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Postdoctoral Associate, Yale School of Public Health


An adult-specific pneumococcal vaccine could substantially reduce pneumococcal disease in all ages

Streptococcus pneumoniae remains a major cause of adulthood disease with ~400,000 pneumonia hospitalisations and 20,000 deaths, costing >US$1 billion annually (USA). This could substantially increase as the elderly population expands.

Asymptomatic colonisation by S. pneumoniae is pre-requisite for its transmission and disease. Young children are most frequently colonised, representing the pneumococcal reservoir in the population. Infants are therefore the target group of vaccination strategies for combating the high rates of morbidity and mortality from pneumococcal disease.

Currently available vaccines target up to 13 of the 90+ pneumococcal polysaccharide capsules (serotypes) and have virtually eradicated vaccine-serotype carriage and disease. Since vaccination prevents transmission, reductions occur both in vaccinated (children) and unvaccinated individuals (e.g. adults). Unfortunately, serotypes not targeted by vaccination are rapidly expanding in carriage and disease, eroding the benefits of vaccination, particularly in elderly.

Adult vaccination using the current vaccines is therefore being considered. However, with vaccine-serotypes disappearing from circulation due to infant vaccination, little economic or health benefit is expected from vaccinating adults with the current formulation used in infant immunisation programmes. New adult vaccination strategies, with alternative vaccine targets, should therefore be considered.

Determining the serotypes for such an adult-specific PCV is a major challenge; manufacturers must make decisions years before relevant surveillance data are available. Therefore, serotypes most likely to cause adulthood disease after new paediatric-PCVs are introduced must be predicted. Developing a system for selecting serotypes for an adult-specific PCV will provide novel information for vaccine manufacturers.

Therefore, by combining experimental microbiology, bioinformatics and epidemiology this research addresses how to select serotypes for an optimised adult-specific vaccine. This issue will gain urgency as current vaccine-serotypes continue to decline and non-vaccine-serotypes increase in adulthood disease. Such an adult-specific vaccine has the potential to substantially reduce the burden of pneumococcal disease in all ages.


Nasopharyngeal microbiota in infants and changes during viral upper respiratory tract infection and acute otitis media.

Abstract: Interferences between pathogenic bacteria and specific commensals are known. We determined the interactions between nasopharyngeal microbial pathogens and commensals during viral upper respiratory tract infection (URI) and acute otitis media (AOM) in infants.We analyzed 971 specimens collected monthly and during URI and AOM episodes from 139 infants. The 16S rRNA V4 gene regions were sequenced on the Illumina MiSeq platform.Among the high abundant genus-level nasopharyngeal microbiota were Moraxella, Haemophilus, and Streptococcus (3 otopathogen genera), Corynebacterium, Dolosigranulum, Staphylococcus, Acinetobacter, Pseudomonas, and Bifidobacterium. Bacterial diversity was lower in culture-positive samples for Streptococcus pneumoniae, and Haemophilus influenzae, compared to cultured-negative samples. URI frequencies were positively associated with increasing trend in otopathogen colonization. AOM frequencies were associated with decreasing trend in Micrococcus colonization. During URI and AOM, there were increases in abundance of otopathogen genera and decreases in Pseudomonas, Myroides, Yersinia, and Sphingomonas. Otopathogen abundance was increased during symptomatic viral infection, but not during asymptomatic infection. The risk for AOM complicating URI was reduced by increased abundance of Staphylococcus and Sphingobium.Otopathogen genera played the key roles in URI and AOM occurrences. Staphylococcus counteracts otopathogens thus Staphylococcal colonization may be beneficial, rather than harmful. While Sphingobium may play a role in preventing AOM complicating URI, the commonly used probiotic Bifidobacterium did not play a significant role during URI or AOM. The role of less common commensals in counteracting the deleterious effects of otopathogens requires further studies.

Pub.: 15 Jul '17, Pinned: 18 Aug '17

Nasopharyngeal Carriage of Streptococcus Pneumoniae and Serotypes Indentified among Nursing Home Residents in Comparison to the Elderly and Patients Younger than 65 Years Living in Domestic Environment.

Abstract: In Slovenia, there is little data available on pneumococcal vaccination rates and no data on asymptomatic NPCR and serotypes in the population of nursing home residents in comparison to the elderly living in domestic environment, therefore the goal was to gain these data.A cross sectional epidemiological study was performed. Nasopharyngeal swabs from 151 nursing home residents, 150 elderly living in domestic environment, and 38 adults less than 65 years old were collected twice (in two consecutive years). The swabs were analysed for pneumococcal identification and serotyping. Patient data were collected from medical files and medical history.No statistically significant differences in NPCR were seen between compared groups in two consecutive years. An average NPCR in two consecutive years in nursing home residents was 1.45%, in the elderly living in domestic environment 0.85%, and in adults less than 65 years old 7.05%. Serotypes identified among nursing home residents were 6B and 9N, among the group of elderly living in domestic environment, 6A and among adults less than 65 years old, 35F, 18C and 3. Pneumococcal vaccination rates were low (3.3% in nursing home residents, 6% in the elderly from domestic environment and 0% in the group of adults less than 65 years old).Our data suggests that NPCR and the proportion of people vaccinated with pneumococcal vaccine among the elderly are low. We identified different serotypes in all groups, only one person was a chronic carrier (serotype 35F).

