Effectiveness of a 3 + 0 pneumococcal conjugate vaccine schedule against invasive pneumococcal disease among a birth cohort of 1.4 million children in Australia

BackgroundMost studies use indirect cohort or case-control methods to estimate vaccine effectiveness (VE) of 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) against invasive pneumococcal disease (IPD). Neither method can measure the benefit vaccination programs afford the unvaccinated and many studies were unable to estimate dose-specific VE. We linked Australia’s national immunisation register with health data from two states to calculate IPD incidence by vaccination status and VE for a 3 + 0 PCV schedule (doses at 2, 4, 6 months, no booster) among a cohort of 1.4 million births.MethodsBirths records for 2001–2012 were probabilistically linked to IPD notifications, hospitalisations, deaths, and vaccination history (available until December 2013). IPD rates in vaccinated and unvaccinated children <2 years old were compared using Cox proportional hazards models (adjusting for potential confounders), with VE = (1 − adjusted hazard ratio) × 100. Separate models were performed for all-cause, PCV7, PCV13 and PCV13-non-PCV7 serotype-specific IPD, and for Aboriginal and non-Aboriginal children.ResultsFollowing introduction of universal PCV7 in 2005, rates of PCV7 serotype and all-cause IPD in unvaccinated children declined 89.5% and 61.4%, respectively, to be similar to rates in vaccinated children. Among non-Aboriginal children, VEs for 3 doses were 94.2% (95%CI: 81.9–98.1) for PCV7 serotype-specific IPD, 85.6% (95%CI: 60.5–94.8) for PCV13-non-PCV7 serotype-specific IPD and 80.1% (95%CI: 59.4–90.3) for all-cause IPD. There were no statistically significant differences between the VEs for 3 doses and for 1 or 2 doses against PCV13 and PCV13-non-PCV7 serotype-specific IPD, or between Aboriginal and non-Aboriginal children.ConclusionOur population-based cohort study demonstrates that >90% coverage in the first year of a universal 3 + 0 PCV program provided high population-level protection, predominantly attributable to strong herd effects. The size of the cohort enabled calculation of robust dose-specific VE estimates for important population sub-groups relevant to vaccination policies internationally.     

Effectiveness of 10-valent pneumococcal conjugate vaccine estimated with three parallel study designs among vaccine-eligible children in Finland

BackgroundTen-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in 9/2010. We estimated the individual-level effectiveness (VE) of PCV10 in children during eight years of vaccine implementation.MethodsData on invasive pneumococcal disease (IPD) were collected from national, population-based surveillance, and vaccination status from the vaccination register. Vaccine-eligible children were followed from six months of age until end of 2018 (born 6/2010 or later, ages 6–102 months). VE was estimated with three parallel approaches: full cohort, nested case-control and indirect cohort designs adjusting with age-group, sex and calendar year.ResultsVE against PCV10 serotype IPD was estimated at 93% (95% credible interval 87–97%), 98% (90–100%) and 100% (98–100%), and against PCV10-related serotypes at 46% (−13–72%), 51% (−24–79%), and 78% (−7–97%), with the full cohort, nested case-control, and indirect cohort designs, respectively.The estimated VE against non-PCV10-related (neither PCV10 nor PCV10-related) serotypes was negative but included zero effectiveness (full cohort VE −67%, −711–52%; nested case-control VE −77%, −929–59%). VE against all IPD was estimated with these two methods at 54% (24–71%) and 61% (26–79%). Over time, VE against PCV10 IPD remained stable but VE against all IPD decreased.DiscussionAll designs provided estimates that were concordant with each other, but those with the full cohort design were usually the most precise. PCV10 offered sustained high VE against PCV10-serotype IPD on vaccinated children during the first decade after introduction into the programme.     

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.     

