Mathematical modelling long-term effects of replacing Prevnar7 with Prevnar13 on invasive pneumococcal diseases in England and Wales

Introduction

England and Wales recently replaced the 7-valent pneumococcal conjugate vaccine (PCV7) with its 13-valent equivalent (PCV13), partly based on projections from mathematical models of the long-term impact of such a switch compared to ceasing pneumococcal conjugate vaccination altogether.

Methods

A compartmental deterministic model was used to estimate parameters governing transmission of infection and competition between different groups of pneumococcal serotypes prior to the introduction of PCV13. The best-fitting parameters were used in an individual based model to describe pneumococcal transmission dynamics and effects of various options for the vaccination programme change in England and Wales. A number of scenarios were conducted using (i) different assumptions about the number of invasive pneumococcal disease cases adjusted for the increasing trend in disease incidence prior to PCV7 introduction in England and Wales, and (ii) a range of values representing serotype replacement induced by vaccination of the additional six serotypes in PCV13.

Results

Most of the scenarios considered suggest that ceasing pneumococcal conjugate vaccine use would cause an increase in invasive pneumococcal disease incidence, while replacing PCV7 with PCV13 would cause an overall decrease. However, the size of this reduction largely depends on the level of competition induced by the additional serotypes in PCV13. The model estimates that over 20 years of PCV13 vaccination, around 5000–62000 IPD cases could be prevented compared to stopping pneumococcal conjugate vaccination altogether.

Conclusion

Despite inevitable uncertainty around serotype replacement effects following introduction of PCV13, the model suggests a reduction in overall invasive pneumococcal disease incidence in all cases. Our results provide useful evidence on the benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch.     

7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement?

Background

The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.

Methods and Findings

A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.

Conclusion

Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.     

Assessment of Health Benefits and Cost-Effectiveness of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccination in Kenyan Children

Background

The GAVI Alliance supported10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects.

Methods

The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose.

Findings

The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26–103) and US$ 1,958 (95% CI 866–3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43–56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively.

Conclusions

Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.     

Cost-Effectiveness of Vaccinating Immunocompetent ≥65 Year Olds with the 13-Valent Pneumococcal Conjugate Vaccine in England

Background

Recently a large clinical trial showed that the use of 13-valent pneumococcal conjugate vaccine (PCV13) among immunocompetent individuals aged 65 years and over was safe and efficacious. The aim of this study was to assess the cost-effectiveness of vaccinating immunocompetent 65 year olds with PCV13 vaccine in England. England is a country with universal childhood pneumococcal conjugate vaccination programme in place (7-valent (PCV7) since 2006 and PCV13 since 2010), as well as a 23-valent pneumococcal polysaccharide (PPV23) vaccination programme targeting clinical risk-groups and those ≥65 years.

Method

A static cohort cost-effectiveness model was developed to follow a cohort of 65 year olds until death, which will be vaccinated in the autumn of 2016 with PCV13. Sensitivity analysis was performed to test the robustness of the results.

Results

The childhood vaccination programme with PCV7 has induced herd protection among older unvaccinated age groups, with a resultant low residual disease burden caused by PCV7 vaccine types. We show similar herd protection effects for the 6 additional serotypes included in PCV13, and project a new low post-introduction equilibrium of vaccine-type disease in 2018/19. Applying these incidence projections for both invasive disease and community-acquired pneumonia (CAP), and using recent measures of vaccine efficacy against these endpoints for ≥65 year olds, we estimate that vaccination of a cohort of immunocompetent 65 year olds with PCV13 would directly prevent 26 cases of IPD, 69 cases of CAP and 15 deaths. The associated cost-effectiveness ratio is £257,771 per QALY gained (using list price of £49.10 per dose and £7.51 administration costs) and is therefore considered not cost-effective. To obtain a cost-effective programme the price per dose would need to be negative. The results were sensitive to disease incidence, waning vaccine protection and case fatality rate; despite this, the overall conclusion was robust.

Conclusions

Vaccinating immunocompetent individuals aged ≥65 years with PCV13 is efficacious. However the absolute incidence of vaccine-type disease will likely become very low due to wider benefits of the childhood PCV13 vaccination programme, such that a specific PCV13 vaccination programme targeting the immunocompetent elderly would not be cost-effective.     

