Pneumococcal infection is associated with high morbidity and mortality in adults ≥65 years of age and young children <5 years of age. There is a higher case fatality ratio due to invasive pneumococcal disease (IPD) (meningitis, sepsis/bacteremia without focus, bacteremic pneumonia) compared with non-IPD (sinusitis, otitis media, nonbacteremic pneumonia).1–3 In infants, IPD occurs as maternal antibodies wane, and bacteremia without focus is the most common manifestation. In the United States, Streptoococcus pneumoniae is a common cause of acute otitis media and leading cause of bacterial meningitis in children younger than 5 years of age.3 With the introduction of pneumococcal vaccines, the mortality estimate has decreased from over 1 million deaths in children <5 years of age in 2000 to approximately 300,000 in children <5 years of age in 2015, with the greatest burden in developing countries.4–7
Several pneumococcal conjugate vaccines (PCVs) have been developed to address the burden of pneumococcal disease in children. A 7-valent PCV containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (PCV7: Prevnar; Pfizer, Philadelphia, PA) was first introduced in 2000 followed later by 10-valent PCV (PCV10: Synflorix; GlaxoSmithKline, Rixensart, Belgium) and 13-valent PCV (PCV13: Prevnar 13; Pfizer, Philadelphia, PA).8,9 Widespread use of PCVs has been associated with significant reduction in hospitalizations for pneumonia, as well as nasopharyngeal carriage and IPD caused by the serotypes included in these vaccines, both in vaccinated children and unvaccinated individuals from other age groups (herd protection).9–18 This impact of PCV13 on IPD caused by serotype 3 has not been observed; in many countries, the incidence of serotype 3 IPD has remained relatively stable.19,20 This in part could be due to the higher estimated IgG concentration needed for protection against IPD caused by serotype 3 than levels measured following vaccination of infants with PCV13.21
In children, IPD due to pneumococcal serotypes not contained in currently available PCVs remains a concern. With the introduction of PCV7 and PCV13, serotype replacement and increased prevalence of IPD due to serotypes not included in the licensed PCV has been observed.22 IPD caused by serotypes 3, 6A, 7F and 19A increased following widespread use of PCV7 in the United States and many countries worldwide.4,9 For example, the proportion of IPD caused by serotype 19A in US children was approximately 3% before the introduction of PCV7; however, after introduction of PCV7, which does not include serotype 19A, the prevalence increased to approximately 47%.4,23,24 A similar increase was observed in other countries, including Australia, Canada, France, Israel, New Zealand and the United Kingdom, where serotype 19A accounted for 4%–10% of IPD but increased to 15%–45% after introduction of PCV7.5,9,22 Following the introduction of PCV13, a similar serotype replacement has been observed in IPD caused by serotypes 22F and 33F. Although only contributing for 1.2% of all IPD cases in US children under 5 years of age in 1998–1999, IPD caused by these 2 serotypes increased between 2010 and 2014 to approximately 11%–17% and 10%–12% for 22F and 33F, respectively.4,22,25,26 This phenomenon of serotype replacement substantiates the need for the development of more broadly based pneumococcal conjugate vaccines.25,27–29
V114 is an investigational 15-valent pneumococcal conjugate vaccine (diphtheria CRM197 protein; Merck & Co., Inc.) that contains the 13 serotypes in PCV13 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) plus serotypes 22F and 33F.30 Early studies of V114 tested hypotheses related to pneumococcal polysaccharide concentrations, adjuvant amount and conjugation process parameters as it relates to immunogenicity, which led to an improved formulation that demonstrated improved antibody responses in infants.31,32 In consideration of the findings from the small phase 1/2 study evaluating the new vaccine formulation, and to demonstrate reproducibility in a larger number of infants, this phase 2 study was conducted to compare the safety, tolerability and immunogenicity of V114 compared with PCV13 in healthy infants (V114-008; NCT02987972; EudraCT 2016-001117-25).
This randomized, multisite, double-blind phase 2 study compared the safety, tolerability and immunogenicity profiles of 2 different lots of V114 compared with PCV13 in healthy infants 6–12 weeks of age. It was conducted from March 21, 2017, through July 9, 2019, at 47 sites (Finland , Spain , Israel , Denmark , Canada  and the United States ). The study was designed to enroll approximately 1050 participants randomized in a 1:1:1 ratio to either V114 Lot 1, V114 Lot 2 or PCV13 vaccination groups. Two different lots of V114 were included in the study to ensure manufacturing consistency and support for further clinical development. A 0.5-mL dose of study vaccine was administered intramuscularly to healthy infants at approximately 2, 4, 6 and 12–15 months of age. Study vaccines were administered concomitantly with other routine pediatric vaccines per local guidelines.
