Vaccine-type Invasive Pneumococcal Disease Research Articles

Efficacy and Safety of the Pneumococcal Conjugate-13 Valent Vaccine in Adults.

Invasive pneumococcal disease and pneumococcal pneumonia cause substantial morbidity and mortality in the elderly. This review focuses on the immunogenicity, safety, efficacy and effectiveness data on the use of the 13-valent conjugate pneumococcal vaccine (PCV13) in adults. A MEDLINE literature search was performed from January 1946 to December 2017. Additional references were identified from a review of literature citations. All English-language randomized trials, observational studies and meta-analyses assessing the immunogenicity, efficacy, effectiveness and safety of PCV13 in adults were evaluated. Six randomized controlled studies evaluated immunogenicity and safety of PCV13 in adults and showed that the conjugated vaccine elicited a greater immune response to the majority of the 13 serotypes compared to the 23-valent polysaccharide pneumococcal vaccine (PPV23). Administering PCV13 prior to PPV23 elicits greater immune responses and multiple doses of PCV13 demonstrated modest advantage. PCV13 titers declined after a year but remained above baseline. A randomized clinical trial (CAPiTA) showed that PCV13 was effective in preventing community-acquired pneumonia (CAP) and vaccine-type invasive pneumococcal disease, but not any cause pneumonia. Safety data shows PCV13 elicits minor local reactions, such as pain at the injection site. Major side effects that were commonly reported included muscle fatigue and headache. Both local and systemic adverse events were comparable to PPV23. While PCV13 has a well-established immunogenicity and safety profile in adults, there is sparse data on sequential or multiple dosing, efficacy and effectiveness in adults. As there are few countries who have adopted PCV13 for routine adult immunization, there is a need to evaluate the effectiveness of PCV13 in a real-world setting.

Effectiveness of 10-valent pneumococcal conjugate vaccine against vaccine-type invasive pneumococcal disease in Pakistan

ObjectiveTo assess the effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) against invasive pneumococcal disease (IPD) due to vaccine serotypes of Streptococcus pneumoniae post introduction of the vaccine into the routine immunization program in Pakistan. MethodsA matched case–control study was conducted at 16 hospitals in Sindh Province, Pakistan. Children aged <5years (eligible to receive PCV10) who presented with radiographically confirmed pneumonia and/or meningitis were enrolled as cases. PCR for the lytA gene was conducted on blood (for radiographic pneumonia) and cerebrospinal fluid (for meningitis) samples to detect S. pneumoniae. The proportion of IPD due to vaccine serotypes (including vaccine-related serogroups) was determined through serial multiplex PCR. For each case, at least five controls were enrolled from children hospitalized at the same institution, matched for age, district, and season. ResultsOf 92 IPD patients enrolled during July 2013 to March 2017, 24 (26.0%) had disease caused by vaccine serotypes. Most case (87.5% of 24) and control (66.4% of 134) children had not received any PCV10 doses. The estimated effectiveness of PCV10 against vaccine-type IPD was 72.7% (95% confidence interval (CI) −7.2% to 92.6%) with at least one dose, 78.8% (95% CI −11.9% to 96.0%) for at least two doses, and 81.9% (95% CI −55.7% to 97.9%) for all three doses of vaccine. ConclusionsThe vaccine effectiveness point estimates for PCV10 were high and increased with increasing number of doses. However, vaccine effectiveness estimates did not reach statistical significance, possibly due to low power. The findings indicate the likely impact of vaccine in reducing the burden of vaccine-type IPD if vaccine uptake can be improved.

