Raul Isturiz

Redefining risk categories for pneumococcal disease in adults: critical analysis of the evidence

OBJECTIVEnTo analyze the available published data (2005-2014) describing the prevalence of multimorbidity in adult patients with pneumococcal disease, with a focus on the comorbidities considered by the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention to increase the risk of pneumococcal disease in adults (immunocompetent persons with chronic medical conditions (at risk) and immunocompromised or immunosuppressed persons (high risk)). An analysis of case-control and population-based surveillance studies that have evaluated risk factors for community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) was also performed in order to estimate the importance of risk stacking.nnnMETHODSnStudies that established the enrolment procedure for patients and reported the incidence of multimorbidity and risk factors for CAP and/or IPD were included. In order to obtain a risk stacking value based on the at-risk comorbidity odds ratios (OR), the multiplicative method described by Campbell was used.nnnRESULTSnThirty-eight articles were selected, 19 for multimorbidity and 19 for risk factors for CAP/IPD. With regard to multimorbidity, the prevalence among adults aged ≥65 years ranged from 23% to 98.7% for two or more comorbidities and from 18% to 89.7% for three or more comorbidities. Diabetes (DBT), chronic heart disease (CHD), and chronic obstructive pulmonary disease (COPD) were the three most frequent comorbidities described (7.6-28.5%, 6.9-25.8%, and 3.8-15.4%, respectively). With regard to risk factors, based on the multiplicative method, the hypothetical scenario of concurrence of the three most frequent at-risk conditions (DBT+CHD+COPD) showed an OR of ≥7.5. In this group of patients, the addition of smoking, another common at-risk factor for CAP (stacking four concurrent conditions) increased the OR from 8.5 to >40. These ORs were generally similar to rates described by other authors in persons with a high risk.nnnCONCLUSIONSnThe ORs for CAP and IPD of patients with two or more comorbidities, with or without smoking, were found to be similar to the ORs for CAP and IPD described in the literature for patients currently classified as high risk. The potential impact of multiple, stacking comorbidities is underestimated and there is a need for the risk categories for pneumococcal disease to be redefined.

Streptococcus pneumoniae serotype 19A: Worldwide epidemiology.

ABSTRACT Introduction: Streptococcus pneumoniae causes mucosal and invasive diseases with high morbidity and mortality. Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs worldwide resulted in serotype 19A becoming a leading cause of the remaining pneumococcal disease burden in vaccinated and nonvaccinated individuals. This article reviews the impact of the latest generation PCVs (10-valent PCV, PCV10, and 13-valent PCV, PCV13) on serotype 19A. Areas covered: This article covers immune responses elicited by PCV7, PCV10 and PCV13 against serotype 19A and their impact on nasopharyngeal (NP) carriage and disease in vaccinated and unvaccinated populations using data from surveillance systems, randomized controlled trials, and observational studies. Expert commentary: As expected from a PCV containing serotype 19A, PCV13 elicits significantly higher functional immune responses against serotype 19A than PCV7 and PCV10. Higher responses are likely to be linked to both direct impact in vaccinated populations and reductions in 19A NP carriage in children, thus inducing herd protection and reducing 19A invasive pneumococcal disease (IPD) in nonvaccinated children and adults. In contrast, PCV7 and PCV10 have shown mixed evidence of direct short-lived cross-protection and little to no impact on 19A carriage, resulting in continued transmission and disease.

Prevention of adult pneumococcal pneumonia with the 13-valent pneumococcal conjugate vaccine: CAPiTA, the community-acquired pneumonia immunization trial in adults

The aging of the world population is expected to be accompanied by increased pneumococcal pneumonia in older adults. To address this, the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA), a large, randomized, placebo-controlled trial conducted to assess the 13-valent pneumococcal conjugate vaccine (PCV13) in adults ≥65 years, found statistically significant vaccine efficacy for first episodes of vaccine-type community-acquired pneumonia (VT-CAP; 46%), nonbacteremic/noninvasive VT-CAP (45%), and VT invasive pneumococcal disease (75%), along with an acceptable safety profile. Study results were presented to the US Advisory Committee on Immunization Practices in June 2014, which subsequently recommended sequential PCV13 and 23-valent pneumococcal polysaccharide vaccination for adults ≥65 years. Thus, appropriate protection of adults at risk for pneumococcal CAP will include vaccination with PCV13.

Pneumococcal vaccination of older adults: Conjugate or polysaccharide?