Pneumococcal Transmission and Disease In Silico: A Microsimulation Model of the Indirect Effects of Vaccination

Background

The degree and time frame of indirect effects of vaccination (serotype replacement and herd immunity) are key determinants in assessing the net effectiveness of vaccination with pneumococcal conjugate vaccines (PCV) in control of pneumococcal disease. Using modelling, we aimed to quantify these effects and their dependence on coverage of vaccination and the vaccine''s efficacy against susceptibility to pneumococcal carriage.

Methods and Findings

We constructed an individual-based simulation model that explores the effects of large-scale PCV programmes and applied it in a developed country setting (Finland). A population structure with transmission of carriage taking place within relevant mixing groups (families, day care groups, schools and neighbourhoods) was considered in order to properly assess the dependency of herd immunity on coverage of vaccination and vaccine efficacy against carriage. Issues regarding potential serotype replacement were addressed by employing a novel competition structure between multiple pneumococcal serotypes. Model parameters were calibrated from pre-vaccination data about the age-specific carriage prevalence and serotype distribution. The model predicts that elimination of vaccine-type carriage and disease among those vaccinated and, due to a substantial herd effect, also among the general population takes place within 5–10 years since the onset of a PCV programme with high (90%) coverage of vaccination and moderate (50%) vaccine efficacy against acquisition of carriage. A near-complete replacement of vaccine-type carriage by non-vaccine-type carriage occurs within the same time frame.

Conclusions

The changed patterns in pneumococcal carriage after PCV vaccination predicted by the model are unequivocal. The overall effect on disease incidence depends crucially on the magnitude of age- and serotype-specific case-to-carrier ratios of the remaining serotypes relative to those of the vaccine types. Thus the availability of reliable data on the incidence of both pneumococcal carriage and disease is essential in assessing the net effectiveness of PCV vaccination in a given epidemiological setting.     

Population structure of invasive Streptococcus pneumoniae in The Netherlands in the pre-vaccination era assessed by MLVA and capsular sequence typing

The introduction of nationwide pneumococcal vaccination may lead to serotype replacement and the emergence of new variants that have expanded their genetic repertoire through recombination. To monitor alterations in the pneumococcal population structure, we have developed and utilized Capsular Sequence Typing (CST) in addition to Multiple-Locus Variable number tandem repeat Analysis (MLVA).To assess the serotype of each isolate CST was used. Based on the determination of the partial sequence of the capsular wzh gene, this method assigns a capsular type of an isolate within a single PCR reaction using multiple primersets. The genetic background of pneumococcal isolates was assessed by MLVA. MLVA and CST were used to create a snapshot of the Dutch pneumococcal population causing invasive disease before the introduction of the 7-valent pneumococcal conjugate vaccine in The Netherlands in 2006. A total of 1154 clinical isolates collected and serotyped by the Netherlands Reference Laboratory for Bacterial Meningitis were included in the snapshot. The CST was successful in discriminating most serotypes present in our collection. MLVA demonstrated that isolates belonging to some serotypes had a relatively high genetic diversity whilst other serotypes had a very homogeneous genetic background. MLVA and CST appear to be valuable tools to determine the population structure of pneumococcal isolates and are useful in monitoring the effects of pneumococcal vaccination.     

An assessment of the screening method to evaluate vaccine effectiveness: the case of 7-valent pneumococcal conjugate vaccine in the United States

The screening method, which employs readily available data, is an inexpensive and quick means of estimating vaccine effectiveness (VE). We compared estimates of effectiveness of heptavalent pneumococcal conjugate vaccine (PCV7) against invasive pneumococcal disease (IPD) using the screening and case-control methods. Cases were children aged 19-35 months with pneumococcus isolated from normally sterile sites residing in Active Bacterial Core surveillance areas in the United States. Case-control VE was estimated for 2001-2004 by comparing the odds of vaccination among cases and community controls. Screening-method VE for 2001-2009 was estimated by comparing the proportion of cases vaccinated to National Immunization Survey-derived coverage among the general population. To evaluate the plausibility of screening-method VE findings, we estimated attack rates among vaccinated and unvaccinated persons. We identified 1,154 children with IPD. Annual population PCV7 coverage with ≥1 dose increased from 38% to 97%. Case-control VE for ≥1 dose was estimated as 75% against all-serotype IPD (annual range: 35-83%) and 91% for PCV7-type IPD (annual range: 65-100%). By the screening method, the overall VE was 86% for ≥1 dose (annual range: -240-70%) against all-serotype IPD and 94% (annual range: 62-97%) against PCV7-type IPD. As cases of PCV7-type IPD declined during 2001-2005, estimated attack rates for all-serotype IPD among vaccinated and unvaccinated individuals became less consistent than what would be expected with the estimated effectiveness of PCV7. The screening method yields estimates of VE that are highly dependent on the time period during which it is used and the choice of outcome. The method should be used cautiously to evaluate VE of PCVs.     

