Long-term population impact of infant 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in adults in Finland

BackgroundLimited data are available on long-term indirect effects of ten-valent pneumococcal conjugate vaccine (PCV10) programmes. We evaluated changes in invasive pneumococcal disease (IPD) incidence, mortality, and serotype distribution in adults up to 9 years after infant PCV10 introduction.MethodsCulture-confirmed IPD cases ≥18 years (n = 5610; 85% were pneumonia) were identified through national, population-based laboratory surveillance; data were linked with population registry to conduct nationwide follow-up study. In a time-series model, we compared serotype-specific IPD incidence and associated 30-day mortality rates before and after PCV10 by using negative binomial regression models.ResultsDuring pre-PCV10 period (7/2004–6/2010), overall IPD incidence in adults ≥18 years increased yearly by 4.8%. After adjusting for trend and seasonality, the observed PCV10 serotype IPD incidence in 7/2018–6/2019 was 90% (12/100,000 person-years) lower than the expected rate without PCV10 program. Non-PCV10 serotype incidence was 40% (4.4/100,000 person-years) higher than expected; serotypes 3, 19A, 22F, and 6C accounted for most of the rate increase. However, incidence of non-PCV10 IPD levelled off by end of follow-up. The observed-expected incidence rate-ratio (IRR) was 0·7 (95 %CI 0·5–0.8) for all IPD and 0·7 (95 %CI 0·3–1·3) for IPD-associated 30-day mortality. Case-fatality proportion decreased from 11·9% to 10.0% (p < 0.01). In persons ≥65 years, the IRR was 0·7 (95 %CI 0·5–0.95).ConclusionsSignificant indirect effects were seen for vaccine-serotype IPD and for overall IPD in all adult age groups. For non-vaccine IPD, the incidence stabilized 5 years after infant PVC10 program introduction, resulting in a steady state in which non-vaccine IPD accounted for nearly 90% of overall IPD. Substantial pneumococcal disease burden remains in older adults.     

Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland

BackgroundThe ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross-protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types).MethodsWe used data on IPD from the national, population-based surveillance. A target cohort of vaccine-eligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. For the indirect effect, another cohort of older PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of season- and age-matched reference cohorts before NVP introduction.ResultsAmong vaccine-eligible children, the incidence of all IPD decreased by 79% (95% CI 74–83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant.In the unvaccinated older children, the incidence of all IPD decreased by 33% (95% CI 8–52%) compared to the reference cohort, and there was no impact on serotype 6A or 19A IPD.ConclusionOverall, the impact of PCV10 vaccination on IPD was high in vaccine-eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained.     

Effectiveness of 10 and 13-valent pneumococcal conjugate vaccines against invasive pneumococcal disease in European children: SpIDnet observational multicentre study

BackgroundPneumococcal conjugate vaccines covering 10 (PCV10) and 13 (PCV13) serotypes have been introduced in the infant immunization schedule of most European countries in 2010–11. To provide additional real-life data, we measured the effectiveness of PCV10 and PCV13 against invasive pneumococcal disease (IPD) in children of 12 European sites (SpIDnet).MethodsWe compared the vaccination status of PCV10 and PCV13 serotype IPD (cases) to that of nonPCV13 serotype IPD (controls) reported in 2012–2018. We calculated pooled effectiveness as (1-vaccination odds ratio)*100, and measured effectiveness over time since booster dose.ResultsThe PCV13 and PCV10 studies included 2522 IPD cases from ten sites and 486 cases from four sites, respectively. The effectiveness of ≥ 1 PCV13 dose was 84.2% (95 %CI: 79.0–88.1) against PCV13 serotypes (n = 2353) and decreased from 93.1% (87.8–96.1) < 12 months to 85.1% (72.0–92.1) ≥ 24 months after booster dose. PCV13 effectiveness of ≥ 1 dose was 84.7% (55.7–94.7) against fatal PCV13 IPD, 64.5% (43.7–77.6), 83.2% (73.7–89.3) and 85.1% (67.6–93.1) against top serotypes 3, 19A and 1, respectively, and 85.4% (62.3–94.4) against 6C. Serotype 3 and 19A effectiveness declined more rapidly. PCV10 effectiveness of ≥ 1 dose was 84.8% (69.4–92.5) against PCV10 serotypes (n = 370), 27.2% (-187.6 to 81.6) and 85.3% (35.2–96.7) against top serotypes 1 and 7F, 32.5% (-28.3 to 64.5) and ?14.4% (-526.5 to 79.1) against vaccine-related serotypes 19A and 6C, respectively.ConclusionsPCV10 and PCV13 provide similar protection against IPD due to the respective vaccine serotype groups but serotype-specific effectiveness varies by serotype and vaccine. PCV13 provided individual protection against serotype 3 and vaccine-related serotype 6C IPD. PCV10 effectiveness was not significant against vaccine-related serotypes 19A and 6C. PCV13 effectiveness declined with time after booster vaccination. This multinational study enabled measuring serotype-specific vaccine effectiveness with a precision rarely possible at the national level. Such large networks are crucial for the post-licensure evaluation of vaccines.     