1427. A Dynamic Modeling Study of the Effect of Introducing a New Higher Valent Pneumococcal Conjugate Vaccine in a Paediatric Population in the United States

BackgroundRoutine use of pneumococcal conjugate vaccines (PCVs) in young children has substantially reduced vaccine-type invasive pneumococcal disease (IPD) in the United States and Europe. However, increases in disease and colonization caused by nonvaccine serotypes have been observed, suggesting the need for new PCVs with broader serotype coverage. The aim of this study was to estimate the population-level impact of new PCVs to replace the existing 13-valent vaccine (PCV13) in infants.MethodsAn age-structured dynamic transmission model of Streptococcus pneumoniae before and after PCVs introduction was developed. The model was fit to longitudinal Active Bacterial Core surveillance (ABCs) data (1997–2015) in the United States on distribution and cases of IPD, as well as population level prevalence and serotype distribution data. It was assumed that total S. pneumoniae carriage remains constant over time, with full carriage replacement within four years of introduction of any PCV. Two alternative new PCVs with differing IPD coverage are tested with an introduction date of 2024.ResultsWhen compared with continuing vaccination of infants with PCV13, 10 years after a new PCV is introduced (2,034) cases of IPD are substantially reduced (shown in the table below). Broader serotype coverage leads to greater reductions in IPD. The greatest IPD reduction occurs in the directly vaccinated infant groups, however similar reductions are also observed in the unvaccinated elderly population due to herd protection.Additional Vaccine Coverage Over PCV13 (2016/2024)aIPD Incidence Rate Reduction [%] (2,024 vs. 2,034)<2 Years2–5 Years50–64 Years≥65 YearsAll Ages11–21%/32–35%363533313115–30%/42–45%4242413940 aDefined as the proportion of IPD cases that are caused by serotypes covered by the new PCV in 2016/2024 (a range of values is given because of differences by age group; values differ between 2016 and 2024 as serotype prevalence has not reached steady state as of 2016).ConclusionA new, higher valent PCV given to infants in the United States has the potential to reduce future cases of IPD. Vaccination of infants may also have a substantial indirect benefit on IPD cases in adults and the elderly.Disclosures M. Madin-Warburton, Sanofi Pasteur: Consultant, IQVIA received consultancy fee. A. B. Pitcher, Sanofi Pasteur: Consultant, IQVIA received consultancy fee. M. H. Kyaw, Sanofi Pasteur: Employee, Salary. A. Kieffer, Sanofi Pasteur: Employee, Salary.

Limited impact of pneumococcal vaccines on invasive pneumococcal disease in Nunavik (Quebec).

In 2002, a mass immunization campaign using the 23-valent pneumococcal polysaccharide vaccine (PPV23) was carried out in Nunavik to control an outbreak caused by a virulent clone of serotype 1 Streptococcus pneumoniae. At the same time, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced for routine immunization of infants, replaced by the 10-valent vaccine (PCV10) in 2009, and the 13-valent vaccine (PCV13) in 2011. The objective of this study was to describe the epidemiology of invasive pneumococcal disease (IPD) in relation to pneumococcal vaccine use. Retrospective analysis of IPD cases identified by the Quebec Public Health Laboratory during the period 1997-2016. One hundred thirty-two IPD cases were identified during the study period. In adults, serotype 1 incidence decreased following the 2002 PPV23 mass campaign, but breakthrough cases occurred. Following PCV use, the incidence of vaccine-type IPD decreased markedly in children and also in adults but serotypes not covered by conjugate vaccines increased. The overall IPD rate was 43/100,000 person-years in the 1997-1999 pre-vaccine era and 58/100,000 person-years in 2010-2016. The 2002 PPV23 mass immunization campaign may have contributed to control the serotype 1 outbreaks in Nunavik, but its effect was short-lived as IPDs caused by serotypes included in this vaccine continued to occur after 2005. PCV use in children induced important modifications in the epidemiology of IPD, but most of thebenefits were eroded by serotype replacement.

Impact of the 13-Valent Pneumococcal Conjugate Vaccine Among Adults: A Systematic Review and Meta-analysis.