Pneumococcal Carriage in Young Children One Year after Introduction of the 13-Valent Conjugate Vaccine in Italy

Background

In mid 2010, the 7-valent pneumococcal conjugate vaccine (PCV7) was replaced by the 13-valent conjugate vaccine (PCV13) for childhood immunization in Italy. Our objective in this study was to obtain a snapshot of pneumococcal carriage frequency, colonizing serotypes, and antibiotic resistance in healthy children in two Italian cities one year after PCV13 was introduced.

Methods

Nasopharyngeal swabs were obtained from 571 children aged 0-5 years from November 2011-April 2012. Pneumococcal isolates were serotyped and tested for antimicrobial susceptibility. Penicillin and/or erythromycin non-susceptible isolates were analyzed by Multi Locus Sequence Typing (MLST).

Results

Among the children examined, 81.2% had received at least one dose of PCV7 or PCV13 and 74.9% had completed the recommended vaccination schedule for their age. Among the latter, 57.3% of children had received PCV7, 27.1% PCV13, and 15.6% a combination of the two vaccines. The overall carriage rate was 32.9%, with children aged 6-35 months the most prone to pneumococcal colonization (6-23 months OR: 3.75; 95% CI: 2.19-6.43 and 24-35 months OR: 3.15, 95%CI: 2.36-4.22). A total of 184 pneumococcal isolates were serotyped and divided into PCV7 (5.4%), PCV13 (18.0%), and non-PCV13 (82.0%) serotypes. Serotypes 6C, 24F, and 19A were the most prevalent (10.3%, 8.6%, and 8.1%, respectively). The proportion of penicillin non-susceptible (MIC >0.6 mg/L) isolates was 30.9%, while 42.3% were erythromycin resistant. Non-PCV13 serotypes accounted for 75.4% and 70.8% of the penicillin and erythromycin non-susceptible isolates, respectively.

Conclusions

Our results revealed low rates of PCV7 and PCV13 serotypes in Italian children, potentially due to the effects of vaccination. As the use of PCV13 continues, its potential impact on vaccine serotypes such as 19A and cross-reactive serotypes such as 6C will be assessed, with this study providing a baseline for further analysis of surveillance isolates.     

Serotypes and Clonal Diversity of Streptococcus pneumoniae Causing Invasive Disease in the Era of PCV13 in Catalonia,Spain

The aim of this study was to study the serotypes and clonal diversity of pneumococci causing invasive pneumococcal disease in Catalonia, Spain, in the era of 13-valent pneumococcal conjugate vaccine (PCV13). In our region, this vaccine is only available in the private market and it is estimated a PCV13 vaccine coverage around 55% in children. A total of 1551 pneumococcal invasive isolates received between 2010 and 2013 in the Molecular Microbiology Department at Hospital Sant Joan de Déu, Barcelona, were included. Fifty-two serotypes and 249 clonal types—defined by MLST—were identified. The most common serotypes were serotype 1 (n = 182; 11.7%), 3 (n = 145; 9.3%), 19A (n = 137; 8.8%) and 7F (n = 122; 7.9%). Serotype 14 was the third most frequent serotype in children < 2 years (15 of 159 isolates). PCV7 serotypes maintained their proportion along the period of study, 16.6% in 2010 to 13.4% in 2013, whereas there was a significant proportional decrease in PCV13 serotypes, 65.3% in 2010 to 48.9% in 2013 (p<0.01). This decrease was mainly attributable to serotypes 19A and 7F. Serotype 12F achieved the third position in 2013 (n = 22, 6.4%). The most frequent clonal types found were ST306 (n = 154, 9.9%), ST191 (n = 111, 7.2%), ST989 (n = 85, 5.5%) and ST180 (n = 80, 5.2%). Despite their decrease, PCV13 serotypes continue to be a major cause of disease in Spain. These results emphasize the need for complete PCV13 vaccination.     