Four years of universal pneumococcal conjugate infant vaccination in Germany: Impact on incidence of invasive pneumococcal disease and serotype distribution in children

Introduction

Vaccination with pneumococcal conjugate vaccine (PCV) for all children <2 years was recommended in Germany in July 2006. Initially PCV7 was exclusively used; PCV10 became available from April 2009 and PCV7 was replaced by PCV13 in December 2009.

Objective

To compare the incidence and serotype distribution of invasive pneumococcal disease (IPD) for pneumococcal meningitis and non-meningitis IPD in children from 2007 to 2010 with reference to the pre-vaccination period from 1997 to 2001.

Methods

Nationwide surveillance of IPD for children <16 years in Germany was based on two independent reporting sources: active surveillance in paediatric hospitals and passive web-based surveillance through microbiological laboratories. Serotyping was performed using the Neufeld Quellung reaction. Case definition: isolation of Streptococcus pneumoniae from a normally sterile body site. IPD incidence was estimated by capture–recapture analysis. Rate ratios comparing post- to pre-vaccination incidence were calculated as well as PCV7 and non-PCV7 serotype specific incidences.

Results

While PCV7 incidence decreased by 88% (95%CI: 83 to 91) in children <16 years both in pneumococcal meningitis and non-meningitis IPD, an increase in Non-PCV7 serotypes was observed which was more pronounced in non-meningitis cases (168%; 95%CI: 140–257) than in pneumoccocal meningitis (65%; 95%CI: 23–123). The changes in incidence after four years were: <16 years: −35% (95%CI: −49 to −19), <2 years: −46% (95%CI: −61 to −27) for pneumococcal meningitis and + 11% (95%CI: −4 to  + 29) and −26% (95%CI: −41 to −7) for non-meningitis IPD respectively.

Conclusion

Infant PCV7 vaccination in Germany prompted a decrease in the incidence of pneumococcal meningitis similar to that observed in England/Wales. In non-meningitis IPD the decrease was smaller and confined to the age group <2 years with no change or an increase in incidence in other age groups pointing to potential ascertainment bias due to increased blood-culturing.     

Effects of 10-valent pneumococcal conjugate (PCV10) vaccination on the nasopharyngeal microbiome

Pathogenic bacteria, such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis, are important vaccine targets. The 10-valent pneumococcal conjugate vaccine (PCV10) acts on 10 differents S. pneumoniae serovars. However, this vaccine could also act on other bacteria genera, leading to dysbiosis. Moreover, the vaccination has also been associated with imbalances in the ratio between commensal and potentially pathogenic bacteria. Despite the wealth of studies assessing the influence of the microbiome on vaccine effects, how vaccination can influence the microbiome remains poorly understood. Herein, we assessed the effects of PCV10 on infant nasopharyngeal microbiome composition. Nasopharyngeal aspirates were collected from children with acute respiratory infection (ARI) aged 6–23 months. Two groups were composed of 48 vaccinated and 36 unvaccinated subjects. 16S ribosomal RNA sequencing was performed to assess bacterial composition and results were analyzed with QIIME. Similar bacterial compositions were observed in the unvaccinated and vaccinated samples. Principal component analysis also indicated a similar bacterial composition between the groups. In addition, bacterial diversity was not different between the vaccinated and unvaccinated samples. Accordingly, our results suggest that PCV10 vaccination promotes a specific response against its targets, thereby preserving the nosocomial microbiome. Although not statistically significant, Streptococcus and Haemophilus genera were increased in the vaccinated group, while Moraxella was decreased. Increases in Streptococcus may be associated with vaccine-target taxa replacement by non-pathogenic species. In sum, we observed that PCV10 vaccination acts by promoting a target-specific action against pathogenic bacteria and also induces commensal bacteria colonization without substantially changing the nasopharyngeal microbiome.     

