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.     

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.     

Characterization of pneumococcal meningitis before and after introduction of 13-valent pneumococcal conjugate vaccine in Niger, 2010–2018

Pneumococcal meningitis in the African meningitis belt is primarily caused by Streptococcus pneumoniae serotype 1, a serotype contained in the 13-valent pneumococcal conjugate vaccine (PCV13). In 2014, Niger introduced PCV13 with doses given at 6, 10, and 14 weeks of age. We leveraged existing meningitis surveillance data to describe pneumococcal meningitis trends in Niger.As a national reference laboratory for meningitis, Centre de Recherche Médicale et Sanitaire (CERMES) receives cerebrospinal fluid specimens from suspected bacterial meningitis cases and performs confirmatory testing for an etiology by culture or polymerase chain reaction (PCR). Specimens with S. pneumoniae detection during 2010–2018 were sent to the Centers for Disease Control and Prevention for serotyping by sequential triplex real-time PCR. Specimens that were non-typeable by real-time PCR underwent serotyping by conventional multiplex PCR. We tested differences in the distribution of pneumococcal serotypes before (2010–2012) and after (2016–2018) PCV13 introduction.During January 2010 to December 2018, CERMES received 16,155 specimens; 5,651 (35%) had bacterial etiology confirmed. S. pneumoniae accounted for 13.2% (744/5,651); 53.1% (395/744) were serotyped. During 2010–12, PCV13-associated serotypes (VT) constituted three-fourths of serotyped pneumococcus-positive specimens; this proportion declined in all age groups in 2016–18, most substantially in children aged < 5 years (74.0% to 28.1%; P < 0.05). Among persons aged ≥ 5 years, VT constituted > 50% of pneumococcal meningitis after PCV13 introduction; serotype 1 remained the most common VT among persons aged ≥ 5 years, but not among those < 5 years.VT as a group caused a smaller proportion of reported pneumococcal meningitis cases after PCV13 introduction in Niger. Serotype 1, however, remains the major cause of pneumococcal meningitis in older children and adults. Different vaccination strategies, such as changing the infant vaccination schedule or extending vaccine coverage to older children and adults, are needed, in addition to stronger surveillance.     

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naïve adults ≥50 years of age

BackgroundPneumococcal disease remains a public health priority in adults. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) containing 13 serotypes included in 13-valent pneumococcal conjugate vaccine (PCV13) plus 2 additional serotypes (22F and 33F) was evaluated in adults ≥50 years old (NCT01513551).Methods691 adults received one dose of PCV15, PCV13, or 23-valent pneumococcal polysaccharide vaccine (PPV23) and were followed 14 days for safety. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured immediately prior and 1-month postvaccination.ResultsSafety profiles were comparable across vaccination groups. PCV15 induced comparable levels of IgG GMCs and OPA GMTs to PCV13 and PPV23 for shared serotypes. Serotype-specific antibodies were numerically higher among recipients of PCV15 than PCV13 and PPV23 for 7 and 12 shared serotypes, respectively; and lower for 4 and 1 serotype(s), respectively. PCV15 induced higher IgG and OPA antibodies than PCV13 or PPV23 for serotypes unique to PCV15 (22F and 33F not in PCV13; 6A not in PPV23).ConclusionsPCV15 displayed an acceptable safety profile and induced IgG and OPA to all 15 serotypes included in the vaccine, at levels comparable to PCV13 and PPV23 for shared serotypes with these vaccines.Study identification: V114-002.CLINICALTRIALS.GOV identifier: NCT01513551.© 2018 Merck & Co., Inc.     

