Reduction In Invasive Disease Research Articles

Distribution of Streptococcus pneumoniae serotypes in isolates collected from sterile body sites in the United States (US), 2004-2015

Background: Streptococcus pneumoniae remains a leading cause of disease in children and adults. Serotypes differ in invasiveness, virulence and antibiotic resistance; therefore, serotype surveillance is necessary to monitor the seroepidemiology of invasive pneumococcal disease. The serotypes and antibiotic susceptibilities of 2,105 S. pneumoniae isolates (from sterile body sites) collected in the US through the Tigecycline Evaluation Surveillance Trial, (TEST) 2004-2015, were evaluated. Methods & Materials: Serotypes were determined by PCR; isolates non-typeable by PCR were serotyped by the Quellung reaction. Minimum inhibitory concentrations were determined by broth microdilution and interpreted using CLSI guidelines. Results: In the US, in the 2010-2015 time period, serotypes 19A (27.3%), 35B (18.2%), 3 (9.1%), and 34 (6.8%) were the most common in children under 2 y. In adults ≥65 y, serotypes 19A (10.0%), 22F (8.2%), 23A (8.2%), 35B (7.8%), and 3 (7.3%) were most common. Overall, the proportion of isolates with PCV13 serotypes declined when comparing the pre-PCV13 and post-PCV13 time periods [Figure 1]. The proportion of isolates of serotype 19A that were penicillin-susceptible (PSSP) decreased in the post-PCV13 period (74.8% (2004-2009) compared to 44.6% (2010-2015)). However, the overall proportion of PSSP changed only modestly between 2004-2009 (92.5%) and 2010-2015 (91.2%). The proportion of erythromycin-resistant isolates increased in the later time period and shifted in serotype distribution, with the highest percentages found in serotypes 19A, 33F, 15A, 33A, and 35B in 2010-2015, compared to 15A, 9 V, 19F, 14, and 19A in 2004-2009. Conclusion: These data, although limited in numbers, demonstrate that vaccination of infants with PCVs has resulted in reductions in invasive disease caused by PCV7/13 serotypes, but some residual disease remains in all age groups. The 2014 recommendation to vaccinate all adults ≥65 with PCV13 was warranted to further reduce invasive disease in this age group. Susceptibility of S. pneumoniae to antimicrobial agents commonly used as part of empiric therapy further documents the value of vaccination programs and the need for ongoing monitoring of the seroepidemiology of this important pathogen.

Association between maternal Group B Streptococcus surface-protein antibody concentrations and invasive disease in their infants

Objectives: Group B Streptococcus (GBS) surface-proteins have been shown to be immunogenic and potential vaccine candidates. We aim to determine the association between maternal IgG antibodies to select GBS surface-proteins and invasive GBS disease in their infants. Methods: Using a matched case–control study, maternal antibody levels for GBS-immunogenic bacterial adhesin, fibrinogen-binding protein A and pilus-island (PI) PI-1, PI-2a, PI-2b were compared between infants with invasive GBS disease and well-baby controls. Results: The absolute risk of disease did not differ between cases and colonized controls with increasing antibody concentrations for these surface-proteins. There was, however, a relative risk reduction in invasive disease associated with fibrinogen-binding protein A, with an adjusted odds ratio of 0.04 (95% CI: 0.01–0.69) at antibody levels ≥10,000 AU/ml. Conclusion: We have not demonstrated an association between naturally occurring fibrinogen-binding protein A, GBS-immunogenic bacterial adhesin, and PI surface-protein antibodies and the risk of invasive disease in young infants. These surface-proteins may not be suitable GBS vaccine candidates.

Haemophilus influenzae Type b Disease among Children in Rural Mozambique: Impact of Vaccine Introduction

Haemophilus influenzae type b (Hib) conjugate vaccine has dramatically reduced invasive Hib disease worldwide. Yet, data on protection against pneumonia and among children with HIV are limited. We evaluated the impact of Hib conjugate vaccine introduction in 2009 in a rural, high-HIV prevalence area in Mozambique. From 2006-2011, we conducted hospital-based surveillance for invasive Hib disease and clinical pneumonia (classified as severe and very severe) among children <5 years of age. Incidences calculated using population denominators were compared between baseline (2006-2008) and post-Hib conjugate vaccine (2010-2011) periods. Surveillance data for radiologically-confirmed pneumonia among children <2 years of age in 2011 were compared with baseline data from 2004-2006. Among 50 cases of invasive Hib disease, 5 occurred after Hib conjugate vaccine introduction; 1 case-patient was age-eligible for Hib conjugate vaccine (and had received 3 doses). Four post-Hib conjugate vaccine case-patients (including Hib conjugate vaccine failure) had HIV. Among children <1 and <5 years of age, significant reductions occurred in rates of invasive Hib disease (91% and 85%, respectively) and very severe pneumonia (29% and 34%, respectively). Radiologically-confirmed pneumonia incidence fell significantly (33%) in children <2 years of age. Severe pneumonia incidence did not decline. We demonstrate important reductions in invasive disease and pneumonia following Hib conjugate vaccine introduction in a high-HIV area. Continued surveillance is needed to monitor long-term Hib conjugate vaccine effects, particularly among children with HIV.

