Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older

Background

Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations.

Methods

This was an extension of a previous study in pneumococcal vaccine-naïve adults aged 50–64 years in which adults 60–64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50–59 were given PCV13. In this follow up study conducted about 4 years later, the 60–64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50–59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination.

Results

A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non-inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes.

Conclusion

In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

Background

The currently recommended single dose of the 23-valent pneumococcal free polysaccharide vaccine (PPSV23) for adults 65 years of age and older does not provide extended protection into older age. This reflects a significant unmet medical need for alternative strategies to protect older adults against pneumococcal infection, which may be met by the 13-valent polysaccharide conjugate vaccine (PCV13).

Methods

We performed a randomized, modified double-blind trial in 936 adults aged 70 years and older who had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23. At 1 year after enrollment, all subjects received a follow-on dose of PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and at 1 month after each vaccination.

Results

Following the enrollment vaccination, OPA titers were significantly greater in the PCV13 group compared to the PPSV23 group for 10 of the 12 serotypes common to both vaccines and to serotype 6A which is unique to PCV13. Responses were noninferior for the other 2 common serotypes. Responses to PCV13 given at 1 year were generally lower in the group that received PPSV23 at enrollment.

Conclusion

In adults aged 70 years and older previously vaccinated with PPSV23, PCV13 was significantly more immunogenic than PPSV23 for most of the common serotypes and for serotype 6A. The OPA responses after a follow-on dose of PCV13 one year later indicate that a prior dose of PPSV23, but not PCV13, diminishes the response to the subsequent administration of PCV13.     

Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine–naïve adults 60–64 years of age

Background

Unlike free pneumococcal polysaccharide vaccines (PPSVs), pneumococcal conjugate vaccines (PCVs) induce a T–cell–dependent immune response. The study assessed potential influence of initial 13-valent PCV (PCV13) or 23-valent PPSV (PPSV23) on subsequent vaccine administrations.

Methods

We conducted a randomized, modified double-blind study in 720 pneumococcal vaccine–naïve adults 60–64 years of age. Subjects received either PCV13 at year 0 and PCV13 at year 1; PCV13 at year 0 and PPSV23 at year 1; or PPSV23 at year 0 and PCV13 at year 1. Antipneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after each vaccination.

Results

OPA titers following PPSV23 given 1 year after PCV13 (PCV13/PPSV23) (a) were noninferior for the 12 common serotypes and significantly higher for 6 of 12 common serotypes than those following only an initial PPSV23; and (b) were significantly higher for 11 of 12 common serotypes compared with PPSV23 followed by PCV13 (PPSV23/PCV13). In addition, PPSV23 followed 1 year later by PCV13 (PPSV23/PCV13) elicited significantly lower OPA titers than after only an initial dose of PCV13 for all 13 serotypes. Responses after a second vaccination with either PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for 9 of 13 and 8 of 12 common serotypes compared with the initial PCV13 dose.

Conclusion

In pneumococcal vaccine–naïve adults 60–64 years of age, an initial PCV13 augmented the antipneumococcal response to subsequent administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, an initial PPSV23 resulted in a diminished response to subsequent administration of PCV13 for all serotypes. With a relatively short 1-year interval between doses, responses after a second vaccination with PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for a majority of serotypes compared with the initial PCV13 dose, probably reflecting the need for a longer interval between vaccine administrations.ClinicalTrials.gov Identifier: NCT00574548.     

Cost-effectiveness of administering 13-valent pneumococcal conjugate vaccine in addition to 23-valent pneumococcal polysaccharide vaccine to adults with immunocompromising conditions

Background

In June, 2012 a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) was added to the recommendation for immunocompromised adults who were previously recommended to receive only 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 may be more effective, though it covers fewer disease-causing strains.

Objective

We examined the incremental cost-effectiveness of adding one dose of PCV13 to the pre-2012 recommendation of PPSV23 for adults with 4 immunocompromising conditions who are at increased risk of pneumococcal disease: HIV/AIDS, hematologic cancer, solid organ transplants, and end stage renal disease.