A notable reduction of the pneumococcal disease burden among adults was observed after the introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in childhood immunization programs. In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in many jurisdictions; a comparative assessment of PCV13's impact was missing. Our objective was to summarize the available data and assess the change in the incidence of invasive pneumococcal disease (IPD) in adults after the introduction of PCV13 in childhood immunization programs. We conducted a systematic literature search from January 1946 to May 2017 of randomized, controlled trials and observational studies OBS reporting the incidence of IPD, non-invasive pneumococcal disease, hospitalizations, and mortality in adults for the periods before and after the introduction of PCV13. Incidence rate ratios (IRRs) were pooled across studies using restricted, maximum-likelihood, random-effects models. From 3306 records,we included 29 OBS studies and 2033961 cases. Significantly lower IPD rates were seen after PCV13 introduction in adults aged <65 years (IRR 0.78, 95% confidence interval [CI] 0.72-0.85) and those aged ≥65 years (IRR 0.86, 95% CI 0.81-0.91). Lower rates of IPD were seen with PCV7 (IRR 0.45, 95% CI 0.38-0.54) and PCV13 serotypes (IRR 0.60, 95% CI 0.54-0.68). A significantly higher IRR of 1.10 (95% CI 1.04-1.17) for non-vaccine serotypes was observed, especially among those aged 65 years and older (IRR 1.20, 95% CI 1.11-1.29). PCV13 use in children had a moderate impact on reducing the overall and vaccine-type IPDs, but there was a significant increase in non-vaccine type IPDs among adults, especially in those over 65 years.

PIN82 - IN SMALL DOSES: MISSING THE BOOSTER DOSE IN A REDUCED PNEUMOCOCCAL CONJUGATE VACCINATION SCHEDULE

Policymakers in the UK are considering modifying the pneumococcal conjugate vaccination (PCV) program from a 2+1 to a 1+1 schedule. Our dynamic transmission model estimated an increase in invasive pneumococcal disease (IPD) in <2 year-olds due to the proposed schedule. This study builds upon previous work by investigating differential risk of IPD in those who do not receive the booster dose in the two schedules. An established transmission dynamic model was parameterized using UK serotype-specific IPD data and published literature to predict 5-year cumulative IPD incidence per 100,000. For children ages 1 - <2, IPD incidence risk ratios (IRR) were calculated as the risk of IPD without a booster dose compared to no booster dose. These IRR were then compared between 2+1 and 1+1 schedules. Scenario analyses examined the impact of modeling assumptions and parameter uncertainty. For a 2+1 schedule, the model predicted a 5-year cumulative IRR of vaccine-type IPD in 1 - <2 year-olds of 1.08 for those who miss the booster dose versus those receiving the booster dose. In a 1+1 schedule, this IRR was 1.37, a 27.3% relative increase compared to a 2+1 schedule. Scenario analyses found that effectiveness of a priming dose was the main driver of increased disease when individuals miss a booster, with relative increases ranging from 16.7% to 45.6%. Results demonstrate continued use of a 2+1 schedule would provide greater IPD protection to younger populations than the proposed 1+1 schedule. This outcome is magnified if single priming dose effectiveness is lower than hypothesized. Policymakers should consider the decreased protection afforded to children who may be more likely to miss their booster dose.

Invasive Pneumococcal Disease in Refugee Children, Germany.

Refugee children in Germany are not routinely given a pneumococcal conjugate vaccine. Cases of invasive pneumococcal disease (IPD) in 21 refugee children were compared with those in 405 Germany-born children for 3 pneumococcal seasons. Refugee children had significantly higher odds of vaccine-type IPD and multidrug-resistant IPD than did Germany-born children.