Cost-effectiveness of conjugate pneumococcal vaccination in Singapore: comparing estimates for 7-valent, 10-valent, and 13-valent vaccines

Introduction

Although multiple studies of cost-effectiveness of pneumococcal conjugate vaccines have been conducted, no such study has examined Singapore's situation nor compared the licensed conjugate vaccines in an Asian population. This paper estimates the costs and public health impacts of pneumococcal conjugate vaccine programs, varying estimates of serotype replacement and herd immunity effects as key parameters in the analysis. Based in part on a 2008 analysis also presented here, Singapore has approved the PCV-7, PHiD-10, and PCV-13 pneumococcal conjugate vaccines as part of its National Childhood Immunisation Programme.

Methods

An economic evaluation was performed using a Markov simulation model populated with Singapore-specific population parameters, vaccine costs, treatment costs, and disease incidence data. The vaccinated infant and child cohort of 226,000 was 6% of the Singapore resident population of 3.8 million. Vaccine efficacy estimates were constructed for PCV-7, PHiD-10, and PCV-13 vaccines based on their serotype coverage in Singapore and compared to ‘no vaccination’. The model estimated impacts over a five-year time horizon with 3% per year discounting of costs and health effects. Costs were presented in 2010 U.S. dollars (USD) and Singapore dollars (SGD). Sensitivity analyses included varying herd immunity, serotype replacement rates, vaccine cost, and efficacy against acute otitis media.

Results

Under base case assumptions for the revised analysis (i.e., herd effects in the unvaccinated population equivalent to 20% of direct effects) PCV-13 prevented 834 cases and 7 deaths due to pneumonia, meningitis, and bacteremia in the vaccinated population, and 952 cases and 191 deaths in the unvaccinated population over the 5-year time horizon. Including herd effects, the cost-effectiveness ratio for PCV-13 was USD $37,644 (SGD $51,854) per QALY. Without herd effects, however, the ratio was USD $204,535 (SGD $281,743) per QALY. The PCV-7 cost per QALY including herd effects was USD $43,275 (SGD $59,610) and for PHiD-10 the ratios were USD $45,100 (SGD $62,125). The original 2008 analysis, which had higher estimates of pneumonia prevention due to herd immunity and lower estimates of cost per dose, had found a cost-effectiveness ratio of USD $5562 (SGD $7661) per QALY for PCV-7.

Conclusions

When compared to cost-effectiveness thresholds recommended by the World Health Organization (WHO), our 2008 analysis found that vaccination of infants in Singapore with PCV-7 was very cost-effective if herd immunity effects were present. However, knowledge on herd immunity and serotype replacement that emerged subsequent to this analysis changed our expectations about indirect effects. Given these changed inputs, our current estimates of infant vaccination against pneumococcal disease in Singapore find such programs to be moderately cost-effective compared to WHO thresholds. The different findings from the 2008 and 2011 analyses suggest that the dynamic issue of serotype replacement should be monitored post-licensure and, as changes occur, vaccine effectiveness and cost-effectiveness analyses should be re-evaluated.     

Pneumococcal meningitis before the introduction of 10-valent pneumococcal conjugate vaccine into the National Childhood Immunization Program in Poland

Background

Poland introduced the 10-valent conjugate pneumococcal vaccine (PCV10) into the childhood immunization program in January 2017. During previous decades, considerable changes had occurred in the surveillance system for invasive pneumococcal disease. Therefore, to provide baseline data on pneumococcal diseases before PCV10 introduction, we evaluated the epidemiology of pneumococcal meningitis (PM), the only syndrome monitored consistently since 1970.