Pneumococcal polysaccharide vaccines have demonstrated effectiveness in prevention of invasive pneumococcal disease (IPD).1 However, their effectiveness against non-invasive pneumococcal pneumonia or all-cause community-acquired pneumonia (CAP) has not been established; two recently published meta-analyses concluded that prevention of pneumococcal pneumonia could not be demonstrated for pneumococcal polysaccharide vaccines.2,3 By contrast, conjugated pneumococcal vaccines have proven effective against pneumococcal pneumonia and all-cause pneumonia in infants and young children.4-6 This success generated interest in their potential use in adults for the prevention of pneumococcal CAP, which remains a major unmet medical need. n nConsequently, the United States Food and Drug Administration granted accelerated approval of the 13-valent pneumococcal conjugate vaccine (PCV13) based on immunologic non-inferiority to 23-valent pneumococcal polysaccharide vaccine (PPSV23). In their review, Drs Fedson and Guppy note that the immunogenicity of the predecessor 7-valent pneumococcal conjugate vaccine was similar to that of PPSV23, but does not describe the results of the pivotal clinical trials that supported the licensure of PCV13 for adults aged 50 y and older.7 Functional antibody responses to PCV13 were compared with those generated by PPSV23 for the 12 shared serotypes and serotype 6A, unique to PCV13. In subjects not previously vaccinated with PPSV23, functional antibody responses to a single dose of PCV13 were not only similar (noninferior) to responses to PPSV23 for all shared serotypes, but were statistically significantly higher for 9 of the 13 serotypes.8 This pattern was repeated in adults who had previously received a dose of PPSV23 at least 5 y earlier; functional antibody responses to PCV13 were not only similar (noninferior) to responses to PPSV23 for all shared serotypes but were statistically significantly higher for 11 of the 13 serotypes.9 n nDrs Fedson and Guppy also maintain that “repeat vaccination with PPV23 was found to be safe and effective with no evidence of hyporesponsiveness.” In the PCV13 study summarized above, subjects returned for a dose of either PCV13 or PPSV23 3 to 4 y after their initial dose of PCV13 or PPSV23.10 Prior to the second vaccination, functional antibody levels had declined in all groups. However, a second dose of PCV13 generated functional antibody responses comparable to those seen after the first dose of PCV13 for all of the serotypes and a statistically significantly higher response to the second dose for 6 of the 13 serotypes. A similar result was observed when a dose of PCV13 was followed 3 to 4 y later by a dose of PPSV23. These results contrasted to the responses seen when subjects received two doses of PPSV23 3 to 4 y apart. In these subjects, the second dose of PPSV23 elicited a response that was statistically significantly lower for 8 of the 12 serotypes shared by both vaccines when compared with the response after the first dose of PPSV23. Furthermore, responses to two doses of PCV13 were significantly higher for all 12 serotypes shared by both vaccines when compared with response in subjects who received two doses of PPSV23. These results suggest that PCV13 primed the immune system for an anamnestic response to subsequent vaccination with either PCV13 or PPSV23, and contrasts with the blunted response to repeat doses of PPSV23. n nDrs Fedson and Guppy also discuss the relevance of the PCV13 serotypes for adults in countries where PCVs have been used in pediatric immunization programs. We do not argue that the indirect effects of PCV7 implementation on rates of vaccine-type IPD in adults have been profound. However, the most frequent presentation of pneumococcal disease in adults is non-invasive pneumococcal pneumonia, and drawing firm conclusions regarding the magnitude of indirect effects in adults for pneumonia is more difficult. Studies have reported contrasting results, noting either a reduction or no effect on all-cause pneumonia hospitalizations.6,11-13 Data emerging from studies of CAP, which utilize a validated serotype-specific urinary antigen detection assay, are likely to be extremely helpful in this regard; a study recently completed in the US suggests that the PCV7 serotypes remain a notable cause of CAP in US adults 10 to 12 y post-introduction of PCV7.14,15 Therefore, indirect effects alone may not be sufficient to tackle this significant public health burden in older adults. We contend that even in settings of high uptake of conjugate vaccine in the pediatric population there remains a need to offer direct protection to prevent pneumococcal CAP. Furthermore, cost-effectiveness analyses have been conducted, taking into consideration indirect effects of pediatric programs, and have shown that adult age- and risk-based recommendations for PCV13 are still expected to be cost-effective.16-18

Pneumococcal conjugate vaccine use in adults

ABSTRACT Streptococcus pneumoniae is a leading cause of illness and death in adults. A polysaccharide vaccine has been available for over 30 years, but despite significant use, the public health impact of this vaccine has been limited. The 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed by the US Food and Drug Administration and other international regulatory authorities with the assumption that induction of a T cell–dependent immune response and noninferior immunogenicity to vaccine antigens when compared with the polysaccharide vaccine would be important to satisfy a significant unmet medical need. PCV13 efficacy against vaccine-type pneumococcal community-acquired pneumonia was confirmed in a large randomized controlled trial in older adults and its use is now increasingly recommended globally.

Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Hospitalization for Community-Acquired Pneumonia in Older US Adults: A Test-Negative Design

Our study demonstrated real-world, direct effectiveness of 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia following introduction into a routine immunization program among adults aged ≥65 years, many of whom had immunocompromising and chronic medical conditions.

Rethinking number-needed-to-vaccinate for pneumococcal conjugate vaccines in older adults: Current and future implications

BACKGROUNDnNumber-needed-to-vaccinate (NNV) is increasingly used to inform decisions about vaccine use, but it is not calculated uniformly across studies. This study compared two methodologies for calculating NNV with 13-valent pneumococcal conjugate vaccine (PCV13) to prevent one case of community-acquired pneumonia (CAP) among US adults aged ≥65years: (i) using one-year absolute rate differences as was originally performed by the Centers for Disease Control and Prevention (CDC) and (ii) using absolute risk reduction over 5years.nnnMETHODSnWe constructed a hypothetical fixed cohort of 200,000 adults aged ≥65years equally separated into PCV13-vaccinated and PCV13-unvaccinated groups. We incorporated the same conservative assumptions used by CDC in 2014 regarding annual incidence of hospitalized (1375 per 100,000) and outpatient (2010 per 100,000) CAP, the initial (2014) proportion of adult PCV13-type CAP (10%), and PCV13 efficacy against vaccine-type CAP (45%). To model PCV13 impact over time, we assumed annual mortality was 5% for both groups, the percentage of adult PCV13-type CAP declined annually due to pediatric herd effects, and PCV13 efficacy did not wane over 5years.nnnRESULTSnAmong adults aged ≥65years, NNV with PCV13 to prevent one hospitalized and one outpatient case of CAP as originally calculated by CDC in 2014 were 1620 and 1110, respectively. Accounting for 5-year cumulative effects, NNV with PCV13 to prevent one hospitalized and one outpatient case of CAP over 5years were 576 and 394, respectively. These revised NNV estimates are roughly one third of initial estimates in which cumulative effects were ignored. NNV to prevent any CAP (inpatient or outpatient) over 5years with one PCV13 dose was 234.nnnCONCLUSIONnAccounting for cumulative preventive effects of PCV13 vaccination over time is critical. Failing to do so, even when using conservative disease burden parameters, can grossly underestimate the public health impact of adult PCV13 use.

The stubborn persistence of adult pneumococcal pneumonia as a public health problem

Sirs: We appreciate the opportunity to respond to Dr Fedson’s reply to our letter in which we stated that effectiveness of polysaccharide pneumococcal vaccines for the prevention of noninvasive pneumococcal pneumonia or all-cause community acquired pneumonia has not been established. We stand by that statement. We did not overlook any reviews or meta-analyses previously published; we cited two of the most recent because their methodology is sound. Furthermore, we contend that if the positive or negative effects of pneumococcal polysaccharide vaccines (PPSVs) were clear cut, we would not still be debating after nearly 30 y of worldwide use. The impact of 23-valent PPSV (PPSV23) has been recently estimated in the United Kingdom. In England and Wales, the PPSV23 program was expanded over the years 2003–2005 to include all those aged 65 y and older. As a result, the proportion of those aged ≥65 y who received PPSV23 increased from approximately 30% to 75%. The impact of this program was evaluated by the Health Protection Agency (now Public Health England) using national invasive pneumococcal disease (IPD) surveillance data. Between 1998 and 2006, IPD incidence due to PPSV23 serotypes in the targeted age groups was unchanged. At an individual level, the case-control study reported PPSV23 vaccine effectiveness for prevention of IPD declined from 48% (95% CI; 32% to 60%) within two years of vaccination to 15% (-3% to 30%) after five years. Furthermore, vaccine efficacy varied significantly by serotype, ranging from -23% (−85% to 19%) for serotype 3 to 63% (29% to 81%) for 12F (P = 0.005). Dr Fedson discusses his reference to the 7-valent pneumococcal conjugate vaccine (PCV7) rather than the 13-valent PCV (PCV13) data in the original review. Although the pivotal clinical immunogenicity studies that supported licensure for PCV13 for adults ≥50 y of age were not published in a peer-reviewed journal until July 2013, these data are presented in the package inserts for this product which, for example, has been publicly available in the United States since December 2011. They are also presented and discussed in the FDA briefing document that supported licensing discussions in the United States, as well as in the European Public Assessment Report, which was made publicly available in September 2011. Referring to earlier studies of PCV7 that do not assess functional antibodies is misleading. When appraising any vaccine, hyporesponsiveness must not be taken lightly. In immunocompetent individuals, absent or low responses to pneumococcal polysaccharide vaccine antigens 7F and 23F preceded cases of pneumococcal pneumonia due to these serotypes; if re-vaccination results in lower antibody responses than the first vaccination, it appears likely that hyporesponsiveness will be the precursor of clinical failure. Dr Fedson states, incorrectly, that the conclusions of the costeffectiveness studies of Weycker et al. and Smith et al. are unreliable because of their assumed levels of indirect effects. His argument relies on selective data from a single study, a retrospective evaluation of hospital administrative records (2005–2006 compared with 1997–1999); this is but one piece of evidence in an accumulating body of literature on herd effects due to conjugate vaccines. For example, for all-serotype IPD, Simonsen et al. reported a 36% reduction in cases among persons aged 40–64 y and 47% among persons aged ≥65 y from widespread PCV7 use in children. However, these estimates are higher (substantially so for younger adults), than those reported by Pilishvili et al. for laboratory-confirmed cases from the Centers for Disease Control and Prevention’s (CDC) Active Bacterial Core (ABC) surveillance (2007 compared with 1998–1999), which report an 18% reduction among persons aged 50–64 y and a 37% reduction among persons aged ≥65 y. It is unlikely that studies utilizing healthcare utilization data are more accurate than studies describing the impact on laboratory-confirmed cases. The Weycker et al. evaluation was informed by the herd effects reported by the CDC’s ABC data, with estimated reductions ranging from 26–32%, depending on age. For non-bacteremic pneumococcal pneumonia, Simonsen et al. reported a 44% reduction in hospitalized cases among persons aged 40–64 y and 54% among persons aged ≥65 y. In the only other study that evaluated pneumococcal pneumonia, Grijalva et al. reported much smaller reductions in hospitalized cases (2004 compared with 1997–1999); 10% among persons aged 40–64 y and 20% among persons aged ≥65 y. Both of these studies operationally defined pneumococcal pneumonia based on the appearance of

