningitis. The findings of this study provide evidence to support the implementation of V114 into national infant immunization programs, broadening serotype coverage and potential protection against IPD, while continuously protecting against IPDs caused by shared serotypes with the current PCV.Citation36
Conclusion
In Japan, V114 administered via SC or IM routes in healthy infants at approximately 3, 4, 5, and 12–15 months of age is generally well tolerated and induces immune responses for all 15 serotypes. The results of this study support the routine use of V114, via the SC or IM route, co-administered with DTaP–IPV in infants and toddlers.
Author contributions
Y.I., H.K., H.H., and K.I. acquired and interpreted data and reviewed the manuscript.
K.W., M. Shirakawa and M. Sawata designed and conceived the study, analyzed and interpreted the data, and prepared and reviewed the manuscript.
Data sharing
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 EngageZone site or via e-mail to [email protected].
Supplemental Material
Download PDF (220.2 KB)Acknowledgments
The authors thank the patients, their families, and all investigators involved in this study. Medical writing support was provided by Lauren Moreton, MRes, and editorial support, including fact checking, referencing, figure preparation, formatting, proofreading, and submission was provided by Ian Norton, PhD, both of Scion, London, UK, according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22-1460).
Disclosure statement
H.K. has received honoraria for lectures from MSD K.K. K.W., M. Shirakawa and M. Sawata are employees of MSD K.K., Tokyo, Japan and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. Y.I., H.H., and K.I. have no conflicts of interest to report.
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2180973
Additional information
Funding
References
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