Blood samples were collected at 3 time points: (1) approximately 1 month following the third study vaccination (postdose 3 [PD3]), (2) immediately before administration of the fourth study vaccination (predose 4) and (3) approximately 1 month following the fourth study vaccination (PD4). Sera were used to measure vaccine-induced pneumococcal-specific immune responses (IgG and opsonophagocytic killing activity [OPA]). These serum samples were assayed using the pneumococcal electrochemiluminescence assay, which was developed by Merck & Co., Inc., for the measurement of serotype-specific pneumococcal capsular polysaccharide IgG antibodies.33,34 Serum samples were also assayed using a microcolony multiplex opsonophagocytic assay (MOPA), developed by Merck & Co., Inc.35
To ensure that infants achieved adequate protection against pneumococcal disease caused by PCV13 serotypes before reaching 12 months of age, a rescue criterion was implemented after measurement of immune responses following the primary infant series. The use of the ≥0.35-μg/mL threshold value has been recommended as an acceptable threshold value for evaluating the clinical performance of pneumococcal conjugate vaccines.36,37 As soon as serologic results were available, any study subject who had serotype-specific IgG geometric mean concentration (GMC) <0.35 µg/mL for serotype 19A individually or ≥4 serotypes in common between V114 and PCV13 was discontinued from the study for lack of efficacy and given 1 dose of licensed PCV13, typically by 10–11 months of age (Table, Supplemental Digital Content 1, http://links.lww.com/INF/E54).
Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination on a validated hand-held electronic Vaccine Report Card. Solicited injection-site AEs included redness, swelling, hard lump and pain/tenderness, and solicited systemic AEs included irritability, drowsiness, hives/welts and loss of appetite. Body temperature was measured days 1 through 7 postvaccination. Serious AEs were collected from the time the consent form was signed through the duration of participation in the study at 1-month PD4.
Serotype-specific antibody responses were assessed PD3 to test the hypothesis that V114 (either Lot 1 or Lot 2) was noninferior to PCV13 for the 13 shared serotypes based on the proportion of participants meeting serotype-specific IgG threshold value of ≥0.35 µg/mL. The statistical criterion for noninferiority corresponds to the lower bound of the adjusted 95% confidence interval (CI) of the proportion difference (V114 − PCV13) being greater than −0.15 for each of the 13 shared serotypes. The Miettinen and Nurminen approach was used for the comparison.38 Additionally, at PD3, within-group GMCs and GMC ratios (V114/PCV13) along with 2-sided 95% CIs were computed for each of the 2 V114 lots relative to PCV13 for all 15 serotypes included in V114. All statistical tests were conducted at the α = 0.05 (2-sided) level.
The secondary study objective was to evaluate the serotype-specific IgG GMCs of V114 Lot 1, V114 Lot 2 and PCV13, and the IgG GMC ratios between each of the 2 V114 lots and PCV13 for all 15 serotypes included in V114 at predose 4 and 1-month PD4. Additional study objectives were to: evaluate the serotype-specific IgG response rates of V114 Lot 1, V114 Lot 2 and PCV13, and the differences in IgG response rates between each of the 2 V114 lots and PCV13 for the 2 serotypes unique to V114 (22F and 33F) at 1-month PD3 and all 15 serotypes included in V114 at predose 4 and 1-month PD4; and to describe the proportions of subjects with OPA titer ≥lower limit of quantification and OPA geometric mean titers (GMTs) as measured by MOPA in subjects receiving V114 Lot 1, V114 Lot 2 and PCV13 for all 15 serotypes included in V114 at 1-month PD3, predose 4 and 1-month PD4.
The per-protocol (PP) population served as the primary population for the analysis of immunogenicity data in this study. The PP population consisted of those subjects who received the scheduled doses of study vaccine and had valid serology results available for each specific dose. The OPA analysis was conducted on a subset of the PP population which included approximately 50% of subjects enrolled from US sites with sufficient sera available to perform both the pneumococcal electrochemiluminescence and the MOPA testing on all 15 serotypes in V114 using a validated assay with serotype-specific lower limit of quantification values. The all-subjects-as-treated population was used for the analysis of safety data in this trial. The all-subjects-as-treated population consists of all randomized subjects who received at least 1 dose of study vaccine.
