106 results on '"Hausdorff WP"'
Search Results
2. Multinational study of pneumococcal serotypes causing acute otitis media in children
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Hausdorff, WP Yothers, G Dagan, R Kilpi, T Pelton, SI and Cohen, R Jacobs, MR Kaplan, SL Levy, C Lopez, EL and Mason, EO Syriopoulou, V Wynne, B Bryant, J
- Abstract
Background. Streptococcus pneumoniae is a major cause of acute otitis media (AOM) in young children. More than 90 immunologically distinct pneumococcal serotypes have been identified, but limited information is available regarding their relative importance in AOM. Methods. We analyzed nine existing datasets comprising pneumococcal isolates from middle ear fluid samples collected from 1994 through 2000 from 3232 children with AOM from Finland, France, Greece, Israel, several East European countries, the US and Argentina. We examined the distribution of pneumococcal serotypes in relation to several demographic and epidemiologic variables, including gender, age, antibiotic resistance and source of culture material. Results. The major serotypes identified included 19F and 23F, each comprising 13 to 25% of pneumococcal middle ear fluid isolates in most datasets; 14 and 6B, comprising 6 to 18%; whereas 6A, 19A and 9V each comprised 5 to 10%. Despite differences in location, study design and antibiotic susceptibility, each major serotype was prominent in most age groups of each dataset. Serotypes represented in the 7-valent pneumococcal conjugate vaccine (PCV-7, 4, 6B, 9V, 14, 18C, 19F, 23F) accounted for 60 to 70% of all pneumococcal isolates in the 6- to 59-month age range, but only 40 to 50% of isolates in children 59 months of age.
- Published
- 2002
3. Serotype replacement after pneumococcal vaccination.
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Hausdorff WP, Van Dyke MK, and Van Effelterre T
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- 2012
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4. Do pneumococcal conjugate vaccines provide any cross-protection against serotype 19A?
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Hausdorff WP, Hoet B, Schuerman L, Hausdorff, William P, Hoet, Bernard, and Schuerman, Lode
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Background: Introduction of the 7-valent pneumococcal conjugate vaccine (7vCRM) in several countries has led to a rapid, significant drop in vaccine-type invasive pneumococcal disease (IPD) in immunized children. In the United States and some other countries with high antibiotic use, a subsequent rise in serotype 19A IPD has been taken to indicate that the 19F conjugate in the vaccine provides no cross-protection against the immunologically related 19A.Discussion: We systematically assessed the clinical efficacy and effectiveness of 19F-containing vaccines against 19A disease or nasopharyngeal carriage by searching English-language articles in the electronic databases PubMed, Current contents, Scopus, and Embase from 1985 to 2008. The vaccine efficacy and effectiveness point estimates were consistently positive for modest protection against 19A IPD and acute otitis media (AOM). However, statistical significance was not reached in any individual study. No consistent impact of 7vCRM on 19A nasopharyngeal colonization could be detected. These findings are discussed in context of immunogenicity analyses indicating that 7vCRM induces functionally active anti-19A antibodies after the booster dose, and that other 19F-containing vaccine formulations may elicit higher levels of such antibodies after both primary and booster doses.Summary: Taken together, these results suggest that 19F-conjugates can provide some protection against 19A disease. The magnitude of this protection in a given setting will likely depend on several factors. These include the anti-19A immunogenicity of the specific vaccine formulation, the number of doses of that formulation needed to elicit the response, and the burden of 19A disease that occurs after those doses. It is possible that a modest protective effect may be obscured by the presence of countervailing selection pressures (such as high antibiotic use) that favor an increase in colonization with antibiotic-non-susceptible strains of 19A. [ABSTRACT FROM AUTHOR]- Published
- 2010
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5. Survey of childhood empyema in Asia: implications for detecting the unmeasured burden of culture-negative bacterial disease.
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Nyambat B, Kilgore PE, Yong DE, Anh DD, Chiu CH, Shen X, Jodar L, Ng TL, Bock HL, Hausdorff WP, Nyambat, Batmunkh, Kilgore, Paul E, Yong, Dong Eun, Anh, Dang Duc, Chiu, Chen-Hsun, Shen, Xuzhuang, Jodar, Luis, Ng, Timothy L, Bock, Hans L, and Hausdorff, William P
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Background: Parapneumonic empyema continues to be a disease of significant morbidity and mortality among children despite recent advances in medical management. To date, only a limited number of studies have assessed the burden of empyema in Asia.Methods: We surveyed medical records of four representative large pediatric hospitals in China, Korea, Taiwan and Vietnam using ICD-10 diagnostic codes to identify children <16 years of age hospitalized with empyema or pleural effusion from 1995 to 2005. We also accessed microbiology records of cultured empyema and pleural effusion specimens to describe the trends in the epidemiology and microbiology of empyema.Results: During the study period, we identified 1,379 children diagnosed with empyema or pleural effusion (China, n = 461; Korea, n = 134; Taiwan, n = 119; Vietnam, n = 665). Diagnoses of pleural effusion (n = 1,074) were 3.5 times more common than of empyema (n = 305), although the relative proportions of empyema and pleural effusion noted in hospital records varied widely between the four sites, most likely because of marked differences in coding practices. Although pleural effusions were reported more often than empyema, children with empyema were more likely to have a cultured pathogen. In addition, we found that median age and gender distribution of children with these conditions were similar across the four countries. Among 1,379 empyema and pleural effusion specimens, 401 (29%) were culture positive. Staphylococcus aureus (n = 126) was the most common organism isolated, followed by Streptococcus pneumoniae (n = 83), Pseudomonas aeruginosa (n = 37) and Klebsiella (n = 35) and Acinetobacter species (n = 34).Conclusion: The age and gender distribution of empyema and pleural effusion in children in these countries are similar to the US and Western Europe. S. pneumoniae was the second leading bacterial cause of empyema and pleural effusion among Asian children. The high proportion of culture-negative specimens among patients with pleural effusion or empyema suggests that culture may not be a sufficiently sensitive diagnostic method to determine etiology in the majority of cases. Future prospective studies in different countries would benefit from standardized case definitions and coding practices for empyema. In addition, more sensitive diagnostic methods would improve detection of pathogens and could result in better prevention, treatment and outcomes of this severe disease. [ABSTRACT FROM AUTHOR]- Published
- 2008
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6. Pediatric Parapneumonic Empyema, Spain
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David Tarragó, L.A. Arroyo, Angela B. Brueggemann, William P. Hausdorff, Carmen Muñoz-Almagro, Juan J. Garcia-Garcia, David Moreno-Pérez, Susanna Hernández-Bou, Cristina Esteva, Ignacio Obando, David Sanchez-Tatay, Sahar S. Dhillon, [Obando,I, Arroyo,LA, Sanchez-Tatay,D] Virgen del Rocio Children’s Hospital, Seville, Spain. [Muñoz-Almagro,C, Esteva,S, Hernandez-Bou,S, Garcia-Garcia,JJ] Sant Joan de Deu Hospital, Barcelona, Spain. [Tarrago,D] Spanish Reference Laboratory for Pneumococci, Madrid, Spain. [Moreno-Perez,D] Carlos de Haya Children’s Hospital, Malaga, Spain. [Dhillon,SS, Brueggemann,B] University of Oxford, Oxford, UK. [Hausdorff,WP] GlaxoSmithKline Biologicals, Rixensart, Belgium., and This research was supported by Fondo de Investigaciones Sanitarias (PI050924 and CP05/00068), the Spanish Pneumococcal Infection Study Network (G03-103) and the Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008) of the Spanish Ministry of Health, and GlaxoSmithKline Biologicals. L.A.A. was supported by Fundacion CajaSol and D.S.-T. was supported by Consejería de Salud from the Andalusian Government.
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Serotype ,Pathology ,IMPACT ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies::Retrospective Studies [Medical Subject Headings] ,MENINGITIS ,España ,DIVERSITY ,Organisms::Bacteria::Gram-Positive Bacteria::Gram-Positive Cocci::Streptococcaceae::Streptococcus::Streptococcus pneumoniae [Medical Subject Headings] ,lcsh:Medicine ,CHILDREN ,Estudios Retrospectivos ,medicine.disease_cause ,STREPTOCOCCUS-PNEUMONIAE SEROTYPE-1 ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Preescolar ,1108 Medical Microbiology ,Epidemiology ,Prospective Studies ,Child ,Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings] ,Molecular Epidemiology ,Named Groups::Persons::Age Groups::Child::Child, Preschool [Medical Subject Headings] ,Neumonía Neumocócica ,pediatric parapneumonic empyema ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology [Medical Subject Headings] ,Empiema Pleural ,Estudios Prospectivos ,Antimicrobial ,Diseases::Bacterial Infections and Mycoses::Bacterial Infections::Gram-Positive Bacterial Infections::Streptococcal Infections::Pneumococcal Infections::Pneumonia, Pneumococcal [Medical Subject Headings] ,Humanos ,Infectious Diseases ,Streptococcus pneumoniae ,1117 Public Health And Health Services ,PNEUMOCOCCAL CONJUGATE VACCINE ,Child, Preschool ,Niño ,Diseases::Bacterial Infections and Mycoses::Infection::Respiratory Tract Infections::Empyema, Pleural [Medical Subject Headings] ,epidemiology ,Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings] ,Named Groups::Persons::Age Groups::Infant [Medical Subject Headings] ,Life Sciences & Biomedicine ,Microbiology (medical) ,medicine.medical_specialty ,serotype 1 ,Genotype ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings] ,Immunology ,DIAGNOSIS ,Microbiology ,lcsh:Infectious and parasitic diseases ,INVASIVE-DISEASE ,stomatognathic system ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Humans ,lcsh:RC109-216 ,Empyema, Pleural ,Named Groups::Persons::Age Groups::Child [Medical Subject Headings] ,Retrospective Studies ,Science & Technology ,research ,Molecular epidemiology ,CAPSULAR TYPES ,business.industry ,lcsh:R ,Infant ,1103 Clinical Sciences ,Lactante ,Pneumonia, Pneumococcal ,medicine.disease ,Empyema ,Pneumonia ,Spain ,Multilocus sequence typing ,business ,Genotipo ,Epidemiología Molecular ,CLONES - Abstract
Increased incidence is principally due to highly invasive nonvaccine serotypes of pneumococci, especially serotype 1., Pediatric parapneumonic empyema (PPE) has been increasing in several countries including Spain. Streptococcus pneumoniae is a major PPE pathogen; however, antimicrobial pretreatment before pleural fluid (PF) sampling frequently results in negative diagnostic cultures, thus greatly underestimating the contribution of pneumococci, especially pneumococci susceptible to antimicrobial agents, to PPE. The study aim was to identify the serotypes and genotypes that cause PPE by using molecular diagnostics and relate these data to disease incidence and severity. A total of 208 children with PPE were prospectively enrolled; blood and PF samples were collected. Pneumococci were detected in 79% of culture-positive and 84% of culture-negative samples. All pneumococci were genotyped by multilocus sequence typing. Serotypes were determined for 111 PPE cases; 48% were serotype 1, of 3 major genotypes previously circulating in Spain. Variance in patient complication rates was statistically significant by serotype. The recent PPE increase is principally due to nonvaccine serotypes, especially the highly invasive serotype 1.
