Implications of Cross-Reactivity and Cross-Protection for Pneumococcal Vaccine Development.

Pneumococcal vaccines are a cornerstone for the prevention of pneumococcal diseases, reducing morbidity and mortality in children and adults worldwide. Pneumococcal vaccine composition is based on the polysaccharide capsule of Streptococcus pneumoniae, which is one of the most important identified contributors to the pathogen's virulence. Similarities in the structural composition of polysaccharides included in licensed pneumococcal vaccines may result in cross-reactivity of immune response against closely related serotypes, including serotypes not included in the vaccine. Therefore, it is important to understand whether cross-reactive antibodies offer clinical protection against pneumococcal disease. This review explores available evidence of cross-reactivity and cross-protection associated with pneumococcal vaccines, the challenges associated with the assessment of cross-reactivity and cross-protection, and implications for vaccine design and development.

Cost-Effectiveness Analysis of Routine Childhood Immunization with 20-Valent versus 15-Valent Pneumococcal Conjugate Vaccines in Germany.

This study aimed to evaluate the cost-effectiveness of routine childhood immunization with the 20-valent pneumococcal conjugate vaccine (PCV20) in a four-dose regimen (3 + 1 schedule) versus the 15-valent PCV (PCV15/V114) in a three-dose regimen (2 + 1) in Germany. The study utilized a decision-analytic Markov model to estimate lifetime costs and effectiveness outcomes for a single birth cohort in Germany. The model tracked the incidence of acute pneumococcal infections and long-term pneumococcal meningitis sequelae for both vaccination strategies. The vaccine effectiveness data were derived from published clinical trials and observational studies of PCV7 and PCV13. Indirect effects, such as herd protection and serotype replacement, were included in the model. The model adopted a societal perspective, including direct medical, direct non-medical, and indirect costs. Scenario and sensitivity analyses were performed. In the base case, PCV20 prevented more pneumococcal disease cases and deaths, with an expected gain of 96 quality-adjusted life years (QALYs) compared to V114. However, PCV20 was associated with a total incremental cost of EUR 48,358,424, resulting in an incremental cost-effectiveness ratio (ICER) of EUR 503,620/QALY. Most of the scenario and sensitivity analyses estimated that the ICER for PCV20 exceeded EUR 150,000/QALY. Routine childhood immunization with PCV20 instead of V114 may not be an economically efficient use of healthcare resources in Germany.

Immunogenicity of Current and Next-Generation Pneumococcal Conjugate Vaccines in Children: Current Challenges and Upcoming Opportunities.

Global use of pneumococcal conjugate vaccines (PCVs) with increasingly broader serotype coverage has helped to reduce the burden of pneumococcal disease in children and adults. In clinical studies comparing PCVs, higher-valency PCVs have met noninferiority criteria (based on immunoglobulin G geometric mean concentrations and response rates) for most shared serotypes. A numeric trend of declining immunogenicity against shared serotypes with higher-valency PCVs has also been observed; however, the clinical relevance is uncertain, warranting additional research to evaluate the effectiveness of new vaccines. Novel conjugation processes, carriers, adjuvants, and vaccine platforms are approaches that could help maintain or improve immunogenicity and subsequent vaccine effectiveness while achieving broader protection with increasing valency in pneumococcal vaccines.

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).

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.

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.

Potential serotype-specific effectiveness against IPD of pneumococcal conjugate vaccines V114 and PCV20 in children given a 2+1 dosing regimen.

BACKGROUND: Next generation, higher valency pneumococcal conjugate vaccines (PCVs) are assessed and licensed by comparing the immune response across serotypes shared with the PCVs that are standard of care for prevention of pneumococcal disease. METHODS: Using a previously qualified method we predicted the serotype-specific vaccine effectiveness (VE) against invasive pneumococcal disease of V114 and PCV20 for the serotypes shared with PCV13 in an EU, Russian, and Australian pediatric population that is recommended to receive a 2 + 1 dosing regimen. RESULTS: The estimated protective antibody concentrations ranged from 0.03 (serotype 23F) to 1.49 µg/mL (serotype 19F). Predicted VE values for V114 ranged from 79% (serotype 5) to 100% (serotype 23F). V114 had comparable effectiveness to PCV13 for all but one of shared serotypes, with predicted higher effectiveness (in V114) against serotype 3 (93% vs. 65%). Predicted VE values for PCV20 ranged from 47% (serotype 3) to 91% (serotype 14). PCV20 predicted VE was lower than PCV13's for serotypes 4, 19F, 23F, 1, 3, 5, 6A, 7F, and 19A. CONCLUSIONS: Predicted serotype-specific VE values suggest that, with a 2 + 1 dosing regimen, V114 will have greater effectiveness than PCV20 against PCV13 serotypes, particularly for the still-prevalent serotype 3. Real-world VE studies will ultimately provide clarity on the effectiveness of novel PCVs and support further confidence in and/or improvements to modeling efforts.