Methods

We used a probabilistic model following a single cohort of 302,397 immunocompromised adults. We used vaccination coverage and disease incidence data specific to each immunocompromising condition. Assumptions about PPSV23 and PCV13 vaccine effectiveness were based on two randomized controlled trials and several observational studies conducted among HIV-infected adults. Because no such studies have been conducted among other immunocompromised populations, we made further assumptions about the relative vaccine effectiveness in those groups. Cost-effectiveness ratios were determined for each condition and for all 4 groups in total.

Results

Our model indicated that adding one dose of PCV13 to adults in the United States with 4 immunocompromising conditions would cost $16 million (in 2009$) but provide off-setting savings of $21 million per cohort from the societal perspective. These savings come largely from decreased medical costs among adults with end stage renal disease. This dose of PCV13 would prevent 57 cases of invasive pneumococcal disease, 619 cases of hospitalized all-cause pneumonia, avert 93 deaths, and save 1360 quality adjusted life years per cohort.

Conclusion

The addition of one dose of PCV13 to the previously recommended PPSV23 doses for adults with selected immunocompromised conditions potentially reduces both disease and costs.     

Immune response to 13-valent pneumococcal conjugate vaccine with a reduced dosing schedule

Background

The 7-valent pneumococcal conjugate vaccine (PCV7) has demonstrated effectiveness against pneumococcal illnesses when administered as 3 infant doses plus a toddler dose (3+1 schedule) or as an abbreviated schedule of 2 infant doses plus a toddler dose (2+1 schedule). The 13-valent pneumococcal conjugate vaccine (PCV13) is approved and World Health Organization-prequalified for administration in a 2+1 schedule when used as part of routine immunization programs.

Objective

To summarize immunologic responses elicited by PCV13 administered in a 2+1 schedule and following 2 doses in a 3+1 schedule.

Methods

Studies were double-blind, randomized, active-controlled, multicenter studies except the Mexico study (open-label, single-arm). In 2+1 studies, PCV13 was administered at 2, 4, and 12 (UK) or 3, 5, and 11 (Italy) months. In 3+1 studies (Spain and Mexico), assessment was made postdose 2 of the primary series (2, 4, and 6 months). The primary immunogenicity endpoint was the proportion of participants achieving serotype-specific antipolysaccharide immunoglobulin (Ig)G concentrations ≥0.35 μg/mL (i.e., responders) 1 month postdose 2. Pneumococcal IgG geometric mean concentrations (GMCs), opsonophagocytic activity (OPA), and concomitant vaccine responses were assessed.

Results

PCV13 and PCV7 elicited comparable immune responses for the 7 common serotypes after 2 infant doses. The proportion of PCV13 responders postdose 2 was >85% for most of the 7 common and 6 additional serotypes, except common serotypes 6B (27.9–81.4%) and 23F (55.8–77.5%) and additional serotypes 3 (73.8–96.9%) and 6A (79.2–94.4%). Serotypes 6B and 23F elicited lower IgG GMCs postdose 2 compared with other serotypes; all serotypes demonstrated boosting posttoddler dose. All serotypes demonstrated functional activity; >95% of participants achieved OPA levels ≥1:8 postdose 2. Concomitant vaccine responses were similar between PCV13 and PCV7 groups.

Conclusion

Immune responses elicited by PCV13 following 2 infant doses support transition from PCV7 to PCV13 in countries using a 2+1 schedule.Clinical trial registration numbers: UK (Study 007) NCT00384059; Italy (Study 500) NCT00366899; Spain (Study 501) NCT00368966; Spain (Study 3007) NCT00474539; and Mexico (Study 3009) NCT00708682.     

Evaluation of 13-valent pneumococcal conjugate vaccine and concomitant meningococcal group C conjugate vaccine in healthy infants and toddlers in Spain

Background

Given the concurrent administration of multiple vaccines during routine pediatric immunizations, efforts to elucidate the potential interference of any vaccine on the immune response to the concomitantly administered antigens are fundamental to prelicensure clinical research.

Methods

This phase 3 randomized controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) versus 7-valent PCV (PCV7) assessed immune responses of concomitantly administered meningococcal group C conjugated to diphtheria toxin cross-reactive material 197 (MnCCV-CRM₁₉₇) in a 2-dose infant series and 15-month toddler dose.

