Invasive Pneumococcal Disease 3 Years after Introduction of 10-Valent Pneumococcal Conjugate Vaccine,the Netherlands

Three years after a 7-valent pneumococcal conjugate vaccine was replaced by a 10-valent pneumococcal conjugate vaccine in the Netherlands, we observed a decrease in incidence of invasive pneumococcal disease caused by Streptococcus pneumoniae serotypes 1, 5, and 7F. Our data do not support or exclude cross-protection against serotype 19A.     

The potential cost-effectiveness of infant pneumococcal vaccines in Australia

Over the last decade infant pneumococcal vaccination has been adopted as part of routine immunisation schedules in many developed countries. Although highly successful in many settings such as Australia and the United States, rapid serotype replacement has occurred in some European countries. Recently two pneumococcal conjugate vaccines (PCVs) with extended serotype coverage have been licensed for use, a 10-valent (PHiD-CV) and a 13-valent (PCV-13) vaccine, and offer potential replacements for the existing vaccine (PCV-7) in Australia. To evaluate the cost-effectiveness of PCV programs we developed a static, deterministic state-transition model. The perspective for costs included those to the government and healthcare system. When compared to current practice (PCV-7) both vaccines offered potential benefits, with those estimated for PHiD-CV due primarily to prevention of otitis media and PCV-13 due to a further reduction in invasive disease in Australia. At equivalent total cost to vaccinate an infant, compared to no PCV the base-case cost per QALY saved were estimated at A$64,900 (current practice, PCV-7; 3 + 0), A$50,200 (PHiD-CV; 3 + 1) and A$55,300 (PCV-13; 3 + 0), respectively. However, assumptions regarding herd protection, serotype protection, otitis media efficacy, and vaccination cost changed the relative cost-effectiveness of alternative PCV programs. The high proportion of current invasive disease caused by serotype 19A (as included in PCV-13) may be a decisive factor in determining vaccine policy in Australia.     

The immunogenicity and safety of pneumococcal conjugate vaccine in human immunodeficiency virus-infected Thai children

Background

HIV-infected children have high risk of invasive pneumococcal disease (IPD) despite receiving highly active antiretroviral therapy (HAART). This study aimed to determine the immunogenicity and safety of a 7-valent pneumococcal conjugate vaccine (PCV-7) in Thai HIV-infected children compared to HIV-exposed uninfected children.

Methods

A prospective study was conducted among children 2 months to 9 years. The number of PCV-7 doses depended upon age and HIV status; 2-6 months of age: 3 doses; 7-23 months of age: 2 doses; HIV-infected child ≥24 months: 2 doses and HIV-exposed child ≥24 months: 1 dose. Serotype-specific pneumococcal IgG antibody concentrations were measured at baseline and 28 days after complete vaccination. The primary end point was the proportion of children who achieved serotype-specific IgG antibody concentration at a cut off level ≥0.35 μg/mL. Secondary end points were a 4-fold increase in serotype-specific IgG antibody, rates of adverse events and predictors for seroconversion among HIV-infected children.

Results

Fifty-nine HIV-infected and 30 HIV-exposed children were enrolled. The median (IQR) age was 97 (67-111) and 61 months (51-73), respectively (p < 0.001). Among HIV-infected children, current and nadir CD4 counts were 1079 cell/mm³ and 461 cell/mm³, respectively. The proportion of children who achieved pneumococcal IgG ≥0.35 μg/mL was in the range of 85-98% in HIV-infected and 83-100% in HIV-exposed children depending on serotype. The lowest response was to serotype 6B in both groups. The 4-fold increase in serotype-specific IgG concentrations was similar between HIV-infected and HIV-exposed groups, except for serotype 9V (p = 0.027). HIV-infected children who had a history of AIDS had a lower antibody response to serotype 23F (p = 0.025). Seven (12%) HIV-infected children had a grade 3 local reaction.

Conclusion

PCV-7 is highly immunogenic and safe among HIV-infected children treated with HAART. The use of the pneumococcal conjugate vaccine among HIV-infected children is encouraged in order to prevent IPD.     