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- 2008
7. Global Meningococcal Initiative: Insights on antibiotic resistance, control strategies and advocacy efforts in Western Europe.
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Borrow R, Campbell H, Caugant DA, Cherkaoui A, Claus H, Deghmane AE, Dinleyici EC, Harrison LH, Hausdorff WP, Bajanca-Lavado P, Levy C, Mattheus W, Mikula-Pratschke C, Mölling P, Sáfadi MA, Smith V, van Sorge NM, Stefanelli P, Taha MK, Toropainen M, Tzanakaki G, and Vázquez J
- Abstract
In Western Europe, many countries have robust and well-established surveillance systems and case reporting mechanisms. IMD incidence across Western Europe is low with a predominance of meningococcal serogroup B (MenB). Case confirmation and antimicrobial susceptibility testing is often standardised in this region, with many countries also having robust vaccination programmes in place. Both MenB and MenACWY vaccines form part of National Immunisation Programmes (NIPs) in most European countries, with Sweden only offering vaccination in special circumstances. Despite these established programmes, there remains a critical need for advocacy efforts in affecting change in diagnosis, testing, and treatment. Recent campaigns, such as the World Meningitis Day digital toolkit, have helped raise awareness and draw attention to meningococcal disease. Awareness around antibiotic resistance has also led to the identification of antibiotic-resistant meningococcal strains, with an increase, albeit small, in these strains noted across the region. Countries such as Spain, Portugal, Germany, Switzerland, and France have either reported strains resistant to penicillin, ciprofloxacin and/or isolates with a reduced susceptibility to third-generation cephalosporins., Competing Interests: Declaration of Competing Interest Ray Borrow performs contract research on behalf of UKHSA for GSK, PATH, Pfizer and Sanofi. Heike Claus has received personal fee for scientific presentation for Sanofi. Ener Cagri Dinleyici performs contract work for the Eskisehir Osmangazi University funded by GSK, Sanofi Pasteur and Pfizer. Lee Harrison has served on advisory boards and/or made scientific presentations for GSK, Pfizer, Sanofi, and Merck, for which he does not receive any personal fees. William P. Hausdorff has served on advisory boards for Sanofi, Merck, and Vaxcyte, for which he does not receive any personal fees or reimbursement. Corinne Levy reports personal fees for advisory board and scientific presentations for MSD and Pfizer. Wesley Mattheus reports research grants funded by GSK and Pfizer. Marco A. P. Sáfadi reports research grants and personal fees for advisory boards from GSK, Pfizer, and Sanofi. Vinny Smith works for Meningitis Research Foundation that receives income from grants, sponsorship and consultancy income from GSK, MSD, Pfizer, Sanofi and Serum Institute of India. M.K. Taha performs contract work for the Institut Pasteur funded by GSK, Pfizer and Sanofi. M.K. Taha and A-E Deghmane have a patent NZ630133A Patent with GSK “Vaccines for serogroup X meningococcus” issued. Georgina Tzanakaki reports contract work on behalf of the University of West Attica as participation on advisory boards and scientific presentations for Pfizer, Sanofi and Merck. J.A. Vázquez performs contract work for the Institute of Health Carlos III funded by GSK and Pfizer and he has received personal fees from Pfizer and Sanofi. Nina van Sorge receives fee for service and presentations (directly paid to the institution) from MSD and GSK. Finnish Institute for Health and Welfare has received research funding from Pfizer and GSK for projects in which Maija Toropainen has acted as a researcher without personal remuneration., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)
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- 2024
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8. Implications of Cross-Reactivity and Cross-Protection for Pneumococcal Vaccine Development.
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Feemster K, Hausdorff WP, Banniettis N, Platt H, Velentgas P, Esteves-Jaramillo A, Burton RL, Nahm MH, and Buchwald UK
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Pneumococcal vaccines are a cornerstone for the prevention of pneumococcal diseases, reducing morbidity and mortality in children and adults worldwide. Pneumococcal vaccine composition is based on the polysaccharide capsule of Streptococcus pneumoniae , which is one of the most important identified contributors to the pathogen's virulence. Similarities in the structural composition of polysaccharides included in licensed pneumococcal vaccines may result in cross-reactivity of immune response against closely related serotypes, including serotypes not included in the vaccine. Therefore, it is important to understand whether cross-reactive antibodies offer clinical protection against pneumococcal disease. This review explores available evidence of cross-reactivity and cross-protection associated with pneumococcal vaccines, the challenges associated with the assessment of cross-reactivity and cross-protection, and implications for vaccine design and development.
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- 2024
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9. The role of vaccines in reducing antimicrobial resistance: A review of potential impact of vaccines on AMR and insights across 16 vaccines and pathogens.
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Hasso-Agopsowicz M, Sparrow E, Cameron AM, Sati H, Srikantiah P, Gottlieb S, Bentsi-Enchill A, Le Doare K, Hamel M, Giersing BK, and Hausdorff WP
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- Humans, Vaccines immunology, Drug Resistance, Bacterial, Vaccine Development, Bacterial Vaccines immunology, Bacterial Vaccines administration & dosage, Anti-Bacterial Agents pharmacology
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In 2019, an estimated 4.95 million deaths were linked to antimicrobial resistance (AMR). Vaccines can prevent many of these deaths by averting both drug-sensitive and resistant infections, reducing antibiotic usage, and lowering the likelihood of developing resistance genes. However, their role in mitigating AMR is currently underutilized. This article builds upon previous research that utilizes Vaccine Value Profiles-tools that assess the health, socioeconomic, and societal impact of pathogens-to inform vaccine development. We analyze the effects of 16 pathogens, covered by Vaccine Value Profiles, on AMR, and explore how vaccines could reduce AMR. The article also provides insights into vaccine development and usage. Vaccines are crucial in lessening the impact of infectious diseases and curbing the development of AMR. To fully realize their potential, vaccines must be more prominently featured in the overall strategy to combat AMR. This requires ongoing investment in research and development of new vaccines and the implementation of additional prevention and control measures to address this global threat effectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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10. Facilitating the development of urgently required combination vaccines.
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Hausdorff WP, Madhi SA, Kang G, Kaboré L, Tufet Bayona M, and Giersing BK
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- Humans, Vaccine Development, Health Policy, Vaccines, Combined
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The essence of a vaccine lies in its ability to elicit a set of immune responses specifically directed at a particular pathogen. Accordingly, vaccines were historically designed, developed, registered, recommended, procured, and administered as monopathogen formulations. Nonetheless, the control and elimination of an astonishing number of diseases was realised only after several once-separate vaccines were provided as combinations. Unfortunately, the current superabundance of recommended and pipeline vaccines is now at odds with the number of acceptable vaccine administrations and feasible health-care visits for vaccine recipients and health-care providers. Yet, few new combinations are in development because, in addition to the scientific and manufacturing hurdles intrinsic to coformulation, developers face a gauntlet of regulatory, policy, and commercialisation obstacles in a milieu still largely designed for monopathogen vaccines. We argue here that national policy makers and public health agencies should prospectively identify and advocate for the development of new multipathogen combination vaccines, and suggest ways to accelerate the regulatory pathways to licensure of combinations and other concrete, innovative steps to mitigate current obstacles., Competing Interests: Declaration of interests WPH reports receiving a travel grant from GSK. SAM reports receiving funds from the Bill & Melinda Gates Foundation, GSK, Pfizer, Minervax, Novavax, Merck, Providence, Gritstone, and Immunity Bio. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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11. Lassa fever vaccine use cases and demand: Perspectives from select West African experts.
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Kaboré L, Pecenka C, and Hausdorff WP
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- Humans, Female, Pregnancy, Lassa virus, Africa, Western epidemiology, Nigeria epidemiology, Lassa Fever epidemiology, Lassa Fever prevention & control, Viral Vaccines
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Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic to several West African countries. Approximately 300-500,000 cases occur annually across all ages with 10-20% case fatality rates. A LF vaccine is a recognized public health priority, with several candidates entering clinical trials. However, the perspectives of regional experts regarding critical vaccine properties, ideal delivery methods, and priority target populations remain unclear. Using a mixed methods approach with a standardized questionnaire, we individually interviewed 8 West African stakeholders, each with extensive knowledge and experience of LF. They strongly favored the use of a mass, proactive campaign strategy to immunize a wide age range of people in high-risk areas, including pregnant women and health care workers. We estimated that these and other plausible delivery scenarios could result in an initial demand of anywhere from 1 to 100 million doses, with most demand coming from Nigeria. These findings may help inform LF vaccine development and deployment efforts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PATH (William Hausdorff) reports financial support was provided by Emergent BioSolutions Inc. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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12. Reassessing potential economic value and health impact of effective Shigella vaccines.
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Hausdorff WP, Anderson JD 4th, Bourgeois AL, Clifford A, Fleming JA, Muhib F, Pecenka C, Puett C, Riddle MS, Scheele S, and Bagamian KH
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- Child, Humans, Diarrhea prevention & control, Diarrhea microbiology, Global Health, Shigella Vaccines, Shigella, Vaccines
- Abstract
The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella -containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries., ((c) 2024 The authors; licensee World Health Organization.)
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- 2024
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13. Vaccine value profile for enterotoxigenic Escherichia coli (ETEC).