Of the 1051 participants randomized, 1044 participants received at least 1 dose of study vaccine, 927 (88.2%) completed the 4-dose vaccine regimen and 921 completed the final study visit (87.6%) (Figure, Supplemental Digital Content 2, http://links.lww.com/INF/E54). Overall, 130 (12.4%) participants discontinued the study. The number of participants who discontinued the study was generally comparable across vaccination groups. The 2 most common reasons for discontinuation were withdrawal by parent/guardian and meeting rescue criteria due to a lack of immune response at PD3.
The intervention groups were generally balanced for baseline characteristics such as age, gender, race and ethnicity (Table, Supplemental Digital Content 3, http://links.lww.com/INF/E54). The reported medical history conditions, prior medications and concomitant medications were balanced across vaccination groups.
Vaccination with V114 Lot 1, V114 Lot 2 or PCV13 was generally well tolerated. Most participants (>96%) experienced ≥1 AEs after any vaccination, and the overall proportions of injection-site or systemic AEs were generally comparable across vaccination groups (Table 1); summaries of AEs following each dose are shown in Tables, Supplemental Digital Content 4, http://links.lww.com/INF/E54-7 and http://links.lww.com/INF/E54.
Most participants (75%) experienced ≥1 injection-site AEs following any vaccination through the end of study. Injection site AEs were more frequent PD1 and PD2 in the V114 groups compared with the PCV13 group, although the frequency of injection site AEs, including injection site pain, was comparable across all vaccination groups PD3 and PD4 (Tables, Supplemental Digital Content 4, http://links.lww.com/INF/E54-7; and http://links.lww.com/INF/E54). The majority of solicited injection site reactions across the 3 treatment groups were mild to moderate in intensity (Fig. 1).
The majority of vaccine-related systemic AEs were those solicited in the trial, including irritability, drowsiness (somnolence) and appetite loss (decreased appetite) (Table, Supplemental Digital Content 8, http://links.lww.com/INF/E54). Other vaccine-related systemic AEs reported with a frequency of ≥5% included pyrexia and diarrhea. The overall proportions of participants with vaccine-related systemic AEs were comparable across vaccination groups. Similar trends were observed following each vaccination (Tables, Supplemental Digital Content 4, http://links.lww.com/INF/E54-7; and http://links.lww.com/INF/E54).
Elevated temperatures were reported at comparable frequencies across the 3 treatment groups following any vaccination, with comparable frequencies reporting an elevated body temperature ≥39.0°C (≥102.2°F) through 7 days following vaccination.
The incidence of participants who experienced serious adverse events (SAEs) was low (5%) and comparable across vaccination groups. During the study, 1 participant died (sudden infant death of unknown cause; 19 days PD1, V114 Lot 1), and the event was considered not related to study vaccine by the investigator. Two participants experienced vaccine-related SAEs; 1 participant experienced febrile convulsion 2 days PD1 (V114 Lot 2) and discontinued study vaccine. Another participant experienced purpura, categorized as mild, 2 days PD4 (V114 Lot 2).
Antibody Responses 1-Month PD3
For both lots of V114, noninferiority was demonstrated for each of the 13 shared serotypes compared with PCV13 as assessed by IgG response rates at 1-month PD3 (Fig. 2). The lower bound of the 2-sided 95% CI for the between-treatment difference in response rates was >−15% points for all 13 shared serotypes. Response rates at 1-month PD3 were generally comparable across the treatment groups for the 13 common serotypes, with some serotype-specific variability noted. In V114 (either Lot 1 or Lot 2), response rates ranged from 92.3% to 100% for serotype 6B and 19F, respectively, while in PCV13 response rates ranged from 71.7% to 99% for serotype 3 and 7F, respectively. Serotype-specific IgG GMCs at 1-month PD3 were generally comparable between V114 Lot 1, V114 Lot 2 and PCV13 for the 13 shared serotypes (Fig. 3). Serotype-specific concentrations did vary for the serotypes in common, with notably higher and lower concentrations observed for serotype 14 and serotype 3, respectively, irrespective of treatment group. Although numerical differences were observed for some serotypes between V114 (either Lot 1 or Lot 2) and PCV13, no formal hypotheses were tested.