Distribution of serotypes causing invasive pneumococcal disease in older adults from high-income countries and impact of pediatric and adult vaccination policies

BackgroundNeither indirect protection through use of 13-valent and 10-valent pneumococcal conjugate vaccines (PCV13 and PCV10) in pediatric National Immunization Programs (NIPs) nor direct vaccination with the 23-valent polysaccharide vaccine have eliminated vaccine serotype invasive pneumococcal disease (IPD) in older adults. Vaccinating older adults with higher-valency PCV15 and PCV20 could address remaining IPD due to pediatric PCV serotypes plus additional IPD due to serotypes included in these vaccines.MethodsWe collected serotype-specific IPD data in older adults (≥65 years in most countries), from national or regional surveillance systems or hospital networks of 33 high-income countries. Data were from official government websites, online databases, surveillance system reports, published literature, and personal communication with in-country investigators. Average percentages of IPD serotypes were calculated.ResultsAmong 52,905 cases of IPD with a serotype identified, PCV13 serotypes accounted for 33.7% of IPD (55.8% and 30.6% for countries with PCV10 and PCV13 in the pediatric NIP), most commonly serotypes 3 (14.9%) and 19A (7.0%). PCV15 and PCV20 would cover an additional 10.4% and 32.9% of older adult IPD beyond PCV13 serotypes (PCV10 countries: 7.7% and 23.3%; PCV13 countries: 10.6% and 34.6%). The most common of these additional serotypes were 8 (9.9%), 22F (7.9%), 12F (4.6%), and 11A (3.3%). PPSV23 policies for older adults were not correlated with lower IPD percentages due to PPSV23 serotypes.ConclusionsVaccinating older adults with higher-valency PCVs, especially PCV20, could substantially reduce the remaining IPD burden in high-income countries, regardless of current PCV use in pediatric NIPs and adult PPSV23 policies.     

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.     

Incidence of invasive pneumococcal disease before and during an era of use of three different pneumococcal conjugate vaccines in Quebec

BackgroundIn Quebec, 7-valent (PCV7), 10-valent (PCV10) and 13-valent (PCV13) pneumococcal conjugate vaccines were successively used for the immunization of children according to a 2+1 doses schedule.ObjectiveOur aim was to assess the impact of this program on the epidemiology of invasive pneumococcal disease (IPD) in children and adults.MethodsNotification and laboratory surveillance data were analyzed and the immunization status of IPD cases in children was checked.ResultsIn children < 5 years, the IPD rate decreased from 69/100,000 in 2003 to 12/100,000 in 2016 (83% reduction). Following PCV7 introduction in 2004, there has been a rapid decline in PCV7-type IPD cases and 6A. 7F and 19A serotypes emerged but their incidence decreased following PCV10 introduction in 2009 and PCV13 in 2011, whereas decrease in serotype 3 IPD was modest. Non-PCV13 types increased and represented 79% of cases in 2016. The same pattern was seen in adults but replacement was complete and there was no decrease in overall IPD rate. In those 65 years and over, PCV13 serotypes represented 28% of cases in 2016 and 62% were serotypes included in the 23-valent polysaccharide vaccine. Out of 10 IPD cases caused by serotype 3 in children vaccinated with PCV13 in 2011–2016, 6 occurred more than one year following the booster dose, which suggests short-term protection. Out of 31 breakthrough 19A cases, 19 occurred in children aged between 8 and 14 months who had received the 2 primary PCV13 doses but not the toddler booster dose, which suggests a window of susceptibility in a 2+1 schedule.ConclusionPCVs had a major impact on the IPD rate in children but not in adults. Among elderly adults, the proportion of cases caused by serotypes included in PCV13 is diminishing year after year but a majority of cases remains covered by the 23-valent polysaccharide vaccine.     

Effectiveness of the seven-valent and thirteen-valent pneumococcal conjugate vaccines in England: The indirect cohort design, 2006–2018

BackgroundThe 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the UK childhood immunisation programme in 2006 and replaced with a 13-valent vaccine (PCV13) in 2010. Both vaccines led to rapid declines in vaccine-serotype invasive pneumococcal disease (IPD). Here, we assessed the long-term vaccine-effectiveness (VE) of both vaccines in England.MethodsPublic Health England conducts enhanced national surveillance of IPD in England. VE against IPD was estimated using vaccine-serotype IPD cases and non-vaccine serotype IPD controls among vaccine-eligible children from September 2006 to June 2018 (the Broome method).ResultsVaccine history was available for 3421 IPD cases, including 1299 due to the additional PCV13 serotypes and the PCV13-related serotype 6C, 274 PCV7 serotypes and 1848 non-PCV13 serotypes. For the complete 2 + 1 schedule, both PCV7 and PCV13 showed high effectiveness against PCV7 serotypes with a combined VE of 92.0% (95%CI, 81.7–96.7). For the 2 + 1 schedule, PCV13 VE against the additional PCV13 serotypes plus 6C was 73.7% (31.1–89.9) compared to 90.0% (75.3 – 96.0) for PCV7 against PCV7 serotypes, although PCV13 VE increased to 84.8% (58.7–94.4) if serotype 3 was excluded; all 36 eligible serotype 3 IPD cases were fully-vaccinated with PCV13. Case numbers were low in older ages but there was evidence of waning, which was significant for serotype 19A for which there were sufficient numbers of cases for analysis.ConclusionsPCVs are highly effective in preventing vaccine-serotype IPD except for serotype 3 which has been increasing in incidence. Serotype 19A IPD has also persisted, likely due to a slightly lower VE and/or more rapid waning of protection.     