Results

619 subjects were randomized, 315 to PCV13 and 304 to PCV7. MnCCV-CRM₁₉₇-induced immune responses were similar between the PCV13 and PCV7 groups, with >97% of the subjects achieving a ≥1:8 meningococcal serum bactericidal assay (SBA) titer after both dose 2 and the toddler dose. Geometric mean titers were lower in the PCV13 group 191.22 (167.72, 218.02) versus 266.19 (234.86, 301.71) following dose 2 and 432.28 (361.22, 517.31) versus 730.84 (642.05, 831.91) following the toddler dose. The geometric mean (GM) meningococcal SBA titer ratios (PCV13/PCV7) were 0.72 after dose 2 and 0.59 after the toddler dose. The criteria for MnCCV-CRM₁₉₇ non-inferiority for GM titers were satisfied after dose 2. Percent responders was similar up to titers of 1:128. PCV13 elicited substantial antipneumococcal responses against all 13 serotypes, with ≥90% of the subjects achieving an antibody concentration ≥0.35 μg/mL after dose 3 in the infant series. Safety and tolerability were similar between the vaccine groups.

Conclusions

Immunogenicity results of MnCCV-CRM₁₉₇ for PCV13 compared with PCV7 included lower GMTs, but the clinical significance of this is unknown as the proportion of infants achieving protective MenC antibody titers was comparable in the two groups. Percent responders were similar up to titers of 1:128. PCV13 has an acceptable safety profile in infants and toddlers, while providing expanded coverage against pneumococcal disease.     

Trends in serotype prevalence in invasive pneumococcal disease before and after infant pneumococcal vaccination in Belgium, 2002–2010

Objectives

We evaluated the effect of the infant 7-valent pneumococcal conjugate vaccine (PCV7) program on the serotype distribution in invasive pneumococcal disease in the Belgian population.

Methods

Serotyping was performed on 13,998 bacteraemic and pleural fluid isolates sent to the National Reference Laboratory between 2002 and 2010. We compared the distribution of serogroups (SGs) between the pre- (2002–2004) and post-PCV7 (2007–2010) era for children (<18 years), adults (18–59 years) and older individuals (≥60 years).

Results

The proportion of cases caused by PCV7-SGs in subjects <18 years decreased from 69% pre-PCV7 to 26% post-PCV7 (p < 0.005) and the majority of cases caused by PCV7-SGs were caused by SG 19. Post-PCV7, the prevalence of PCV7-SGs decreased from 38% to 29% and from 57% to 35% in subjects in the age groups 18–59 and ≥60 years, respectively (p < 0.005). Post-PCV7 the prevalence of SGs 1, 7 and 19 increased significantly in subjects aged <18 years. The increase of SG19 was caused by an increase of serotype 19A in this age group (p < 0.005). After the introduction of infant PCV7 the largest rise in prevalence occurred for SGs 7, 12 and 22 (p < 0.005) in the two older age categories. Post PCV7, the overall PCV13 and 23-valent pneumococcal polysaccharide vaccine coverage rates decreased from 85% to 69% and from 96% to 93%, respectively (p < 0.005).

Conclusions

PCV7 has an impact on SG distribution of invasive pneumococcal disease isolates of vaccinated and unvaccinated subjects. SG replacement forms a major threat to the success of PCV7. PCV13, including several additional replacement serotypes (STs 1, 7F, 19A), represents an attractive alternative.     