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Khalil I, Anderson JD, Bagamian KH, Baqar S, Giersing B, Hausdorff WP, Marshall C, Porter CK, Walker RI, and Bourgeois AL
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- Child, Preschool, Humans, Diarrhea, Infant, Dysentery, Enterotoxigenic Escherichia coli, Escherichia coli Infections, Escherichia coli Vaccines
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Enterotoxigenic Escherichia coli (ETEC) is one of the leading bacterial causes of diarrhoea, especially among children in low-resource settings, and travellers and military personnel from high-income countries. WHO's primary strategic goal for ETEC vaccine development is to develop a safe, effective, and affordable ETEC vaccine that reduces mortality and morbidity due to moderate-to-severe diarrhoeal disease in infants and children under 5 years of age in LMICs, as well as the long-term negative health impact on infant physical and cognitive development resulting from infection with this enteric pathogen. An effective ETEC vaccine will also likely reduce the need for antibiotic treatment and help limit the further emergence of antimicrobial resistance bacterial pathogens. The lead ETEC vaccine candidate, ETVAX, has shown field efficacy in travellers and has moved into field efficacy testing in LMIC infants and children. A Phase 3 efficacy study in LMIC infants is projected to start in 2024 and plans for a Phase 3 trial in travellers are under discussion with the U.S. FDA. Licensing for both travel and LMIC indications is projected to be feasible in the next 5-8 years. Given increasing recognition of its negative impact on child health and development in LMICs and predominance as the leading etiology of travellers' diarrhoea (TD), a standalone vaccine for ETEC is more cost-effective than vaccines targeting other TD pathogens, and a viable commercial market also exists. In contrast, combination of an ETEC vaccine with other vaccines for childhood pathogens in LMICs would maximize protection in a more cost-effective manner than a series of stand-alone vaccines. This 'Vaccine Value Profile' (VVP) for ETEC is intended to provide a high-level, holistic assessment of available data to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the ETEC VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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14. Vaccine value profile for Shigella.
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Hausdorff WP, Anderson JD 4th, Bagamian KH, Bourgeois AL, Mills M, Sawe F, Scheele S, Talaat K, and Giersing BK
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- Child, Preschool, Humans, Diarrhea prevention & control, Infant, Dysentery, Bacillary, Escherichia coli Infections prevention & control, Shigella, Shigella Vaccines
- Abstract
Shigella is the leading bacterial cause of diarrhoea and the second leading cause of diarrhoeal mortality among all ages. It also exhibits increasing levels of antibiotic resistance. The greatest burden is among children under five in low- and middle-income countries (LMICs). As such, a priority strategic goal of the World Health Organization (WHO) is the development of a safe, effective and affordable vaccine to reduce morbidity and mortality from Shigella-attributable dysentery and diarrhea, including long term outcomes associated with chronic inflammation and growth faltering, in children under 5 years of age in LMICs. In addition, a safe and effective Shigella vaccine is of potential interest to travellers and military both to prevent acute disease and rarer, long-term sequelae. An effective Shigella vaccine is also anticipated to reduce antibiotic use and thereby help diminish further emergence of enteric pathogens resistant to antimicrobials. The most advanced vaccine candidates are multivalent, parenteral formulations in Phase 2 and Phase 3 clinical studies. They rely on O-antigen-polysaccharide protein conjugate technologies or, alternatively, outer membrane vesicles expressing penta-acylated lipopolysaccharide that has been detoxified. Other parenteral and oral formulations, many delivering a broader array of Shigella antigens, are at earlier stages of clinical development. These formulations are being assessed in alignment with the WHO Preferred Product Characteristics, which call for a 1 to 2 dose primary immunization series given during the first 12 months of life, ideally starting at 6 months of age. This 'Vaccine Value Profile' (VVP) for Shigella is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the Shigella VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Kawsar Talaat reports a relationship with LimmaTech Biologics AG that includes funding grants., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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15. Exploring Shigella vaccine priorities and preferences: Results from a mixed-methods study in low- and middle-income settings.
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Fleming JA, Gurley N, Knudson S, Kabore L, Bawa JT, Dapaah P, Kumar S, Uranw S, Tran T, Mai LTP, Odero C, Obong'o C, Aburam K, Wanjiru S, Hanh NTM, Dung LP, and Hausdorff WP
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Background: Shigella is the leading bacterial cause of diarrheal mortality in children and can cause long-term effects on growth and development. No licensed Shigella vaccines currently exist but several promising candidates are in development and could be available in the next five years. Despite Shigella being a well-known public health target of the World Health Organization for decades, given current burden estimates and competing preventable disease priorities in low-income settings, whether the availability of an effective Shigella vaccine will lead to its prioritization and widespread introduction among countries at highest risk is unknown., Methods: We conducted a mixed-methods study of national stakeholders and healthcare providers in five countries in Asia and Africa and regional stakeholders in the Pan American Health Organization to identify preferences and priorities for forthcoming Shigella vaccines., Results: In our study of 89 individuals, diarrhea was the most frequently mentioned serious health concern for children under five years. Antimicrobial resistance (AMR) was more often considered very concerning than diarrhea or stunting. Shigella awareness was high but not considered a serious health concern by most stakeholders. Most participants were willing to consider adding a new vaccine to the routine immunization schedule but expressed reservations about a Shigella vaccine because of lower perceived burden relative to other preventable diseases and an already crowded schedule; interest was highest among national stakeholders in countries receiving more financial support for immunization. The priority of a Shigella vaccine rose when participants considered vaccine impacts on reducing stunting and AMR. Participants strongly preferred oral and combination vaccines compared to injectable and a single-antigen presentations, citing greater perceived community acceptability., Conclusions: This study provides a critical opportunity to hear directly from country and regional stakeholders about health priorities and preferences around new vaccines. These findings should inform ongoing Shigella vaccine development efforts and eventual vaccine introduction and implementation planning., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessica A Fleming, Nikki Gurley, Sophia Knudson, Lassane Kabore, John Tanko Bawa, Patience Dapaah, Sandeep Kumar, Thang Tran, Chris Odero, Christopher Obong’o, Kofi Aburam, Stella Wanjiru, and William P Hausdorff report financial support was provided by Wellcome Trust and financial support and article publishing charges were provided by Bill & Melinda Gates Foundation.., (© 2023 The Author(s).)
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- 2023
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16. Projecting the long-term economic benefits of reducing Shigella-attributable linear growth faltering with a potential vaccine: a modelling study.
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Puett C, Anderson JD 4th, Bagamian KH, Muhib F, Scheele S, Hausdorff WP, and Pecenka C
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- Child, Humans, Diarrhea epidemiology, Growth Disorders epidemiology, Child Development, Cost-Benefit Analysis, Vaccines, Shigella
- Abstract
Background: Linear growth is an important outcome of child development with implications for economic productivity. Enteric infections, particularly Shigella, have been linked to linear growth faltering (LGF). However, benefits from potential reductions in LGF are rarely included in economic analyses of enteric infections. We aimed to quantify the economic benefits of vaccination related to reduced Shigella-attributable disease and associated LGF compared with the net costs of a vaccine programme., Methods: In this benefit-cost analysis, we modelled productivity benefits in 102 low-income and middle-income countries that had recent stunting estimates available, at least one Shigella-attributable death annually, and available economic data, particularly on gross national income and growth rate projections. We modelled benefits strictly related to linear growth improvements and no other benefits associated with reducing diarrhoeal burden. The effect size in each country was calculated as shifts in height-for-age Z score (HAZ), representing population average changes for preventing Shigella-attributable less-severe diarrhoea and moderate-to-severe diarrhoea separately for children younger than 5 years. Benefits data were calculated per country and combined with estimated net costs of the vaccine programme in the form of benefit-cost ratios (BCRs); BCRs above parity, or $1 in benefits per $1 in costs (with a 10% margin representing borderline results: 1·10:1), were considered cost-beneficial. Countries were aggregated for analysis by WHO region, World Bank income category, and eligibility for support from Gavi, the Vaccine Alliance., Findings: In the base-case scenario, all regions exhibited cost-beneficial results, with the South-East Asia region and Gavi-eligible countries exhibiting the highest BCRs (21·67 for the South-East Asia region and 14·45 for Gavi-eligible countries), and the Eastern Mediterranean region yielding the lowest BCRs (2·90). All regions exhibited cost-beneficial results from vaccination, except in more conservative scenarios (eg, those assuming early retirement ages and higher discount rates). Our findings were sensitive to assumed returns for increased height, assumptions about vaccine efficacy against linear growth detriments, the anticipated shift in HAZ, and discount rate. Incorporating the productivity benefits of LGF reduction into existing cost-effectiveness estimates resulted in longer-term cost-savings in nearly all regions., Interpretation: LGF is a secondary outcome of Shigella infection and reduction in LGF is not often quantified as a health or economic benefit of vaccination. However, even under conservative assumptions, a Shigella vaccine only moderately effective against LGF could pay for itself from productivity gains alone in some regions. We recommend that LGF be considered in future models assessing the economic and health impacts of interventions preventing enteric infections. Further research is needed on vaccine efficacy against LGF to inform such models., Funding: Bill & Melinda Gates Foundation, Wellcome Trust., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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17. Potential impact and cost-effectiveness of Shigella vaccination in 102 low-income and middle-income countries in children aged 5 years or younger: a modelling study.
