A phase 3, single-arm, open-label study to evaluate the safety, tolerability, and immunogenicity of a 15-valent pneumococcal conjugate vaccine, V114, in a 3+1 regimen in healthy infants in South Korea (PNEU-PED-KOR)

ABSTRACT

There is an ongoing burden of pneumococcal disease in children despite the use of pneumococcal conjugate vaccines (PCVs). This phase 3, open-label, single-arm, multisite, descriptive study was designed to evaluate the safety and immunogenicity of a 3 + 1 regimen of V114 (VAXNEUVANCE™), a 15-valent PCV, in South Korean infants and toddlers. Adverse events (AEs) were reported for 14 d following any vaccination, and throughout the study period for serious AEs. Serotype-specific immunoglobulin G (IgG) response rates (proportion of participants meeting an IgG threshold value of ≥0.35 μg/mL) and geometric mean concentrations (GMCs) for the 15 serotypes at 30 d postdose 3 (PD3) and at 30 d postdose 4 (PD4) were evaluated as endpoints. Healthy infants enrolled at 42–90 d after birth were vaccinated with V114 (N = 57). The most commonly reported AEs were those solicited in the trial. The majority of reported AEs were transient and of mild or moderate intensity. Few serious AEs were reported; none were vaccine related. No participants died nor discontinued the study vaccine because of an AE. V114 was immunogenic for all 15 serotypes contained in the vaccine, as assessed by IgG response rates at 30 d PD3 and IgG GMCs at 30 d PD3 and at 30 d PD4. V114 was well tolerated and immunogenic when administered as a 3 + 1 regimen in healthy South Korean infants and toddlers.

KE Y POINTS

Despite the use of pneumococcal vaccines, the burden of pneumococcal disease in children persists. V114, a 15-valent pneumococcal conjugate vaccine, was immunogenic and well-tolerated in healthy South Korean infants and toddlers.

KEYWORDS:

• Vaxneuvance™
• PCV15
• pneumococcal conjugate vaccine
• infants
• toddlers

Introduction

Streptococcus pneumoniae is the causative pathogenic bacterium for pneumococcal infections and invasive pneumococcal disease (IPD; e.g., meningitis, bacteremia, and bacteremic pneumonia). More than 100 distinct serotypes have been identified for S. pneumoniae.^1–3 Children <5 years of age are more susceptible to pneumococcal disease, which significantly increases the risk of morbidity and mortality, with children <2 years of age being particularly vulnerable.^4,5 The introduction and adoption of pneumococcal conjugate vaccines (PCVs) into pediatric national immunization programs (NIPs) have resulted in significant reductions in IPD incidence caused by vaccine-type (VT) serotypes.² However, worldwide mortality and morbidity caused by pneumococcal disease remain high, in part, due to the emergence of nonvaccine serotypes and the persistence of certain vaccine serotypes, such as serotype 3.^1,2,6

In South Korea, a significant decrease in IPD caused by 7-valent PCV (PCV7) serotypes was observed after its introduction in 2000, with an accompanying increase in infections caused by non-PCV7 serotypes. Similar trends in serotype replacement were observed when 10-valent PCV (PCV10) replaced PCV7 in 2010, and subsequently when PCV10 and 13-valent PCV (PCV13) were both introduced into the NIP of South Korea in 2014.^1,7 While there was a relatively stable drop in the incidence of IPD due to most PCV13 serotypes in children (<1 case of IPD/100 000 population), the rate in the elderly population remained high (1.3/100 000 in 2015–2017 and 2.5/100 000 in 2018–2019).⁸ Despite the introduction of PCV13 (which includes serotype 3), some VT serotypes have persisted with significant prevalence. From 2017 to 2019, the prevalence rates for serotype 3 in South Korean children ≤5 years of age and in adults >18 years of age were 2.3% and 34.8%, respectively.^1,2