Response rates and IgG GMCs at 1-month PD3 were higher for the 2 serotypes unique to V114 (22F and 33F) for both lots of V114 when compared with PCV13 (Figs. 2 and 3).
Antibody Responses Predose 4 and 1-Month PD4
In all treatment groups, response rates generally decreased predose 4 compared with PD3 (Figure, Supplemental Digital Content 9, http://links.lww.com/INF/E54), and response rates increased 1-month PD4 for all serotypes across the treatment groups (Figure, Supplemental Digital Content 10, http://links.lww.com/INF/E54), indicating the establishment of a memory response. Interestingly, higher response rates, IgG GMCs, OPA response rates and OPA GMTs were observed at all time points for serotype 3 in recipients of both lots of V114 compared with PCV13. For the 13 shared serotypes, IgG GMCs predose 4 and 1-month PD4 varied by serotype but were generally comparable across the V114 Lot 1, V114 Lot 2 and PCV13 groups (Figure, Supplemental Digital Content 11, http://links.lww.com/INF/E54). Serotype 22F and 33F response rates and IgG GMCs predose 4 and 1-month PD4 were higher in the V114 Lot 1 and V114 Lot 2 groups compared with the PCV13 group (Figure, Supplemental Digital Content 12, http://links.lww.com/INF/E54).
Reverse cumulative distribution curves show that IgG concentrations at 1-month PD3 and PD4 were generally comparable across the 3 vaccination groups for the 13 shared serotypes between V114 and PCV13 (Figures, Supplemental Digital Content 13, http://links.lww.com/INF/E54-27; http://links.lww.com/INF/E54).
OPA was measured in a subset of approximately 100 infants enrolled in the United States who had sufficient blood volume to measure both IgG and OPA. In general, the trends in serotype-specific OPA response rates and GMTs observed at 1-month PD3 (Table 2), predose 4 and 1-month PD4 were comparable to the trends observed in IgG antibody responses at each respective time point.
There were 33 (3.5%) participants who met the protocol-specified rescue criterion for lack of immune response, and these participants were offered vaccination with licensed PCV13 after discontinuation from the study. The proportion of participants meeting rescue criterion was balanced across vaccination groups (Table, Supplemental Digital Content 1, http://links.lww.com/INF/E54).
This study demonstrated that the immune responses of both V114 Lot 1 and V114 Lot 2 were noninferior to PCV13 for all 13 shared serotypes. Higher immunogenicity for serotype 3 was observed for both lots of V114 compared with PCV13. This is noteworthy given the conflicting evidence regarding effectiveness of PCV13 against serotype 3 IPD and the lack of a well-accepted antibody threshold required for protection.21,39–41 The overall significance of this observation for serotype 3 is unclear, as this observation is limited to immunogenicity. Lower IgG GMC for serotype 6A was observed for both lots of V114 compared with PCV13; however, the difference was more pronounced at the PD3 time point than at the PD4 time point. The observed difference in serotype-specific IgG GMCs may not be clinically relevant as >90% of subjects across the 3 vaccination groups have IgG GMCs >0.35 µg/mL, significantly higher than the estimated IgG threshold value needed for protection against IPD caused by serotype 6A of approximately 0.16 µg/mL. Serotype-specific variability was noted, and GMCs were lower for some serotypes in V114 compared with PCV13, similar to the variability observed when PCV13 was compared with PCV7.42 Importantly, this study was not powered to assess the significance of the differences in GMCs. Additionally, the GMCs represent an average concentration and may be influenced by outliers in a clinical trial. For these reasons, reverse cumulative distribution curves are included to provide a more comprehensive representation of clinical vaccine performance for all serotypes in V114 and PCV13.21
It is important to note the high response rates and IgG GMCs for the 2 serotypes unique to V114 (22F and 33F), as these serotypes are responsible for an increased percentage of IPD cases in children and adults in countries where PCVs are included in the infant immunization program. Including these 2 additional serotypes 22F and 33F in a pneumococcal conjugate vaccine is a relevant approach to address the overall global burden of pneumococcal disease.