Nationwide population-based surveillance of invasive pneumococcal disease in Japanese children: Effects of the seven-valent pneumococcal conjugate vaccine

BackgroundIn Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013.MethodsThe effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008–2013 in 10 prefectures in Japan.Results1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction.ConclusionsOur data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan.     

Characteristics of pediatric invasive pneumococcal diseases and the pneumococcal isolates in Suzhou,China before introduction of PCV13

BackgroundData on characteristics of invasive pneumococcal diseases (IPD) is limited in China. We aimed to understand the clinical features and explore the molecular characteristics of the pneumococcal isolates in China.MethodsSince 2010, we prospectively collected the pneumococcal isolates and the IPD patients’ demographic and clinical information in Suzhou University Affiliated Children’s Hospital (SCH). The antibiotic susceptibility, serotypes, genotypes of Streptococcus pneumoniae strains were identified by E-test, quellung reaction and/or multiplex PCR, and multi-locus sequence typing, respectively.ResultsDuring the period from January 2010 to December 2015, a total of 80 IPD patients were identified. They were diagnosed as meningitis (31.3%), septicemia (27.5%), pneumonia (21.3%) and others (20.0%). About half of them required vancomycin treatment, 42.5% were admitted to ICUs, 36.2% had complications and 6.2% were hospitalized for over 1 year. The most common serotypes of the pneumococcal isolates were serotypes 6B and 14, the coverage of PCV13 was 92.5%, and CC236s and CC199s were the most common clone complexes.ConclusionsPediatric IPD patients had severe clinical symptoms, demanded intensive treatment, suffered poor prognosis and substantial burden. The pneumococcal isolates’ serotype coverage of PCV13 vaccine was high, which leads to implication of PCV vaccine usage among children in China.     

Invasive pneumococcal disease in Canada 2010–2017: The role of current and next-generation higher-valent pneumococcal conjugate vaccines

BackgroundIn 2010–2011, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7- or 10-valent vaccine (PCV7 and PCV10, respectively) in pediatric immunization programs across Canada. For adults aged ≥65 years, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been publicly funded for several decades; PCV13 funding was not recommended in this population, partly due to expected ongoing vaccine-serotype disease decline stemming from herd effects of the pediatric program. Higher-valent PCVs (ie, 15- and 20-valent PCVs [PCV15 and PCV20, respectively]) currently in development may become available in Canada in the coming years.MethodsUsing the National Microbiology Laboratory surveillance reports, annual case counts and serotype distribution of invasive pneumococcal disease (IPD) from 2010 to 2017 in Canada were examined to assess the impact of existing programs on PCV13-serotype IPD and determine the proportion of IPD that can potentially be prevented by current and forthcoming higher-valent PCVs.ResultsThe percentages of PCV13-serotype IPD decreased from 55% [1492/2708] in 2010 to 30% [902/3006] in 2017 in all age groups combined, including a decline from 67% [221/331] to 18% [40/219] in children aged <5 years and from 50% [487/967] to 23% [287/1238] in adults aged ≥65 years. Overall, IPD cases declined mainly before 2014 and have plateaued since then. In 2017, PCV15- and PCV20-serotypes (inclusive of PCV13 serotypes) accounted for 42% and 58% of IPD cases, respectively, in all ages.ConclusionsIn Canada, publicly funded pediatric PCV13 use was associated with large declines in IPD due to vaccine serotypes. Substantial residual PCV13-serotype IPD proportions observed among all ages imply limits to indirect protection afforded by the pediatric PCV13 program at the current uptake level and suggest the adult PPSV23 program alone is insufficient. Higher-valent PCVs have the potential to address a substantial proportion of remaining IPD cases among all age groups.     