The Serotype Distribution among Healthy Carriers before Vaccination Is Essential for Predicting the Impact of Pneumococcal Conjugate Vaccine on Invasive Disease

Pneumococcal conjugate vaccines (PCVs) have substantially reduced morbidity and mortality of pneumococcal disease. The impact of the 7-valent PCV on all-serotype invasive pneumococcal disease (IPD) among children was reported to vary between high-income countries. We investigate the ability to predict this heterogeneity from pre-vaccination data. We propose a parsimonious model that predicts the impact of PCVs from the odds of vaccine serotype (VT) among carriers and IPD cases in the pre-PCV period, assuming that VT are eliminated in a mature PCV programme, that full serotype replacement occurs in carriage and that invasiveness of the NVT group is unchanged. We test model performance against the reported impact of PCV7 on childhood IPD in high-income countries from a recent meta-analysis. The odds of pre-PCV7 VT IPD, PCV schedule, PCV coverage and whether a catch up campaign was used for introduction was gathered from the same analysis. We conducted a literature review and meta-analysis to obtain the odds of pre-PCV7 VT carriage in the respective settings. The model predicted the reported impact on childhood IPD of mature PCV programmes; the ratio of predicted and observed incidence risk ratios was close to 1 in all settings. In the high income settings studied differences in schedule, coverage, and catch up campaigns were not associated with the observed heterogeneity in impact of PCV7 on childhood all-serotype IPD. The pre-PCV7 proportion of VT IPD alone also had limited predictive value. The pre-PCV7 proportion of VT carriage and IPD are the main determinants for the impact of PCV7 on childhood IPD and can be combined in a simple model to provide predictions of the vaccine preventable burden of IPD.     

Serotype Distribution in Non-Bacteremic Pneumococcal Pneumonia: Association with Disease Severity and Implications for Pneumococcal Conjugate Vaccines

Background

There is limited knowledge of serotypes that cause non-bacteremic pneumococcal pneumonia (NBP). Here we report serotypes, their associated disease potential and coverage of pneumococcal conjugate vaccines (PCV) in adults with NBP and compare these to bacteremic pneumonia (BP).

Methods

Adults with pneumonia and Streptococcus pneumoniae isolated from the lower respiratory tract or blood were included 1 year in a population-based design in Denmark. Pneumonia was defined as a new infiltrate on chest radiograph in combination with clinical symptoms or elevated white blood count or plasma C-reactive protein. All isolates were serotyped using type-specific pneumococcal rabbit antisera. All values are medians with interquartile ranges.

Results

There were 272 cases of NBP and 192 cases of BP. Ninety-nine percent were hospitalized. NBP and BP cases were of comparable age and sex but NBP cases had more respiratory symptoms and less severe disease compared to BP cases. In total, 46 different serotypes were identified. Among NBP cases, 5 serotypes accounted for nearly a third of isolates. PCV10 and -13 types covered 17% (95% confidence interval (CI): 11-23%) and 34% (95% CI: 25-43%) of NBP isolates, respectively. In contrast, the five most frequent serotypes accounted for two-thirds of BP isolates. PCV10 and -13 types covered 39% (95% CI: 30-48%) and 64% (95% CI: 48-79) of BP isolates, respectively. More severe NBP disease was associated with infection with invasive serotypes while there was an inverse relationship for BP.

Conclusions

Only a third of cases of adult non-bacteremic pneumococcal pneumonia would potentially be preventable with the use of PCV13 and just one sixth of cases with the use of PCV10 indicating that PCVs with increased valency are needed to increase vaccine coverage for NBP in adults. PCV13 could potentially prevent two-thirds of adult bacteremic pneumococcal pneumonia.     

Antibody and Plasmablast Response to 13-Valent Pneumococcal Conjugate Vaccine in Chronic Lymphocytic Leukemia Patients – Preliminary Report

Background

Chronic lymphocytic leukemia (CLL) leads to significant immune system dysfunction. The predominant clinical presentation in 50% of patients involves recurrent, often severe, infections. Infections are also the most common (60–80%) cause of deaths in CLL patients. The scope of infections varies with the clinical stage of the disease. Treatment-naive patients typically present with respiratory tract infections caused by encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae. Since 2012, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended in the United States and some EU countries for pneumococcal infection prevention in patients with CLL (besides the long-standing standard, 23-valent pneumococcal polysaccharide vaccine, PPV23). The aim of this study was to compare the immune response to PCV13 in 24 previously untreated CLL patients and healthy subjects.