Revaccination with 7-valent pneumococcal conjugate vaccine elicits better serologic response than 23-valent pneumococcal polysaccharide vaccine in HIV-infected adult patients who have undergone primary vaccination with 23-valent pneumococcal polysaccharide vaccine in the era of combination antiretroviral therapy

HIV-infected adults who had received 23-valent pneumococcal polysaccharide vaccine (PPV23) five years or more earlier consecutively underwent revaccination with one dose of PPV23 (127 subjects) from December 2005 through October 2007, or upon change in standard of care, non-randomly one (50) or two doses (44) of 7-valent pneumococcal conjugate vaccine (PCV7) from October 2008 through June 2010. Serologic response was defined as ≥2-fold increase in the IgG level plus a level ≥1000 ng/ml 48 weeks following revaccination. At week 48, the response rate was significantly higher in the 2-dose PCV7 group compared with that in the 1-dose PCV7 or PPV23 group (63.6% vs 32.0% vs 8.7%, respectively; P < 0.05). Revaccination with one dose of PCV7 (AOR, 4.57), two doses of PCV7 (AOR, 22.66), and CD4 >350 cells/μl (AOR, 3.24) and undetectable viral load (AOR, 3.87) at revaccination were statistically significantly associated with a better serologic response at week 48. Despite the limitation that study arms were neither randomized nor contemporaneous, we conclude that revaccination with PCV7 appears to elicit a better serologic response than PPV23 in the HIV-infected adults who have received PPV23 five years or more earlier (clinical trial registration number: NCT00885625).     

Impact of infant pneumococcal conjugate vaccination on community acquired pneumonia hospitalization in all ages in the Netherlands

BackgroundThe long-term impact of pneumococcal conjugate vaccines on pneumonia hospitalizations in all age-groups varies between countries. In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was implemented for newborns in 2006 and replaced by PCV10 in 2011. We assessed the impact of PCVs on community-acquired pneumonia (CAP) hospitalization rates in all age-groups.MethodsA time series analysis using Poisson regression was performed on 155,994 CAP hospitalizations. Hospitalization rates were calculated using the total number of hospitalizations as denominator. The time trend in the pre-PCV period (1999–2006) was extrapolated to predict the hospitalization rate in the post-PCV period (2006–2014) if PCV had not been implemented. Rate ratios over time were calculated by comparing observed and predicted time trends.ResultsIn children <5 years of age, the observed hospitalization rates during the post-PCV period were significantly lower than predicted if PCV had not been implemented (0–6 months: 0.62, 95% CI: 0.41–0.96; 6 months – 1 year: 0.67, 95% CI: 0.50–0.90; 2–4 years: 0.78, 95% CI: 0.61–0.97). In all other age-groups, rate ratios declined over time but did not reach statistical significance.ConclusionsAfter introduction of PCV, CAP hospitalizations declined in young children but no clear impact of PCV on CAP hospitalizations was seen in other age-groups.     

Pharmacoeconomic evaluation of 10- and 13-valent pneumococcal conjugate vaccines

Introduction

There are three different pneumococcal vaccines available for infants, each oriented to a specific set of serotypes. The vaccination of newborns will prevent pneumococcal disease in this vaccinated group via direct effects, and will also affect the non-vaccinated population through indirect or “herd” immunity.

Objective

To develop a model that compares the health and economic consequences between the three vaccines.

Method

We developed a simulation model for an entire population, providing vaccine to children less than 2 years of age. The vaccines varied by serotypes covered and included a 7- (4, 6B, 9V, 14, 18C, 19F and 23F), 10- (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F) and 13-valent (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) vaccines. The base case was PCV-7, and clinical and economic outcomes were estimated for the vaccinated persons and for other persons through assumptions about a herd effect. By comparison, clinical and economic outcomes for the population were also estimated for the 10 and 13 serotype vaccines.