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Anderson JD 4th, Bagamian KH, Pecenka CJ, Muhib F, Puett CA, Hausdorff WP, and Scheele S
- Subjects
- Humans, Child, Infant, Cost-Benefit Analysis, Diarrhea epidemiology, Diarrhea prevention & control, Diarrhea complications, Vaccination, Growth Disorders, Developing Countries, Shigella
- Abstract
Background: Vaccine impact and cost-effectiveness models have mostly focused on acute burden. Shigella-attributable moderate-to-severe diarrhoea has been shown to be associated with childhood linear growth faltering. Evidence also links less severe diarrhoea to linear growth faltering. As Shigella vaccines are in late stages of clinical development, we aimed to estimate the potential impact and cost-effectiveness of vaccination against Shigella burden that includes stunting and the acute burden attributable to less severe diarrhoea and moderate-to-severe diarrhoea., Methods: We used a simulation model to estimate Shigella burden and potential vaccination in children aged 5 years or younger from 102 low-income to middle-income countries from 2025 to 2044. Our model included stunting associated with Shigella-related moderate-to-severe diarrhoea and less severe diarrhoea and we explored vaccination impact on health and economic outcomes., Findings: We estimate 109 million (95% uncertainty interval [UI] 39-204) Shigella-attributable stunting cases and 1·4 million (0·8-2·1) deaths in unvaccinated children over 20 years. We project that Shigella vaccination could avert 43 million (13-92) stunting cases and 590 000 (297 000-983 000) deaths over 20 years. The overall mean incremental cost-effectiveness ratio (ICER) was US$849 (95% uncertainty interval 423-1575; median $790 [IQR 635-1005]) per disability-adjusted life-year averted. Vaccination was most cost-effective in the WHO African region and in low-income countries. Including the burden of Shigella-related less severe diarrhoea improved mean ICERs by 47-48% for these groups and substantially improved ICERs for other regions., Interpretation: Our model suggests that Shigella vaccination would be a cost-effective intervention, with a substantial impact in specific countries and regions. Other regions could potentially benefit upon the inclusion of the burden of Shigella-related stunting and less severe diarrhoea in the analysis., Funding: Bill & Melinda Gates Foundation and Wellcome Trust., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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18. Challenges and opportunities in developing a Shigella-containing combination vaccine for children in low- and middle-income countries: Report of an expert convening.
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Riddle MS, Louis Bourgeois A, Clifford A, Jeon S, Giersing BK, Jit M, Tufet Bayona M, Ovitt J, and Hausdorff WP
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- Infant, Child, Humans, Developing Countries, Diarrhea prevention & control, Vaccines, Combined, Shigella Vaccines, Dysentery, Bacillary, Escherichia coli Infections prevention & control, Enterotoxigenic Escherichia coli, Shigella
- Abstract
The gram-negative bacterium Shigella is an enteric pathogen responsible for significant morbidity and mortality due primarily to severe diarrhea and dysentery, mainly among children younger than five years of age living in low- and middle-income countries (LMICs). Long considered a priority target for vaccine development, recent scientific advances have led to a number of promising Shigella vaccine candidates now entering advanced stages of clinical testing. Yet, there is no guarantee that even a highly efficacious Shigella vaccine will be recommended, prioritized, purchased, and widely adopted-especially if it requires additional doses in the immunization schedule and/or visits within the immunization program. This uncertainty is due to a variety of factors, including continuing declines in Shigella-specific and overall diarrheal disease mortality rates, the increasing complexity and cost of infant immunization programs in LMICs, and the recent availability of other high-priority vaccines. Since combining a Shigella vaccine with an existing infant vaccine would conceivably increase its attractiveness, there is a need to systematically consider the challenges determining the public health value, clinical development, manufacturing, licensure, policy recommendations, and financing for a Shigella-containing combination vaccine. The international non-governmental health organization PATH convened an independent panel of 34 subject matter experts across academic, industry, philanthropic, and global health sectors to discuss hypothetical combinations of a notional parenteral Shigella vaccine with three existing vaccines in order to begin exploring the challenges associated with their development. The resulting insights and recommendations from this meeting contribute to PATH's broader effort to evaluate the public health value of potential Shigella vaccines. They may also help guide future combination vaccine development efforts more broadly., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark S. Riddle reports financial support was provided by PATH. Mark S. Riddle reports a relationship with LimmaTech Biologics AG that includes: consulting or advisory. Jared Ovitt reports financial support was provided by PATH., (Copyright © 2023.)
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- 2023
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19. Potential impact and cost-effectiveness of injectable next-generation rotavirus vaccines in 137 LMICs: a modelling study.
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Debellut F, Pecenka C, Hausdorff WP, and Clark A
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- Child, Cost-Benefit Analysis, Developing Countries, Humans, Immunization Programs, Infant, Infant, Newborn, Vaccination, Rotavirus, Rotavirus Infections prevention & control, Rotavirus Vaccines
- Abstract
While current live, oral rotavirus vaccines (LORVs) are reducing severe diarrhea everywhere, their effectiveness is lower in high burden settings. Alternative approaches are in advanced stages of clinical development, including injectable next-generation rotavirus vaccine (iNGRV) candidates, which have the potential to better protect children, be combined with existing routine immunizations and be more affordable than current LORVs. In an effort to better understand the real public health value of iNGRVs and to help inform decisions by international agencies, funders, and vaccine manufacturers, we conducted an impact and cost-effectiveness analysis examining 20 rotavirus vaccine use cases. We evaluated several currently licensed LORVs, one neonatal oral NGRV (oNGRV), one iNGRV, and one iNGRV-DTP (iNGRV comprising part of a DTP-containing combination) over a ten-year timeframe in 137 low- and middle-income countries. The most promising use case identified was a high efficacy iNGRV-DTP, predicted to have the lowest vaccine program cost (US$1.4 billion), the highest vaccine benefit (750,000 rotavirus deaths averted, 13 million rotavirus hospital admissions averted, US$ 2.7 billion health-care cost averted), and most favorable cost-effectiveness (cost-saving). iNGRV-DTP vaccine remained the most affordable, safe, and cost-effective option even when it was assumed to have equivalent efficacy to the current LORVs. This study shows that while the development of iNGRVs with superior efficacy to currently licensed LORVs would be ideal, iNGRVs with similar efficacy to LORVs would offer substantial public health value. It also highlights the economic value of accelerating the development of DTP-based combination vaccines that include iNGRV to provide rotavirus protection.
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- 2022
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20. The Challenges and Opportunities of Next-Generation Rotavirus Vaccines: Summary of an Expert Meeting with Vaccine Developers.
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Chen J, Grow S, Iturriza-Gómara M, Hausdorff WP, Fix A, and Kirkwood CD
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- Child, Humans, Cost of Illness, Vaccines, Combined, Rotavirus Vaccines, Rotavirus Infections prevention & control, Rotavirus genetics
- Abstract
The 2nd Next Generation Rotavirus Vaccine Developers Meeting, sponsored by PATH and the Bill and Melinda Gates Foundation, was held in London, UK (7-8 June 2022), and attended by vaccine developers and researchers to discuss advancements in the development of next-generation rotavirus vaccines and to consider issues surrounding vaccine acceptability, introduction, and uptake. Presentations included updates on rotavirus disease burden, the impact of currently licensed oral vaccines, various platforms and approaches for next generation rotavirus vaccines, strategies for combination pediatric vaccines, and the value proposition for novel parenteral rotavirus vaccines. This report summarizes the information shared at the convening and poses various topics worthy of further exploration.
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- 2022
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21. Healthcare provider perspectives on delivering next generation rotavirus vaccines in five low-to-middle-income countries.
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Mooney J, Price J, Bain C, Bawa JT, Gurley N, Kumar A, Liyanage G, Mkisi RE, Odero C, Seck K, Simpson E, and Hausdorff WP
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- Developing Countries, Health Personnel, Humans, Infant, Infant, Newborn, Rotavirus, Rotavirus Infections epidemiology, Rotavirus Vaccines
- Abstract
Background: Live oral rotavirus vaccines (LORVs) have significantly reduced rotavirus hospitalizations and deaths worldwide. However, LORVs are less effective in low- and middle-income countries (LMICs). Next-generation rotavirus vaccines (NGRVs) may be more effective but require administration by injection or a neonatal oral dose, adding operational complexity. Healthcare providers (HPs) were interviewed to assess rotavirus vaccine preferences and identify delivery issues as part of an NGRV value proposition., Objective: Determine HP vaccine preferences about delivering LORVs compared to injectable (iNGRV) and neonatal oral (oNGRV) NGRVs., Methods: 64 HPs from Ghana, Kenya, Malawi, Peru, and Senegal were interviewed following a mixed-method guide centered on three vaccine comparisons: LORV vs. iNGRV; LORV vs. oNGRV; oNGRV vs. iNGRV. HPs reviewed attributes for each vaccine in the comparisons, then indicated and explained their preference. Additional questions elicited views about co-administering iNGRV+LORV for greater public health impact, a possible iNGRV-DTP-containing combination vaccine, and delivering neonatal doses., Results: Almost all HPs preferred oral vaccine options over iNGRV, with many emphasizing an aversion to additional injections. Despite this strong preference, HPs described challenges delivering oral doses. Preferences for LORV vs. oNGRV were split, marked by disparate views on rotavirus disease epidemiology and the safety, need, and feasibility of delivering neonatal vaccines. Although overwhelmingly enthusiastic about an iNGRV-DTP-containing combination option, several HPs had concerns. HP views were divided on the feasibility of co-administering iNGRV+LORV, citing challenges around logistics and caregiver sensitization., Conclusion: Our findings provide valuable insights on delivering NGRVs in routine immunization. Despite opposition to injectables, openness to co-administering LORV+iNGRV to improve efficacy suggests future HP support of iNGRV if adequately informed of its advantages. Rationales for LORV vs. oNGRV underscore needs for training on rotavirus epidemiology and stronger service integration. Expressed challenges delivering existing LORVs merit further examination and indicate need for improved delivery., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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22. What Drives the Value of a Shigella Vaccine?
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Hausdorff WP, Scheele S, and Giersing BK
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The development and licensure of a safe and highly efficacious Shigella vaccine has been a priority in international public health circles for decades and would represent a great scientific achievement. Nonetheless, in the context of increasingly crowded and costly childhood immunization programs, and with a myriad of other new and improved vaccines currently or soon on the market, there is no guarantee that even a highly effective Shigella vaccine would become a priority for adoption and introduction by the low- and middle-income countries that could benefit from it the most. We discuss here some of the major determinants and questions regarding the introduction of Shigella vaccines and the importance of developing a succinct, compelling public health value proposition.
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- 2022
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23. National stakeholder preferences for next-generation rotavirus vaccines: Results from a six-country study.