The cost-effectiveness of a 13-valent pneumococcal conjugate vaccination for infants in England

Background

In the immunisation schedule in England and Wales, the 7-valent pneumococcal conjugate vaccine (PCV-7) was replaced by the 13-valent vaccine (PCV-13) in April 2010 after having been used since September 2006. The introduction of PCV-7 was informed by a cost effectiveness analysis using an infectious disease model which projected herd immunity and serotype replacement effects based on the post-vaccine experience in the United States at that time.

Aim

To investigate the cost effectiveness of the introduction of PCV-13.

Method

Invasive disease incidence following vaccination was projected from a dynamic infectious disease model, and combined with serotype specific disease outcomes obtained from a large hospital dataset linked to laboratory confirmation of invasive pneumococcal disease. The economic impact of replacing PCV-7 with PCV-13 was compared to stopping the use of pneumococcal conjugate vaccination altogether.

Results

Discontinuing PCV-7 would lead to a projected increase in invasive pneumococcal disease, costs and loss of quality of life compared to the introduction of PCV-13. However under base case assumptions (assuming no impact on non-invasive disease, maximal competition between vaccine and non-vaccine types, time horizon of 30 years, vaccine price of £49.60 a dose + £7.50 administration costs and discounting of costs and benefits at 3.5%) the introduction of PCV-13 is only borderline cost effective compared to a scenario of discontinuing of PCV-7. The intervention becomes more cost-effective when projected impact of non-invasive disease is included or the discount factor for benefits is reduced to 1.5%.

Conclusion

To our knowledge this is the first evaluation of a transition from PCV-7 to PCV-13 based on a dynamic model. The cost-effectiveness of such a policy change depends on a number of crucial assumptions for which evidence is limited, particularly the impact of PCV-13 on non-invasive disease.     

Declining serotype coverage of new pneumococcal conjugate vaccines relating to the carriage of Streptococcus pneumoniae in young children

Background

Asymptomatic carriage of the opportunistic pathogen Streptococcus pneumoniae is known to precede the development of invasive disease. Young children are one of the major reservoirs for pneumococci and worldwide over 700,000 children under two years old die due to invasive pneumococcal disease each year. Heptavalent conjugate vaccine (PCV-7) was introduced into the UK childhood immunisation schedule in September 2006. Our objective was to assess the emergence of colonising serotypes in young children in the three years following PCV-7 implementation.

Methods

Time-series prevalence survey set in the paediatric outpatients department of a large UK teaching hospital. Participants were children aged four years and under attending the outpatients department during PCV-7 introduction (October 2006-February 2007) and in the same months of the two subsequent years. The main outcome measure was prevalence of pneumococcal carriage by serotype.

Results

The rate of pneumococcal nasopharyngeal carriage remained stable during the three year period. We observed a significant 69% (95% CI, −40% to −118%, p < 0.0001) decrease in carriage of PCV-7 serotypes during PCV-7 implementation and a concomitant increase in the proportion of non PCV-7 serotypes. The most prevalent emerging non-vaccine serotypes were 6C, 11A, 19A and 22F. By March 2009, PCV-13 was predicted to cover only 33.3% (95% CI, 24.2-42.5%) of strains carried in the study population.

Conclusions

Although the overall pneumococcal carriage rate remained stable between 2006 and 2009, we observed a significant decrease in the serotype coverage of PCV-7 and PCV-13. PCV-7 was highly successful in reducing carriage of vaccine serotypes. However, the increase in the proportion of non-vaccine serotypes found both in our study and causing invasive disease currently in the UK, underlines the importance of continued surveillance of carriage and disease.     

Changes in pathogens and pneumococcal serotypes causing community-acquired pneumonia in The Netherlands