Pneumococcal conjugate vaccine herd effects on non-invasive pneumococcal pneumonia in elderly

BackgroundHerd protection from infant pneumococcal conjugate vaccination is well established for invasive pneumococcal disease (IPD) but not for non-IPD pneumococcal community-acquired pneumonia (PCAP). We assessed the contribution of vaccine-serotypes in non-IPD PCAP in adults 65 years and older in the period 2008–2013.MethodsThis is a post hoc analysis of two prospective studies from the Netherlands. Serotype specific urinary antigen detection and routine microbiological testing were used to categorize episodes as IPD or non-IPD PCAP caused by 7-valent pneumococcal conjugate vaccine (PCV7), PCV10-7 (three additional PCV10 serotypes), PCV13-10 (three additional PCV13 serotypes), and non-PCV13 serotypes. Proportions per vaccine-serotype group were assessed per year from June 1st to May 31st. Time trends were compared to national IPD data.ResultsOf 270 non-IPD PCAP episodes with known serotype, PCV7 serotypes decreased from 28% in 2008/2009 to 7% in 2012/2013 (p-value for trend <0.001). No change in PCV10-7 (19% overall) and PCV13-10 (29% overall) serotypes was observed. Non-PCV13 serotypes increased from 30% in 2008/2009 to 37% in 2012/2013 (p-value for trend 0.048). Trends corresponded with national IPD data.ConclusionPCV7 serotypes declined in non-IPD PCAP among elderly between 2008 and 2013, comparable to IPD data. No reduction in the additional PCV10 serotypes could be demonstrated within the first two years after PCV10 introduction.     

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.     

Summary of invasive pneumococcal disease burden among children in the Asia-Pacific region

Invasive pneumococcal disease (IPD) burden is significant in the Asia-Pacific region. This review describes the epidemiology and Streptococcus pneumoniae (SP) serotype distribution of IPD in children in the Asia-Pacific region from studies published from 1999 to 2010. IPD incidence varies widely in Asia-Pacific countries depending on the method of surveillance, the population studied, and the time period. Incidences are highest for younger children, with rates near 100–200 cases per 100,000 children aged <1 or 2 years. Incidences of preventable disease are estimated to be 6–200 cases per 100,000. Heptavalent pneumococcal conjugate vaccine (PCV7) serotype coverage shows a very wide range over the Asia-Pacific region. Ten countries have high vaccine serotype coverage (>70%), and six countries have low vaccine serotype coverage (<50%). The majority of SP serotypes in children with IPD in most countries in the Asia-Pacific region are susceptible to penicillin (intermediate and resistant <50%); a few countries have SP serotypes with high level resistance to penicillin (intermediate and resistant >50%). Japan, Taiwan, and Thailand have high PCV7 serotype coverage. Countries with low pneumococcal resistance to antimicrobials have shown increasingly higher nonsusceptibility with time. National vaccination programmes that include PCV7, 10-valent pneumococcal conjugate vaccine (PCV), or 13-valent PCV would significantly affect IPD burden in children aged <5 years in the Asia-Pacific region, as well as the burden of penicillin-nonsusceptible IPD.     

Efficacy,safety and immunogenicity of a pneumococcal protein-based vaccine co-administered with 13-valent pneumococcal conjugate vaccine against acute otitis media in young children: A phase IIb randomized study

BackgroundNative American populations experience a substantial burden of pneumococcal disease despite use of highly effective pneumococcal conjugate vaccines (PCVs). Protein-based pneumococcal vaccines may extend protection beyond the serotype-specific protection elicited by PCVs.MethodsIn this phase IIb, double-blind, controlled trial, 6–12 weeks-old Native American infants randomized 1:1, received either a protein-based pneumococcal vaccine (dPly/PhtD) containing pneumolysin toxoid (dPly, 10 µg) and pneumococcal histidine triad protein D (PhtD, 10 µg) or placebo, administered along with 13-valent PCV (PCV13) at ages 2, 4, 6 and 12–15 months. Other pediatric vaccines were given per the routine immunization schedule. We assessed vaccine efficacy (VE) against acute otitis media (AOM) and acute lower respiratory tract infection (ALRI) endpoints. Immunogenicity, reactogenicity and unsolicited adverse events were assessed in a sub-cohort and serious adverse events were assessed in all children.Results1803 infants were randomized (900 dPly/PhtD; 903 Control). VE against all episodes of American Academy of Pediatrics (AAP)-defined AOM was 3.8% (95% confidence interval: −11.4, 16.9). Point estimates of VE against other AOM outcomes ranged between 2.9% (−9.5, 14.0) and 5.2% (−8.0, 16.8). Point estimates of VE against ALRI outcomes ranged between −4.4% (−39.2, 21.8) and 2.0% (−18.3, 18.8). Point estimates of VE tended to be higher against first than all episodes but the confidence intervals included zero. dPly/PhtD vaccine was immunogenic and had an acceptable reactogenicity and safety profile after primary and booster vaccination in Native American infants.ConclusionsThe dPly/PhtD vaccine was immunogenic and well tolerated, however, incremental efficacy in preventing AAP-AOM over PCV13 was not demonstrated.Clinical trials registrationNCT01545375 (www.clinicaltrials.gov)     