The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A

The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 dramatically reduced the incidence of invasive pneumococcal disease (IPD) caused by the seven serotypes covered by the vaccine. Following the introduction of PCV7, which contains a serotype 6B conjugate, some decrease in IPD due to serotype 6A was noted suggesting that the serotype 6B conjugate provided some partial cross-protection against serotype 6A. However, no effect on serotype 6C was observed. In 2010, a pneumococcal conjugate vaccine with expanded serotype coverage (PCV13) was introduced that expanded the serotype coverage to 13 serotypes including serotype 6A. To assess whether the 6A conjugate in PCV13 could potentially induce functional anti-6C antibody responses, an opsonophagocytic assay (OPA) for serotype 6C was developed. Randomly chosen subsets of immune sera collected from infants receiving three doses of PCV7 or PCV13 were tested in OPA assays for serotype 6A, 6B and 6C. PCV7 immune sera demonstrated strong OPA responses, defined as percentage of subjects having an OPA titer ≥1:8, to serotype 6B (100% responders), partial responses to serotype 6A (70% responders) but only minimal responses to serotype 6C (22% responders). In contrast, PCV13 immune sera showed strong OPA responses to serotypes 6A (100% responders), 6B (100% responders) and 6C (96% responders). Furthermore, during pre-clinical work it was observed that serotype 7F (included in PCV13) and serotype 7A (not included in PCV13) shared serogroup-specific epitopes. To determine whether such epitopes also may be eliciting cross-functional antibody, PCV13 immune sera were also tested in serotype 7A and 7F OPA assays. All PCV13 immune sera demonstrated OPA responses to both of these serotypes. Taken together these results suggest that immunization with PCV13 has the potential to induce cross-protective responses to related serotypes not directly covered by the vaccine.     

Decreased immune response to pneumococcal conjugate vaccine after 23-valent pneumococcal polysaccharide vaccine in children

Background

Pneumococcal polysaccharide vaccine (PPV) is used in children at high risk of IPD. PPV is generally not considered to induce immunologic memory, whereas pneumococcal conjugate vaccines (PCVs) elicit protective antibody responses in infants and induce immunologic memory. Little is known about the characteristics of immune responses to PCV in children who previously received PCV and PPV in series.

Objective

To characterize immune responses to 13-valent pneumococcal CRM₁₉₇ conjugate vaccine (PCV13; serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in children vaccinated in infancy with 9-valent pneumococcal–meningococcal C-CRM₁₉₇ conjugate combination vaccine (PCV9-MnCC), followed by a toddler dose of PCV9-MnCC or 23-valent pneumococcal polysaccharide vaccine (PPV23).

Methods

Children (n = 89) who received PCV9-MnCC in infancy and PPV23 or PCV9-MnCC at age 12 months in a previous (2002–2003) study were vaccinated at age 7.5 years with PCV13; groups PPV23/PCV13 (n = 50) and PCV9/PCV13 (n = 39). Immunoglobulin (Ig)G antibodies, avidity, and opsonophagocytic activity (OPA) were measured before and at 1 and 4 weeks postvaccination.

Results

One week postvaccination, IgG levels increased significantly for all serotypes in both groups, and >97% of vaccinees achieved IgG ≥0.35 μg/ml 4 weeks after PCV13 vaccination. The PCV9/PCV13 group had higher IgG responses compared with the PPV23/PCV13 group. The upper limits of the 95% confidence intervals of the PPV23/PCV13:PCV9/PCV13 IgG geometric mean concentration ratios were <1.0 for serotypes 1, 4, 5, 9V, 18C, and 23F at 1 week. OPA and avidity results supported these findings.

Conclusions

PPV23 vaccination of toddlers may compromise subsequent responses to pneumococcal conjugate vaccines. The clinical relevance of this finding is unclear.     

Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales

In 2003 the existing 23-valent pneumococcal vaccine (PPV23) programme for high risk groups was extended to include all ≥65 year olds in England and Wales, starting with ≥80 year olds and moving to 75–79 and 65–74 year olds by 2005. We conducted an ecological study to assess the impact of the extended PPV23 programme on serotype-specific incidence of invasive pneumococcal disease (IPD) and a case–control study to assess vaccine effectiveness (VE) using the national IPD surveillance dataset. Between 1998 and 2006 IPD incidence caused by PPV23 serotypes in the targeted age-groups was unchanged. IPD caused by the serotypes covered by the 7-valent conjugate vaccine (PCV7) introduced for children in 2006 declined in ≥65 year olds after 2006 but was offset by an increase in non-PCV7 serotypes. This increase was similar for the additional 16 serotypes covered by PPV23 and the non-PPV23 serotypes. For the VE study, vaccine history was obtained for controls (n = 1270) with non-PPV23 IPD diagnosed between November 2003 and December 2010 and a subset of cases (n = 1272) matched for age and time period. VE declined from 48% (95% confidence interval; 32–60%) within two years of vaccination to 15% (−3% to 30%) after five years. Although differences in VE by age and having risk conditions were not statistically significant the highest estimates were in the youngest age group (65–74 years) and in those without risk conditions with a VE estimate of 65% (23–84%) within 2 years of vaccination for non-risk 65–74 year olds. VE differed by serotype (p = 0.005), from −23% (−85% to 19%) for serotype 3 to 63% (29–81%) for 12F. In conclusion PPV23 was effective, particularly in healthy under 75 year olds, but protection waned after 5 years. There was no discernible impact of PPV23 on IPD incidence or PCV7-induced serotype replacement, consistent with the modest overall effectiveness, the 45% increased coverage over the former risk-based programme and lack of herd immunity from the PPV23 programme. Based on the VE estimates PPV23 was still considered a cost-effective intervention for the low risk elderly.     