Clinical effectiveness of 13-valent and 23-valent pneumococcal vaccination in middle-aged and older adults: The EPIVAC cohort study, 2015–2016

BackgroundClinical benefits using the 23-valent pneumococcal polysaccharide vaccine (PPsV23) or the 13-valent pneumococcal conjugate vaccine (PCV13) in adults are controversial. This study investigated clinical effectiveness for both PPsV23 and PCV13 in preventing pneumonia among middle-aged and older adults.MethodsPopulation-based cohort study involving 2,025,730 persons ≥50 years in Catalonia, Spain, who were prospectively followed between 01/01/2015 and 31/12/2016. Primary outcomes were hospitalisation from pneumococcal or all-cause pneumonia and main explanatory variable was PCV13/PPsV23 vaccination status. Multivariable Cox regression models were used to estimate vaccination effectiveness adjusted for age and baseline-risk conditions.ResultsCohort members were followed for 3,897,151 person-years (17,496 PCV13 vaccinated and 1,551,502 PPsV23 vaccinated), observing 3259 pneumococcal pneumonias (63 in PCV13 vaccinated, 2243 in PPsV23 vaccinated) and 24,079 all-cause pneumonias (566 in PCV13 vaccinated, 17,508 in PPsV23 vaccinated). Global incidence rates (per 100,000 person-years) were 83.6 for pneumococcal pneumonia (360.1 in PCV13 vaccinated, 144.6 in PPsV23 vaccinated) and 617.9 for all-cause pneumonia (3235.0 in PCV13 vaccinated, 1128.5 in PPsV23 vaccinated). In the multivariable analyses, the PCV13 appeared significantly associated with an increased risk of pneumococcal pneumonia (hazard ratio [HR]: 1.52; 95% confidence interval [CI]: 1.17–1.97; p = 0.002) and all-cause pneumonia (HR: 1.76; 95% CI: 1.61–1.92; p < 0.001) whereas the PPsV23 did not alter the risk of pneumococcal pneumonia (HR: 1.08; 95% CI: 0.98–1.19; p = 0.132) and slightly increased the risk of all-cause pneumonia (HR: 1.17; 95% CI: 1.13–1.21; p < 0.001). In stratified analyses focused on specific target population subgroups (i.e., elderly people, at-risk and high-risk individuals), protective effects of vaccination did not emerge either.ConclusionData does not support clinical benefits from pneumococcal vaccination (nor PCV13 neither PPsV23) against pneumonia among Catalonian adults in the current era of universal PCV’s childhood immunisation.     

Immunogenicity and safety of CRM₁₉₇ conjugated 9-valent pneumococcal and meningococcal C combination vaccine in healthy infants

Streptococcus pneumoniae and Neisseria meningitidis cause invasive disease in children aged <2 years. While individual conjugate vaccines are available to protect this age group against these pathogens, availability of a vaccine combining these antigens into a single injection is desirable. This study randomized 467 healthy infants to receive 4 doses of combination 9-valent pneumococcal and meningococcal serogroup C conjugate vaccine (9vPnC-MnCC) or 9-valent pneumococcal conjugate vaccine (9vPnC). Percentages of subjects achieving immunoglobulin G (IgG) antibody concentrations ≥0.35μg/mL and geometric mean IgG concentrations for each pneumococcal serotype in the 9vPnC-MnCC group were noninferior compared to the 9vPnC group. Both vaccines were well-tolerated.     

Who is at risk of 13-valent conjugated pneumococcal vaccine failure?