Methods

Both groups were evaluated for: the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses and selected peripheral blood lymphocyte subpopulations including the frequency of plasmablasts before and after immunization.

Results

Adequate response to vaccination, defined as an at least two-fold increase in specific pneumococcal antibody titers versus pre-vaccination baseline titers, was found in 58.3% of CLL patients and 100% of healthy subjects. Both the CLL group and the control group demonstrated a statistically significant increase in the IgG2 subclass levels following vaccination (P = 0.0301). After vaccination, the frequency of plasmablasts was significantly lower (P<0.0001) in CLL patients in comparison to that in controls. Patients who responded to vaccination had lower clinical stage of CLL as well as higher total IgG, and IgG2 subclass levels. No significant vaccine-related side effects were observed.

Conclusions

PCV13 vaccination in CLL patients is safe and induces an effective immune response in a considerable proportion of patients. To achieve an optimal vaccination response, the administration of PCV13 is recommended as soon as possible following CLL diagnosis.     

Development and clinical evaluation of Prevnar 13, a 13-valent pneumocococcal CRM(197) conjugate vaccine

Pneumococcus is the leading cause of bacterial illness in children worldwide. The development, clinical evaluation, and postlicensure impact of the pneumococcal CRM(197) protein conjugate vaccine, PCV13, (Prevnar 13?) builds upon the excellent safety and substantial effectiveness of PCV7 (Prevnar?) in preventing pneumococcal disease in children. PCV13 adds pneumococcal serotypes 1, 3, 5, 6A, 7F, and 19A to serotypes 4, 6B, 9V, 14, 18C, 19F, 23F in PCV7 to provide comprehensive coverage for over 85% of epidemiologically important pneumococcal serotypes in the United States and throughout the world. PCV13 development required demonstration of immunologic responses to the 13 serotypes contained in the vaccine that were noninferior to the responses elicited by PCV7, and demonstration of a satisfactory safety profile. Studies were also performed to demonstrate compatibility with other childhood vaccines. Now licensed in many countries worldwide, PCV13 shows significant promise for expanded protection against pneumococcal disease in children.     

The Impact of Residency and Urbanicity on Haemophilus influenzae Type b and Pneumococcal Immunization in Shanghai Children: A Retrospective Cohort Study

Background

Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugate vaccine (PCV) are relatively expensive, newly introduced vaccines in China. This study evaluates the impact of residency and urbanicity on Hib vaccine and PCV coverage for children aged 2 to 7 years living in Shanghai, China, in August 2012.

Methods

In this exploratory cohort study, a sample of children aged 2 to 7 years, all of whom were eligible to have received the complete series of Hib vaccine and PCV, was obtained from the Shanghai Immunization Program Information System. Three measures of vaccination coverage for Hib vaccine and PCV were examined: dose 1 coverage, series completion, and timeliness of dose 1 vaccination. Multivariable binomial regression was used to estimate the difference in vaccination coverage between locals and the floating population.

Results

Dose 1 coverage was 50.9% for Hib vaccine and 11.4% for PCV for the 28,141 abstracted pediatric records. For both vaccines, dose 1 coverage was higher in locals than in the floating population. The disparity in coverage between locals and the floating population was greater in suburban areas than urban areas. Of all children who received dose 1, 79.7% completed the Hib vaccine series, and 91.3% completed the PCV series. Timely dose 1 coverage was 8.2% for Hib vaccine and 0.5% for PCV.

Conclusion

Low vaccination coverage and extremely low levels of timely dose 1 vaccination indicate that current vaccination efforts are inadequate to reduce the burden of Hib and pneumococcal disease among Chinese children, especially infants. Government funding of the Hib vaccine and PCV through the Expanded Program on Immunization would increase uptake and could also ensure that improvement in the timeliness of administration and series completion is targeted for all demographic groups.     