Effectiveness of three pneumococcal conjugate vaccines to prevent invasive pneumococcal disease in Quebec,Canada

BackgroundIn Quebec, a pneumococcal conjugate vaccine (PCV) program was implemented in December 2004. The recommended schedule is 2 + 1 doses for low-risk infants. PCV-7 was first used (including catch-up for children <5 years of age), replaced by PCV10 in June 2009, and by PCV13 in January 2011 (no catch-up in both instances). From the beginning, >90% of children received the recommended number of doses.ObjectiveTo assess the effectiveness of the three PCVs sequentially used to prevent invasive infectious disease (IPD).MethodsIPD cases in children 2–59 months during the years 2005–2013 were eligible. Controls were randomly identified in the provincial health insurance registry. Parents were interviewed and immunization records reviewed. Vaccine effectiveness (VE) was computed using multivariate logistic regression models.ResultsOut of 889 IPD cases reported, full participation was obtained for 516 cases (58%) and for 1767 controls. Against vaccine-type IPD, VE (≥1 dose) was 90% (82–95%) for PCV7, 97% (84–99%) for PCV10 and 86% (62–95%) for PCV13. Against 19A IPD, VE was, respectively, 42% (−9% to 69%), 71% (24–89%), and 74% (11–92%). VE (≥2 doses) against PCV13-type IPD was 85% for PCV10 (66–94%), 85% for PCV13 (55–94%), and 89% (58–97%) for a mixed PCV10 + PCV13 schedule.ConclusionsAll three PCV vaccines showed high level of protection against IPD caused by serotypes included in their formulation and there was a high level of cross-protection against 19A for PCV10. No substantial difference was seen between PCV10, PCV13, or a mixed PCV10 + PCV13 schedule.     

Healthcare Costs for Pneumococcal Disease in the Era of Infant Immunization With 13-Valent Pneumococcal Conjugate Vaccine: A Population-Based Study

ObjectivesInvasive pneumococcal disease (IPD) and a variety of clinical syndromes caused by pneumococci, such as acute otitis media (AOM), acute sinusitis (AS), and community-acquired pneumonia (CAP), cause a substantial burden on healthcare systems. Few studies have explored the short-term financial burden of pneumococcal disease after the 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the infant immunization programs. This population-based study evaluated changes in costs associated with healthcare utilization for pneumococcal disease after the PCV13 introduction in the infant immunization program in British Columbia, Canada.MethodsIndividuals with pneumococcal disease were identified using provincial administrative data for the 2000 to 2018 period. Total direct healthcare costs were determined using case-mix methodology for hospitalization and fee-for-service codes for outpatient visits and medications dispensed. Costs were adjusted to 2018 Canadian dollars. Changes in the annual healthcare costs were evaluated across vaccine eras (pre-PCV13, 2000-2010; PCV13, 2011-2018) using generalized linear models, adjusting for the 7-valent pneumococcal conjugate vaccine program (2004-2010).ResultsDuring the 19-year study period, pneumococcal disease resulted in 6.3 million cases among 85 million total patient-years, resulting in total healthcare costs of $7.9 billion. More than 6.2 million cases were treated in outpatient setting, costing $0.65 billion (8% of total costs associated with pneumococcal disease treatment), whereas 370 000 hospitalized cases were 3% of all cases, which accrued $7.25 billion (92% of total costs) in costs. Healthcare costs for all studied infections nearly doubled over the study period from $248 million in 2000 to $476 million in 2018 (P = .003). In contrast, there were large declines in total annual costs in the PCV13 era for IPD (adjusted relative rate (aRR) 0.73; 95% confidence interval [CI] 0.56-0.95; P = .032), AOM (aRR 0.70; 95% CI 0.59-0.83; P = .001), and AS (aRR 0.68; 95% CI 0.54-0.85; P = .004) compared with the pre-PCV13 era. Total costs increased marginally in the PCV13 era for all-cause CAP (aRR 1.04; 95% CI 0.94-1.15; P = .484).ConclusionsThis study confirms a temporal association in declining economic burden for IPD, AOM, and AS after the PCV13 introduction. Nevertheless, the total economic burden continues to be high in the PCV13 era, mainly driven by increasing CAP costs.     