Pediatric pneumococcal conjugate vaccines (PCVs) were first introduced in Europe in the early 2000s and their incorporation into national immunization programs has helped decrease the incidence of invasive pneumococcal disease (IPD) in Europe and globally. However, some IPD persists, due both to the emergence of non-vaccine pneumococcal serotypes and to the persistence of certain vaccine-targeted serotypes. Higher valency vaccines have been developed to help prevent IPD arising from these serotypes. The goal of the present study is to employ a previously developed model to predict the serotype-specific vaccine effectiveness of higher valency PCVs in a pediatric population that is recommended to receive a 2 + 1 dosing schedule.

PCV15, a pneumococcal conjugate vaccine, for the prevention of invasive pneumococcal disease in infants and children.

INTRODUCTION: Streptococcus pneumoniae is a causative agent of pneumonia and acute otitis media (AOM), as well as invasive diseases such as meningitis and bacteremia. PCV15 (V114) is a new 15-valent pneumococcal conjugate vaccine (PCV) approved for use in individuals ≥6 weeks of age for the prevention of pneumonia, AOM, and invasive pneumococcal disease. AREAS COVERED: This review summarizes the V114 Phase 3 development program leading to approval in infants and children, including pivotal studies, interchangeability and catch-up vaccination studies, and studies in at-risk populations. An integrated safety summary is presented in addition to immunogenicity and concomitant use of V114 with other routine pediatric vaccines. EXPERT OPINION: Across the development program, V114 demonstrated a safety profile that is comparable to PCV13 in infants and children. Immunogenicity of V114 is comparable to PCV13 for all shared serotypes except serotype 3, where V114 demonstrated superior immunogenicity. Higher immune responses were demonstrated for V114 serotypes 22F and 33F. Results of the ongoing study to evaluate V114 efficacy against vaccine-type pneumococcal AOM and anticipated real-world evidence studies will support assessment of vaccine effectiveness and impact, with an additional question of whether higher serotype 3 immunogenicity translates to better protection against serotype 3 pneumococcal disease.

Predicted serotype-specific effectiveness of pneumococcal conjugate vaccines V114 and PCV20 against invasive pneumococcal disease in children.

BACKGROUND: Next-generation, higher-valency pneumococcal conjugate vaccines (PCVs), 15-valent PCV V114 and 20-valent PCV (PCV20), have been assessed by comparing their immune responses across serotypes shared with the 13-valent PCV (PCV13). Without efficacy or real-world vaccine effectiveness (VE) it becomes important to relate IgG titers to VE to aid in the interpretation of the immune response elicited by V114 and PCV20. METHODS: We estimated the protective antibody concentrations for each serotype in 7-valent PCV (PCV7) and PCV13 which were then used to predict the serotype-specific VE for each PCV7 and PCV13 non PCV7 serotype present in V114 and PCV20. RESULTS: The predicted effectiveness of V114 was comparable to PCV7 and PCV13 for 11 of the 13 shared serotypes (1, 4, 5, 6B, 7F, 9 V, 14, 18C, 19A, 19F, and 23F), with improved effectiveness against serotype 3 and decreased effectiveness against serotype 6A. PCV20 had predicted effectiveness comparable to PCV7 and PCV13 for 7 of the 13 shared serotypes (5, 6A, 7F, 9 V, 18C, 19F, and 23F), with decreased effectiveness against the remaining serotypes (1, 3, 4, 6B, 14, and 19A). CONCLUSIONS: Prediction of serotype-specific VE values suggests that V114 retains greater effectiveness than PCV20 toward most serotypes present in PCV7 and PCV13.

Pediatric pneumococcal conjugate vaccines (PCVs) first became available in 2000, when the seven-valent PCV (PCV7) was approved. Since then, PCV7 has been replaced by higher-valency vaccines, including the ten-valent (PCV10) and thirteen-valent (PCV13) vaccines and, more recently, fifteen- and twenty-valent vaccines (V114 and PCV20, respectively). The increase in valency provides broader serotype coverage against invasive pneumococcal disease (IPD) in children. However, IPD due to serotypes contained in PCV7 and PCV13 continue to be observed. In the current study, we used a previously published method to estimate the vaccine effectiveness of V114 and PCV20 in a US and Puerto Rican pediatric population that is recommended to receive a 3 + 1 dosing schedule.