Pub.: 18 Jul '17, Pinned: 18 Aug '17

Changes in the Nature and Severity of Invasive Pneumococcal Disease in Children, Before and After the 7-Valent and 13-Valent Pneumococcal Conjugate Vaccine Programs in Calgary, Canada.

Abstract: Since the introduction of childhood pneumococcal conjugate vaccines, invasive pneumococcal disease (IPD) incidence has decreased in children and the predominant serotypes causing disease have changed. This study describes changes in the clinical features of IPD in children (<18 years) before and after conjugate vaccine introduction.The Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) study collects information on all IPD cases in Calgary, Alberta, Canada. Descriptive and regression analyses were used to compare IPD in the pre-vaccine (2000-August 2002), post-PCV7 (September 2002-June 2010), and post-PCV13 (July 2010-December 2015) periods; ICU and inpatient admissions were outcome measures.The incidence of IPD in children (<18 years) decreased from an average of 17 cases/100,000/year in 2000/2001 to 4 cases/100,000/year in 2015. The median age of children presenting with IPD shifted from 2.0 years (IQR:2.5) in the pre-vaccine period to 3.9 years (IQR:6.2) in the post-PCV13 period. The proportion of children with a comorbidity that is an indication for pneumococcal vaccination did not change. Invasive disease with focus (meningitis, pneumonia, empyema, peritonitis) compared with invasive disease with bacteremia only increased from 44.6% in pre-vaccine to 64.0% and 61.4% in the post-PCV7 and post-PCV13 periods respectively (P=0.017). Having IPD in the post-PCV13 period compared with the pre-vaccine period was associated with an increased odds of hospitalization (OR: 2.9; 95% CI:1.4-6.2).Clinical features of IPD have changed since pneumococcal conjugate vaccines were introduced, with a shift towards more focal infections requiring hospitalization. Although overall IPD cases have declined, disease that does occur appears to be more severe.

Pub.: 25 Jul '17, Pinned: 18 Aug '17

Mathematical modeling of postcoinfection with influenza A virus and Streptococcus pneumoniae, with implications for pneumonia and COPD-risk assessment.

Abstract: The interaction between influenza and pneumococcus is important for understanding how coinfection may exacerbate pneumonia. Secondary pneumococcal pneumonia associated with influenza infection is more likely to increase respiratory morbidity and mortality. This study aimed to assess exacerbated inflammatory effects posed by secondary pneumococcal pneumonia, given prior influenza infection.A well-derived mathematical within-host dynamic model of coinfection with influenza A virus and Streptococcus pneumoniae (SP) integrated with dose-response relationships composed of previously published mouse experimental data and clinical studies was implemented to study potentially exacerbated inflammatory responses in pneumonia based on a probabilistic approach.We found that TNFα is likely to be the most sensitive biomarker reflecting inflammatory response during coinfection among three explored cytokines. We showed that the worst inflammatory effects would occur at day 7 SP coinfection, with risk probability of 50% (likely) to develop severe inflammatory responses. Our model also showed that the day of secondary SP infection had much more impact on the severity of inflammatory responses in pneumonia compared to the effects caused by initial virus titers and bacteria loads.People and health care workers should be wary of secondary SP infection on day 7 post-influenza infection for prompt and proper control-measure implementation. Our quantitative risk-assessment framework can provide new insights into improvements in respiratory health especially, predominantly due to chronic obstructive pulmonary disease (COPD).

Pub.: 26 Jul '17, Pinned: 18 Aug '17

Serotypes of Streptococcus pneumoniae in Egyptian children: are they covered by pneumococcal conjugate vaccines?

Abstract: In Egypt, pneumococcal vaccines have not yet been introduced as being compulsory. Identification of the circulating serotypes in Egypt is mandatory to determine whether or not the pneumococcal vaccines will be beneficial. The current study aims to identify the serotypes, vaccine coverage, and antimicrobial resistance of Streptococcus pneumoniae colonizing the nasopharynx of Egyptian children younger than 5 years old. The study was conducted in two successive winter seasons (December 2012-February 2013 and December 2013-February 2014). Two hundred children were enrolled, aged from 6 months to 5 years, excluding those with fever, signs of infection, history of antibiotic intake, and hospitalization in the preceding month. Nasopharyngeal (NP) secretions were collected, subjected to culture, and underwent antibiotic susceptibility testing if positive for pneumococci. Real-time polymerase chain reaction (PCR) and serotyping by sequential multiplex PCR for positive cases were included as well. Streptococcus pneumoniae was isolated from 62 subjects. All isolates were sensitive to vancomycin and levofloxacin, but the majority showed resistance to multiple antibiotics. PCR was positive for pneumococci in 113 subjects (56.5%). The most commonly detected serotypes (st) were 6A6B6C (n = 21, 20.8%), 19F (n = 19, 18.8%), 1 (n = 11, 10.9%), 34 (n = 8, 7.9%), and 19A (n = 6, 5.9%). The theoretical coverage of the PCV13 vaccine for the detected serotypes was 72.4%, while that of PCV10 was 65.5%. Based on these percentages, we recommend including pneumococcal conjugate vaccines in the Egyptian national vaccination program.