BackgroundDespite high vaccine coverage rates in children and efficacy of pneumococcal conjugate vaccines, invasive pneumococcal disease (IPD) episodes due to serotypes included in the vaccine following completion of the recommended course of immunisation (i.e. vaccine failure) have been reported.MethodsWe used data gathered from a population-based enhanced passive surveillance for IPD in children under 18 years of age in Massachusetts and an ensemble model composed of three machine-learning algorithms to predict probability of 13-valent pneumococcal conjugated vaccine (PCV13) failure and to evaluate potential associated features including age, underlying comorbidity, clinical presentation, and vaccine schedule. Vaccine failure was defined as diagnosis of IPD due to vaccine serotype (VST), in a child who received age recommended doses recommended by Advisory Committee of Immunization Practices.ResultsDuring the 7-year study period, between April 01, 2010 and March 31, 2017, we identified 296 IPD cases. There were 107 (36%) IPD cases caused by VST, mostly serotype 19A (49, 17%), 7F (21, 7%), and 3 (18, 6%). Thirty-seven (34%) were in children who were completely vaccinated representing 13% of all IPD cases. Vaccine failure was more likely among children older than 60 months (predicted probability 0.40, observed prevalence 0.37, model prediction accuracy 79%), children presenting with pneumonia (predicted probability 0.27, observed prevalence 0.31, model accuracy 77%), and children with underlying comorbidity (predicted probability 0.24, observed prevalence 0.23, model accuracy 96%). Vaccine failure probability for those >60 months of age and had an underlying risk factor was 45% (observed prevalence 0.33, model accuracy 82%). The likelihood of vaccine failure was lowest among children who had completed 3 primary doses plus one booster dose PCV13 (predicted probability 0.14, observed prevalence 0.14, model prediction accuracy 100%).ConclusionPCV13 vaccine failure is more frequent among older children with underlying comorbidity, and among those who present with pneumococcal pneumonia. Our study provides a preliminary framework to predict the patterns of vaccine failures and may contribute to decision-making processes to optimize PCV immunization schedules.     

Public health and economic impact of 13-valent pneumococcal conjugate vaccine in US adults aged ≥50 years

Background

A 13-valent pneumococcal conjugate vaccine (PCV13) was recently developed for use in older adults, and may be effective not only against invasive pneumococcal disease (IPD) but also nonbacteremic pneumococcal pneumonia. The potential public health and economic impact of PCV13 in this population is unknown.

Methods

A microsimulation model depicting risk and costs of IPD and all-cause nonbacteremic pneumonia (NBP) in US adults aged ≥50 years (n = 96.1 million), as well as expected impact of vaccination, was developed. Effectiveness of PPSV23 was based on published literature, and for all-cause NBP, was zero; effectiveness of PCV13 was based on PCV7 data in children, and for all-cause NBP, was varied across a reasonable range. Lifetime outcomes and costs were projected assuming: (1) use of PCV13 in all subjects at model entry, with and without periodic revaccination; and (2) use of PPSV23 per current ACIP recommendations.

Results

Use of PCV13 in all subjects at model entry without revaccination – in lieu of PPSV23 use per recommendations – reduced cases of IPD by 15,000 (95% CI 9000–21,000); cases of NBP by 1.2 million (0.9–1.5); total healthcare costs by $3.5 billion (1.9–5.2); and total societal costs by $7.4 billion (5.3–9.8). Use of PCV13 with revaccination every 5–10 years resulted in fewest cases of disease and lowest total costs. Findings were largely unchanged in sensitivity analyses.

Conclusions

Assuming that the effectiveness of PCV13 in adults is comparable to that observed for PCV7 in children and under reasonable assumptions regarding the underlying risks and costs of IPD and NBP, model projections suggest that routine use of PCV13 – in lieu of PPSV23 – would result in a greater reduction in the overall burden of pneumococcal disease in older US adults.     

Can the response to 23-valent pneumococcal vaccine in splenectomised patients be predicted?

The 23-valent pneumococcal vaccine has unequal effectiveness in splenectomised patients. We performed a longitudinal study (2005-2008) whose main objective was to characterize the profile of non-responders among splenectomised patients treated at our institution and identify potential predictive indicators of the response to the vaccine. The immune response was evaluated in 96 subjects. The proportion of responders was 70% (95% CI: 60-78%). Immunosuppression (OR=3.19, 95% CI 1.04-9.73) and the reason for splenectomy (hematologic neoplasia versus non-malignant hematologic diseases, OR=7.37, 95% CI 1.71-31.7) were independent predictors of non-response to vaccination. However, the positive predictive value of the model and the likelihood ratio for a positive result were low (PPV=76.6%, 95% CI 66.2-84.4%, LR(+)=1.41, 95% CI 1.08-1.86). We recommend determining the response to pneumococcal vaccine in these patients when possible.     