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.

Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study

We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines. Nasopharyngeal swabs were taken from children <5 y old and family members (n=400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76-1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence. Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs. Please see later in the article for the Editors' Summary.

A steady-state, population-based model to estimate the direct and indirect effects of pneumococcal vaccines

This paper estimated the clinical impact of routine vaccination of infants with a new 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared with the 7-valent pneumococcal conjugate vaccine (PCV-7) and no vaccination in Canada using a new steady-state, population-based model. A deterministic, compartmental model was developed to simulate the effect of vaccination for a 1-year time period for a steady-state population, allowing for the incorporation of herd and replacement effects across all age groups. Annual clinical outcomes in the steady-state year for a population of 32.9 million were calculated for all three vaccination strategies. The no vaccination strategy was included for the purpose of validating the model. The model estimated that PHiD-CV prevented more cases of disease and more deaths than PCV-7 and no vaccination, with the largest incremental impact on acute otitis media (AOM). Compared with PCV-7, vaccination with PHiD-CV was estimated to prevent an additional 10 cases of invasive disease, 416 cases of pneumonia, 155,757 cases of AOM, 8943 myringotomy procedures, and 6 deaths nationwide. For the comparison between PCV-7 and no vaccination, the model estimated a 36.8% reduction in invasive disease; this result was similar to other models and a recent observational study in Canada, providing preliminary validation of the model.

Prevention of ventilator-associated pneumonia

Ventilator-associated pneumonia (VAP) is an important source of morbidity and mortality in critically ill patients. Many interventions are touted to prevent VAP but studies supporting these interventions are difficult to interpret owing to an exceedingly poor correlation between clinical diagnosis of VAP and the presence of an invasive pneumonia. There is consequently a risk that purported decreases in VAP rates may reflect decreases in oropharyngeal colonization rates more than reductions in invasive disease. To circumvent this source of error, it is critical to assess the impact of intervention measures on patient outcomes rather than on VAP rates alone. This article will review selected VAP prevention methods using this framework and advocate for the development of a new surveillance definition that will more reliably predict patient outcomes.

Rethinking Replacement and Resistance

Before 2000, the year in which the 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar, Wyeth) was introduced into the US infant immunization schedule, most antibiotic-resistant strains of Streptococcus pneumoniae belonged to serotypes included in PCV7. During just the first 3 years after vaccine introduction, we observed profound reductions in the incidence of invasive pneumococcal disease (e.g., bacteremia and meningitis) caused by vaccine serotypes and their associated antibiotic-resistant strains, not only among vaccinated children but also among persons too young [1] and too old [2] to receive the vaccine. The dramatic success of PCV7 in reducing pneumococcal disease in wealthy countries [3-6] and the potential benefits to poor countries [7, 8] have led to World Health Organization recommendations for the global introduction of conjugate vaccines [9] and to extraordinary efforts to finance vaccine purchase and delivery to the poorest countries of the world [10]. At the same time we were heralding the benefits of PCV7, we were alert to the unintended consequence of serotype replacement. This phenomenon, demonstrated convincingly in randomized, controlled trials [11], occurs when serotypes not included in a conjugate vaccine colonize the nasopharynx and replace the vaccine serotypes whose colonization is prevented by the vaccine. The net effect is that PCV7 does not reduce the overall prevalence of nasopharyngeal colonization. PCV7 serotypes are, on average, better suited to causing invasive disease than non-PCV7 serotypes [12, 13]; therefore, vaccine-induced elimination of PCV7 serotypes from the nasopharynx leads to a net reduction in invasive disease and antibiotic resistance. Of all the serotypes, 19A may come closest to having certain characteristics that make it a successful

Anti-Polyribosylribitol Phosphate Antibody Concentrations and Avidities in Children since the Start ofHaemophilus influenzaeType b Immunization of Infants in the United Kingdom