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 6 years, 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.     

Early Streptococcus pneumoniae serotype changes in Utah adults after the introduction of PCV13 in children

IntroductionPneumococcal conjugate vaccines (PCV) have indirect effects due to decreased Streptococcus pneumoniae colonization in vaccine recipients. We sought to determine whether the introduction of PCV13 in children led to changes in the epidemiology and clinical manifestations of invasive pneumococcal disease (IPD) in adults.MethodsWe described demographics, comorbidities, clinical manifestations, and serotypes of IPD in Utah adults before (November 2009−February 2010) and after (March 2010−March 2012) the introduction of PCV13 in children. We also compare serotypes causing IPD in Utah adults and children.ResultsAfter the introduction of PCV13 in the childhood vaccine program, the proportion of IPD due to PCV13 exclusive serotypes decreased significantly in Utah adults (64−40%, p = 0.009), primarily due to a decline in serotype 7F (36−15%, p = 0.008). There were non-significant increases in IPD due to Pneumococcal polysaccharide 23 (PPV23) unique serotypes and non-vaccine serotypes, most notably serotype 22F. Changes in the proportions of vaccine and non-vaccine serotypes were similar in adults and children. Meningitis was more commonly due to non-vaccine serotypes relative to non-meningitis cases (47% vs. 18%, p = 0.007). When stratified by sex, decreases in PCV13 serotype IPD were only noted in men (76−33%, p = 0.001).ConclusionsSerotype epidemiology of IPD in adults closely follows that of children in the PCV13 era. Continued surveillance is needed to confirm whether replacement serotypes will lead to increases in pneumococcal meningitis and whether there are sex differences in the indirect effects of PCV vaccination in children.     

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 ⩾65 years. 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 ⩾65 years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263.     

Impact of the pneumococcal conjugate vaccines on invasive pneumococcal disease in France, 2001–2012

Context and aimsVaccination with the 7-valent pneumococcal conjugate vaccine (PCV7) was recommended in France in 2003 for children <2 years. The 13-valent conjugate vaccine (PCV13) replaced PCV7 in 2010. We assessed the impact of PCVs vaccination on the incidence of invasive pneumococcal diseases (IPD) in French children (0–15 years) and adults (>15 years).MethodsIPD rates were calculated using cases reported from 2001 to 2012 to Epibac, a laboratory network. The distribution of serotypes was assessed from invasive isolates serotyped at the National reference Centre for Pneumococci. IPD incidence rates were compared between the pre-PCV7 (2001–2002), late PCV7 (2008–2009) and post PCV13 (2012) periods.ResultsThe PCVs coverage increased from 56% in the 2004 birth-cohort to 94% in the 2008 and following birth-cohorts. Following PCV7 introduction, IPD incidence decreased by 19% between 2001–2002 and 2008–2009 in children <2 years, but increased in children aged 2–15 years and adults, despite a sharp decline in PCV7-IPD in all age-groups. After PCV13 introduction, IPD incidence decreased by 34% in children <5 years, by 50% in those aged 5–15 years and 15% in adults from 2008–2009 to 2012. The incidence of PCV13-Non PCV7-IPD decreased by 74% in children <5 years and by 60% in those aged 5–15 years.ConclusionsVaccination with PCV13 was rapidly followed by a decrease in the incidence of all-type IPD in children, in relation with a sharp decrease in the incidence of PCV13-Non PCV7-IPD. Moreover, all-type IPD decreased after PCV13 introduction in older non-vaccinated age-groups, with a shift in the distribution of serotypes. Considering the whole 2001–2012 period, the vaccination with PCV7 and PCV13 resulted in a decline in the incidence of IPD in children up to the age of 5 but not in older children and adults.