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.⁹ These additional serotypes have been associated with serious clinical outcomes (including meningitis, bacteremia, sepsis, osteomyelitis, bacteremic pneumonia, and septic arthritis), which indicate their relatively high degree of severity in comparison with other serotypes not currently covered by licensed PCVs.^2,10,11 Moreover, serotypes 22F and 33F have demonstrated resistance to several important classes of antibiotic.^2,12 From 2017 to 2019 in South Korea, serotypes 22F and 33F accounted for 6.1% and 0.7% of the IPD burden in the overall population, respectively (N = 411), and 2.3% each in children ≤5 years of age (n = 43).¹ V114 is currently licensed in 52 countries globally. In the European Union, V114 is indicated for active immunization for the prevention of invasive disease, pneumonia, and acute otitis media caused by S. pneumoniae in infants, children, and adolescents from 6 weeks to <18 years of age, and for the prevention of IPD and pneumonia in individuals ≥18 years of age.¹³

The present study, PNEU-PED-KOR (Protocol V114–036), is a phase 3 study that evaluated the safety, tolerability, and immunogenicity of V114 administered in a 3 + 1 regimen in healthy South Korean infants.¹⁴ The 3 + 1 PCV immunization schedule is currently recommended by the Korean Advisory Committee on Immunization Practices (KAIC) for infants and toddlers.¹⁵

Methods

Study design

This study was a phase 3, open-label, single-arm, multicenter study to evaluate the safety, tolerability, and immunogenicity of a four-dose regimen of V114 (three doses in the infant primary series followed by a toddler dose) in healthy South Korean infants.¹⁴ Overall, 58 infants were enrolled to receive V114 at 2, 4, 6, and 12–15 months of age.

This study was conducted in accordance with local and/or national regulations (including all applicable data protection laws and regulations), International Conference on Harmonization Good Clinical Practice guidelines, and the ethical principles that have their origin in the Declaration of Helsinki regarding Independent Ethics Committee review, informed consent, and the protection of human participants in biomedical research.

Participants

South Korean infants who were healthy (based on the clinical judgment of the investigator) and approximately 42–90 days of age (inclusive) at the time of informed consent were enrolled in the study. Written informed consent was provided by a parent or legally acceptable representative who understood the study procedures and risks involved with the study. Key exclusion criteria included history of IPD or other known culture-positive pneumococcal disease; known hypersensitivity to a vaccine component; recent febrile illness (rectal temperature ≥38.1°C or axillary temperature ≥37.8°C 72 h prior to receipt of study vaccine); known/suspected impairment of immunologic function or congenital or acquired immunodeficiency; and having received a dose of any pneumococcal vaccine before study entry.

The study permitted the concomitant administration of routine childhood vaccines according to the local recommended pediatric vaccination schedule. Immunizations with any live vaccine within 28 days before and 14 days after receipt of the study vaccine, or any non-live vaccine 14 days before/after study vaccine, were not permitted. Inactivated influenza vaccination was allowed if given at least 7 days before or 15 days after the study vaccine. Non-study medications were permitted prior to, or during, the study, with a few exceptions (recent systemic corticosteroids, immunosuppressive therapies, or receipt of blood transfusion/products, including immunoglobulin G [IgG]).

Study vaccine and administration

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.⁹

Safety assessment

Safety endpoints and objectives

The primary objective was to evaluate the safety and tolerability of V114 in healthy South Korean infants. Primary endpoints included solicited injection-site adverse events (AEs) from days 1–7 following any vaccination, solicited systemic AEs from days 1–7 postvaccination, and vaccine-related serious AEs (SAEs) following dose 1 through the study completion.

Safety analysis

Using a paper Vaccination Report Card (VRC), parents or legal guardians of participants recorded safety data for 14 days after each vaccine dose for non-serious AEs, and throughout the study period for SAEs. In addition, solicited daily maximum body temperatures (rectal/axillary) were recorded via VRC on days 1–7 following each vaccination, and on days 8–14 postvaccination if fever was suspected. Solicited AEs in the study were injection-site AEs (swelling, erythema, pain/tenderness, and induration) and systemic AEs (irritability, somnolence, loss of appetite, and urticaria). Pyrexia was an unsolicited AE.