BackgroundIn 2006 a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the immunisation programme for infants in The Netherlands and replaced by PCV10 in 2011. Limited data exist about the impact of PCV on the aetiology of CAP as a whole. The aim of the present study is to describe the overall changes in microbial aetiology, pneumococcal burden (including non-bacteraemic pneumococcal pneumonia) and its serotypes in adult community-acquired pneumonia (CAP) after the introduction of these PCVs.MethodsHospitalised adult CAP patients who participated in three consecutive trials were studied (2004–2006 (n = 201), 2007–2009 (n = 304) and 2012–2016 (n = 300) and considered as pre-PCV7, PCV7 and PCV10 period). Extensive conventional microbiological testing was applied for all patients. In addition, patients with a serotype-specific pneumococcal antibody response were diagnosed with pneumococcal CAP. Changes in proportions of causative pathogens and distributions of pneumococcal serotypes were calculated.ResultsThe proportion of pneumococcal CAP decreased from 37% (n = 74/201) to 26% (n = 77/300) comparing the pre-PCV7 period with the PCV10 period (p = 0.01). For other pathogens, including Legionella spp., Mycoplasma pneumoniae, S. aureus, H. influenzae, and respiratory viruses, no sustained shifts were observed in their relative contribution to the aetiology of CAP. Within the pneumococcal CAP patients, we observed a decrease in PCV7 and an increase in non-PCV10 serotype disease. PCV10-extra type disease did not decrease significantly comparing the PCV10 period with the pre-PCV7 and PCV7 period, respectively. Notably, PCV7 type disease decreased both in bacteraemic and non-bacteraemic patients.ConclusionsOur findings confirm that PCV introduction in infants impact the microbial aetiology of adult CAP and suggest herd effects in adults with CAP after introduction of PCVs in children.     

Invasive pneumococcal diseases in birth cohorts vaccinated with PCV-7 and/or PHiD-CV in the province of Quebec,Canada

Background

The 10-valent protein D pneumococcal conjugate vaccine (PHiD-CV) was licensed on the basis of immunogenicity studies and there are no published data on its effectiveness to prevent invasive pneumococcal disease (IPD). In the province of Quebec, Canada, PHiD-CV was introduced in the summer of 2009, replacing the 7-valent CRM197 vaccine (PCV-7). Transition to the new vaccine was recommended regardless of the number of PCV7 doses already administered.

Methods

IPD rates in children born in 2007–2010 and observed up to the end of 2010 were computed from laboratory surveillance data. The main vaccine used for the infant primary immunization series (mainly 2 doses at 2–4 months) and the toddler (12 months) booster dose was inferred from the Quebec City Immunization Registry data.

Results

IPD rates were significantly lower in the cohorts exposed to PHiD-CV (35/100,000 person-years) as compared with those exposed to PCV-7 (64/100,000 person-years; p = 0.03). There was no breakthrough vaccine-type IPD case among children who had received ≥2 PHiD-CV doses for the primary series or a single PHiD-CV dose as a booster. There was also a statistically non-significant lower frequency of 19A and other non-vaccine types IPD cases in children exposed to 2+1 PHiD-CV doses as compared with those exposed to PCV-7.

Interpretation

Results are compatible with a high level of protection induced by PHiD-CV against IPD caused by homologous serotypes.     

Pharmacoeconomic assessment of implementing a universal PCV-13 vaccination programme in the Valencian public health system (Spain)

Background

Heptavalent pneumococcal conjugate vaccine (PCV-7) was licensed to provide immunity against pneumococcal disease caused by seven serotypes of S. pneumoniae. Thirteen-valent pneumococcal conjugate vaccine (PCV-13) includes 6 additional serotypes for preventing invasive pneumococcal disease.

Objective

The objective of this study was to estimate the potential health benefits, costs, and cost-effectiveness of vaccination with PCV-13 in the Community of Valencia and to generate valuable information for policy makers at regional and country levels.

Methods

A decision tree was designed to determine the health and economic outcomes in hypothetical cohorts of vaccinated and unvaccinated children followed over their lifetime. Information about disease incidence and serotype distribution were gathered from local databases and from published and unpublished local records. PCV-13 effectiveness was extrapolated from PCV-7 efficacy data. A 5% of herd effect and a serotype replacement of 25% were considered for the base case scenario. Only direct costs were taken into account and results were expressed in terms of life-years gained (LYG) and quality adjusted life years (QALY).

Results

Implementing a universal PCV-13 vaccination program in the Community of Valencia would decrease the number of hospital admitted pneumonia to less than 4571 cases while avoiding 310 cases of IPD and 82,596 cases of AOM throughout the cohort lifetime. A total of 190 S. pneumoniae related deaths would be averted over the same period. Total medical costs of non-vaccinating the cohort of newborns would reach up to 403,850.859 € compared to 438,762.712 € that would represent vaccinating the cohort. The incremental cost of vaccinating the children was estimated in 12,794 €/LYG and 10,407 €/QALY, respectively.

Conclusions

A universal PCV-13 vaccination program in the Community of Valencia would be a cost-effective intervention from the payer perspective after preventing for pneumococcal infections and for decreasing its associated mortality and morbidity.     