While there was a higher incidence of solicited injection-site pain observed with V114 PD1 and PD2, this finding was not observed at the other postdose time points. Rates of systemic AEs, elevated temperatures and SAEs were generally comparable across the 3 vaccination groups and of mild-to-moderate intensity, and the safety profile observed in this study was consistent with safety reported in previous V114 pediatric trials.31,32 The majority of the reported injection-site and systemic AEs in all 3 vaccination groups were transient and mild-to-moderate intensity. Overall, vaccination with V114 was generally well tolerated, with a safety profile generally comparable to PCV13.
These study results showed reproducibility of immune response rates of the new V114 formulation demonstrated in an earlier study.31,32 Where earlier studies investigated different formulations of polysaccharide and adjuvant concentrations, the results from this study give confidence to the current formulation and demonstrate manufacturing consistency. Additionally, the results were reproduced in a larger, geographically diverse patient population, thus increasing generalizability. Similarly, acceptable immune responses with this formulation have also been demonstrated in adult populations 50 years of age and older.39,43
The results of this study are limited to immunogenicity because noninferiority for the 13 serotypes shared by V114 and PCV13 was demonstrated based on the difference in response rates using the World Health Organization-accepted threshold value of 0.35 µg/mL, which does represent a correlate of efficacy against IPD for many serotypes included in PCV13. Additionally, while high response rates and GMCs were observed for serotypes 22F and 33F, there are no data on the antibody threshold needed to protect against IPD due to these serotypes.
In conjunction with comparable general tolerability and an acceptable safety profile, V114 demonstrated noninferior immune responses for all serotypes in common with PCV13 and higher immune responses for the 2 unique serotypes, thus supporting the continued evaluation of this more broadly based PCV in phase 3 development.
The V114-008 Study Group would like to thank all of the patients and parents who participated in this trial. We also thank Jon E. Stek and Karyn Davis of Merck, Sharp, & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA for their assistance with this publication. The trial was approved by the institutional review board or independent ethics committee at each participating site and conducted in adherence with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines and local regulatory requirements. Safety and tolerability were monitored throughout the trial by both the sponsor in accordance with standard procedures and by an external Data Monitoring Committee. The members of V114-008 study group are as follows: Canada: Marc Dionne, Caroline Quach, Earl Rubin and Bruce Tapiero; Denmark: Jens Fuglsang and Pernille Ravn; Finland: Anitta Ahonen, Aino Forsten, Satu Kokko, Tiina Karppa, Marita Paassilta, Ilkka Seppa, Benita Ukkonen and Miia Virta; Israel: David Greenberg; Spain: Alfonso Carmona and Federico Martinon Torres; United States: Claude T. Ashley, Christopher V. Chambers, Robert A. Clifford, Marilou G. Cruz, Cheryl A. Duffy, Daniel J. Finn, Byron L. Haney, Marie Harper, David C. Hurley, Michael P. Husseman, William H. Johnston Jr., Sherif Z. Khamis, Nicola P. Klein, Joseph B. Leader, Joseph A. Ley, Gary S. Marshall, Christopher B. Peltier, Kevin G. Rouse, Richard E. Rupp, Martha K. Saunders, Shelly D. Senders, Steven A. Shapiro, Julie S. Shepard, Mary D. Tipton, Meera Varman, Leonard B. Weiner, Paul P. Wisman Jr and Mark Wolffarth.
1. Robinson KA, Baughman W, Rothrock G, et alActive Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network. Epidemiology of invasive Streptococcus pneumoniae
infections in the United States, 1995-1998: opportunities for prevention in the conjugate vaccine era. JAMA. 2001;285:1729–1735.
2. Center for Disease Control and Prevention. Active bacterial core surveillance (abcs) report emerging infections program network streptococcus pneumonia. 1997 [web-based report]. Available at: https://www.cdc.gov/abcs/index.html
. Accessed March 29, 2018.
3. Hamborsky J, Kroger A, Wolfe SCenters for Disease Control and Prevention. In: Epidemiology and Prevention of Vaccine-Preventable Disease. 2015.13th ed. Washington, DC: Public Health Foundation,
4. Pilishvili T, Lexau C, Farley MM, et alActive Bacterial Core Surveillance/Emerging Infections Program Network. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32–41.
5. Wahl B, O’Brien KL, Greenbaum A, et al.Burden of Streptococcus pneumoniae
and Haemophilus influenzae
type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15. Lancet Glob Health. 2018;6:e744–e757.
6. O’Brien KL, Wolfson LJ, Watt JP, et alHib and Pneumococcal Global Burden of Disease Study Team. Burden of disease caused by Streptococcus pneumoniae
in children younger than 5 years: global estimates. Lancet. 2009;374:893–902.