Post hoc analysis of the efficacy of the 13-valent pneumococcal conjugate vaccine against vaccine-type community-acquired pneumonia in at-risk older adults

BACKGROUNDnIndividuals with certain chronic medical conditions are at higher risk of developing pneumonia and pneumococcal disease than those without. Using data from the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), this post hoc analysis assessed the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥65u202fyears with at-risk conditions.nnnMETHODSnThe Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) was a double-blind, parallel-group, randomized, placebo-controlled study in the Netherlands in which adults aged ≥65u202fyears received either PCV13 or placebo. Outcomes of interest were identified using prespecified clinical criteria, radiographic confirmation, routine microbiologic testing, and a serotype-specific urinary antigen detection assay. In this post hoc analysis, participants were classified by at-risk status based on self-reporting of any of the following chronic medical conditions: heart disease, lung disease, asthma, diabetes, liver disease, and smoking. The objective of this analysis was to assess PCV13 vaccine efficacy (VE) against a first episode of vaccine-serotype community-acquired pneumonia (VT-CAP) in at-risk participants.nnnRESULTSnOf the 84,496 adults enrolled in the study, 41,385 (49.2%) were considered at risk owing to chronic medical conditions. Of the 139 VT-CAP cases, 115 (82.7%) occurred in these participants. VE of PCV13 against a first episode of VT-CAP among participants with at-risk conditions was 40.3% (95.2% CI: 11.4%, 60.2%). Average duration of follow-up since vaccination was 3.95u202fyears for at-risk participants; protection did not wane over the study period.nnnCONCLUSIONSnThis post hoc analysis of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed significant and persistent efficacy of PCV13 against VT-CAP in at-risk older adults. ClinicalTrials.gov identifier: NCT00744263.

Comment on: “Cost-Effectiveness Evaluation of the 10-Valent Pneumococcal Non-Typeable Haemophilus influenzae Protein D Conjugate Vaccine and 13-Valent Pneumococcal Vaccine in Japanese Children”

Because all important assumptions used in the model are simultaneously biased toward PCV10, the model results are erroneous and misleading. Routine infant pneumococcal vaccination in Japan would undoubtedly bring substantial reductions in morbidity and mortality. However, given the current epidemiologic landscape in Japan and the current evidence, the clinical and economic gains from the use of PCV13 would, undoubtedly, far exceed those potentially observed from the use of PCV10. We urge those who conduct, critique, and consider cost-effectiveness studies to evaluate the strength of the evidence of clinical claims for the products and the influence these assumptions have on the overall findings. In addition, when performing economic predictive modeling, it is critical to provide a balanced perspective by weighing the strengths and weaknesses of all available data to construct the base case analysis.