Compared effectiveness of the 7-valent pneumococcal conjugate vaccine in children with the 13-valent vaccine in adults

13-valent-pneumococcal conjugated vaccine was recently approved in the USA and Europe for adults 50 years of age or more. But this approval was followed by recommendations limiting its use to immunocompromised and asplenic patients. The extension of indications to adults was based on the well-demonstrated clinical effectiveness in infants less than 2 years of age, and on a better immune response either quantitatively or qualitatively with conjugated vaccines compared to the immunogenicity of plain polysaccharide vaccines. Nevertheless, the issue was to know whether results observed with the 7-valent pneumococcal conjugate vaccine in children are reproducible in adults with the 13-valent. The answer was given by comparing the epidemiological and physiopathological data, and the immunological response of the two populations. Very few clinical effectiveness studies in adults are available. We had for aim to assess these various issues in infants and adults. A lot of questions remain, such as the unknown impact of serotype replacement with the 13-valent pneumococcal conjugated vaccine on the clinical epidemiology and emergent Streptococcus pneumoniae pathogenicity, while waiting for the CAPITA study results expected in 2014.     

Safety and immunogenicity of sequential pneumococcal immunization in preschool asthmatics

Objective

Respiratory infections are major triggers of exacerbations in preschool asthma. Many countries’ guidelines recommend immunization against pneumococci for patients suffering from chronic airway disease. Beyond infancy, however, data on the immunogenicity and safety are scarce. Also, the interval between priming and booster is a matter of debate.

Patients and Methods

Seventy preschool asthmatics (2–5-year-old; mild to moderate asthma) underwent sequential immunization: one dose of seven-valent pneumococcal conjugate vaccine (PCV-7) followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23). We randomly assigned half of the vaccinees to receive PPV-23 eight weeks after PCV-7 (group A), and the rest to a 10-month interval (group B). Pneumococcal antibody concentrations to serotype 4, 5, 6B, 7, 9V, 14, 18c, 19F and 23F were determined initially, after two and 12 months after PCV-7. Local and systemic reactions to each vaccine were recorded.

Results

Initially, depending on the serotype, up to 79.4% (group A) or 80.4% (group B) individuals did not reach the protective antibody threshold of 0.35 μg/ml. Sequential pneumococcal immunization was immunogenic in preschool asthmatics, inducing protection in the majority of our children. Subjects boostered after eight weeks had significantly lower antibody levels than those boostered after 10 months. Local and systemic adverse events were mild in character and self-limiting.

Conclusions

Although both sequential pneumococcal vaccine regimens were safe and immunogenic among preschool asthmatics, immunogenicity was higher when the booster was given after 10 months.     

Changes in Capsule and Drug Resistance of Pneumococci after Introduction of PCV7, Japan, 2010–2013

We aimed to clarify changes in serotypes and genotypes mediating β-lactam and macrolide resistance in Streptococcus pneumoniae isolates from Japanese children who had invasive pneumococcal disease (IPD) after the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into Japan; 341 participating general hospitals conducted IPD surveillance during April 2010–March 2013. A total of 300 pneumococcal isolates were collected in 2010, 146 in 2011, and 156 in 2012. The proportion of vaccine serotypes in infectious isolates decreased from 73.3% to 54.8% to 14.7% during the 3 years. Among vaccine serotype strains, genotypic penicillin-resistant S. pneumoniae strains also declined each year. Among nonvaccine serotype strains, 19A, 15A, 15B, 15C, and 24 increased in 2012. Increases were noted especially in genotypic penicillin-resistant S. pneumoniae isolates of serotypes 15A and 35B, as well as macrolide resistance mediated by the erm(B) gene in 15A, 15B, 15C, and 24.     

Cost-effectiveness analysis of the 10- and 13-valent pneumococcal conjugate vaccines in Argentina

Objective

Since the 10-valent pneumococcal conjugate vaccine (PCV-10) and 13-valent pneumococcal conjugate vaccine (PCV-13) were recently licensed for use in Argentina, both vaccines were evaluated to estimate the costs, health benefits and cost-effectiveness of adding a PCV to the routine child immunization schedule.