Impact of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on childhood pneumonia hospitalizations in Brazil two years after introduction

Introduction

Pneumococcal disease is a major public health problem worldwide. From March to September of 2010, 10-valent pneumococcal non-typeable Haemophilus influenzae protein conjugate vaccine (PHiD-CV) was introduced in the Brazilian childhood National Immunization Program (NIP) in all 27 Brazilian states. The aim of the present study is to report national time-trends in incidence of hospital admissions for childhood pneumonia in Brazil before and after two years of introduction of this new pneumococcal conjugate vaccine.

Methods

Analysis of hospitalization data of children aged 0–4 years in Brazilian public health system with an admission diagnosis of pneumonia from 2002 to 2012 was performed comparing pre (2002–2009) and post-vaccination periods (2011–2012). Hospital number of admission due to pneumonia and all non-respiratory diseases were obtained from DATASUS, the Brazilian government open-access public health database system. Incidence of pneumonia hospitalization was compared to incidence of all non-respiratory admissions.

Results

Admission rates for pneumonia decreased steadily from 2010 to 2012. In children aged less than four years, incidence of pneumonia hospitalizations decreased 12.65% when pre (2002–2009) and post-vaccination introduction periods (2011–2012) were compared and adjusted for seasonality and secular-trend (p < 0.001). On the other hand, non-respiratory admission rates remained stable comparing both periods (p = 0.39).

Conclusion

Childhood pneumonia hospitalization rates were fluctuating prior to 2010 and decreased significantly in the two years after PHiD-CV introduction. Conversely, rate of non-respiratory admissions has shown no decrease. These data are an evidence of the effectiveness and public health impact of this new pneumococcal vaccine.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 18–49 years of age,naive to 23-valent pneumococcal polysaccharide vaccine

BackgroundBased on the success of vaccination with pneumococcal conjugate vaccines (PCVs) in children, recent studies have focused on PCVs in adults. Data from a randomized, double-blind study comparing the immunogenicity, tolerability, and safety of the 13-valent PCV (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in PPSV23-naive adults 60–64 years of age have been published. The same study also included a cohort of adults aged 18–49 years that received open-label PCV13. The purpose of this cohort was to examine the immunogenicity, safety, and tolerability of PCV13 in adult subjects 18–49 years of age compared with adults 60–64 years of age for whom PCV13 is approved.MethodsAdults naive to PPSV23 were grouped by age into 2 cohorts: 18–49 years (n = 899; further stratified by age into 3 subgroups 18–29, 30–39, and 40–49 years) and 60–64 years (n = 417). All subjects received 1 dose of PCV13. In both age groups, immunogenicity was assessed by antipneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) 1 month after vaccination. Safety and tolerability were evaluated.ResultsIn adults aged 18–49 years, OPA GMTs and IgG GMCs were noninferior for all 13 serotypes and statistically significantly higher for all except 1 serotype (OPA GMT) and 5 serotypes (IgG GMCs) compared with adults 60–64 years. Immune responses were highest in the youngest age subgroup (18–29 years). Local reactions and systemic events were more common in adults 18–49 years compared with 60–64 years and were self-limited.ConclusionImmune responses to PCV13 are robust in adults ≥18 years of age, with highest responses observed in the youngest subgroup. Based on its safety and immunologic profile, PCV13 may serve an important therapeutic role in younger adults, particularly those with underlying medical conditions who have an increased risk of serious pneumococcal infections.     