High effectiveness of PCV13 Vaccine to Prevent Community-Acquired Pneumonia in Adults over 65

Background: CAPiTA study found significant efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) for first episode of vaccine-type community-acquired pneumonia (CAP), nonbacteremic/noninvasive vaccine-type CAP and vaccine-type CAP invasive pneumococcal disease. In 2012 a population-based surveillance of CAP aimed to estimate incidence rate of CAP in adults started in Roca City, Argentina (population older than 18 years old 62667, population 65 years and older 9312). Patients with radiographic confirmed diagnosis of CAP, treated on ambulatory basis or hospitalized, were invited to participate in the study and to sign inform consent. Preliminary results of the population-based surveillance showed a high incidence rate of CAP, particularly in elderly subjects. Based on this data a pilot vaccination program with PCV13 was implemented by the National and Provincial Ministry of Health offering PCV13 to subjects 65 years and older in Roca City. During a two years period 39% of subjects 65 years and older received PCV13. The aim of this analysis is to assess effectiveness of vaccination program to prevent all cause CAP in subjects 65 years and older. Methods & Materials: Cohort study assessed vaccine effectiveness in preventing CAP among adults 3 65 years and older. Data were gathered from the population-based surveillance database paired with national immunization registry during 2014-2016. Vaccine effectiveness was calculated (1 - (Incidence [vaccinated] ÷ Incidence [unvaccinated]). Multivariable logistic regression was performed, adjusted odds ratios (OR) were computed to obtain vaccine effectiveness (1-OR). We adjusted vaccine effectiveness for influenza vaccination status, age, chronic obstructive pulmonary (COPD), cardiovascular disease, diabetes and nephropathic diseases. Results: During the study period 3640 adults 65 years and older were vaccinated and 34 (0.93%) suffered CAP. In 5672 unvaccinated adults 65 years and older, 467 (8.23%) suffered the same event. Vaccine effectiveness was 90.0% (CI 95%: 85.0%-93.0%), p < 0.01. Adjusted vaccine effectiveness for influenza vaccination status, age, COPD, cardiovascular disease, diabetes and nephropathic diseases was 62.0% (CI 95%: 40.0-75.0), p < 0.01. Conclusion: Our results show a 62% effectiveness to prevent all cause CAP in adults 65 years and older. Studies of effectiveness are relevant to determine the role of PCV13 to prevent CAP in adults.

Adult invasive pneumococcal disease in the Republic of Korea: Risk medical conditions and mortality stratified by age group

ObjectivesThis study aimed to characterize the risk factors for mortality in adult patients with invasive pneumococcal disease (IPD) stratified by age groups, after implementation of the national immunization program of 23-valent polysaccharide vaccine (PPSV23) for those aged ≥65 years in the Republic of Korea (ROK). MethodsClinical data and pneumococcal isolates from adult patients with IPD (≥18 years of age) were collected prospectively from 20 hospitals through the nationwide surveillance program from March 2013 to October 2015. ResultsA total of 319 patients with IPD were enrolled. Median age was 69 years. Overall in-hospital mortality was 34.2%: 17.1% in those aged 18–49 years, 23.7% in those aged 50–64 years, 33.0% in those aged 65–74 years, and 51.0% in those aged ≥75 years (p<0.001). In particular, early death within 7days of hospitalization accounted for 60.6% (66/109). While old age (≥65 years), higher Pitt bacteremia score (≥4), and bacteremic pneumonia were independently associated with IPD mortality in all age groups, an additional mortality risk factor of immunocompromised status was identified for patients aged 50–64 years. PPSV23 serotypes accounted for 64.4% (122/189) of the pneumococcal isolates serotyped. ConclusionsThis study suggests that vaccine-type IPD continues to place a substantial burden on older adults in the ROK, necessitating an effective vaccination strategy for those at higher risk.

Pneumococcal Conjugate Vaccine impact assessment in Bangladesh

The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh’s national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3-59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case-control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia . This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh.

Why is the rate of pneumococcal pneumonia declining?