Pneumococcal Vaccine Breakthrough and Failure in Infants and Children: A Narrative Review.

Globally, Streptococcus pneumoniae is a leading cause of vaccine-preventable morbidity and mortality in infants and children. In recent decades, large-scale pediatric immunization programs have substantially reduced the incidence of invasive pneumococcal disease. Despite this, residual vaccine-type pneumococcal disease remains in the form of vaccine breakthrough and vaccine failure. This targeted literature review aims to discuss aspects of vaccine breakthrough and failure in infants and children, including disease epidemiology, clinical presentation, risk factors, vaccination schedules, vaccine serotypes, correlates of protection, comorbidities, disease surveillance, and potential implications for future vaccine development.

An indirect treatment comparison (ITC) and matching-adjusted indirect comparison (MAIC) between a 15-valent (V114) and a 20-valent (PCV20) pneumococcal conjugate vaccine among healthy infants.

OBJECTIVES: Immunogenicity between 15-valent V114 (PCV15) and 20-valent PCV20 pneumococcal conjugate vaccines in healthy infants is compared in an indirect treatment comparison and matching-adjusted indirect comparison. Hypotheses: immunogenicity of V114 is non-inferior to PCV20 for all PCV13 serotypes, and superior to PCV20 for serotype 3 based on lower bound margins. METHODS: Two phase 3 pivotal studies on 3 + 1 pediatric vaccination schedule at age 2, 4, 6, and 12-15 months compared V114 (N = 858) to PCV13 (N = 856) and PCV20 (N = 1001) to PCV13 (N = 987). Infant's age and race in V114 study were matched to those in PCV20 study. Primary endpoints were serotype-specific Immunoglobulin G (IgG) response rate difference (RRD) 30 days post-dose (PD)3; IgG geometric mean concentration (GMC) ratios 30 days PD3 and PD4. RESULTS: V114 was non-inferior (marginRRD>-10%-point; marginGMCratio >0.5) to PCV20 (p-value <0.001) for all endpoints. V114 was superior (marginRRD >0%-point; marginGMCratio >1.2) to PCV20 (p-value <0.001) for serotype 3: RRD was 34.5% (95%CI 27.9%-41.1%) PD3, and IgG GMC ratios were 2.39 (95%CI 2.12-2.68) PD3 and 2.15 (95%CI 1.90-2.41) PD4. CONCLUSION: Immune response to V114 administered in a 3 + 1 schedule in healthy infants was considered non-inferior to PCV20 for all 13 PCV13 serotypes and superior for serotype 3 PD3 and PD4. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers NCT03893448, NCT04382326.

Safety and Immunogenicity of V114 in Preterm Infants: A Pooled Analysis of Four Phase Three Studies.

BACKGROUND: Risk of invasive pneumococcal disease is 3-fold higher in preterm versus full-term infants. V114 is a 15-valent pneumococcal conjugate vaccine (PCV) containing the 13 serotypes in PCV13 plus 2 unique serotypes, 22F and 33F. A pooled subgroup analysis was performed in preterm infants (<37 weeks gestational age) enrolled in 4 pediatric phase 3 studies evaluating the safety and immunogenicity of different 4-dose regimens of V114 or PCV13. METHODS: Healthy preterm infants were randomized 1:1 to receive V114/PCV13 in the 4 studies. Safety was evaluated as the proportion of participants with adverse events (AEs) following receipt of PCV. Serotype-specific antipneumococcal immunoglobulin G (IgG) geometric mean concentrations, IgG response rates and opsonophagocytic activity geometric mean titers were measured at 30 days postdose 3, pretoddler dose and 30 days postdose 4. RESULTS: V114 and PCV13 were administered to 174 and 180 participants, respectively. Mean gestational age was 35.4 weeks (range: 27 - <37 weeks). Proportions of participants with AEs were comparable between vaccination groups; most AEs experienced were of short duration (≤3 days) and mild-to-moderate intensity. V114-elicited IgG geometric mean concentrations, IgG response rates and opsonophagocytic activity geometric mean titers were generally comparable to PCV13 for the 13 shared serotypes and higher for serotypes 22F and 33F at 30 days postdose 3 and postdose 4. CONCLUSIONS: In preterm infants, V114 was well tolerated and induced comparable immune responses to PCV13 for the 13 shared serotypes and higher immune responses to serotypes 22F and 33F. Results support the use of V114 in preterm infants.