The introduction of routine infant immunization with Haemophilus influenzae type b (Hib) conjugate vaccines in the United Kingdom in 1992 led to a significant reduction in invasive disease due to this organism. Subsequently, between 1999 and 2003 there was an increase in the number of immunized children with Hib infection. We investigated whether the rise in cases was related to changes in anti-polyribosylribitol phosphate (PRP) antibody concentration or avidity. Using stored sera, we analyzed temporal changes in antibody levels among 3- to 5-year-old children immunized between 1991 and 2000. Anti-PRP antibody concentrations were higher in 3- to 5-year-olds who received infant immunization in 1991 than those in subsequent years. This difference may be related to changes in either the mode of administration of Hib conjugate vaccines or the rates of Hib nasopharyngeal carriage. This study emphasizes the factors affecting anti-PRP antibody concentration following immunization with conjugate vaccines and the importance of these in long-term protection from invasive disease.

Pneumococcal conjugate vaccine--a health priority.

Pneumonia is a major cause of childhood mortality and morbidity. Streptococcus pneumoniae is the most important bacterial pathogen causing pneumonia in children. The HIV epidemic has increased the burden and severity of childhood pneumococcal pneumonia and invasive disease fortyfold. Pneumococcal conjugate vaccine (PCV) is a highly effective intervention to reduce invasive pneumococcal disease and pneumonia. Studies evaluating a 9-valent PCV in South Africa and The Gambia reported a 72 - 77% reduction in vaccine-serotype-specific invasive disease in vaccinated children. As many of the pneumococcal serotypes associated with antibiotic resistance are included in PCV, vaccination has also been associated with a reduction in antimicrobial-resistant invasive disease. PCV may also reduce childhood mortality, especially in places with limited access to health care, as shown in Gambian study in which PCV reduced childhood mortality by 16%. In addition to the direct effects of PCV, there is a substantial reduction in disease burden through indirect protection of non-vaccinated populations. PCV is immunogenic in HIV-infected children and provides protection against invasive disease or pneumonia in a substantial number of children. Although the efficacy of PCV for prevention of invasive disease or pneumonia is lower in HIV-infected compared to -uninfected children, the overall burden of disease prevented is much greater in HIV-infected children because of the higher burden of pneumococcal disease in these children. Consequently, vaccine-preventable invasive disease is almost 60 times higher in HIV-infected compared to -uninfected children, while the reduction in pneumonia in HIV-infected children is 15 times greater. However, the long-term efficacy of PCV wanes in HIV-infected children who are not taking antiretroviral therapy, and booster doses are probably indicated. Although there is concern about the potential for replacement disease due to non-vaccine serotypes, a substantial and sustained reduction in invasive disease has occurred overall in populations with widespread childhood immunisation. Routine childhood immunisation is now the standard of care in most developed countries. However, PCV is much less accessible to children in developing countries due to cost and availability. Cost-effectiveness analysis indicates that use of PCV is potentially highly cost-effective, at tiered pricing, even in very low-income countries. Widespread availability and vaccination with PCV is urgently needed for all children under 2 years of age in South Africa. In addition, the use of PCV for all HIV-infected children under 9 years should be prioritised.

Short- and long-term effects of pneumococcal conjugate vaccination of children on penicillin resistance.

Recent observations have shown that wide-scale vaccination with pneumococcal conjugate vaccines was associated with a reduction in invasive disease, supporting the expectation that vaccination could help reduce carriage of Streptococcus pneumoniae and control the spread of resistant strains. However, it is too early to assess whether these effects can be sustained in the long term. Here, we used mathematical modeling to investigate time changes in pneumococcal colonization and resistance induced by conjugate vaccination in an environment where antibiotic exposure is high and resistance is widespread. According to model predictions, vaccination induced a decrease in carriage of vaccine-type pneumococci to very low levels, typically in 10 to 15 years under epidemiologically realistic conditions. Almost simultaneously, non-vaccine-type pneumococci spread in the community. Consequently, while there was a short-term decrease in the overall carriage rate, it was followed after a few years by a renewed, although limited, increase. Vaccination with a heptavalent vaccine did not affect the extent to which antibiotic resistance was selected: in all cases, the distribution of resistance levels peaked at high levels (MIC > 2 microg/ml) after 20 years. With a vaccine optimally designed to include all serotypes currently exhibiting decreased susceptibility to penicillin G, the selection of resistance was slowed down, although not prevented. These results suggest that because of serotype replacement, the effects of vaccination observed today may not be sustained in the long term. As a consequence, vaccination alone may not be successful in controlling selection for resistance in S. pneumoniae.