Clinical inquiries. Should patients receive 23-valent pneumococcal vaccination more than once?

No patient-oriented evidence supports pneumococcal revaccination of any patient (high-risk or otherwise). Antibody levels may be augmented by revaccination; however, the clinical efficacy of revaccination, even among high-risk patients, is unknown. Revaccination is recommended by the Advisory Committee on Immunization Practices (ACIP) in certain circumstances (strength of recommendation [SOR]: C, expert opinion based on physiology/bench research). Revaccination once appears to be safe, especially if provided 5 years or more after primary vaccination (SOR: B, based upon consistent results of cohort studies and nonrandomized prospective trials).     

The effect of 23-valent pneumococcal polysaccharide vaccine on immunological priming induced by 7-valent conjugate vaccine in asplenic subjects with β-thalassemia

The effect of the 23-valent pneumococcal polysaccharide vaccine (PPV) on the 7-valent conjugate (PCV) vaccine-induced priming was evaluated in 35 splenectomised β-thalassemics [median (range) age: 30 (12–41) years] vaccinated with either PCV/PPV or two PCVs 1 month apart, followed by a PPV booster 12 months later. 28/35 had already received 1–3 PPVs in the past. Different schedules induced similar anamnestic responses; however priming for 3/5 serotypes induced by one or two PCVs, was inferior in subjects who had received ≥2 PPVs in the past when compared with 23 aged-matched PPV-naïve β-thalassemics. One PPV following PCV does not affect PCV priming; multiple PPVs induce hyporesponsiveness for some serotypes in splenectomised subjects with β-thalassemia.     

Invasive pneumococcal disease and 13-valent pneumococcal conjugate vaccine (PCV13) coverage among children aged ≤59 months---selected U.S. regions, 2010--2011

On March 12, 2010, the Advisory Committee on Immunization Practices (ACIP) published recommendations for use of a newly licensed, 13-valent pneumococcal conjugate vaccine (PCV13) to replace the 7-valent vaccine (PCV7) for all children and for a supplemental dose for those aged 14 through 59 months. PCV is given routinely to children at ages 2, 4, and 6 months, and a booster dose is given at 12--15 months. PCV13 includes antigens of six pneumococcal serotypes in addition to those in PCV7. Children only vaccinated with PCV7 are susceptible to those six serotypes, which can cause invasive pneumococcal disease (IPD) and death. During 2010 and 2011, CDC evaluated available data to assess the occurrence of PCV13-type IPD cases and PCV13 vaccination coverage among children aged ≤59 months. During May 1, 2010--April 30, 2011, 63 vaccine-eligible children with IPD caused by a serotype that would have been prevented by PCV13 were identified within 12 study regions. Most of those children were aged 24 through 59 months and were vaccinated completely with PCV7 but had not received the recommended supplemental dose of PCV13. Immunization Information System (IIS) sentinel site data from March 2010--June 2011 indicated that the proportion of PCV7-vaccinated children who had received the PCV13 supplemental dose was only 37%. Similarly, among children aged ≤59 months requiring additional primary series doses, PCV13 coverage was only 46%. Given the potential for missed PCV13 vaccination, health-care providers should recommend PCV13 vaccination for all eligible children aged 14 through 59 months during all visits, and continue to ensure receipt of the full PCV13 primary series for younger children.     