The 15-valent pneumococcal conjugate vaccine V114 induces cross-reactive antibodies against pneumococcal serotype 6C.

Pneumococcal serogroups consist of structurally related serotypes, and serotype-specific antibodies can cross-react against other serotypes within the same serogroup. Cross-reactivity of vaccine-induced serotype 6A antibodies, and, to a lesser extent, serotype 6B antibodies, to serotype 6C has been demonstrated following receipt of the 13-valent pneumococcal conjugate vaccine (PCV13), which contains serotypes 6A and 6B. V114 is a 15-valent PCV containing the 13 PCV13 serotypes plus two additional serotypes, 22F and 33F. This study assessed cross-reactivity to serotype 6C in recipients of V114 and PCV13 as well as specificity of opsonophagocytic activity (OPA) responses in serogroup 6. Following receipt of V114 or PCV13, the observed OPA geometric mean titers to serotypes 6A, 6B, and 6C were comparable across both vaccination groups (post-single dose in adults ≥50 years of age [n = 250] and from pre- to post-dose 4 in pediatric participants 12-15 months of age [n = 150]). Based on OPA inhibition studies, V114 induced cross-reactive antibodies to serotype 6C in adult and pediatric populations that were specific and comparable to those induced by PCV13. Based on experience with PCV13, V114 may also provide comparable protection against pneumococcal disease caused by serotype 6C; however, this will have to be evaluated in real-world studies.

Safety and Tolerability of V114 Pneumococcal Vaccine in Infants: A Phase 3 Study.

BACKGROUND AND OBJECTIVES: Disease caused by Streptococcus pneumoniae is associated with considerable morbidity and mortality in children. Pneumococcal conjugate vaccines (PCVs) are well tolerated and effective at reducing pneumococcal disease caused by vaccine serotypes. VAXNEUVANCE (V114) is a 15-valent PCV containing 13 serotypes in Prevnar 13 (PCV13), plus serotypes 22F and 33F. This large phase 3 study evaluated safety and tolerability of V114 in infants. METHODS: In total, 2409 infants were randomized to receive V114 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety was evaluated as the proportion of participants with adverse events (AEs). Solicited and unsolicited injection-site and systemic AEs were collected for 14 days after each study vaccination, and serious AEs up to 6 months after the last PCV dose. RESULTS: The proportions of participants with injection-site, systemic, vaccine-related, and serious AEs were generally comparable between recipients of V114 and PCV13. The most frequently reported AEs were solicited, with irritability and somnolence being the most frequent in both groups. Although the incidence of some AEs was higher in the V114 group, the between-group differences were small. The majority of experienced AEs were of mild-to-moderate intensity and lasted ≤3 days. There were 2 vaccine-related serious AEs of pyrexia in the V114 group, and 2 nonvaccine-related deaths, 1 in each group. No participant discontinued study vaccine because of AEs. CONCLUSIONS: V114 is well tolerated and has a generally comparable safety profile to that of PCV13. These study results support routine use of V114 in infants.

A Phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of V114 compared with PCV13 in healthy infants (PNEU-PED-EU-1).

BACKGROUND: V114 (15-valent pneumococcal conjugate vaccine [PCV]) contains all serotypes in 13-valent PCV (PCV13) and additional serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 compared with PCV13 in healthy infants, and concomitant administration with DTPa-HBV-IPV/Hib and rotavirus RV1 vaccines. METHODS: V114 and PCV13 were administered in a 2+1 schedule at 2, 4, and 11-15 months of age. Adverse events (AEs) were collected on Days 1-14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series (PPS), immediately prior to a toddler dose, and 30 days post-toddler dose (PTD). Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for the two additional serotypes. RESULTS: 1184 healthy infants 42-90 days of age were randomized 1:1 to V114 (n = 591) or PCV13 (n = 593). Proportions of participants with solicited AEs and serious AEs were comparable between vaccination groups. V114 met pre-specified non-inferiority criteria for all 13 shared serotypes, based on the difference in proportions of participants with serotype-specific IgG concentrations ≥0.35 µg/mL (response rate; lower bound of two-sided 95% confidence interval [CI] >-10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5), and pre-specified superiority criteria for serotypes 22F and 33F (lower bound of two-sided 95% CI >10.0 for response rates and >2.0 for GMC ratios). Antibody responses to DTPa-HBV-IPV/Hib and RV1 vaccines met pre-specified non-inferiority criteria, based on antigen-specific response rates to DTPa-HBV-IPV/Hib and anti-rotavirus IgA geometric mean titers. CONCLUSIONS: After a 2+1 schedule, V114 elicited non-inferior immune responses to 13 shared serotypes and superior responses to the two additional serotypes compared with PCV13, with comparable safety profile. These results support the routine use of V114 in infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04031846; EudraCT: 2018-003787-31.