Methodology

The integrated TRIVAC vaccine cost-effectiveness model from Pan American Health Organization's ProVac Initiative (Version 1.0.65) was used to assess the health outcomes of 20 successive cohorts from birth to 5 years of age. PCV-10 and PCV-13 were each compared to a scenario assuming no PCV vaccination. A 3 + 1 (three doses + booster) schedule and a vaccination price of US$ 20.75 per dose was assumed in the base case for both vaccines.

Results

Introduction of PCV-13 rather than PCV-10 would increase the number of life years gained (LYG) by at least 10%. The number of LYG (and LYG after adjustment for DALY morbidity weights) was 56,882 (64,252) for PCV-10 compared to 65,038 (71,628) for PCV-13. From the health system perspective, the cost per DALY averted was US$ 8973 and US$ 10,948 for PCV-10 and PCV-13 respectively, and US$ 8546 and US$ 10,510 respectively, after incorporating costs saved by households. When PCV13 was compared to PCV10 directly, the additional benefits of PCV-13 was conferred at a cost of US$ 28,147 per DALY averted. Cost-effectiveness was influenced mainly by vaccine price, serotype replacement, pneumonia mortality and discount rate.

Conclusion

Routine vaccination against S. pneumoniae in Argentina would be cost-effective with either PCV-10 or PCV-13. PCV-13, with higher coverage of local serotypes, would prevent more cases of pneumonia, invasive pneumococcal disease, sequelae and deaths with a higher number of LYG and DALYs averted, but PCV-10, due its higher impact in the prevention of AOM, would save more costs to the healthcare system.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) when given as a toddler dose to children immunized with PCV7 as infants

13-Valent pneumococcal conjugate vaccine (PCV13) administered as a 4-dose series in infants, and as a toddler dose in infants previously vaccinated with PCV7 elicited comparable vaccine serotypes IgG responses to the seven common serotypes. PCV13 elicited functional responses to the six additional serotypes in both schedules after the toddler dose. The toddler dose boosted immune responses. The two regimens had comparable safety profiles. A toddler dose of PCV13 given in children previously vaccinated with PCV7 should be effective in preventing pneumococcal disease caused by common serotypes, providing protection against the additional serotypes, and supporting the transition from PCV7 to PCV13.     

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.     

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

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

Pre-clinical evaluation of a 15-valent pneumococcal conjugate vaccine (PCV15-CRM197) in an infant-rhesus monkey immunogenicity model

The incidence of invasive pneumococcal disease (IPD), caused by the approximately 91 serotypes of Streptococcus pneumoniae (PN), varies geographically and temporally as a result of changing epidemiology and vaccination patterns as well as due to regional measurement differences. Prevnar^® (Pfizer), the first licensed pneumococcal conjugate vaccine (PCV), comprises polysaccharides (PS) from 7 serotypes conjugated to the mutant diphtheria toxin carrier protein, CRM197. In the United States and elsewhere, this vaccine has been highly efficacious in reducing the incidence of IPD caused by vaccine serotypes, however, the incidence of non-vaccine serotypes (e.g., 19A, 22F, and 33F) has increased, resulting in the need for vaccines with higher valencies. In response, 10- and 13-valent PCVs have recently been licensed. To further increase serotype coverage, we have developed a 15-valent PCV containing PS from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to CRM197 and formulated on aluminum phosphate adjuvant. Vaccine immunogenicity was evaluated in infant rhesus monkeys since they, like human infants, respond poorly to unconjugated PN PS. Infant (2-3 month old) rhesus monkeys were vaccinated three times with PCV-15 or Prevnar^® at 2 month intervals, and serotype-specific IgG antibodies were measured using a multiarray electrochemiluminescence (ECL) assay. The results indicate that antibody responses to PCV-15 and Prevnar^® were comparable for the 7 common serotypes and that post-vaccination responses to PCV-15 were >10-fold higher than baseline for the 8 additional serotypes.     