Safety was evaluated after each vaccine dose in the 'all participants as treated' population, which included all enrolled participants who received study vaccine. Recorded events and complaints were subsequently assessed by the study investigator to determine whether they met protocol-defined AE criteria and to assess the causality relationship to study vaccine, event duration, maximum size (solicited injection-site swelling, erythema, and induration), and intensity (solicited injection-site pain, irritability, loss of appetite, somnolence, and urticaria). Solicited injection-site swelling, erythema, and induration were classified as mild (measuring 0 to ≤1 inch [~2.5 cm]), moderate (>1 to ≤3 inches [~7.6 cm]), or severe (>3 inches). Estimated confidence intervals (CIs) were calculated based on the exact binomial method proposed by Clopper and Pearson, provided in accordance with the statistical analysis plan. The limb used for administration of the study vaccine was recorded at the time of vaccination.

Immunogenicity assessment

Immunogenicity endpoints and objectives

The primary immunogenicity objectives and endpoints were to evaluate serotype-specific IgG response rates for all 15 serotypes contained in V114 at 30 days postdose 3 (PD3) and serotype-specific IgG geometric mean concentrations (GMCs) at 30 days PD3. The secondary objective for the study was to evaluate serotype-specific IgG GMCs at 30 days postdose 4 (PD4) for all 15 serotypes contained in V114.

Immunogenicity analysis

The per-protocol population, defined as all enrolled participants without any deviations from protocol that could potentially affect the immunogenicity endpoints, was analyzed for primary and secondary immunogenicity. Blood samples were collected approximately 30 days PD3 and approximately 30 days PD4 for analysis of serotype-specific antibodies. Evaluation of IgG response rates and IgG GMCs at 30 days PD3 included descriptive summaries and 95% CIs. No formal statistical hypothesis testing was done for this study. 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).¹⁶ The 95% CIs for IgG response rates were calculated based on the Clopper and Pearson exact binomial method. Point estimates for IgG GMCs were calculated by exponentiating the estimates of the mean of the natural log values based on the t-distribution.

Results

Participants

A total of 58 participants in South Korea were enrolled in the study to receive V114. Of the participants enrolled, 57 (98.3%) were vaccinated with at least one dose of V114, 53 (91.4%) completed the study, and five (8.6%) discontinued. Four of five discontinuations were related to participant withdrawal from the study by the parent or legal guardian. One participant was enrolled in error (had received previous administration of PCV13 and was discontinued from the study without receipt of the study vaccine [Supplementary Figure S1]). Overall, the median age (range) of the study participants was 9 weeks (6–11) and 56.1% were female. All participants who received at least one dose of the study vaccine were of Asian descent (all South Koreans). Some participants (8.8%) of the study population were pre-term (born <37 weeks gestational age) (Table 1).

Table 1. Participant demographics and characteristics (all vaccinated participants).

	V114 (N = 57)^a
Sex
Female	32 (56.1)
Male	25 (43.9)
Age (weeks)
6	1 (1.8)
7	6 (10.5)
8	20 (35.1)
9	17 (29.8)
10	8 (14.0)
11	5 (8.8)
Mean (SD)	8.7 (1.2)
Median (range)	9.0 (6–11)
Country
South Korea	57 (100.0)
Gestational age at birth (weeks)
<37	5 (8.8)
≥37	52 (91.2)

Abbreviations: n, number of participants contributing to the analysis; N, number of participants enrolled and vaccinated; SD, standard deviation; V114, 15-valent pneumococcal conjugate vaccine.

^aData are n (%) unless otherwise indicated.

Safety

The majority of participants experienced one or more AE (n = 56, 98.2%). No participant died nor discontinued the study vaccine due to an AE (Table 2). A total of five SAEs (pyrexia, asymptomatic coronavirus disease 2019 [COVID-19], gastroenteritis norovirus, urinary tract infection, bacterial urinary tract infection) were reported in four (7%) participants (Supplementary Table S1). No SAEs were determined by the investigator to be related to the study vaccine. The majority of the solicited AEs reported were transient (≤3 days) (Supplementary Table S2) and of mild or moderate intensity (Figure 1).