Safety, tolerability, and immunogenicity of V114 pneumococcal vaccine compared with PCV13 in a 2+1 regimen in healthy infants: A phase III study (PNEU-PED-EU-2).

BACKGROUND: This phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F. METHODS: Healthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1-14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F. RESULTS: 1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 µg/mL (lower bound of two-sided 95% confidence interval [CI] >-10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose. Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates. CONCLUSION: A two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F.

A phase 3, multicenter, randomized, double-blind, active-comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of a 4-dose regimen of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants (PNEU-PED).

BACKGROUND: Pneumococcal disease (PD) remains a major health concern with considerable morbidity and mortality in children. Currently licensed pneumococcal conjugate vaccines (PCVs) confer protection against PD caused by most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and additional serotypes 22F and 33F. This pivotal phase 3 study compared safety and immunogenicity of V114 and PCV13. METHODS: 1720 healthy infants were randomized 1:1 to receive a 4-dose regimen of V114 or PCV13 concomitantly with other routine pediatric vaccines. Safety was evaluated after each dose as proportion of participants with adverse events (AEs). Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured at 1-month post-dose 3 (PD3), pre-dose 4, and 1-month post-dose 4 (PD4). IgG response rates, geometric mean concentrations (GMCs), and opsonophagocytic activity (OPA) were compared between vaccination groups. RESULTS: The proportion, maximum intensity, and duration of injection-site, systemic, and serious AEs were generally comparable between V114 and PCV13 groups. In comparison to PCV13, V114 met non-inferiority criteria for all 15 serotypes based on IgG response rates at PD3. V114 met non-inferiority criteria by IgG GMCs for all serotypes at PD3 and PD4, except for serotype 6A at PD3. V114-induced antibodies had bactericidal activity as assessed by OPA. Further, V114 met superiority criteria for shared serotype 3 and unique serotypes 22F and 33F compared to PCV13 by serotype-specific IgG GMCs at both PD3 and PD4. Immunogenicity of concomitantly administered routine pediatric vaccines was comparable in V114 and PCV13 groups. CONCLUSIONS: In healthy infants, V114 displays acceptable safety and tolerability profiles and generates comparable immune responses to PCV13. V114 also met superiority criteria for serotypes 3, 22F, and 33F. These results support use of V114 for prevention of PD as part of routine infant vaccination schedules. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03893448; EudraCT: 2018-004109-21.

A phase 3, multicenter, randomized, double-blind study to evaluate the interchangeability of V114, a 15-valent pneumococcal conjugate vaccine, and PCV13 with respect to safety, tolerability, and immunogenicity in healthy infants (PNEU-DIRECTION).

BACKGROUND: Pneumococcal disease (PD) remains a major health concern globally. In children, pneumococcal conjugate vaccines (PCVs) provide protection against PD from most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and public health important serotypes 22F and 33F. This phase 3 study evaluated safety and immunogenicity of mixed PCV13/V114 regimens using a 3 + 1 dosing schedule when changing from PCV13 to V114 at doses 2, 3, or 4. METHODS: 900 healthy infants were randomized equally to 5 intervention groups. PCVs were administered in a 3-dose infant series at 2, 4, and 6 months of age followed by a toddler dose at 12-15 months along with concomitant routine vaccines. Safety was evaluated as the proportion of participants with adverse events (AEs). Immunoglobulin G (IgG) responses to the 15 serotypes in V114 were measured at 30 days post-dose 3 and 30 days post-dose 4 (PD4). RESULTS: Frequencies of injection-site and systemic AEs were generally comparable across all intervention groups. At 30 days PD4 (primary endpoint), IgG geometric mean concentrations (GMCs) for the 13 shared serotypes were generally comparable between mixed V114/PCV13 and 4-dose regimens of PCV13 or V114. In mixed regimens at 30 days PD4, a toddler dose of V114 was sufficient to achieve IgG GMCs comparable to a 4-dose regimen of V114 for serotype 22F, while at least one infant dose was needed in addition to the toddler dose to achieve IgG GMCs comparable to a 4-dose regimen of V114 for serotype 33F. CONCLUSIONS: V114 was well tolerated with a generally comparable safety profile to PCV13. For 13 shared serotypes, both mixed regimens and the V114 4-dose regimen induced generally comparable antibody responses to 4-dose regimen with PCV13. Study results support interchangeability of V114 with PCV13 in infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03620162; EudraCT: 2018-001151-12.