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Price J, Mooney J, Bain C, Bawa JT, Gurley N, Kumar A, Liyanage G, Mkisi RE, Odero C, Seck K, Simpson E, and Hausdorff WP
- Subjects
- Hospitalization, Humans, Infant, Infant, Newborn, Poverty, Rotavirus, Rotavirus Infections prevention & control, Rotavirus Vaccines
- Abstract
Background: Currently available live, oral rotavirus vaccines (LORVs) have significantly reduced severe rotavirus hospitalizations and deaths worldwide. However, LORVs are not as effective in low- and middle-income countries (LMIC) where rotavirus disease burden is highest. Next-generation rotavirus vaccine (NGRV) candidates in development may have a greater public health impact where they are needed most. The feasibility and acceptability of possible new rotavirus vaccines were explored as part of a larger public health value proposition for injectable NGRVs in LMICs., Objective: To assess national stakeholder preferences for currently available LORVs and hypothetical NGRVs and understand rationales and drivers for stated preferences., Methods: Interviews were conducted with 71 national stakeholders who influence vaccine policy and national programming. Stakeholders from Ghana, Kenya, Malawi, Peru, Senegal, and Sri Lanka were interviewed using a mixed-method guide. Vaccine preferences were elicited on seven vaccine comparisons involving LORVs and hypothetical NGRVs based on information presented comparing the vaccines' attributes. Reasons for vaccine preference were elicited in open-ended questions, and the qualitative data were analyzed on key preference drivers., Results: Nearly half of the national stakeholders interviewed preferred a highly effective standalone, injectable NGRV over current LORVs. When presented as having similar efficacy to the LORV, however, very few stakeholders preferred the injectable NGRV, even at substantially lower cost. Similarly, a highly effective standalone injectable NGRV was generally not favored over an equally effective oral NGRV following a neonatal-infant schedule, despite higher cost of the neonatal option. An NGRV-DTP-containing combination vaccine was strongly preferred over all other options, whether delivered alone with efficacy similar to current LORVs or co-administered alongside an LORV (LORV + NGRV-DTP) to increase efficacy., Conclusion: Results from these national stakeholder interviews provide valuable insights to inform ongoing and future NGRV research and development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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24. Does Anybody Want an Injectable Rotavirus Vaccine, and Why? Understanding the Public Health Value Proposition of Next-Generation Rotavirus Vaccines.
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Hausdorff WP, Price J, Debellut F, Mooney J, Torkelson AA, Giorgadze K, and Pecenka C
- Abstract
Routine infant immunization with live, oral rotavirus vaccines (LORVs) has had a major impact on severe gastroenteritis disease. Nevertheless, in high morbidity and mortality settings rotavirus remains an important cause of disease, partly attributable to the sub-optimal clinical efficacy of LORVs in those settings. Regardless of the precise immunological mechanism(s) underlying the diminished efficacy, the introduction of injectable next-generation rotavirus vaccines (iNGRV), currently in clinical development, could offer a potent remedy. In addition to the potential for greater clinical efficacy, precisely how iNGRVs are delivered (multiple doses to young infants; alongside LORVs or as a booster; co-formulated with Diphtheria-Tetanus-Pertussis (DTP)-containing vaccines), their pricing, and their storage and cold chain characteristics could each have major implications on the resultant health outcomes, on cost-effectiveness as well as on product preferences by national stakeholders and healthcare providers. To better understand these implications, we critically assessed whether there is a compelling public health value proposition for iNGRVs based on potential (but still hypothetical) vaccine profiles. Our results suggest that the answer is highly dependent on the specific use cases and potential attributes of such novel vaccines. Notably, co-formulation of iNGRVs with similar or greater efficacy than LORVs with a DTP-containing vaccine, such as DTP-Hib-HepB, scored especially high on potential impact, cost-effectiveness, and strength of preference by national stakeholders and health care providers in lower and middle income countries.
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- 2022
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25. Antimicrobial resistance in paediatric Streptococcus pneumoniae isolates amid global implementation of pneumococcal conjugate vaccines: a systematic review and meta-regression analysis.
- Author
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Andrejko K, Ratnasiri B, Hausdorff WP, Laxminarayan R, and Lewnard JA
- Subjects
- Anti-Bacterial Agents pharmacology, Cephalosporins pharmacology, Child, Drug Resistance, Bacterial, Humans, Macrolides pharmacology, Penicillins pharmacology, Pneumococcal Vaccines therapeutic use, Regression Analysis, Streptococcus pneumoniae, Sulfamethoxazole pharmacology, Tetracycline pharmacology, Trimethoprim pharmacology, Vaccines, Conjugate, Anti-Infective Agents pharmacology, Pneumococcal Infections drug therapy
- Abstract
Background: Pneumococcal diseases are a leading cause of morbidity and mortality among children globally, and the burden of these diseases might be worsened by antimicrobial resistance. To understand the effect of pneumococcal conjugate vaccine (PCV) deployment on antimicrobial resistance in pneumococci, we assessed the susceptibility of paediatric pneumococcal isolates to various antimicrobial drugs before and after PCV implementation., Methods: We did a systematic review of studies reporting antimicrobial susceptibility profiles of paediatric pneumococcal isolates between 2000 and 2020 using PubMed and the Antimicrobial Testing Leadership and Surveillance database (ATLAS; Pfizer). Population-based studies of invasive pneumococcal disease or nasopharyngeal colonisation were eligible for inclusion. As primary outcome measures, we extracted the proportions of isolates that were non-susceptible or resistant to penicillin, macrolides, sulfamethoxazole-trimethoprim, third-generation cephalosporins, and tetracycline from each study. Where available, we also extracted data on pneumococcal serotypes. We estimated changes in the proportion of isolates with reduced susceptibility or resistance to each antibiotic class using random-effects meta-regression models, adjusting for study-level and region-level heterogeneity, as well as secular trends, invasive or colonising isolate source, and countries' per-capita gross domestic product., Findings: From 4910 studies screened for inclusion, we extracted data from 559 studies on 312 783 paediatric isolates. Susceptibility of isolates varied substantially across regions both before and after implementation of any PCV product. On average across all regions, we estimated significant absolute reductions in the proportions of pneumococci showing non-susceptibility to penicillin (11·5%, 95% CI 8·6-14·4), sulfamethoxazole-trimethoprim (9·7%, 4·3-15·2), and third-generation cephalosporins (7·5%, 3·1-11·9), over the 10 years after implementation of any PCV product, and absolute reductions in the proportions of pneumococci resistant to penicillin (7·3%, 5·3-9·4), sulfamethoxazole-trimethoprim (16·0%, 11·0-21·2), third-generation cephalosporins (4·5%, 0·3-8·7), macrolides (3·6%, 0·7-6·6) and tetracycline (2·0%, 0·3-3·7). We did not find evidence of changes in the proportion of isolates non-susceptible to macrolides or tetracycline after PCV implementation. Observed changes in penicillin non-susceptibility were driven, in part, by replacement of vaccine-targeted serotypes with non-vaccine serotypes that were less likely to be non-susceptible., Interpretation: Implementation of PCVs has reduced the proportion of circulating pneumococci resistant to first-line antibiotic treatments for pneumonia. This effect merits consideration in assessments of vaccine impact and investments in coverage improvements., Funding: Bill & Melinda Gates Foundation., Competing Interests: JAL has received grants and consulting fees from Pfizer and Merck Sharp & Dohme; and consulting fees from VaxCyte and Kaiser Permanente, unrelated to the submitted work. All other authors declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)
- Published
- 2021
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26. Leveraging Vaccines to Reduce Antibiotic Use and Prevent Antimicrobial Resistance: A World Health Organization Action Framework.
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Vekemans J, Hasso-Agopsowicz M, Kang G, Hausdorff WP, Fiore A, Tayler E, Klemm EJ, Laxminarayan R, Srikantiah P, Friede M, and Lipsitch M
- Subjects
- Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial, Humans, World Health Organization, Antimicrobial Stewardship, Vaccines
- Published
- 2021
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27. Hausdorff and Flores Author Reply to Letter to the Editor by Prof G. Bauer (THEIJID-D-21-00652).
- Author
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Hausdorff WP and Flores J
- Subjects
- Humans, COVID-19, SARS-CoV-2
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- 2021
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28. Low-dose and oral exposure to SARS-CoV-2 may help us understand and prevent severe COVID-19.
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Hausdorff WP and Flores J
- Subjects
- Humans, Public Health, Young Adult, COVID-19 prevention & control, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
- Abstract
Background: The effectiveness and sustainability of current public health interventions designed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission remain of great concern in many settings, especially in the absence of a transmission-preventing vaccine., Hypothesis: It was hypothesized that a more targeted set of interventions focusing on preventing severe coronavirus disease 2019 (COVID-19), rather than SARS-CoV-2 transmission, would be less disruptive to society. To identify these, it would be helpful to better understand how the infecting dose of SARS-CoV-2 and its route of infection influence the clinical outcome, immunological protection, and likelihood of onward transmission., Proposal: It is suggested that carefully controlled human infection model (CHIM) studies involving intranasal and oral administration of progressively increasing doses of SARS-CoV-2, starting with low levels, to healthy young adult volunteers may be the most expeditious and definitive way to answer these questions. Such studies would differ in objective from CHIM proposals designed to expedite vaccine development, although the latter might be adapted to address some of the questions raised here., Implications: Results from the studies proposed here could help elucidate the relationship of infection to COVID-19 and thereby provide a scientific basis for more targeted and sustainable application of public health control measures, and inform the design of improved immunotherapeutics and more targeted vaccine development., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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29. High levels of inherent variability in microbiological assessment of bronchoalveolar lavage samples from children with persistent bacterial bronchitis and healthy controls.
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Craven V, Hausdorff WP, and Everard ML
- Subjects
- Bronchoalveolar Lavage, Child, Preschool, Female, Humans, Infant, Intubation, Intratracheal, Male, Bacterial Infections microbiology, Bronchitis microbiology, Bronchoalveolar Lavage Fluid microbiology
- Abstract
Bronchoalveolar lavage (BAL) is widely regarded as providing "gold standard" samples for infective lower respiratory tract disease. Current approaches have been adopted empirically without robust assessment and hence carry many assumptions that have not been tested. Many of these uncertainties were highlighted in the ATS pediatric bronchoscopy guidelines. This study was designed to explore some of these issues. BAL was undertaken via an endotracheal tube in 13 subjects aged less than 6 years with persistent bacterial bronchitis and five healthy controls. Aliquots of the same pooled BAL sample were sent to two accredited laboratories. one producing semiquantitative results and the other quantitative results. For five patients potentially pathogenic bacteria were grown by one laboratory but not the other, while in three more there were discrepancies in the organisms reported. Despite being symptomatic and off antibiotics, only 3 of 13 patients were reported to have a pathogen at a density of more than 1 × 10
4 colony forming unit. There was at best a poor correlation between semiquantitative and quantitative data. Potential pathogens were cultured in two of five control samples. The results suggest that the results from conventional microbiological assessment of BAL samples can be highly variable and that the proposal that a discrete cut-off is of value in patients with chronic endobronchial infection is probably invalid., (© 2020 Wiley Periodicals LLC.)- Published
- 2020
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30. Effect of vaccination on the use of antimicrobial agents: a systematic literature review.