Results

In the base case (PCV-7), with the seven serotype vaccine, there were 9.38 cases of hospitalized pneumonia, 0.22 cases of meningitis, 3.69 cases of bacteremia, 60.19 cases of otitis media, and 373 cases of pneumonia, per 100,000 persons in the population, at all ages. With the 10-valent vaccine and a herd effect, invasive pneumonia fell to 8.71 cases, meningitis to 0.21 cases, and bacteremia to 3.39 cases. Otitis media fell to 57 cases and pneumonia to 344 cases. There were further reductions with the 13-valent vaccine, with invasive pneumonia falling to 8.37 cases, bacteremia to 3.33 cases, otitis media to 51.9 cases and all-cause pneumonia to 336.2 cases. Among the vaccines evaluated, PCV-13 was associated with the lowest health services costs and the greatest improved health outcomes.

Conclusions

Increased serotype coverage of the 13-valent vaccine is expected to have a substantial public health and economic impact on infectious disease, when considering direct and indirect effects.     

Huge impact of assumptions on indirect effects on the cost-effectiveness of routine infant vaccination with 7-valent conjugate vaccine (Prevnar)

Several recently published European cost-effectiveness studies on the 7-valent pneumococcal conjugate vaccine (PCV-7: Prevnar^®) have included net-indirect vaccine benefits for non-vaccine protected groups into their studies, which might be too optimistic an approach given recent data. Net-indirect effects result from herd protection minus serotype replacement effects. In this study we analyze the impact of net-indirect effects in non-vaccine protected groups of 5 years of age and older with updated assumptions regarding epidemiologic data and health care unit costs. Without net-indirect benefits for non-vaccine protected groups included the cost-effectiveness ratio is estimated at €72,360 per QALY. In order to obtain cost-effectiveness ratios below the threshold of €50,000 per QALY – which is in the middle of the range that is often referred to in the Netherlands – the net-indirect protective effect should at least be 16% of which has been observed in the USA after the introduction of PCV-7.     

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

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

Impact of private use of the 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal carriage among Portuguese children living in urban and rural regions

In Portugal, the 13-valent pneumococcal conjugate vaccine (PCV13) was commercially available between 2010 and 2015, following a decade of private use of PCV7. We evaluated changes on serotype distribution and antimicrobial susceptibility of pneumococci carried by children living in two regions of Portugal (one urban and one rural). Three epidemiological periods were defined: pre-PCV13 (2009–2010), early-PCV13 (2011–2012), and late-PCV13 (2015–2016). Nasopharyngeal samples (n = 4,232) were obtained from children 0–6 years old attending day-care centers. Private use of PCVs was very high in both regions (>75%). Pneumococcal carriage remained stable and high over time (62.1%, 62.4% and 61.6% (p = 0.909) in the urban region; and 59.8%, 62.8%, 59.5% (p = 0.543) in the rural region). Carriage of PCV7 serotypes remained low (5.3%, 7.8% and 4.3% in the urban region; and 2.5%, 3.7% and 4.8% in the rural region). Carriage of PCV13 serotypes not targeted by PCV7 decreased in both the urban (16.4%, 7.3%, and 1.6%; p < 0.001) and rural regions (13.2%, 7.8%, and 1.9%; p < 0.001). This decline was mostly attributable to serotype 19A (14.1%, 4.4% and 1.3% in the urban region; and 11.1%, 3.6% and 0.8% in the rural region, both p < 0.001). Serotype 3 declined over time in the urban region (10.1%, 4.4%, 0.8%; p < 0.001) and had no obvious trend in the rural region (4.2%, 6.7%, 2.4%; p = 0.505). Serotype 6C decreased in both regions while serotypes 11D, 15A/B/C, 16F, 21, 22F, 23A/B, 24F, 35F, and NT were the most prevalent in the late-PCV13 period. Intermediate resistance to penicillin and non-susceptibility to erythromycin decreased significantly in both regions (19.5%, 13.3%, and 9.3%; and 25.4%, 25.9%, and 13.4%; both p < 0.001, respectively in the urban region; and 12.4%, 11.1%, and 2.8% (p < 0.001); and 15.3%, 14.7%, and 9.2% (p = 0.037), respectively, in the rural region). In conclusion, private use of PCV13 led to significant changes on the pneumococcal population carried by children in Portugal.     