Figure 1. Participants with solicited AEs (incidence >0%) by maximum intensity following any dose of V114.

Solicited AEs were collected from day 1 through day 7. For injection-site erythema, induration, and swelling, mild events were those measuring 0 to ≤1 inch (~2.5 cm), moderate events >1 to ≤3 inches (~7.6 cm), and severe events were >3 inches. Every participant is counted a single time for each applicable specific injection-site AE and is classified according to the highest non-missing size rating.

Abbreviations: AE, adverse event; V114, 15-valent pneumococcal conjugate vaccine.

Table 2. Summary of AEs following any dose (APaT population).

	V114 (N = 57)
	n (%)	95% CI^a
≥1 AE	56 (98.2)	(90.6–100.0)
Injection-site AEs	42 (73.7)
Systemic AEs	55 (96.5)
Vaccine-related AEs^b	56 (98.2)	(90.6–100.0)
Injection-site AEs	42 (73.7)
Systemic AEs	47 (82.5)
Serious AEs	4 (7.0)	(1.9–17.0)
Serious vaccine-related AEs^b	0 (0.0)	(0.0–6.3)
Deaths	0 (0.0)	(0.0–6.3)
Discontinued due to an AE	0 (0.0)	(0.0–6.3)

Abbreviations: AE, adverse event; APaT, all participants as treated; CI, confidence interval; n, number of participants contributing to the analysis; N, number of participants enrolled and vaccinated; V114, 15-valent pneumococcal conjugate vaccine.

^aEstimated CIs are calculated based on the exact binomial method proposed by Clopper and Pearson and are provided in accordance with the statistical analysis plan.

^bDetermined by the investigator to be related to the study vaccine.

Reported AEs include non-serious AEs that occurred within 14 days of any vaccinations and serious AEs that occurred from ~2 months of age (following dose 1) through completion of study participation.

The most frequently reported AEs following any V114 dose were the solicited systemic events of irritability (89.5%), somnolence (82.5%), and decreased appetite (71.9%) (Figure 1). The majority of solicited injection-site AEs of erythema, induration, and swelling, as reported by the parents or legal representative of participants, had events with maximum size of ≤1 inch (Supplementary Table S3). The majority of participants (61.4%) reported maximum body temperatures <39°C following any V114 dose (Supplementary Table S4).

Immunogenicity

IgG response rates were ≥95% for each of the 15 serotypes at 30 days PD3 (Supplementary Figure S2). At 30 days PD3, serotype-specific IgG GMCs ranged from 1.69 µg/mL (serotype 1) to 7.47 µg/mL (serotype 14) (Figure 2a). At 30 days PD4, serotype-specific IgG GMCs were generally numerically higher than 30 days PD3 for most serotypes and ranged from 1.32 µg/mL (serotype 3) to 9.20 µg/mL (serotype 22F) (Figure 2b). Reverse cumulative distribution curves for IgG concentrations were consistent with the results of the above immunogenicity analyses (Figure 3 and Supplementary Figure S3).

Figure 2. Summary of IgG GMCs at 30 days PD3 (a) and 30 days PD4 (b) of V114 (per-protocol population).

^aThe within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution.

Abbreviations: CI, confidence interval; GMC, geometric mean concentration; IgG, immunoglobulin G; N, number of participants enrolled and vaccinated; PD3, postdose 3; PD4, postdose 4; V114, 15-valent pneumococcal conjugate vaccine.

Figure 3. Serotype-specific reverse cumulative distribution curves of IgG concentrations for select serotypes at 30 days PD3 and 30 days PD4.

Abbreviations: n, number of participants contributing to this analysis; PD3, postdose 3; PD4, postdose 4; ST, serotype; V114, 15-valent pneumococcal conjugate vaccine.

Discussion

This open-label, single-arm clinical study was designed to evaluate the safety, tolerability, and immunogenicity of V114 when administered as a four-dose (3 + 1) regimen at approximately 2, 4, 6, and 12–15 months of age to healthy South Korean infants and toddlers, per standard of care, as recommended by the KAIC.