A phase III, multicenter, randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of catch-up vaccination regimens of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants, children, and adolescents (PNEU-PLAN).

BACKGROUND: Despite widespread use of pneumococcal conjugate vaccines (PCVs) in children, morbidity and mortality caused by pneumococcal disease (PD) remain high. In addition, many children do not complete their PCV course on schedule. V114 is a 15-valent PCV that contains two epidemiologically important serotypes, 22F and 33F, in addition to the 13 serotypes present in PCV13, the licensed 13-valent PCV. METHODS: This phase III descriptive study evaluated safety and immunogenicity of catch-up vaccination with V114 or PCV13 in healthy children 7 months-17 years of age who were either pneumococcal vaccine-naïve or previously immunized with lower valency PCVs (NCT03885934). Overall, 606 healthy children were randomized to receive V114 (n = 303) or PCV13 (n = 303) via age-appropriate catch-up vaccination schedules in three age cohorts (7-11 months, 12-23 months, or 2-17 years). RESULTS: Similar proportions of children 7-11 months and 2-17 years of age reported adverse events (AEs) in the V114 and PCV13 groups. A numerically greater proportion of children 12-23 months of age reported AEs in the V114 group (79.0%) than the PCV13 group (59.4%). The proportions of children who reported serious AEs varied between different age cohorts but were generally comparable between vaccination groups. No vaccine-related serious AEs were reported, and no deaths occurred. At 30 days after the last PCV dose, serotype-specific immunoglobulin G geometric mean concentrations were comparable between vaccination groups for the 13 shared serotypes and higher in the V114 group for 22F and 33F. CONCLUSIONS: Catch-up vaccination with V114 in healthy individuals 7 months-17 years of age was generally well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of prior pneumococcal vaccination. These results support V114 catch-up vaccination in children with incomplete or no PCV immunization per the recommended schedule.

Phase 3, open-label, Russian, multicenter, single-arm trial to evaluate the immunogenicity of varicella vaccine (VARIVAX™) in healthy adults.

Varicella (chickenpox) is a common, highly contagious disease caused by primary infection with varicella zoster virus (VZV). Adults typically experience more severe symptoms than children and have a higher risk of developing complications. Stage 1 of this Phase 3 open-label study enrolled healthy adults in Russia aged 18-75 years without a clinical history of varicella infection. Eligible participants (n = 50) were administered 2 doses of VARIVAX™ (Varicella Virus Vaccine Live [Oka/Merck]) 0.5 mL 6 weeks apart. For participants seronegative at baseline (VZV antibody titer <1.25 glycoprotein enzyme-linked immuno-sorbent assay [gpELISA] units/mL), immunogenicity was assessed by seroconversion (VZV antibody titer ≥5 gpELISA units/mL) and assessment of geometric mean titers of VZV antibody as measured by gpELISA 6 weeks after Dose 2. For VZV seropositive participants at baseline (VZV antibody titer ≥1.25 gpELISA units/mL), immunogenicity was assessed by geometric mean fold rise in antibody titer and percentage of participants with a ≥ 4-fold rise in antibody titer 6 weeks after Dose 2. A Vaccine Report Card was used to record solicited and unsolicited adverse events through 42 days post-vaccination. All participants who were seronegative (n = 26) at baseline demonstrated seroconversion 6 weeks after Dose 2. Among participants who were seropositive at baseline (n = 23), 60.9% had a ≥4-fold rise in antibody titer 6 weeks after Dose 2. Vaccination was generally well tolerated, with no new safety signals identified. Administration of 2 doses of VARIVAX in adults in Russia results in acceptable immune responses with safety data consistent with the licensed product (Clinicaltrials.gov identifier: NCT03843632).

Association of Routine Chlamydia trachomatis Screening During Pregnancy and Seroprevalence of Chlamydial Infection in Children, 1991-2015.

We performed a seroepidemiologic study of sera from children in Brooklyn, New York, before and after the implementation of prenatal chlamydial screening almost 20% of children aged ≤10 years in the prescreening group had anti-Chlamydia trachomatis immunoglobulin G compared with none in the postscreening group.