Immunogenicity and safety of a booster dose of the 13-valent pneumococcal conjugate vaccine in children primed with the 10-valent or 13-valent pneumococcal conjugate vaccine in the Czech Republic and Slovakia

BackgroundAlthough both the 13-valent pneumococcal conjugate vaccine (PCV13) and the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) are widely used, it is unclear how interchangeable they are in terms of immunogenicity.MethodsTwo phase 3, open-label, multicenter studies were conducted to assess the immunogenicity and safety of a booster dose of PCV13 in children primed with PHiD-CV or PCV13. In the Czech Republic, 12–15-month-old children received a PCV13 booster after 3-dose priming with either PHiD-CV or PCV13. In Slovakia, 11–12-month-old children received PCV13 following 2-dose priming with either PHiD-CV or PCV13. Serum IgG concentrations were assessed by enzyme-linked immunosorbent assay and functional antibodies were assessed by opsonophagocytic assay (OPA) before the booster and at 1 and 12 months afterward. The primary objective of these studies was to assess non-inferiority of OPA titers for serotype 19A in PHiD-CV-primed subjects compared to those in PCV13-primed children 1 month post-booster.ResultsA total of 98 subjects in the Czech Republic and 89 subjects in Slovakia were included. One month after the PCV13 booster dose, the IgG and OPA immune responses to serotype 19A in subjects primed with 2 or 3 doses of PHiD-CV were non-inferior to those in subjects primed with PCV13. Non-inferior and persistent immune responses to most other vaccine serotypes were also observed after the PCV13 booster in PHiD-CV-primed subjects. No safety issues were raised in either study.ConclusionsOverall, robust IgG and OPA immunological responses were observed after booster vaccination with PCV13 in children primed with 2 or 3 doses of PHiD-CV or PCV13, including for serotypes not included in PHiD-CV. These results suggest that these vaccines are interchangeable in terms of safety and immunogenicity and that PCV13 can be used as a booster in the context of mixed schedules. (EudraCT numbers: 2012-005366-35 and 2012-005367-27).     

接种13价肺炎球菌结合疫苗对就诊儿童肺炎链球菌血清型和耐药性的影响

目的  了解就诊儿童肺炎链球菌(Streptococcus pneumoniae, Spn)血清型分布和耐药特征,探索接种13价肺炎球菌结合疫苗(13-valent pneumococcal conjugate vaccine, PCV13)对Spn的影响。方法  收集2017—2019年苏州大学附属儿童医院疫苗接种信息明确的就诊儿童的Spn菌株,根据疫苗接种情况进行分组,并采用荚膜肿胀法进行血清分型,E-test法检测菌株抗生素的耐药性,比较是否接种PCV13对Spn血清型和耐药性的差别。结果  共收集692株Spn,其中20株分离自接种PCV13儿童。接种组中常见的血清型为19F、6B、19A、23F,对照组中常见的血清型为19F、6B、23F、19A、14,两组血清型分布差别无统计学意义(P=0.868),PCV13血清型覆盖率分别为70.0% 和72.4%(P=0.491)。所有菌株对红霉素、四环素、克林霉素高度耐药,且多重耐药率达98.5%。接种组和对照组的Spn菌株对青霉素的不敏感率分别为5.0%和9.1%(P=0.804)。结论  苏州大学附属儿童医院监测就诊儿童Spn血清型以PCV13覆盖的血清型为主,菌株对β-内酰胺类抗生素的耐药性有所下降,但对红霉素等其他常用抗菌药物的耐药性依旧严峻,并存在大量的多重耐药情况。尚未观察到接种PCV13对菌株血清型分布及降低抗生素耐药性的明显效果。     

Comparative impact of pneumococcal conjugate vaccines on pneumococcal meningitis according to underlying conditions