Clinical effectiveness of 23-valent pneumococcal polysaccharide vaccine against pneumonia in middle-aged and older adults: A matched case–control study

The 23-valent polysaccharide pneumococcal vaccine is currently recommended in elderly and high-risk adults. Its efficacy against invasive pneumococcal disease has been demonstrated, but its effectiveness in preventing pneumonia remains uncertain. This study assessed the clinical effectiveness of vaccination against pneumonia among middle-aged and older adults. We conducted a population-based case–control study including 304 case patients over 50 years old with radiographically confirmed pneumococcal pneumonia (94 bacteremic and 210 nonbacteremic cases) and 608 outpatient control subjects (matched by primary care centre, age, sex and risk stratum). Adjusted odds ratios (ORs) for vaccination were calculated using conditional logistic regression, controlling for underlying conditions. Vaccine effectiveness against all pneumococcal pneumonia was 48% (OR: 0.52; 95% confidence interval [CI]: 0.37–0.73). Vaccination was effective against bacteremic cases (OR: 0.34; 95% CI: 0.27–0.66) as well as nonbacteremic cases (OR: 0.58; 95% CI: 0.39–0.86). Vaccine effectiveness was highest against bacteremic infections caused by vaccine types (OR: 0.24; 95% CI: 0.09–0.66). These findings confirm the effectiveness of the vaccine against invasive disease, but they also support the benefit of vaccination in preventing nonbacteremic pneumococcal pneumonia.     

Invasive pneumococcal disease: Clinical outcomes and patient characteristics 2–6 years after introduction of 7-valent pneumococcal conjugate vaccine compared to the pre-vaccine period,the Netherlands

BackgroundImplementation of 7-valent pneumococcal conjugate vaccine (PCV7) in the Dutch national immunization program for infants led to a shift from vaccine to non-vaccine serotypes in invasive pneumococcal disease (IPD) in all age groups. We studied the impact of the serotype shift on clinical syndromes and outcomes.MethodsPneumococcal isolates from hospitalized IPD patients obtained from nine sentinel microbiology laboratories, covering 25% of the Dutch population, were serotyped. Clinical syndromes, outcomes and patient characteristics in the post-PCV7 (2008–2012) period were compared with the pre-PCV7 period (2004–2006). Serotype specific propensity of the association with empyema, meningitis and death was calculated.ResultsInvasive pneumonia incidence significantly decreased in children <5 years and elderly ≥65 years, but increased in 5–64 years old from 4.92 to 5.58 cases/100.000/year (RR 1.13 95% CI 0.99–1.29). Empyema incidence significantly increased in elderly 65 years and older from 0.61 to 2.60 cases/100.000/year (RR 4.28 95% CI 1.97–9.33), mainly due to serotype 1. The incidence of meningitis only declined significantly in children <5 years. IPD case-fatality decreased in children <5 years from 5% to 3%, in 5–64 years old from 9% to 7% and in elderly ≥65 years significantly from 22% to 17%, due to lower case-fatality rates for most emerging non-PCV7 serotypes.ConclusionsAn increase in empyema incidence was observed in persons ≥65 years old in the post-PCV7 era, mainly due to the emergence of serotype 1, although overall IPD case-fatality decreased. Extended conjugate vaccines that target serotype 1 or serotypes with high case-fatality may offer further reduction of pneumococcal disease burden.     

Cost-utility analysis of 10- and 13-valent pneumococcal conjugate vaccines: Protection at what price in the Thai context?

Objective

This study aims to evaluate the costs and outcomes of offering the 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13) in Thailand compared to the current situation of no PCV vaccination.

Methods

Two vaccination schedules were considered: two-dose primary series plus a booster dose (2 + 1) and three-dose primary series plus a booster dose (3 + 1). A cost-utility analysis was conducted using a societal perspective. A Markov simulation model was used to estimate the relevant costs and health outcomes for a lifetime horizon. Costs were collected and values were calculated for the year 2010. The results were reported as incremental cost-effectiveness ratios (ICERs) in Thai Baht (THB) per quality adjusted life year (QALY) gained, with future costs and outcomes being discounted at 3% per annum. One-way sensitivity analysis and probabilistic sensitivity analysis using a Monte Carlo simulation were performed to assess parameter uncertainty.