Overall, V114 was well tolerated in South Korean infants. Most postvaccination AEs were transient and generally of mild or moderate intensity. The most common AEs were those solicited in the study. There were no vaccine-related SAEs or discontinuations due to AEs. The safety and tolerability results of V114 observed in this study are generally comparable to the results from other published pediatric studies in the United States and globally.^17–21

V114 was robustly immunogenic for all 15 serotypes contained in the vaccine in infants and toddlers, as assessed by IgG response rates and IgG GMCs at 30 days PD3 and PD4. There were numerically higher immune responses at 30 days PD4 than at 30 days PD3 for all serotypes, except serotype 3; however, the immune response at PD4 was robust for serotype 3. The immune responses observed in South Korean infants herein are consistent with findings from a systematic review and meta-analysis after immunization with primary series of PCV7, PCV10, and PCV13, compared with each other in different geographical regions.²² As such, it is expected that V114 will offer protection against all vaccine serotypes, including expansion to two serotypes (22F and 33F) of substantial public health importance.

Conclusion

V114 was immunogenic and well tolerated when administered as a four-dose regimen (three-dose primary series followed by a toddler dose) in healthy South Korean infants and toddlers. These results support the routine use of V114 in children.

Author contributions

Alvino Maestri was involved in the acquisition of data, drafting of manuscript, interpretation of results, and critically reviewing or revising the manuscript.

Su Eun Park was involved in the acquisition of data and critically reviewing or revising the manuscript.

Fiona Fernandes was involved in the conception, design, or planning of the study, acquisition of data, and drafting of the manuscript.

Zhongyi “Lucy” Li was involved in the conception, design, or planning of the study, acquisition of data, analysis of data, interpretation of results, drafting manuscript, and critically reviewing or revising the manuscript.

Yae Jean Kim was involved in the acquisition of data, and critically reviewing or revising the manuscript.

Yun-Kyung Kim was involved in the acquisition of data and interpretation of results.

Jin Lee was involved in the acquisition of data, analysis of data, interpretation of results, and critically reviewing or revising the manuscript.

Ji Young Park was involved in the acquisition of data and analysis of data.

Dong Hyun Kim was involved in the acquisition of data, and critically reviewing or revising the manuscript.

GyongSeon Yang was involved in the conception, design, or planning of the study, and critically reviewing or revising the manuscript.

Hyunjung Lim was involved in the acquisition of data, analysis of data, and critically reviewing or revising the manuscript.

Jin Oh Kim was involved in the conception, design, or planning of the study, analysis of data, interpretation of results, and critically reviewing or revising the manuscript.

Robert Lupinacci was involved in the conception, design, or planning of the study, analysis of data, and interpretation of results.

Tina M. Sterling was involved in the interpretation of results, and critically reviewing or revising the manuscript.

Marissa Wilck was involved in the conception, design, or planning of the study, and critically reviewing or revising the manuscript.

Alejandra Esteves-Jaramillo was involved in the acquisition of data, interpretation of results, drafting manuscript, and critically reviewing or revising the manuscript.

Natalie Banniettis was involved in analysis of data, and critically reviewing or revising 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://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html).

Acknowledgments

The authors would like to thank the patients, their families, and all investigators involved in this study. Medical writing support, including assisting authors with the development of the outline and initial draft and incorporation of comments, was provided by Martina Kusi-Mensah, PharmD, of Scion, London, and editorial support, including fact checking, referencing, figure preparation, formatting, proofreading, and submission was provided by Ian Norton, PhD, of Scion, London, UK, according to Good Publication Practice 2022 guidelines (Link). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure statement

Fiona Fernandes is an ex-employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. Jin Oh Kim, GyongSeon Yang, and Hyunjung Lim are employees of MSD Korea and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. Jin Lee, Ji Young Park, Su Eun Park, Yun-Kyung Kim, and Dong Hyun Kim have no conflicts to disclose at this time. Yae-Jean Kim is an employee of MSD Korea and may have received funding for this research, provision of study materials, and article processing charges from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All other authors are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2321035.

Additional information

Funding

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