BackgroundSeveral underlying conditions increase the risk of pneumococcal meningitis (PM) in childhood. Patients with these diseases are initially considered as an important target of pneumococcal conjugate vaccines (PCVs). Limited data are available for PM in children with underlying conditions. To understand the benefits of PCV7 followed by PCV13 in this vulnerable population, we analyzed the data for a large cohort of pediatric patients with PM in France from 2001 to 2014.MethodsWe conducted hospital-based active surveillance with 227 pediatric wards working with 168 microbiology departments throughout France. Standardized inclusion criteria for PM were used and data were analyzed by a pre-PCV7, post-PCV7 and post-PCV13 period.ResultsFrom 2001 to 2014, among the 1582 cases of PM, 62.5% were reported in children less than 2 years old. Underlying conditions (n = 255, 16.1%) accounted for 7.3% of the cases in these young children versus 30.8% for children ⩾2–18 years old (p < 0.001). After PCV13 implementation, PM cases decreased by 44.0% from 2009 to 2014, mainly in children without underlying conditions. Though the number of children with underlying conditions remained stable, their proportion among overall PM cases increased by 79.1%. Among children with underlying conditions, PCV7 serotypes, 6 additional PCV13 serotypes, additional 11 serotypes in PPV23 and other serotypes accounted for 24.5%, 14.7%, 25.0% and 35.8%, respectively (p < 0.001). After PCV13 implementation, 50.0% of PM cases with underlying conditions and 37.9% without underlying conditions were caused by serotypes included in neither PCV13 nor PPV23.ConclusionBesides the reduced numbers of PM, its profile has changed, with an increase in cases in proportion of children with underlying conditions accompanied by a striking change in serotype distribution. This underlines the importance of detecting underlying conditions in children with PM in the PCV13 era.     

Retrospective economic evaluation of childhood 7-valent pneumococcal conjugate vaccination in Australia: Uncertain herd impact on pneumonia critical

BackgroundRetrospective cost-effectiveness analyses of vaccination programs using routinely collected post-implementation data are sparse by comparison with pre-program analyses. We performed a retrospective economic evaluation of the childhood 7-valent pneumococcal conjugate vaccine (PCV7) program in Australia.MethodsWe developed a deterministic multi-compartment model that describes health states related to invasive and non-invasive pneumococcal disease. Costs (Australian dollars, A$) and health effects (quality-adjusted life years, QALYs) were attached to model states. The perspective for costs was that of the healthcare system and government. Where possible, we used observed changes in the disease rates from national surveillance and healthcare databases to estimate the impact of the PCV7 program (2005–2010). We stratified our cost-effectiveness results into alternative scenarios which differed by the outcome states included. Parameter uncertainty was explored using probabilistic sensitivity analysis.ResultsThe PCV7 program was estimated to have prevented ∼5900 hospitalisations and ∼160 deaths from invasive pneumococcal disease (IPD). Approximately half of these were prevented in adults via herd protection. The incremental cost-effectiveness ratio was ∼A$161,000 per QALY gained when including only IPD-related outcomes. The cost-effectiveness of PCV7 remained in the range A$88,000–$122,000 when changes in various non-invasive disease states were included. The inclusion of observed changes in adult non-invasive pneumonia deaths substantially improved cost-effectiveness (∼A$9000 per QALY gained).ConclusionUsing the initial vaccine price negotiated for Australia, the PCV7 program was unlikely to have been cost-effective (at conventional thresholds) unless observed reductions in non-invasive pneumonia deaths in the elderly are attributed to it. Further analyses are required to explore this finding, which has significant implications for the incremental benefit achievable by adult PCV programs.     

Modeling the decline in pneumococcal acute otitis media following the introduction of pneumococcal conjugate vaccines in the US