As Streptococcus pneumoniae was considered the etiological agent of nearly all the cases of pneumonia at the beginning of the 20th century, and today is identified in fewer than 10-15% of cases, we analyze the possible causes of such a decline. Extensive use of early empiric antimicrobial therapy, discovery of previously unrecognized pathogens, availability to newer diagnostic methods for the recognition of the pneumonia pathogens (PCR, urinary antigens, monoclonal antibodies etc.) and of improved preventive measures, including vaccines, are some of possible explanations of the declining role of S. pneumoniae in the cause of pneumonia. The 14-valent and the 23-valent capsular polysaccharide pneumococcal vaccines were licensed in 1977 and 1983, respectively. The seven-valent protein-conjugated capsular polysaccharide vaccine, approved for routine use in children starting at 2 months of age, was highly effective in preventing invasive pneumococcal disease in children but also in adults because of the herd effect. In 2010, the 13-valent protein-conjugated capsular polysaccharide vaccine replaced seven-valent protein-conjugated capsular polysaccharide vaccine. With the use of conjugated vaccines, a decrease of the vaccine-type invasive pneumococcal disease for all age groups was observed. Both the direct effect of the vaccine and the so-called herd immunity are considered responsible for much of the decline.

Pneumococcal Conjugate Vaccine impact assessment in Bangladesh

The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh's national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3-59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case-control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia . This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh.

Effectiveness of 13-pneumococcal conjugate vaccine (PCV13) against invasive pneumococcal disease in children in the Dominican Republic

BackgroundLimited data are available on the effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in resource-poor settings and PCV naïve populations. The Dominican Republic introduced PCV13 in September 2013 using a 2 + 1 schedule (2, 4, and 12 months) without a catch-up campaign. We evaluated PCV13 effectiveness against vaccine-type (VT) invasive pneumococcal disease (IPD) among children in the Dominican Republic.MethodsWe conducted a matched case-control study. A case-patient was defined as VT-IPD identified by culture or polymerase chain reaction (PCR) from a normally sterile-site in a hospitalized child who was age-eligible to have received ≥1 PCV13 dose. Four age- and neighborhood-matched controls were enrolled for each case-patient. We collected demographic, vaccination history, and risk factor data. Conditional logistic regression was performed. Vaccine effectiveness was calculated as (1- adjusted matched odds ratio for vaccination) X 100%.ResultsWe enrolled 39 case-patients and 149 matched-controls. Most case-patients had pneumonia with pleural effusion (64%), followed by meningitis (28%) and septicemia (13%). The most common pneumococcal serotypes identified included 14 (18%), 3 (13%), 19A (10%), and 1 (8%). Fewer case-patients had ≥1 PCV13 dose as compared to controls (61.5% vs. 80.0%; p = 0.006). Adjusting for malnutrition and socioeconomic status, VE of ≥1 PCV13 dose compared to no doses was 67.2% (95% CI: 2.3% to 90.0%). Only 44% of controls were up-to-date for PCV13, suggesting low vaccine coverage in the population.ConclusionsWe found that PCV13 provided individual protection against VT-IPD in this resource-poor setting with a PCV-naïve population, despite low PCV13 coverage. Expanding vaccination coverage might increase PCV13 impact.

Effectiveness of 7- and 13-Valent Pneumococcal Conjugate Vaccines in a Schedule Without a Booster Dose: A 10-Year Observational Study

Unique among high-income countries, Australia has used a 3 + 0 schedule (3 primary doses, no booster) for infant pneumococcal conjugate vaccine (PCV) since January 2005, initially 7 valent (PCV7) then 13 valent (PCV13) from July 2011. We measured vaccine effectiveness (VE) of both PCVs against invasive pneumococcal disease (IPD) using 2 methods. Cases were IPD notifications to the national surveillance system of children eligible for respective PCVs. For case-control method, up to 10 age-matched controls were derived from the Australian Childhood Immunisation Register. For indirect cohort method, controls were IPD cases due to serotypes not in PCVs. VE was calculated as (1 - odds ratio [OR]) × 100 by logistic regression. VE waning was estimated as odds of vaccine type (VT) IPD in consecutive 12-month periods post-dose 3. Between 2005 and 2014, there were 1209 and 308 IPD cases in PCV7-eligible and PCV13-eligible cohorts, respectively. Both methods gave comparable VE estimates. In infants, VE for 3 doses against VT IPD was 92.9% (95% confidence interval [CI], 27.7% to 99.3%) for PCV7 and 86.5% (95% CI, 11.7% to 97.9%) for PCV13. From 12 months post-dose 3, the odds of VT IPD by 24-36 months increased significantly for PCV7 (5.6, 95% CI, 1.2-25.4) and PCV13 (5.9, 95% CI, 1.0-35.2). For both PCVs in a 3 + 0 schedule, despite similar VE, progressive increase in breakthrough cases only occurred post-PCV13. This supports the importance of a booster dose of PCV13 in the second year of life to maintain protection.