Cost-effectiveness analysis of pneumococcal vaccination for infants in China

BackgroundAlthough China has a high burden of pneumococcal disease among young children, the government does not administer publicly-funded pneumococcal conjugate vaccines (PCV) through its Expanded Program on Immunization (EPI). We evaluated the cost-effectiveness of publicly-funded PCV-7, PCV-10, and PCV-13 vaccination programs for infants in China.MethodsUsing a Markov model, we simulated a cohort of 16 million Chinese infants to estimate the impact of PCV-7, PCV-10, and PCV-13 vaccination programs from a societal perspective. We extrapolated health states to estimate the effects of the programs over the course of a lifetime of 75 years. Parameters in the model were derived from a review of the literature.ResultsWe found that PCV-7, PCV-10, and PCV-13 vaccination programs would be cost-effective compared to no vaccination. However, PCV-13 had the lowest incremental cost-effectiveness ratio ($11,464/QALY vs $16,664/QALY for PCV-10 and $18,224/QALY for PCV-7) due to a reduction in overall costs. Our sensitivity analysis revealed that the incremental cost-effectiveness ratios were most sensitive to the utility of acute otitis media, the cost of PCV-13, and the incidence of pneumonia and acute otitis media.ConclusionsThe Chinese government should take steps to reduce the burden of pneumococcal diseases among young children through the inclusion of a pneumococcal conjugate vaccine in its EPI. Although all vaccinations would be cost-effective, PCV-13 would save more costs to the healthcare system and would be the preferred strategy.     

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

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

Evaluation of impact of 23 valent pneumococcal polysaccharide vaccine following 7 valent pneumococcal conjugate vaccine in Australian Indigenous children

BackgroundHigh incidence and serotype diversity of invasive pneumococcal disease (IPD) in Indigenous children in remote Australia led to rapid introduction of 7-valent conjugate pneumococcal vaccine (7vPCV) at 2, 4 and 6 months in 2001, followed by 23-valent polysaccharide pneumococcal vaccine (23vPPV) in the second year of life. All other Australian children were offered 3 doses of 7vPCV without a booster from 2005. This study evaluated the impact of the unique pneumococcal vaccine schedule of 7vPCV followed by the 23vPPV booster among Indigenous Australian children.MethodsChanges in IPD incidence derived from population-based passive laboratory surveillance in Indigenous children <5 years eligible for 23vPPV were compared to non-Indigenous eligible for 7vPCV only from the pre-vaccine introduction period (Indigenous 1994–2000; non-Indigenous 2002–2004) to the post-vaccine period (2008–2010 in both groups) using incidence rate ratios (IRRs) stratified by age into serotype groupings of vaccine (7v and 13vPCV and 23vPPV) and non-vaccine types. Vaccine coverage was assessed from the Australian Childhood Immunisation Register.ResultsAt baseline, total IPD incidence per 100,000 was 216 (n = 230) in Indigenous versus 55 (n = 1993) in non-Indigenous children. In 2008–2010, IRRs for 7vPCV type IPD were 0.03 in both groups, but for 23v-non7v type IPD 1.2 (95% CI 0.8–1.8) in Indigenous versus 3.1 (95% CI 2.5–3.7) in non-Indigenous, difference driven primarily by serotype 19A IPD (IRR 0.6 in Indigenous versus 4.3 in non-Indigenous). For non-7vPCV type IPD overall, IRR was significantly higher in those age-eligible for 23vPPV booster compared to those younger, but in both age groups was lower than for non-Indigenous children.ConclusionThese ecologic data suggest a possible “serotype replacement sparing” effect of 23vPPV following 7vPCV priming, especially for serotype 19A with supportive evidence from other immunogenicity and carriage studies. Applicability post 10vPCV or 13v PCV priming in similar settings would depend on local serotype distribution of IPD.     

The effect of anti-TNF treatment on the immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis

Our aim was to study the effect of anti-TNF treatment on immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Thirty-one children (mean age:12.9 ± 4.6 years) treated with anti-TNFs plus Disease Modifying Anti-Rheumatic Drugs (DMARDs) and 32 age-matched children treated only with DMARDs were vaccinated with two doses of PCV7. After the first vaccine dose geometric mean titers (GMTs) were significantly increased for all vaccine serotypes (p < 0.0001) in both groups and were found to be protective (>0.35 μg/ml) in 87–100% of all children, depending on the serotype. Children receiving anti-TNFs achieved a significantly lower GMTs against serotypes 4, 14 and 23F (p < 0.05). A ≥4-fold increase of the baseline titers to ≥5 vaccine serotypes was observed in 50% and 75% of the anti-TNF and control patients, respectively (p = 0.0697). No patient developed vaccine-associated serious adverse events or disease flares.