Two variants among Haemophilus influenzae serotype b strains with distinct bcs4, hcsA and hcsB genes display differences in expression of the polysaccharide capsule

Background  

Despite nearly complete vaccine coverage, a small number of fully vaccinated children in the Netherlands have experienced invasive disease caused by Haemophilus influenzae serotype b (Hib). This increase started in 2002, nine years after the introduction of nationwide vaccination in the Netherlands. The capsular polysaccharide of Hib is used as a conjugate vaccine to protect against Hib disease. To evaluate the possible rise of escape variants, explaining the increased number of vaccine failures we analyzed the composition of the capsular genes and the expressed polysaccharide of Dutch Hib strains collected before and after the introduction of Hib vaccination.     

Genetic Characterisation of Malawian Pneumococci Prior to the Roll-Out of the PCV13 Vaccine Using a High-Throughput Whole Genome Sequencing Approach

Background

Malawi commenced the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant immunisation schedule in November 2011. Here we have tested the utility of high throughput whole genome sequencing to provide a high-resolution view of pre-vaccine pneumococcal epidemiology and population evolutionary trends to predict potential future change in population structure post introduction.

Methods

One hundred and twenty seven (127) archived pneumococcal isolates from randomly selected adults and children presenting to the Queen Elizabeth Central Hospital, Blantyre, Malawi underwent whole genome sequencing.

Results

The pneumococcal population was dominated by serotype 1 (20.5% of invasive isolates) prior to vaccine introduction. PCV13 is likely to protect against 62.9% of all circulating invasive pneumococci (78.3% in under-5-year-olds). Several Pneumococcal Molecular Epidemiology Network (PMEN) clones are now in circulation in Malawi which were previously undetected but the pandemic multidrug resistant PMEN1 lineage was not identified. Genome analysis identified a number of novel sequence types and serotype switching.

Conclusions

High throughput genome sequencing is now feasible and has the capacity to simultaneously elucidate serotype, sequence type and as well as detailed genetic information. It enables population level characterization, providing a detailed picture of population structure and genome evolution relevant to disease control. Post-vaccine introduction surveillance supported by genome sequencing is essential to providing a comprehensive picture of the impact of PCV13 on pneumococcal population structure and informing future public health interventions.     

Epidemiology of Streptococcus pneumoniae Serogroup 6 Isolates from IPD in Children and Adults in Germany

This study presents serogroup 6 isolates from invasive pneumococcal disease (IPD) before and after the recommendation for childhood pneumococcal conjugate vaccination in Germany (July 2006). A total of 19,299 (children: 3508, adults: 15,791) isolates were serotyped. Serogroup 6 isolates accounted for 9.5% (children) and 6.7% (adults), respectively. 548 isolates had serotype 6A, 558 had serotype 6B, 285 had serotype 6C, and 4 had serotype 6D. Among children, serotype 6B was most prevalent (7.5% of isolates) before vaccination, followed by 6A and 6C. After the 7-valent pneumococcal conjugate vaccine (PCV7), the prevalence of serotype 6B significantly decreased (p = 0.040), a pattern which continued in the higher-valent PCV period (PCV10, PCV13). Serotype 6A prevalence showed a slight increase directly after the start of PCV7 vaccination, followed by a decrease which continued throughout the PCV10/13 period. Serotype 6C prevalence remained low. Serotype 6D was not found among IPD isolates from children. Among adults, prevalence of both 6A and 6B decreased, with 6B reaching statistical significance (p = 0.045) and 6A showing a small increase in 2011–2012. Serotype 6C prevalence was 1.5% or lower before vaccination, but increased post-vaccination to 3.6% in 2011/12 (p = 0.031). Four serotype 6D isolates were found post-PCV7 childhood vaccination, and two post-PCV10/13. Antibiotic resistance was found mainly in serotype 6B; serotype 6A showed lower resistance rates. Serotype 6C isolates only showed resistance among adults; serotype 6D isolates showed no resistance. Multilocus sequence typing showed that sequence type (ST) 1692 was the most prevalent serotype 6C clone. Thirty-two other STs were found among serotype 6C isolates, of which 12 have not been previously reported. The four serotype 6D isolates had ST 948, ST 2185 and two new STs: 8422 and 8442. Two serogroup 6 isolates could not be assigned to a serotype, but had STs common to serogroup 6.     