Characteristics and Serotype Distribution of Childhood Cases of Invasive Pneumococcal Disease Following Pneumococcal Conjugate Vaccination in England and Wales, 2006-2014.

The 7-valent and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) are highly effective in preventing invasive pneumococcal disease (IPD) caused by vaccine serotypes. Vaccine failure (vaccine-type IPD after age-appropriate immunization) is rare. Little is known about the risk, clinical characteristics, or outcomes of PCV13 compared to PCV7 vaccine failure. Public Health England conducts IPD surveillance and provides a national reference service for serotyping pneumococcal isolates in England and Wales. We compared the epidemiology, rates, risk factors, serotype distribution, clinical characteristics, and outcomes of IPD in children with PCV13 and PCV7 vaccine failure. A total of 163 episodes of PCV failure were confirmed in 161 children over 8 years (4 September 2006 to 3 September 2014) in 10 birth cohorts. After 3 vaccine doses, PCV7 and PCV13 failure rates were 0.19/100000 (95% confidence interval [CI], .10-.33 [57 cases]) and 0.66/100000 (95% CI, .44-.95 [104 cases]) vaccinated person-years, respectively. Children with PCV13 failure were more likely to be healthy (87/105 [82.9%] vs 37/56 [66.1%]; P = .02), present with bacteremic lower respiratory tract infection (LRTI) (61/105 [58.1%] vs 11/56 [19.6%]; P < .001), and develop empyema (41/61 [67.2%] vs 1/11 [9.1%]; P < .001) compared to PCV7 failures. Serotypes 3 (n = 38 [36.2%]) and 19A (n = 30 [28.6%]) were responsible for most PCV13 failures. Six children died (4% [95% CI, 1%-8%]), including 5 with comorbidities. PCV failure is rare and, compared to PCV7 serotypes, the additional PCV13 serotypes are more likely to cause bacteremic LRTI and empyema in healthy vaccinated children.

Sustained reduction in vaccine-type invasive pneumococcal disease despite waning effects of a catch-up campaign in Kilifi, Kenya: A mathematical model based on pre-vaccination data.

In 2011, Kenya introduced the 10-valent pneumococcal conjugate vaccine together with a catch-up campaign for children aged <5years in Kilifi County. In a post-vaccination surveillance study based in Kilifi, there was a substantial decline in invasive pneumococcal disease (IPD). However, given the continued circulation of the vaccine serotypes it is possible that vaccine-serotype disease may re-emerge once the effects of the catch-up campaign wear off. We developed a compartmental, age-structured dynamic model of pneumococcal carriage and invasive disease for three serotype groups: the 10-valent vaccine serotypes and two groups of non-vaccine serotypes based on their susceptibility to mutual competition. The model was calibrated to age- and serotype-specific data on carriage and IPD in the pre-vaccination era and used to predict carriage prevalence and IPD up to ten years post-vaccination in Kilifi. The model was validated against the observed carriage prevalence after vaccine introduction. The model predicts a sustained reduction in vaccine-type pneumococcal carriage prevalence from 33% to 8% in infants and from 30% to 8% in 1-5year olds over the 10-year period following vaccine introduction. The incidence of IPD is predicted to decline across all age groups resulting in an overall reduction of 56% in the population, corresponding to 10.4 cases per 100,000 per year. The vaccine-type IPD incidence is estimated to decline by 83% while non-vaccine-type IPD incidence is predicted to increase by 52%. The model's predictions of carriage prevalence agrees well with the observed data in the first five years post-vaccination. We predict a sustained and substantial decline in IPD through PCV vaccination and that the current regimen is insufficient to fully eliminate vaccine-serotype circulation in the model. We show that the observed impact is likely to be sustained despite waning effects of the catch-up campaign.