Pub.: 27 Jul '17, Pinned: 18 Aug '17

Using pneumococcal carriage data to monitor postvaccination changes in invasive disease.

Abstract: Pneumococcal conjugate vaccines (PCVs) have been introduced worldwide. However, few developing countries have high-quality surveillance systems available for monitoring vaccine impact. We evaluated whether data from nasopharyngeal carriage studies can be used to accurately monitor post-PCV changes in the incidence of invasive pneumococcal disease (IPD) among children under 5 years of age. For various dates during 1991-2010, data on nasopharyngeal pneumococcal carriage and on IPD before and after administration of 7-valent PCV (PCV7) were available from England and Wales, the Netherlands, the Navajo and White Mountain Apache American Indian populations, and the US states of Massachusetts and Alaska. We estimated the change in carriage prevalence for each serotype in each study and then either calculated the average change (inverse variance-weighted) among vaccine and nonvaccine serotypes (model 1) or used mixed-effects models to estimate the change for each serotype individually, pooling serotype data within or between studies (models 2 and 3). We then multiplied these values by the proportion of IPD caused by each serotype during the pre-PCV7 period to obtain an estimate of post-PCV7 disease incidence. Model 1 accurately captured overall changes in IPD incidence following PCV7 introduction for most studies, while the more detailed models, models 2 and 3, were less accurate. Carriage data can be used in this simple model to estimate post-PCV changes in IPD incidence.

Pub.: 10 Sep '13, Pinned: 20 Jul '17

Relating Pneumococcal Carriage Among Children to Disease Rates Among Adults Before and After the Introduction of Conjugate Vaccines.

Abstract: The use of pneumococcal conjugate vaccines (PCVs) in children has a strong indirect effect on disease rates in adults. When children are vaccinated with PCVs, other serotypes that are not targeted by the vaccine can increase in frequency (serotype replacement) and reduce the direct and indirect benefits of the vaccine. To understand and predict the likely impacts of serotype replacement, it is important to know how patterns in the transmission of serotypes among children relate to disease rates in adults. We used data on pneumococcal carriage and disease from Navajo Nation children and adults collected before and after the routine use of PCVs (1998-2012). Using regression models within a Bayesian framework, we found that serotype-specific carriage and invasiveness (disease incidence divided by carriage prevalence) had similar patterns in children and adults. Moreover, carriage in children, invasiveness in children, and a serotype-specific random intercept (which captured additional variation associated with the serotypes) could predict the incidence serotype-specific pneumococcal disease in adults 18-39 years of age and those 40 years of age or older in the era of routine use of PCVs. These models could help us predict the effects of future pneumococcal vaccine use in children on disease rates in adults, and the modeling approach developed here could be used to test these findings in other settings.

Pub.: 18 May '16, Pinned: 20 Jul '17

Carriage of Streptococcus pneumoniae in aged adults with influenza-like-illness.

Abstract: Incidence of pneumococcal disease is disproportionally high in infants and elderly. Nasopharyngeal colonisation by Streptococcus pneumoniae is considered a prerequisite for disease but unlike in children, carriage in elderly is rarely detected. Here, we tested for S. pneumoniae in nasopharyngeal and saliva samples collected from community-dwelling elderly with influenza-like-illness (ILI). Trans-nasal nasopharyngeal, trans-oral nasopharyngeal and saliva samples (n = 270 per sample type) were collected during winter/spring 2011/2012 from 135 persons aged 60-89 at onset of ILI and 7-9 weeks later following recovery. After samples were tested for pneumococci by conventional culture, all plate growth was collected. DNA extracted from plate harvests was tested by quantitative-PCRs (qPCR) specific for S. pneumoniae and serotypes included in the 13-valent pneumococcal conjugated vaccine (PCV13). Pneumococci were cultured from 14 of 135 (10%) elderly with none of the sampled niches showing superiority in carriage detection. With 76/270 (28%) saliva, 31/270 (11%) trans-oral and 13/270 (5%) trans-nasal samples positive by qPCR, saliva was superior to nasopharyngeal swabs (p<0.001) in qPCR-based carriage detection. Overall, from all methods used in the study, 65 of 135 (48%) elderly carried pneumococci at least once and 26 (19%) at both study time points. The difference between carriage prevalence at ILI (n = 49 or 36%) versus recovery (n = 42 or 31%) was not significant (p = 0.38). At least 23 of 91 (25%) carriage events in 19 of 65 (29%) carriers were associated with PCV13-serotypes. We detected a large reservoir of pneumococci in saliva of elderly, with PCV13-serotype distribution closely resembling the contemporary carriage of serotypes reported in the Netherlands for PCV-vaccinated infants.

Pub.: 20 Mar '15, Pinned: 20 Jul '17