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Doherty TM, Hausdorff WP, and Kristinsson KG
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antimicrobial Stewardship, Child, Child, Preschool, Drug Resistance, Bacterial drug effects, Humans, Infant, Middle Aged, Young Adult, Anti-Bacterial Agents therapeutic use, Influenza Vaccines administration & dosage, Pneumococcal Vaccines administration & dosage, Practice Patterns, Physicians' statistics & numerical data
- Abstract
Background: Antimicrobial resistance is a growing global health threat. To preserve the effectiveness of antimicrobials, it is important to reduce demand for antimicrobials., Objectives: The objective of the study was to screen the existing peer-reviewed literature to identify articles that addressed the potential impact of influenza or Pneumococcus vaccination on antibiotic usage. Data sources: PubMed, Embase Study eligibility criteria: Clinical studies where antimicrobial prescribing was assessed in both vaccinated and unvaccinated populations. Participants and interventions: All patient populations were included (infants, children, adults and elderly), where the effects of the intervention (vaccination) was assessed., Results: We identified unique 3638 publications, of which 26 were judged to be of sufficiently high quality to allow the calculation of the potential impact of vaccination. Of these studies 23/26 found a significant reduction in antibiotic use by at least one of the parameters assessed., Limitations: Different measures used to define anti-microbial use, studies typically focus on specific risk groups and most studies are from high-income countries. Conclusions and implications of key findings: Despite the limitations of the review, the evidence indicates that improved coverage with existing vaccines may significantly reduce antimicrobial demand. This suggests it may be a valuable tool for antimicrobial stewardship. Key messages While vaccines against a number of pathogens have been studied for their ability to reduce antimicrobial use, currently only vaccination against influenza or pneumococcus has generated sufficient data for analysis Vaccination against either influenza or pneumococcus significantly reduced overall antimicrobial prescribing rates, both in vaccinated individuals and at a population level Maintaining and expanding vaccination coverage thus appears to be a key tool for antimicrobial stewardship.
- Published
- 2020
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31. Geographical variability in anticapsular IgG levels elicited by pneumococcal conjugate vaccines: Implications for clinical protection?
- Author
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Hausdorff WP
- Subjects
- Humans, Immunoglobulin G, Vaccines, Conjugate, Pneumococcal Infections, Pneumococcal Vaccines
- Published
- 2020
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32. Pneumococcal conjugate vaccines in different settings.
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Hausdorff WP
- Subjects
- Humans, Serogroup, Vaccines, Conjugate, Pneumococcal Infections, Pneumococcal Vaccines
- Published
- 2019
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33. The choice of analytical methodology can alter conclusions regarding herd effects of paediatric pneumococcal vaccination programmes.
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Pirçon JY, Talarico CA, Bollaerts K, Hausdorff WP, and Clarke CJ
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- Aged, Aged, 80 and over, Australia epidemiology, Biostatistics methods, Europe epidemiology, Female, Health Services Research methods, Humans, Incidence, Interrupted Time Series Analysis, Male, Pneumococcal Vaccines administration & dosage, United States epidemiology, Bacteremia epidemiology, Bacteremia prevention & control, Epidemiologic Methods, Immunity, Herd, Meningitis, Pneumococcal epidemiology, Meningitis, Pneumococcal prevention & control, Pneumococcal Vaccines immunology
- Abstract
Background: Estimation of the magnitude of the herd effect on invasive pneumococcal disease (IPD) is important when evaluating health benefits and cost-effectiveness of paediatric pneumococcal conjugate vaccine (PCV) programmes and may influence policy makers' decisions on PCV use. Several epidemiological, programmatic, and immunological factors can affect the magnitude of the PCV herd effect. We investigated to what extent the choice of analytical methodology may also influence herd effect estimates., Methods: To estimate the magnitude of the herd effect from paediatric PCV programmes, we examined overall IPD incidence rates in ≥65-year-olds from Finland, Australia, England/Wales, and the United States under different analytical scenarios. We used two different statistical methods: before/after comparison of average IPD incidence rates and interrupted time series (ITS) analysis accounting for underlying time trends. We also investigated how varying the length of the pre- and post-PCV analysis periods influenced the outcomes., Results: The estimated impact of paediatric PCV programmes on IPD incidence rates in adults ≥65 years varied substantially across the different scenarios within each country. The choice of statistical method and analysis periods contributed to this variation, and their influence varied by setting. For the datasets from England/Wales and the United States, the different scenarios produced relatively minor variation in estimated impact. For the Australian and Finnish datasets, differences were more prominent. In particular, for Finland, opposite conclusions could be drawn depending on the methodology: while no estimated herd effect was seen with the before/after method, a herd effect was evident with the ITS method., Conclusions: The choice of statistical method and analysis periods can substantially influence the magnitude of estimated herd effects from paediatric PCV programmes. It is important to consider the reliability and presence of pre-PCV patterns in the IPD surveillance data used for analysis, the methodology and associated assumptions used to estimate herd effects., (Copyright © 2018 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2018
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34. Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.
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Jokinen J, Snellman M, Palmu AA, Saukkoriipi A, Verlant V, Pascal T, Devaster JM, Hausdorff WP, and Kilpi TM
- Subjects
- Aged, Aged, 80 and over, Bacteriological Techniques statistics & numerical data, Community-Acquired Infections diagnosis, Community-Acquired Infections microbiology, Community-Acquired Infections prevention & control, Female, Finland epidemiology, Humans, Latent Class Analysis, Male, Pneumonia, Pneumococcal microbiology, Pneumonia, Pneumococcal prevention & control, Sensitivity and Specificity, Streptococcus pneumoniae immunology, Treatment Outcome, Bacteriological Techniques methods, Pneumococcal Vaccines therapeutic use, Pneumonia, Pneumococcal diagnosis, Streptococcus pneumoniae growth & development
- Abstract
Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumonia Epidemiology study during 2005-2007. Compared with the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of pneumococcal etiology for each CAP case based on individual test profiles, and we used the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared with the conventional laboratory criteria of encapsulated pneumococci in culture, in blood culture or high-quality sputum culture, or urine antigen positivity, our optimized case definition for pneumococcal CAP resulted in a trial sample size that was almost 20,000 subjects smaller. We believe that the novel application of LCA detailed here to determine a case definition for pneumococcal CAP could also be similarly applied to other diseases without a gold standard.
- Published
- 2018
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35. lytA Quantitative PCR on Sputum and Nasopharyngeal Swab Samples for Detection of Pneumococcal Pneumonia among the Elderly.
- Author
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Saukkoriipi A, Palmu AA, Pascal T, Verlant V, Hausdorff WP, and Jokinen J
- Subjects
- Aged, Aged, 80 and over, Community-Acquired Infections diagnosis, Diagnostic Tests, Routine, Female, Finland, Humans, Male, Sensitivity and Specificity, Streptococcus pneumoniae genetics, Nasopharynx microbiology, Pneumonia, Pneumococcal diagnosis, Real-Time Polymerase Chain Reaction, Sputum microbiology
- Abstract
Real-time quantitative PCR (qPCR) assay of sputum or nasopharyngeal specimens has shown promising results in the detection of pneumococcal community-acquired pneumonia (PncCAP). We applied qPCR for the autolysin gene ( lytA ) and compared sputum and nasopharyngeal swab (NPS) pneumococcal loads in elderly patients with community-acquired pneumonia (CAP), and specifically in patients with PncCAP, to those in patient groups with other respiratory diseases. We studied patients aged ≥65 years with radiologically confirmed CAP, clinical CAP not retrospectively radiologically confirmed, other acute respiratory infections, or stable chronic lung disease. Pneumococcal etiology of CAP was ascertained by using a combination of multiple diagnostic methods. We analyzed sputum and NPS specimens by lytA qPCR with 10
4 pneumococcal genome equivalents (GE)/ml as a cutoff for positivity. Among PncCAP patients, lytA qPCR detected pneumococci in 94% of the sputum samples and in large quantities (mean, 6.82 ± 1.02 log10 GE/ml) but less frequently in NPS (44%) and in smaller quantities (5.55 ± 0.92 log10 GE/ml). In all other patient groups, ≤10% of the sputum samples and <5% of the NPS samples were lytA qPCR positive; but when they were positive, the sputum pneumococcal loads were similar to those in the PncCAP patients, suggesting a pneumococcal etiology in these patients. This was supported by other pneumococcal assay results. Overall, sputum lytA qPCR positivity was more common in PncCAP patients than in the other patient groups, but the quantitative results were mainly similar. NPS lytA qPCR was less sensitive than sputum lytA qPCR in detecting PncCAP., (Copyright © 2017 Saukkoriipi et al.)- Published
- 2017
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36. What is the heterogeneity in the impact seen with pneumococcal conjugate vaccines telling us?
- Author
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Hausdorff WP and Black S
- Subjects
- Age Factors, Geography, Humans, Pneumococcal Vaccines administration & dosage, Vaccines, Conjugate administration & dosage, Vaccines, Conjugate immunology, Pneumococcal Infections prevention & control, Pneumococcal Vaccines immunology
- Abstract
Pneumococcal conjugate vaccines have proven highly effective in decreasing invasive disease and pneumonia in young children. However, there is considerable geographic variability in the impact of these vaccines on other disease endpoints and in other age groups. Investigation of the possible causes of this variability would greatly improve our understanding of pneumococcal pathophysiology and stimulate the effort to design more broadly effective vaccines., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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37. Efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and nasopharyngeal carriage in Panamanian children - A randomized controlled trial.