Phase 1 trial of a 20-valent pneumococcal conjugate vaccine in healthy adults

IntroductionStreptococcus pneumoniae is a leading cause of bacteremia, bacterial pneumonia, and meningitis, and is associated with substantial morbidity and mortality, particularly in those under 2 years of age and those over 65 years of age. While significant progress against S. pneumoniae-related disease has been made as a result of the introduction of pneumococcal conjugate vaccines (PCV7, PCV10 and PCV13), there remains value in further expanding pneumococcal vaccine serotype coverage. Here we present the first report of a 20-valent pneumococcal conjugate vaccine (PCV20) containing capsular polysaccharide conjugates present in PCV13 as well as 7 new serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) which are important contributors to pneumococcal disease.MethodsThis Phase I first-in-human study was a randomized, controlled, observer-blinded study with a two-arm parallel design to assess the safety, tolerability, and immunogenicity of PCV20 in adults. A total of 66 healthy adults 18–49 years of age with no history of pneumococcal vaccination were enrolled and randomized to receive a single dose of PCV20 or a licensed tetanus, diphtheria, acellular pertussis combination vaccine (Tdap) control. Local injection site reactions, select systemic symptoms, laboratory studies, and adverse events were assessed. Opsonophagocytic activity (OPA) titers and IgG concentrations were measured in sera collected prior to, and approximately one month (28–35 days) after vaccination.ResultsVaccination with PCV20 elicited substantial IgG and functional bactericidal immune responses as demonstrated by increases in IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) to the 20 vaccine serotypes. The overall safety profile of PCV20 was similar to Tdap, and generally consistent with that observed after PCV13 administration.ConclusionsVaccination with PCV20 was well tolerated and induced substantial functional (OPA) and IgG responses to all vaccine serotypes. There were no safety issues identified in this Phase 1 study, and the data supported further evaluation of PCV20.     

Randomized clinical trial of a single versus a double dose of 13-valent pneumococcal conjugate vaccine in adults 55 through 74 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

IntroductionIn older adults, prior administration of 23-valent pneumococcal polysaccharide vaccine (PPSV23) blunts the opsonophagocytic antibody (OPA) response to subsequent administration of 13-valent pneumococcal conjugate vaccine (PCV13). To determine whether a higher dose of PCV13 could mitigate this effect in adults 55 through 74 years of age, we compared OPA responses to a double dose of PCV13 in persons previously vaccinated with PPSV23 with responses to a single dose of PCV13 in previously vaccinated persons, and with a single dose in PPSV23 naïve persons.MethodsSubjects previously vaccinated with PPSV23 were randomly assigned to receive either a single injection or two concurrent injections of 0.5 mL PCV13. Naïve subjects received a single injection of 0.5 mL PCV13. Serotype-specific OPA responses to 12 of the PCV13 serotypes were assessed on samples collected on Day 29 and Day 181. Comparisons of the OPA titers between study groups were based on the lower bound of the 95% confidence interval of the log geometric mean ratio to define superiority (>1) and non-inferiority (>0.5).ResultsAt Day 29, the OPA responses to one dose in previously vaccinated (n = 284) versus one dose in naïve subjects (n = 311) achieved the threshold for non-inferiority for only 3 of the 12 serotypes. In previously vaccinated subjects, responses to a double dose (n = 288) versus a single dose met the threshold for superiority for 7 serotypes. The responses to a double dose in previously vaccinated subjects versus a single dose in naïve subjects met the threshold for non-inferiority for 9 serotypes.ConclusionsThere is a dose response to PCV13 in older adults and the higher response to a double dose in previously vaccinated adults is non-inferior to that of a single dose in naïve adults for 9 of the 12 PCV13 serotypes evaluated.     