Levels of pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: An observational study

BackgroundThere is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children.Methods and findingsBirth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged <5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received <2 doses of PCV at <12 months of age and no doses at ≥12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph.There were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% confidence interval [CI] 0.958 to 0.975, p-value < 0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990 to 0.994, p-value < 0.001) among undervaccinated children. Subgroup analyses for children <4 months old, urban, rural, and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Approximately 50% coverage of PCV7 among children <5 years of age was estimated to prevent up to 72.5% (95% CI 51.6 to 84.4) of PCV7-type IPD among undervaccinated children, while 90% coverage was estimated to prevent 95.2% (95% CI 89.4 to 97.8). The main limitations of this study include the potential for differential loss to follow-up, geographical misclassification of children (based on residential address at birth only), and unmeasured confounders.ConclusionsIn this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described—challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.

In an observational study, Jocelyn Chan and colleagues investigate associations between pneumococcal conjugate vaccine coverage and incidence of invasive pneumococcal disease and pneumonia among children under 5 years in Australia.     

Serotype distribution of invasive Streptococcus pneumoniae in Canada during the introduction of the 13-valent pneumococcal conjugate vaccine, 2010

A baseline serotype distribution was established by age and region for 2058 invasive Streptococcus pneumoniae isolates collected during the implementation period of the 13-valent pneumococcal conjugate vaccine (PCV13) program in many parts of Canada in 2010. Serotypes 19A, 7F, and 3 were the most prevalent in all age groups, accounting for 57% in <2 year olds, 62% in 2-4 year olds, 45% in 5-14?year olds, 44% in 15-49?year olds, 41% in 50-64?year olds, and 36% in ≥65?year olds. Serotype 19A was most predominant in Western and Central Canada representing 15% and 22%, respectively, of the isolates from those regions, whereas 7F was most common in Eastern Canada with 20% of the isolates. Other prevalent serotypes include 15A, 23B, 12F, 22F, and 6C. PCV13 serotypes represented 65% of the pneumococci isolated from?<2 year olds, 71% of 2-4 year olds, 61% of 5-14 year olds, 60% of 15-49 year olds, 53% of 50-64 year olds, and 49% of the?≥65?year olds. Continued monitoring of invasive pneumococcal serotypes in Canada is important to identify epidemiological trends and assess the impact of the newly introduced PCV13 vaccine on public health.     

Direct Comparison of Immunogenicity Induced by 10- or 13-Valent Pneumococcal Conjugate Vaccine around the 11-Month Booster in Dutch Infants

Background & Aims

Since 2009/10, a 10- and a 13-valent pneumococcal conjugate vaccine (PCV) are available, but only the 10-valent vaccine is now being used for the children in the Netherlands. As the vaccines differ in number of serotypes, antigen concentration, and carrier proteins this study was designed to directly compare quantity and quality of the antibody responses induced by PCV10 and PCV13 before and after the 11-month booster.

Methods

Dutch infants (n = 132) were immunized with either PCV10 or PCV13 and DTaP-IPV-Hib-HepB at the age of 2, 3, 4 and 11 months. Blood samples were collected pre-booster and post-booster at one week and one month post-booster for quantitative and qualitative immunogenicity against 13 pneumococcal serotypes, as well as quantitative immunogenicity against diphtheria, tetanus, pertussis and Haemophilus influenzae type b. We compared immunogenicity induced by PCV13 and PCV10 for their ten shared serotypes.

Results

One month post-booster, pneumococcal serotype-specific IgG geometric mean concentrations (GMCs) for the PCV13 group were higher compared with the PCV10 group for six serotypes, although avidity was lower. Serotype 19F showed the most distinct difference in IgG and, in contrast to other serotypes, its avidity was higher in the PCV13 group. One week post-booster, opsonophagocytosis for serotype 19F did not differ significantly between the PCV10- and the PCV13 group.

Conclusion

Both PCV10 and PCV13 were immunogenic and induced a booster response. Compared to the PCV10 group, the PCV13 group showed higher levels for serotype 19F GMCs and avidity, pre- as well as post-booster, although opsonophagocytosis did not differ significantly between groups. In our study, avidity is not correlated to opsonophagocytotic activity (OPA) and correlations between IgG and OPA differ per serotype. Therefore, besides assays to determine IgG GMCs, assays to detect opsonophagocytotic activity, i.e., the actual killing of the pneumococcus, are important for PCV evaluation. How differences between the two vaccines relate to long-term protection requires further investigation.

Trial Registration

www.trialregister.nl NTR3069