- Author
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Sáez-Llorens X, Rowley S, Wong D, Rodríguez M, Calvo A, Troitiño M, Salas A, Vega V, Castrejón MM, Lommel P, Pascal TG, Hausdorff WP, Borys D, Ruiz-Guiñazú J, Ortega-Barría E, Yarzabal JP, and Schuerman L
- Subjects
- Double-Blind Method, Ear, Middle microbiology, Exudates and Transudates microbiology, Female, Follow-Up Studies, Haemophilus Vaccines administration & dosage, Humans, Infant, Male, Nasopharynx microbiology, Panama, Pneumococcal Vaccines administration & dosage, Treatment Outcome, Bacterial Proteins immunology, Carrier Proteins immunology, Carrier State prevention & control, Haemophilus Infections prevention & control, Haemophilus Vaccines immunology, Immunoglobulin D immunology, Lipoproteins immunology, Otitis Media prevention & control, Pneumococcal Infections prevention & control, Pneumococcal Vaccines immunology
- Abstract
We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.
- Published
- 2017
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38. Etiology of Acute Otitis Media in Children Less Than 5 Years of Age: A Pooled Analysis of 10 Similarly Designed Observational Studies.
- Author
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Van Dyke MK, Pirçon JY, Cohen R, Madhi SA, Rosenblüt A, Macias Parra M, Al-Mazrou K, Grevers G, Lopez P, Naranjo L, Pumarola F, Sonsuwan N, and Hausdorff WP
- Subjects
- Acute Disease epidemiology, Anti-Bacterial Agents pharmacology, Child, Preschool, Cohort Studies, Female, Haemophilus Infections epidemiology, Haemophilus Infections microbiology, Haemophilus influenzae drug effects, Haemophilus influenzae isolation & purification, Humans, Infant, Male, Microbial Sensitivity Tests, Otitis Media epidemiology, Pneumococcal Infections epidemiology, Pneumococcal Infections microbiology, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae isolation & purification, Otitis Media microbiology, Vaccination statistics & numerical data
- Abstract
Background: Acute otitis media (AOM) is an important cause of childhood morbidity and antibiotic prescriptions. However, the relative importance of the well-known otopathogens, Streptococcus pneumoniae (Spn) and Haemophilus influenzae (Hflu), remains unclear because of a limited number of tympanocentesis-based studies that vary significantly in populations sampled, case definitions and heptavalent pneumococcal conjugate vaccine use., Methods: We conducted a pooled analysis of results from 10 AOM etiology studies of similar design, the protocols of which were derived from a common protocol and conducted in children 3 months to 5 years of age in different countries. Generalized estimating equations were used to account for within-study correlations., Results: The majority, 55.5% (95% confidence interval: 47.0%-65.7%) of 1124 AOM episodes, were bacterial pathogen positive: 29.1% (24.8%-34.1%) yielded Hflu and 23.6% (19.0%-29.2%) Spn. Proportions of Hflu and Spn were higher and lower, respectively, in heptavalent pneumococcal conjugate vaccine-vaccinated children. Hflu and Spn were each isolated from 20% to 35% of children in every 1-year age range. Hflu was less likely to be isolated from first (vs. subsequent) episodes [relative risk (RR): 0.71 (0.60-0.84)]. Spn was more often isolated from sporadic (vs. recurrent) cases [RR: 0.76 (0.61-0.97)]; the opposite was true for Hflu [RR: 1.4 (1.00-1.96)]. Spn cases were more likely to present with severe (vs. mild) symptoms [RR: 1.42 (1.01-2.01)] and Hflu cases with severe tympanic membrane inflammation [RR: 1.35 (1.06-1.71)]., Conclusions: Spn and Hflu remain the leading otopathogens in all populations examined. While associated with overlapping symptoms and severity, they exhibit some differences in their likelihood to cause disease in specific subpopulations.
- Published
- 2017
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39. Healthcare-seeking behaviour of primary caregivers for acute otitis media in children aged 6 months to <30 months in Panama: results of a cross-sectional survey.
- Author
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Villarreal I, Turner R, Jo H, Park J, Gemmen E, Pirçon JY, Castrejon MM, and Hausdorff WP
- Subjects
- Acute Disease, Adult, Child, Preschool, Cross-Sectional Studies, Female, Humans, Incidence, Infant, Male, Otitis Media epidemiology, Panama epidemiology, Severity of Illness Index, Surveys and Questionnaires, Urban Population, Caregivers psychology, Otitis Media therapy, Patient Acceptance of Health Care
- Abstract
Background: Acute otitis media (AOM) is the most common bacterial childhood infection. However, caregivers with children having mild episodes often do not seek healthcare services, which may lead to an under-appreciation of the disease experienced by the community. The objectives of this survey were to estimate the proportion of primary caregivers who went to a healthcare facility when they suspected that their child aged 6 to <30 months was having an AOM episode during the past 6 months and to assess what factors influenced their decision., Methods: This observational, cross-sectional survey of primary caregivers (≥18 years), with at least one child aged 6 to <30 months was performed in 19 healthcare facilities in Panama (March to May 2013). A 28-item paper questionnaire was administered to assess demographic data, AOM symptoms, as well as potential healthcare-seeking behaviour and factors influencing this behaviour. Potential confounding effects were individually assessed using Chi-squared or Cochran-Mantel-Haenszel tests, and all together in logistic regression models., Results: The total number of eligible participants was 1330 (mean age 28.5 ± 8.0 years). Of these, 245 participants had at least one child whom they suspected had an AOM episode during the past 6 months. Of the 245 participants, 213 (86.9%) sought healthcare at a facility. Several factors were associated with healthcare usage: perceived severity of illness (p = 0.001), occupational status of the caregiver (p = 0.002), household income (p = 0.016) and length of time since the last suspected AOM episode (p = 0.032)., Conclusions: When confronted with a child with obvious symptoms of AOM, the majority of caregivers reported seeking healthcare. This behaviour appeared to be associated with factors related to the severity of the illness, the length of time since the last episode, as well as with the income and occupational status of the caregivers themselves. As many episodes of AOM present with non-specific respiratory symptoms, our results apply only to caregivers who were confronted with children with an obvious symptom.
- Published
- 2017
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40. Epidemiology of invasive pneumococcal disease in Saudi Arabian children younger than 5years of age.
- Author
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Almazrou Y, Shibl AM, Alkhlaif R, Pirçon JY, Anis S, Kandeil W, and Hausdorff WP
- Subjects
- Child, Preschool, Drug Resistance, Multiple, Female, Haemophilus influenzae drug effects, Humans, Incidence, Infant, Infant, Newborn, Male, Prospective Studies, Saudi Arabia epidemiology, Streptococcus pneumoniae drug effects, Anti-Bacterial Agents therapeutic use, Haemophilus influenzae isolation & purification, Pneumococcal Infections drug therapy, Pneumococcal Infections epidemiology, Pneumococcal Vaccines therapeutic use, Streptococcus pneumoniae isolation & purification
- Abstract
This study evaluated the incidence, serotype distribution, and antimicrobial susceptibility of invasive pneumococcal disease (IPD) in Saudi Arabian children. This multicenter, prospective, clinical surveillance study included children under 5years of age, residents of one of the seven study health areas, who were brought to a study hospital with suspicion of IPD. Bacterial isolates from sterile site samples, collected less than 24h after hospital visit/admission, were identified, serotyped, and tested for antibiotic susceptibility. Between June 2007 and January 2009, 631 episodes of suspected IPD were recorded, and 623 were included in the analysis. One child (0.2%) had previously received one dose of a pneumococcal vaccine. Forty-seven episodes were positive for Streptococcus pneumoniae and three for Haemophilus influenzae. The incidence of confirmed IPD cases was estimated to be 2.5-21.6 per 100,000 children (<5years). Among the 46 S. pneumoniae isolates serotyped and tested for antibiotic susceptibility, the most common serotypes were 5 and 23F (20% each), 6B (17%), and 1 and 14 (11% each). Sixty-three percent of isolates were multidrug-resistant. Vaccination of Saudi Arabian children with expanded-coverage conjugate pneumococcal vaccines containing serotypes 1 and 5 could have a substantial impact to prevent IPD in this population., (Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2016
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41. Impact of the introduction of the pneumococcal conjugate vaccine in the Brazilian routine childhood national immunization program.
- Author
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Moreira M, Cintra O, Harriague J, Hausdorff WP, and Hoet B
- Subjects
- Brazil epidemiology, Carrier State microbiology, Child, Preschool, Humans, Immunity, Herd, Meningitis, Pneumococcal prevention & control, Nasopharynx microbiology, Observational Studies as Topic, Otitis Media prevention & control, Pneumonia, Pneumococcal prevention & control, Population Surveillance, Randomized Controlled Trials as Topic, Immunization Programs, Pneumococcal Infections prevention & control, Pneumococcal Vaccines therapeutic use
- Abstract
Brazil introduced the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix™, GSK Vaccines) in the routine childhood immunization program in 2010 with a 3+1 schedule (with catch-up for children <2 years-old). This review represents the first analysis of the overall impact of a second-generation pneumococcal conjugate vaccine on nasopharyngeal carriage and all the major pneumococcal disease manifestations in a single, pneumococcal conjugate vaccine-naïve, developing country. A total of 15 published articles and 13 congress abstracts were included in the analysis. In children <5 years-old, studies showed a positive impact of PHiD-CV on the incidence of vaccine-type and any-type invasive pneumococcal disease (including decreases in pneumococcal meningitis morbidity and mortality), on pneumonia incidence and mortality, and on otitis media. Nasopharyngeal carriage of vaccine-type and any-type pneumococci decreased after the primary doses, with no early signs of replacement with other pathogens. Finally, herd protection against vaccine-type invasive pneumococcal disease and pneumonia in unvaccinated subjects was shown in some studies for some age groups. In conclusion, pneumococcal disease decreased after the introduction of PHiD-CV into the Brazilian national immunization program. Further follow-up is needed to evaluate the long-term overall impact of PHiD-CV in the Brazilian population., (Copyright © 2016 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
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42. Interim results of an ecological experiment - Conjugate vaccination against the pneumococcus and serotype replacement.