Results

Under the base case-scenario of 2 + 1 dose schedule and a five-year protection, without indirect vaccine effects, the ICER for PCV10 and PCV13 were THB 1,368,072 and THB 1,490,305 per QALY gained, respectively. With indirect vaccine effects, the ICER of PCV10 was THB 519,399, and for PCV13 was THB 527,378. The model was sensitive to discount rate, the change in duration of vaccine protection and the incidence of pneumonia for all age groups.

Conclusions

At current prices, PCV10 and PCV13 are not cost-effective in Thailand. Inclusion of indirect vaccine effects substantially reduced the ICERs for both vaccines, but did not result in cost effectiveness.     

Dynamic changes in clinical characteristics and serotype distribution of invasive pneumococcal disease among adults in Japan after introduction of the pediatric 13-valent pneumococcal conjugate vaccine in 2013–2019

Nationwide population-based surveillance for invasive pneumococcal disease (IPD) is being conducted in few Asian countries. We aimed to evaluate the clinical characteristics and serotype distribution among Japanese adult patients with IPD after introduction of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) in 2013. IPD surveillance was conducted among adults between 2013 and 2019, and 1,995 patients were analyzed by time period (early, 2013–2015; middle, 2016–2017; late, 2018–2019). We found that the period of 2018–2019 was independently associated with a lower risk of fatal outcome, compared with the period of 2013–2015. The proportion of those with serotype PCV13-nonPCV7 decreased significantly in patients aged 15–64 years and in those aged ≥ 65 years within 3 years after the introduction of pediatric PCV13. By contrast, the proportion of those with nonvaccine serotype increased significantly in those aged ≥ 65 years, but not in those aged 15–64 years. No significant change was found in the proportion of 23-valent polysaccharide pneumococcal vaccine (PPSV23)-nonPCV13 in both of adults aged 15–64 years and ≥ 65 years. The proportions of PCV15-, PCV20- and PCV24-covered serotypes were 38%, 56% and 58% in adult patients with IPD aged ≥ 65 years during the late period. Our data on the serotype distribution support an indirect effect from pediatric PCV13 use among adults, and afford a basis for estimates of protection against IPD by vaccination with newly developed PCVs in older adults in Japan.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine and an MF59-adjuvanted influenza vaccine after concomitant vaccination in ⩾60-year-old adults

BackgroundConcomitant administration of influenza and pneumococcal vaccines could be an efficient strategy to increase vaccine uptake among older adults. Nevertheless, immune interference and safety issues have been a concern when more than one vaccines are administered at the same time.MethodsSubjects aged ⩾60 years were randomized in a 1:1:1 ratio to receive MF59-adjuvanted trivalent inactivated influenza vaccine (MF59-aTIV) + 13-valent pneumococcal conjugate vaccine (PCV13) (Group 1), PCV13 alone (Group 2), or MF59-aTIV alone (Group 3). Hemagglutination inhibition (HI) and opsonophagocytic activity (OPA) assays were used to compare immunogenicity after single or concomitant vaccination.ResultsA total of 1149 subjects (Group 1, N = 373; Group 2, N = 394; Group 3, N = 382) were available for the assessment of immunogenicity and safety. All groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroprotection rates, seroconversion rates, and geometric mean titer (GMT) fold-increases, irrespective of concomitant vaccination. For each pneumococcal serotype, OPA titers increased markedly after the PCV13 vaccination, irrespective of the concomitant influenza vaccination. After concomitant administration, the non-inferiority criteria of GMT ratios were met for all three influenza subtypes and 13 pneumococcal serotypes. No vaccine-related serious adverse events occurred.ConclusionsConcomitant MF59-aTIV and PCV13 administration showed no interference with antibody response and showed good safety profiles.(Clinical Trial Number – NCT02215863).     