7. World Health Organization. Estimates of disease burden and cost-effectiveness. 2015. Available at: https://www.who.int/immunization/monitoring_surveillance/burden/estimates/en/
. Accessed June 16, 2020.
8. Huang SS, Johnson KM, Ray GT, et al.Healthcare utilization and cost of pneumococcal disease in the United States. Vaccine. 2011;29:3398–3412.
9. Izurieta P, Bahety P, Adegbola R, et al.Public health impact of pneumococcal conjugate vaccine
infant immunization programs: assessment of invasive pneumococcal disease burden and serotype distribution. Expert Rev Vaccines. 2018;17:479–493.
10. Kaplan SL, Center KJ, Barson WJ, et al.Multicenter surveillance of Streptococcus pneumoniae isolates from middle ear and mastoid cultures in the 13-valent pneumococcal conjugate vaccine
era. Clin Infect Dis. 2015;60:1339–1345.
11. Richter SS, Diekema DJ, Heilmann KP, et al.Changes in pneumococcal serotypes and antimicrobial resistance after introduction of the 13-valent conjugate vaccine in the United States. Antimicrob Agents Chemother. 2014;58:6484–6489.
12. Desai AP, Sharma D, Crispell EK, et al.Decline in pneumococcal nasopharyngeal carriage of vaccine serotypes after the introduction of the 13-Valent Pneumococcal conjugate vaccine
in children in Atlanta, Georgia. Pediatr Infect Dis J. 2015;34:1168–1174.
13. Angoulvant F, Levy C, Grimprel E, et al.Early impact of 13-valent pneumococcal conjugate vaccine
on community-acquired pneumonia in children. Clin Infect Dis. 2014;58:918–924.
14. Griffin MR, Zhu Y, Moore MR, et al.U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155–163.
15. Simonsen L, Taylor RJ, Schuck-Paim C, et al.Effect of 13-valent pneumococcal conjugate vaccine
on admissions to hospital 2 years after its introduction in the USA: a time series analysis. Lancet Respir Med. 2014;2:387–394.
16. Synflorix [package insert]. Rixensart, belgium: Glaxosmithkline biologicals s.A. 2018. Availalbe at: https://www.who.int/immunization_standards/vaccine_quality/Synflorix_WHO_leaflet_EN_May_2011.pdf
. Accessed March 29, 2018.
17. Palmu AA, Jokinen J, Nieminen H, et al.Vaccine effectiveness of the pneumococcal Haemophilus influenzae
protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial. Lancet Respir Med. 2014;2:717–727.
18. Tregnaghi MW, Sáez-Llorens X, López P, et alCOMPAS Group. Efficacy of pneumococcal nontypable Haemophilus influenzae
protein D conjugate vaccine (PHiD-CV) in young Latin American children: a double-blind randomized controlled trial. PLoS Med. 2014;11:e1001657.
19. Pilishvili T13-valent pneumococcal conjugate vaccine
(pcv-13) effects on disease caused by serotype 3. National center for immunization and respiratory disease. Advisory committee on immunization practices. Available at https://stacks.cdc.gov/view/cdc/78091
. Accessed June 19, 2020.
20. Tin Tin Htar M, Morato Martínez J, Theilacker C, et al.Serotype evolution in Western Europe: perspectives on invasive pneumococcal diseases (IPD). Expert Rev Vaccines. 2019;18:1145–1155.
21. Andrews NJ, Waight PA, Burbidge P, et al.Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine
: a postlicensure indirect cohort study. Lancet Infect Dis. 2014;14:839–846.
22. Balsells E, Guillot L, Nair H, et al.Serotype distribution of Streptococcus pneumoniae
causing invasive disease in children in the post-PCV era: a systematic review and meta-analysis. PLoS One. 2017;12:e0177113.
23. Kaplan SL, Barson WJ, Lin PL, et al.Serotype 19A is the most common serotype causing invasive pneumococcal infections in children. Pediatrics. 2010;125:429–436.
24. Pelton SI, Huot H, Finkelstein JA, et al.Emergence of 19A as virulent and multidrug resistant Pneumococcus in Massachusetts following universal immunization of infants with pneumococcal conjugate vaccine
. Pediatr Infect Dis J. 2007;26:468–472.