Assessment of functional antibacterial opsonophagocytic antibodies elicited by 13-valent pneumococcal conjugate vaccine administered concomitantly with trivalent influenza vaccine in a randomized clinical trial in adults aged ≥65 years

A randomized, double-blind clinical trial compared immune responses elicited by concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (PCV13 + TIV), with PCV13 given 1 month after TIV, in healthy, pneumococcal vaccine-naïve adults aged ≥65 years. Serotype-specific pneumococcal anti-polysaccharide IgG antibody concentrations 1-month post-vaccination were uniformly lower after PCV13 + TIV, than after PCV13 alone (Vaccine 2011;29:5195–202). Therefore, post hoc analyses to evaluate the functional antibody titers at 1-month post-vaccination, as measured by opsonophagocytic activity (OPA) assays, were performed. The anti-pneumococcal functional responses, while also generally lower after vaccine co-administration, nonetheless showed a greater degree of similarity between the two vaccine groups than was apparent from the anti-polysaccharide antibody responses. In particular, the proportion of OPA responders after PCV13 and TIV co-administration was similar to that observed after PCV13 alone for all serotypes evaluated. Concomitant use of PCV13 and TIV should therefore be guided by clinical circumstances.     

Dynamics of pneumococcal carriage among day-care center attendees during the transition from the 7-valent to the higher-valent pneumococcal conjugate vaccines in Greece

Background

In Greece recently, higher-valent pneumococcal conjugate vaccines (PCVs) replaced the 7-valent (PCV7); the 10-valent (PCV10) became available in May 2009 and the 13-valent (PCV13) in June 2010.

Methods

We investigated the nasopharyngeal colonization with Streptococcus pneumoniae in day-care center attendees in Athens and the prefecture of Viotia. Between December 2010 and June 2011, nasopharyngeal cultures were obtained 4 times, at enrollment and then every 6 to 8 weeks.

Results

Among the 233 children, 225 (96.6%) had been vaccinated with ≥1 dose of PCV7. One tenth of the PCV7 vaccinated attendees had also received ≥1 dose of PCV13 or PCV10. During the 4 samplings, 358 isolates were recovered from a total of 874 samples. Of the 233 children, 183 (78.5%) were found to carry S. pneumoniae at least once. The overall serotype distribution among carriers was similar regardless of the time lapsed since the last PCV7 dose. A high frequency of 19A (17.1%) coincided with a low frequency of 19F (1.4%). Non-PCV13 serotypes accounted for 73.1% of the isolates; 23B, 15B/C, 16F, 21, 11A, 15A, 6C, 10A, 22F and 23A were the most common. Among attendees aged 24–59 months (median age 42 months), prolonged carriage of a non-PCV13 serotype was relatively common, mainly for 21 and 16F. One out of 4 cases of colonization with the prevalent non-PCV13 serotypes was followed by persistent carriage for 5 to 14 weeks.

Conclusions

During this period of transition to the higher-valent PCVs in the day-care center setting, non-PCV13 serotypes dominated and exhibited prolonged colonization. The frequency and the duration of prolonged carriage tends to be increased, if sampling frequency increases and the carriage time before and after positive cultures is taken into consideration. Further studies regarding the fitness of the colonizing non-PCV13 serotypes will likely to be seen in the future.     

A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination

IntroductionA 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination.MethodsThis phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine [PPSV23], PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed.ResultsThe percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination.ConclusionsPCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens.Clinicaltrials.gov NCT03835975.     

Functional immune responses to 11 non-PCV13 serotypes after immunization with a 23-valent pneumococcal polysaccharide vaccine in older adults

BackgroundThe 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for adults aged ≥65 years. To evaluate functional immune response against the additional 11 serotypes that are included in PPSV23, but not the 13-valent pneumococcal conjugate vaccine (PCV13), serotype-specific anti-pneumococcal antibodies were examined using an opsonophagocytic assay (OPA).MethodsParticipants ≥65 years of age that were naïve to the pneumococcal vaccine were enrolled. They were divided into two groups according to their age: group 1 (N = 30; aged 65–74 years) and group 2 (N = 32; aged ≥75 years). The functional antibody response prior to and 4 weeks post-immunization with PPSV23 was determined, using a multiplexed OPA (MOPA) for 11 pneumococcal serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, and 33F).ResultsGeometric mean OPA titers (GMTs) to 11 serotypes were significantly increased in both groups post-immunization compared to those prior to immunization. The GMTs for all serotypes were not significantly different between the two groups after immunization. The proportion of subjects with OPA titers post-immunization of ≥8 and ≥64 was 93–100% and 80–100% for the 11 serotypes, respectively, while subjects with a ≥4-fold increase in OPA titers ranged from 9 to 90% for the 11 serotypes.ConclusionsThis study revealed that PPSV23 vaccination induced significant functional immune responses to 11 non-PCV13 serotypes in older adults. The MOPA has been shown to be a useful tool for future application in evaluating new PCVs in older adults.The clinical trial registration number is KCT 0001963 (CRIS, https://cris.nih.go.kr/cris/en/).     