The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel

BackgroundIntroduction of pneumococcal conjugate vaccine (PCV) has nearly eliminated vaccine-type (VT) invasive pneumococcal disease (IPD) in children, yet the reported resulting reduction of adult IPD is variable. We present the indirect impact of sequential PCV7/PCV13 implementation in Israel on adult IPD. MethodsAn ongoing nationwide active surveillance was initiated on July 2009 when PCV7 was implemented (with Catch-up). PCV7 was gradually replaced by PCV13 since November 2010. Comorbidity and outcome data were collected from medical files. Incidence rates were calculated for overall and vaccine-type IPD. ResultsA total of 2579 IPD cases were diagnosed among a population of 5.0–5.5 million adults >18y (2009–2015). Incidence rates were 9.15/100,000 and 10.16/100,000 in the first and second study years, respectively. However, after PCV13 implementation, the rates decreased to 7.19 within four years, and remained stable in the two following years. Within 6years, PCV7-VT-IPD incidence decreased from 2.52 to 0.52 (79%) and PCV13-VT-IPD from 6.15 to 1.81 (71%). Concurrently, non-VT13 incidence increased from 2.99 to 5.25.Approximately 50% of all patients were adults ≥65y, in whom the decrease in PCV13-VT-IPD incidence was smaller and slower (65% vs. >80% decrease in adults <50y). ConclusionsDespite continued reduction in PCV13-VT-IPD, overall IPD was stable during the last two years due to serotype replacement. Yet, the significant decrease in adult IPD, six years post-PCV7/13 implementation emphasizes the importance of indirect protection in achieving overall population impact and should be considered when discussing the potential additional benefits of direct adult PCV vaccination.

Exploratory efficacy endpoints in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA)

BackgroundThe Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) assessed vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) prevention with 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾65years. We report vaccine efficacy (VE) of PCV13 for the remaining 23 exploratory endpoints and serotype distributions for pneumococcal CAP and IPD. MethodsThis was a parallel-group, randomised, placebo-controlled, double-blind trial comparing single-dose PCV13 with placebo. Exploratory CAP endpoints included first episode of confirmed non-VT (NVT) pneumococcal CAP; all confirmed episodes of NVT pneumococcal CAP, pneumococcal CAP, nonbacteraemic/noninvasive (NB/NI) VT pneumococcal CAP, and NB/NI pneumococcal CAP; and first and all episodes of culture-confirmed VT pneumococcal CAP, culture-confirmed pneumococcal CAP, culture-confirmed NVT pneumococcal CAP, probable VT pneumococcal CAP, probable NVT pneumococcal CAP, and probable and possible pneumococcal CAP. Exploratory IPD endpoints included all episodes of VT-IPD and IPD, and first and all episodes of NVT-IPD. The per-protocol and modified intent-to-treat (mITT) populations were evaluated. ResultsIn total, 84,496 participants were enrolled. Eight of 23 exploratory CAP and IPD endpoints were statistically significant in both populations. In the per-protocol population, these included VE of 29% for all episodes of confirmed pneumococcal CAP, 43% for all NB/NI episodes of VT pneumococcal CAP, 52% for all episodes of culture-confirmed pneumococcal CAP, and 53% for all episodes of IPD. Comparable VE estimates were observed in the mITT population. The most common VT serotypes were 1 (10 first episodes of confirmed pneumococcal CAP; 2 first episodes of IPD) and 7F (22; 7) among PCV13 and placebo recipients, respectively. ConclusionsThe results of this analysis yielded statistically significant PCV13 VE for all episodes of confirmed pneumococcal CAP (including NB/NI and culture-confirmed episodes) and for all episodes of IPD in adults aged ⩾65years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263.