We hypothesized that following the introduction of PCV7, the exchange of vaccine serotypes (VST) for non-vaccine serotypes (NVST) in the nasopharynx has resulted in fewer episodes of pneumococcal acute otitis media (AOM) due to the reduced capacity for common NVST strains to cause disease. We modeled the change in the proportion of children colonized with S. pneumoniae who would develop pneumococcal AOM that would occur due to serotype replacement, and projected the future impact of PCV13. Our model is based on observed changes in the nasopharyngeal pneumococcal serotype distribution from the pre- to post-PCV7 era, and an estimated capacity of each serotype to produce pneumococcal AOM given colonization; the latter was derived by dividing serotype-specific disease prevalence by serotype-specific carriage prevalence in the same population. Our results indicate a 12% (95% CI 0.5-26) decline in the number of AOM episodes attributable to S. pneumoniae in children less than 3 years of age between 2000 and 2007 due to the combined effects of PCV7 vaccine efficacy and vaccine-induced serotype replacement, and predicts that PCV13 will further decrease pneumococcal AOM an additional 27% (95% CI 13-40) from 2007 to 2013. Evaluation of changes in VST disease revealed a 91% (95% CI 83-97) decrease in PCV7-VST AOM from 2000 to 2007, and predicted an additional 65% (95% CI 57-74) decrease in PCV13-VST AOM from 2007 to 2013. Our model indicates that following vaccination, nasopharyngeal replacement of VST by NVST has led to a decrease in the amount of pneumococcal AOM despite a consistent rate of S. pneumoniae colonization, and that pneumococcal AOM may continue to decrease as pneumococcal serotypes with greater capacity to cause disease are replaced by less locally invasive serotypes.     

Indirect cohort analysis of 10-valent pneumococcal conjugate vaccine effectiveness against vaccine-type and vaccine-related invasive pneumococcal disease

We applied the indirect cohort method to estimate effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) among young children in Brazil. Cases of invasive pneumococcal disease (IPD), i.e., Streptococcus pneumoniae, detected in normally sterile fluid identified through laboratory-based surveillance and previously enrolled in a matched case-control effectiveness study are included. We estimated PCV10 effectiveness using multivariable logistic regression comparing PCV10 vaccination among children with vaccine-type or vaccine-related IPD vs. children with non-vaccine-type disease. The adjusted effectiveness of ≥1 doses against vaccine-type (72.8%, 95% confidence interval [CI] [44.1, 86.7]) and vaccine-related (61.3%, 95%CI [14.5, 82.5]) IPD were similar to the effectiveness observed in the original case-control study (which required enrollment >1200 controls). We also found significant protection of ≥1 dose against individual vaccine serotypes (14, 6B, 23F, 18C) and against vaccine-related serotype 19A. The indirect cohort methods leverages existing surveillance is a feasible approach for evaluating pneumococcal conjugate vaccines, particularly in resource-limited settings.     

The impact of 10-valent and 13-valent pneumococcal conjugate vaccines on hospitalization for pneumonia in children: A systematic review and meta-analysis

BackgroundThis systematic review and meta-analysis aimed at summarizing available data on the impact of PCV10 and PCV13 in reducing the incidence of CAP hospitalizations in children aged <5 years.MethodsA systematic search of the literature was conducted. We included time-series analyses and before-after studies, reporting the incidence of hospitalization for pneumonia in the periods before and after the introduction of PCV10 or PCV13 into the immunization program. Pooled estimates of Incidence Rate Ratio (IRR) were calculated by using a random-effects meta-analytic model. Results were stratified according to age-groups (<24 months and 24–59 months) and case definitions of pneumonia (clinically and radiologically confirmed pneumonia).ResultsA total of 1533 potentially relevant articles were identified. Of these, 12 articles were included in the analysis. In children aged <24 months, the meta-analysis showed a reduction of 17% (95%CI: 11–22%, p-value < 0.001) an of 31% (95%CI: 26–35%, p-value < 0.001) in the hospitalization rates respectively for clinically and radiologically confirmed pneumonia, respectively, after the introduction of the novel PCVs.In children aged 24–59 months, the meta-analysis showed a reduction of 9% (95%CI: 5–14%, p-value < 0.001) and of 24% (95%CI: 12–33%, p-value < 0.001) in the hospitalization rates for clinically and radiologically confirmed pneumonia, respectively, after the introduction of the novel PCVs.High heterogeneity was detected among studies evaluating the hospitalization rate for clinically and radiologically confirmed pneumonia.ConclusionsThe results of this study revealed a significant impact of PCV10 and PCV13 in reducing the hospitalizations for pneumonia, particularly in children aged <24 months and for radiologically confirmed disease. Further appropriately designed studies, comparing the impact of PCV10 and PCV13, are needed in order to obtain solid data on which to establish future immunization strategies.