Effectiveness of 23-valent pneumococcal polysaccharide vaccine and seasonal influenza vaccine for pneumonia among the elderly – Selection of controls in a case-control study

We conducted a case-control study to elucidate associations between pneumonia in elderly individuals and 23-valent pneumococcal polysaccharide vaccine (PPSV23) and seasonal influenza vaccine (influenza vaccine). Here, we examined selection of controls in our study using an analytic epidemiology approach. The study period was from October 1, 2009 through September 30, 2014. Cases comprised ≥65-year-old patients newly diagnosed with pneumonia. For every case with pneumonia, two patients with other diseases (one respiratory medicine, one non-respiratory medicine) who were sex-, age-, visit date- and visit hospital-matched were selected as controls. Odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for pneumonia were calculated using conditional logistic regression model. Similar analyses were also conducted based on the clinical department of controls. Analysis was conducted in 234 cases and 438 controls. Effectiveness of pneumococcal vaccination or influenza vaccination against pneumonia was not detected. Proportions of either vaccination in controls were greater among respiratory medicine (pneumococcal vaccine, 38%; influenza vaccine, 55%) than among non-respiratory medicine (23%; 48%). Analysis using controls restricted to respiratory medicine showed marginally significant effectiveness of pneumococcal vaccination (OR, 0.59; 95%CI, 0.34–1.03; P = 0.064) and influenza vaccination (0.64; 0.40–1.04; 0.072). However, this effectiveness might have been overestimated by selection bias of controls, as pneumonia cases are not necessarily respiratory medicine patients. In the analysis using controls restricted to non-respiratory medicine, OR of pneumococcal vaccination for pneumonia was close to 1, presumably because the proportion of pneumococcal vaccination was higher in cases than in controls. Because pneumococcal vaccine was not routinely administered during the study period, differences in recommendations of vaccination by physician in different clinical departments might have greatly affected vaccination proportions. When we select controls, we should consider the background factors (underlying diseases, clinical department, etc.) which affect physicians’ recommendation of vaccination.     

Nationwide surveillance of paediatric invasive and non-invasive pneumococcal disease in Japan after the introduction of the 13-valent conjugated vaccine, 2015–2017

Streptococcus pneumoniae is still one of the major causes of morbidity and mortality worldwide. In Japan, pneumococcal conjugate vaccine (PCV)7 and PCV13 were licensed in 2010 and 2013, respectively. We conducted a nationwide paediatric invasive pneumococcal disease (IPD) and non-IPD surveillance study in Japan between 2015 and 2017. We collected 498 IPD isolates and 231 non-IPD isolates from a total of 187 medical institutions in Japan. We performed serotyping, antimicrobial susceptibility testing and multi-locus sequencing typing (MLST) for the collected isolates. Among the 498 IPD isolates, the most prevalent serotype was 24F, followed by 12F, 15A and 15B/C. However, 12F increased and 24F significantly decreased during the study period (p < 0.001), resulting in 12F becoming the most prevalent serotype in 2017. Among the IPD isolates, the PCV7 and PCV13 coverage rates were 0.8% and 9.2%, respectively. The most prevalent serotype among the non-IPD isolates was 15A, followed by 35B, 15B/C and 19A. The overall resistance rates to penicillin (PG), cefotaxime (CTX), meropenem (MEM), erythromycin (EM) and levofloxacin (LFX) were 40.5%, 12.2%, 19.4%, 91.8% and 0.5%, respectively. PG, CTX and MEM resistance rates were significantly higher in non-IPD isolates than in IPD isolates (p < 0.001). Serotype 15A-CC63 and serotype 35B-CC558 tended to be multi-drug resistant. In conclusion, the PCV13 coverage rate was significantly lower than that in a previous surveillance study in Japan between 2012 and 2014, and IPD cases attributable to serotype 19A also decreased. We should note the rapid increase in the prevalence of serotype 12F in IPD cases and the spread of the multi-drug resistant serotype 15A-CC63 and 35B-CC558 lineages.