Long-term Impact of a "3 + 0" Schedule for 7- and 13-Valent Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Australia, 2002-2014.

Australia introduced universal 7-valent pneumococcal conjugate vaccine (PCV7) from 2005, replaced by 13-valent PCV (PCV13) in 2011, uniquely among high-income countries giving doses at 2, 4, and 6 months (3 + 0 schedule). Data on impact of a timely 3 + 0 PCV schedule with high coverage are sparse, with none for PCV13. We used national surveillance of invasive pneumococcal disease (IPD) from 2002 for baseline and appropriate later comparison periods to calculate incidence rate ratios (IRRs) by serotype and age using a Poisson model. PCV coverage was assessed from the Australian Childhood Immunisation Register. After 9 years of timely 3-dose PCV coverage of >92%, all-age IPD in Australia almost halved (IRR, 0.53; 95% confidence interval [CI], .50-.57), but differed by PCV era. Reductions in IPD due to vaccine serotypes from PCV7 (IRR, 0.20; CI, .17-.22) were about 2-fold greater than for IPD due to extra serotypes in PCV13 (13v-non7v) in a similar period (IRR, 0.58; CI, .51-.66). Post-PCV13 declines in serotype 19A IPD in persons aged <2 years (IRR, 0.23; CI, .13-.35) and ≥2 years (IRR, 0.35; CI, .28-.44) differed from other 13v-non7v IPD (IRR, 0.73; CI, .35-1.48 for those aged <2 years and IRR, 0.96; CI, .81-1.15 for those ≥2 years). Meningitis due to vaccine serotypes nearly disappeared in children eligible for 3 PCV13 doses. IPD due to non-PCV13 serotypes increased by 30% compared with 76% for non-PCV7 serotypes in equivalent period of vaccine use. Reductions in vaccine-type IPD post-PCV13 were inferior to Australian experience with PCV7 and reports from high-income countries giving a PCV booster dose. Applicability of findings to other settings would depend on age of IPD onset, serotype profile, and timeliness of vaccination.

Epidemiology of Invasive Pneumococcal Disease in Czech Children under 5 Years of Age after Routine Immunisation.

The introduction of the surveillance of invasive pneumococcal diseases (IPD) in 2007 has helped to monitor changes in serotype occurrence in the Czech population and assess the impact of routine immunisation against IPD on the child population under 5 years of age. Observational study of childhood IPD in the Czech Republic based on the state public health surveillance data comparing pre-immunisation (2007-2008) and post-immunisation (2012-2013) periods. In the child population there was an overall decline in IPD occurrence of 46.6% (95% CI 63.4-21.9) observed during the post-immunisation period. There was even greater decrease of 71.6% (95% CI 50.4-83.8) in vaccinated children. In the post-immunisation period, Prevenar 13 (PCV13) and Synflorix (PCV10) contributed to a vaccine-type IPD reduction of 95.4% (95% CI 67.0-99.4) and 76.9% (95% CI 36.0-91.7), respectively, compared to unimmunised children. The occurrence of 10 serotypes contained in both commercial vaccines also decreased in unvaccinated children by 61.4% (95% CI 14.5-82.6). However, a rise in the risk of non-vaccine and unspecified serotype acquisition by up to 153% was revealed in unimmunised children when comparing post-immunisation and pre-immunisation periods. The findings suggest a shift in IPD caused either by vaccine or non-vaccine serotypes between immunised and unimmunised populations of children, which could result in increased incidence of IPD caused by non-vaccine serotypes. Therefore, routine immunisation using only one vaccine with broader serotype coverage together with a higher vaccination rate could raise hopes of further decrease in IPD in the child population.