25. Moore MR, Link-Gelles R, Schaffner W, et al.Effect of use of 13-valent pneumococcal conjugate vaccine
in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis. 2015;15:301–309.
26. Moore MR, Link-Gelles R, Schaffner W, et al.Effectiveness of 13-valent pneumococcal conjugate vaccine
for prevention of invasive pneumococcal disease in children in the USA: a matched case-control study. Lancet Respir Med. 2016;4:399–406.
27. Yildirim I, Hanage WP, Lipsitch M, et al.Serotype specific invasive capacity and persistent reduction in invasive pneumococcal disease. Vaccine. 2010;29:283–288.
28. Demczuk WH, Martin I, Griffith A, et alToronto Bacterial Diseases Network; Canadian Public Health Laboratory Network. Serotype distribution of invasive Streptococcus pneumoniae
in Canada after the introduction of the 13-valent pneumococcal conjugate vaccine
, 2010-2012. Can J Microbiol. 2013;59:778–788.
29. Waight PA, Andrews NJ, Ladhani SN, et al.Effect of the 13-valent pneumococcal conjugate vaccine
on invasive pneumococcal disease in England and Wales 4 years after its introduction: an observational cohort study. Lancet Infect Dis. 2015;15:535–543.
30. Sobanjo-ter Meulen A, Vesikari T, Malacaman EA, et al.Safety
, tolerability and immunogenicity
of 15-valent pneumococcal conjugate vaccine
in toddlers previously vaccinated with 7-valent pneumococcal conjugate vaccine
. Pediatr Infect Dis J. 2015;34:186–194.
31. Greenberg D, Hoover PA, Vesikari T, et al.Safety
of 15-valent pneumococcal conjugate vaccine
(PCV15) in healthy infants. Vaccine. 2018;36:6883–6891.
32. Rupp R, Hurley D, Grayson S, et al.A dose ranging study of 2 different formulations of 15-valent pneumococcal conjugate vaccine
(PCV15) in healthy infants. Hum Vaccin Immunother. 2019;15:549–559.
33. Marchese RD, Puchalski D, Miller P, et al.Optimization and validation of a multiplex, electrochemiluminescence-based detection assay for the quantitation of immunoglobulin G serotype-specific antipneumococcal antibodies in human serum. Clin Vaccine Immunol. 2009;16:387–396.
34. Nolan KM, Bonhomme ME, Schier CJ, et al.Optimization and validation of a microcolony multiplexed opsonophagocytic killing assay for 15 pneumococcal serotypes. Bioanalysis. 2020. In press.
35. Burton RL, Nahm MHDevelopment and validation of a fourfold multiplexed opsonization assay (MOPA4) for pneumococcal antibodies. Clin Vaccine Immunol. 2006;13:1004–1009.
36. Siber GR, Chang I, Baker S, et al.Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007;25:3816–3826.
37. Nolan K, Zhang Y, Antonello JM, et al.Enhanced anti-pneumococcal antibody electrochemiluminescence assay: validation and bridging to the who reference elisa. Bioanalysis. 2020. In press.
38. Miettinen O, Nurminen MComparative analysis of two rates. Stat Med. 1985;4:213–226.
39. Stacey HL, Rosen J, Peterson JT, et al.Safety
of 15-valent pneumococcal conjugate vaccine
(PCV-15) compared to PCV-13 in healthy older adults. Hum Vaccin Immunother. 2019;15:530–539.
40. World Health Organization, weekly epidemiological report, pneumococcal conjugate vaccines in infants and children under 5 years of age. 2019;94:85–104. Available at: https://www.who.int/wer/2019/wer9408/en/
41. Sings HL, De Wals P, Gessner BD, et al.Effectiveness of 13-valent pneumococcal conjugate vaccine
against invasive disease caused by serotype 3 in children: a systematic review and meta-analysis of observational studies. Clin Infect Dis. 2019;68:2135–2143.
42. Grant LR, O’Brien SE, Burbidge P, et al.Comparative immunogenicity
of 7 and 13-valent pneumococcal conjugate vaccines and the development of functional antibodies to cross-reactive serotypes. PLoS One. 2013;8:e74906.
43. Peterson JT, Stacey HL, MacNair JE, et al.Safety
of 15-valent pneumococcal conjugate vaccine
compared to 13-valent pneumococcal conjugate vaccine
in adults ≥65 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Hum Vaccin Immunother. 2019;15:540–548.