Safety,reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: A phase I/II randomized clinical study

Background

New vaccines containing highly conserved Streptococcus pneumoniae proteins such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) are being developed to provide broader protection against pneumococcal disease. This study evaluated the safety, reactogenicity and immunogenicity of different pneumococcal protein-containing formulations in adults.

Methods

In a phase I double-blind study (www.clinicaltrials.gov: NCT00707798), healthy adults (18–40 years) were randomized (1:2:2:2:2:2:2) to receive two doses of one of six investigational vaccine formulations 2 months apart, or a single dose of the control 23-valent pneumococcal polysaccharide vaccine (23PPV; Pneumovax23™, Sanofi Pasteur MSD) followed by placebo. The investigational formulations contained dPly alone (10 or 30 μg), or both dPly and PhtD (10 or 30 μg each) alone or combined with the polysaccharide conjugates of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix™, GlaxoSmithKline Vaccines). Two groups primed with a formulation containing dPly and PhtD (10 or 30 μg each) continued to the follow-up phase II study (NCT00896064), in which they received a booster dose at 5–9 months after primary vaccination.

Results

Of 156 enrolled and vaccinated adults, 146 completed the primary immunization and 43 adults received a booster dose. During primary and booster vaccination, for any formulation, ≤8.9% of doses were followed by grade 3 solicited local or general adverse events. No fever >39.5 °C (oral temperature) was reported. Unsolicited adverse events considered causally related to vaccination were reported following ≤33.3% of investigational vaccine doses. No serious adverse events were reported for adults receiving investigational vaccine formulations. Formulations containing dPly with or without PhtD were immunogenic for these antigens; polysaccharide conjugate-containing formulations were also immunogenic for those 10 polysaccharides.

Conclusion

Investigational vaccine formulations containing dPly and PhtD were well tolerated and immunogenic when administered to healthy adults as standalone protein vaccine or combined with PHiD-CV conjugates.     

Revaccination with 23-valent pneumococcal polysaccharide vaccine in the Japanese elderly is well tolerated and elicits immune responses

BackgroundFollowing primary vaccination of adults ⩾65 years of age with 23-valent pneumococcal polysaccharide vaccine (PPSV23), immune responses increase and thereafter appear to decrease over time. With increased life expectancy worldwide, revaccination with PPSV23 may be required for continued protection of the elderly population against pneumococcal disease. The present study evaluated the immunogenicity and safety of revaccination with PPSV23 in the Japanese elderly.MethodsDepending on prior history of PPSV23 vaccination, adults aged ⩾70 years were given a first dose (primary group; N = 81) or second dose (revaccination group; N = 161, at least 5 years after first dose) of PPSV23 intramuscularly. Subjects were matched for gender, age, and number and type of comorbidity across both groups. Blood samples were collected before and 4 weeks postvaccination to measure serotype-specific immunoglobulin G (IgG) concentrations and opsonophagocytic killing activity (OPA) antibody titers to serotypes included in the vaccine. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination.ResultsBaseline serotype-specific IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally higher in subjects with a prior history of PPSV23 vaccination than in PPSV23-naïve subjects. The levels of IgG GMCs and OPA GMTs after revaccination were generally comparable to those observed after primary vaccination. Incidences of systemic AEs were comparable between the 2 groups. Although incidences of injection-site AEs were higher following revaccination than primary vaccination, the difference was not clinically significant as most AEs were mild to moderate in intensity and resolved within 5 days after revaccination without treatment.ConclusionRevaccination with PPSV23 was well tolerated and associated with increases in serotype-specific IgG concentrations and OPA titers in the elderly who received a prior PPSV23 dose at least 5 years before. Revaccination with PPSV23 can be safely implemented in the elderly for continued prevention against pneumococcal disease.Clinical trial registry number: NCT02260882