- Author
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Hausdorff WP and Hanage WP
- Subjects
- Carrier State microbiology, Humans, Infant, Nasopharynx microbiology, Serotyping, Vaccination, Heptavalent Pneumococcal Conjugate Vaccine immunology, Pneumococcal Infections prevention & control, Pneumococcal Vaccines immunology, Serogroup, Streptococcus pneumoniae classification, Streptococcus pneumoniae immunology, Vaccines, Conjugate immunology
- Abstract
Streptococcus pneumoniae has more than 95 serotypes, each of which presumably can cause sepsis, meningitis, pneumonia, and acute otitis media. Pneumococcal conjugate vaccines (PCV) targeted against a limited number of serotypes have nonetheless revealed an impressive impact on each manifestation of pneumococcal disease. At the same time, growing evidence of significant non-vaccine type (NVT) replacement disease following implementation of infant PCV programs has raised questions about the long-term viability of PCV immunization strategies and how to optimize PCV formulations. We discuss here theoretical and practical considerations regarding serotype replacement, and provide a snapshot of the most important NVT types seen to date after implementation of the 2 higher-valent PCVs.
- Published
- 2016
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43. Correction: Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial.
- Author
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Tregnaghi MW, Sáez-Llorens X, López P, Abate H, Smith E, Pósleman A, Calvo A, Wong D, Cortes-Barbosa C, Ceballos A, Tregnaghi M, Sierra A, Rodriguez M, Troitiño M, Carabajal C, Falaschi A, Leandro A, Castrejón MM, Lepetic A, Lommel P, Hausdorff WP, Borys D, Ruiz Guiñazú J, Ortega-Barría E, Yarzábal JP, and Schuerman L
- Published
- 2015
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44. Effect of antimicrobial use on pneumococcal diagnostic tests in elderly patients with community-acquired pneumonia.
- Author
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Saukkoriipi A, Palmu AA, Jokinen J, Verlant V, Hausdorff WP, and Kilpi TM
- Subjects
- Aged, Aged, 80 and over, Antibodies, Bacterial blood, Antigens, Bacterial urine, Female, Humans, Male, Nasopharynx microbiology, Polymerase Chain Reaction, Sensitivity and Specificity, Sputum microbiology, Streptococcus pneumoniae isolation & purification, Urinalysis, Anti-Bacterial Agents therapeutic use, Community-Acquired Infections diagnosis, Diagnostic Tests, Routine, Pneumonia, Pneumococcal diagnosis
- Abstract
Antimicrobial treatment decreases bacterial culture yields. We assessed the impact of antimicrobial treatment on pneumococcal assays in a prospective study of community-acquired pneumonia (CAP) in the elderly. We enrolled 323 cases aged ≥65 years with radiologically confirmed CAP and collected detailed data on antimicrobial exposure and pneumococcal assays on various samples. Complete antimicrobial use data were available for 303 (94%) cases; 61% had no antimicrobial exposure, 19% had received antibiotics at the acute visit only, and 20% within 2 weeks before the acute visit (15% ongoing and 5 % completed treatment). Ongoing use before the visit reduced pneumococcal detection by culture (nasopharyngeal swab 2 vs. 16% in the unexposed; high-quality sputum 0 vs. 25%) and sputum lytA polymerase chain reaction (PCR) (0 vs. 25%). Urine antigen test and serology were not affected. Among those who had received antibiotics only at the acute visit before study sampling, serology (29 vs. 15%), urine antigen (19 vs. 8%), and blood culture (9 vs. 2%) were more often positive than among the unexposed. Antimicrobial exposure before the visit reduced both culture and PCR-based detection. Patients given antibiotics at the visit had higher proportions of positive blood culture, serology, and urine antigen tests, suggesting higher pneumococcal CAP prevalence.
- Published
- 2015
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45. Predicting the impact of new pneumococcal conjugate vaccines: serotype composition is not enough.
- Author
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Hausdorff WP, Hoet B, and Adegbola RA
- Subjects
- Carrier State epidemiology, Carrier State microbiology, Carrier State prevention & control, Cross Protection, Cross Reactions, Humans, Immunity, Herd, Pneumococcal Vaccines administration & dosage, Serogroup, Streptococcal Infections epidemiology, Streptococcal Infections microbiology, Streptococcus pneumoniae isolation & purification, Vaccines, Conjugate administration & dosage, Vaccines, Conjugate immunology, Antigens, Bacterial immunology, Pneumococcal Vaccines immunology, Streptococcal Infections prevention & control, Streptococcus pneumoniae immunology
- Abstract
Streptococcus pneumoniae is a major cause of childhood morbidity and mortality worldwide. A heptavalent polysaccharide-protein conjugate vaccine (PCV) has proven highly effective in preventing pneumococcal disease in industrialized countries. Two higher-valent pneumococcal conjugate vaccines are now widely available, even in the poorest countries. These differ from each other in the number of serotypes and carrier proteins used for their conjugation. Some have assumed that the only meaningful clinical difference between PCV formulations is a function of the number of serotypes each contains. A careful review of recent clinical data with these and several unlicensed PCV formulations points to important similarities but also that some key properties of each vaccine likely differ from one another.
- Published
- 2015
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46. Haemophilus influenzae type b as an important cause of culture-positive acute otitis media in young children in Thailand: a tympanocentesis-based, multi-center, cross-sectional study.
- Author
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Intakorn P, Sonsuwan N, Noknu S, Moungthong G, Pirçon JY, Liu Y, Van Dyke MK, and Hausdorff WP
- Subjects
- Amoxicillin-Potassium Clavulanate Combination therapeutic use, Anti-Bacterial Agents therapeutic use, Cefotaxime therapeutic use, Child, Preschool, Cross-Sectional Studies, Drug Resistance, Multiple, Bacterial, Female, Haemophilus Infections drug therapy, Haemophilus Infections epidemiology, Humans, Infant, Male, Otitis Media drug therapy, Pneumococcal Infections drug therapy, Pneumococcal Infections epidemiology, Streptococcus pneumoniae isolation & purification, Suction, Thailand epidemiology, beta-Lactamase Inhibitors therapeutic use, Haemophilus influenzae type b isolation & purification, Otitis Media microbiology
- Abstract
Background: Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae) are considered major causes of bacterial acute otitis media (AOM) worldwide, but data from Asia on primary causes of AOM are limited. This tympanocentesis-based, multi-center, cross-sectional study assessed bacterial etiology and antimicrobial susceptibility of AOM in Thailand., Methods: Children 3 to 59 months presenting with AOM (< 72 hours of onset) who had not received prescribed antibiotics, or subjects who received prescribed antibiotics but remained symptomatic after 48-72 hours (treatment failures), were eligible. Study visits were conducted from April 2008 to August 2009. Bacteria were identified from middle ear fluid collected by tympanocentesis or spontaneous otorrhea swab sampling (< 20% of cases). S. pneumoniae and H. influenzae serotypes were determined and antimicrobial resistance was also assessed., Results: Of the 123 enrolled children, 112 were included in analysis and 48% of the 118 samples were positive for S. pneumoniae (23% (27/118)), H. influenzae (18% (21/118)), Moraxella catarrhalis (6% (7/118)) or Streptococcus pyogenes (3% (4/118)). The most common pneumococcal serotypes were 19F (26%) and 14 (22%). The majority of H. influenzae isolates were encapsulated (18/21), with 13 type b (Hib) representing 62% of all H. influenzae isolate or 11% of all samples (13/118), and there were only 3 non-typeable isolates. Despite high antibiotic resistance, amoxicillin/clavulanate susceptibility was high. No pneumococcal vaccine use was reported., Conclusions: S. pneumoniae and H. influenzae, both frequently antibiotic resistant, were leading causes of bacterial AOM and there was an unexpectedly high burden of Hib in this population unvaccinated by any Hib conjugate vaccine. Conjugate vaccines effective against pneumococcus and H. influenzae could potentially reduce the burden of AOM in this population.
- Published
- 2014
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47. Efficacy of pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in young Latin American children: A double-blind randomized controlled trial.
- Author
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Tregnaghi MW, Sáez-Llorens X, López P, Abate H, Smith E, Pósleman A, Calvo A, Wong D, Cortes-Barbosa C, Ceballos A, Tregnaghi M, Sierra A, Rodriguez M, Troitiño M, Carabajal C, Falaschi A, Leandro A, Castrejón MM, Lepetic A, Lommel P, Hausdorff WP, Borys D, Ruiz Guiñazú J, Ortega-Barría E, Yarzábal JP, and Schuerman L
- Subjects
- Antibodies, Bacterial blood, Child, Preschool, Double-Blind Method, Haemophilus Infections microbiology, Humans, Immunization, Secondary, Infant, Intention to Treat Analysis, Latin America, Otitis Media immunology, Otitis Media microbiology, Otitis Media prevention & control, Pneumococcal Infections immunology, Pneumococcal Infections microbiology, Treatment Outcome, Bacterial Proteins immunology, Carrier Proteins immunology, Haemophilus influenzae immunology, Immunoglobulin D immunology, Lipoproteins immunology, Pneumococcal Infections prevention & control, Pneumococcal Vaccines immunology, Streptococcus pneumoniae immunology, Vaccination, Vaccines, Conjugate immunology
- Abstract
Background: The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed., Methods and Findings: This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases., Conclusions: Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice., Trial Registration: www.ClinicalTrials.gov NCT00466947.
- Published
- 2014
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48. Further evidence for the effectiveness of PCV10 against Streptococcus pneumoniae serotype 19A.
- Author
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Clarke CJ and Hausdorff WP
- Subjects
- Female, Humans, Male, Pneumococcal Infections prevention & control, Pneumococcal Vaccines therapeutic use, Streptococcus pneumoniae immunology
- Published
- 2014
- Full Text
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49. Incidence and etiology of community-acquired pneumonia in the elderly in a prospective population-based study.
- Author
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Palmu AA, Saukkoriipi A, Snellman M, Jokinen J, Torkko P, Ziegler T, Kaijalainen T, Hausdorff WP, Verlant V, and Kilpi TM
- Subjects
- Aged, Aged, 80 and over, Community-Acquired Infections microbiology, Community-Acquired Infections prevention & control, Female, Finland epidemiology, Humans, Incidence, Male, Pneumonia, Pneumococcal epidemiology, Pneumonia, Pneumococcal microbiology, Pneumonia, Pneumococcal prevention & control, Prospective Studies, Community-Acquired Infections epidemiology, Pneumococcal Vaccines administration & dosage
- Abstract
Background: We conducted a prospective population-based epidemiological study to prepare a setting for documentation of the efficacy of novel vaccines against pneumococcal (Pnc) community-acquired pneumonia (CAP) in the elderly. Specific objectives were to demonstrate setting feasibility, to construct a case definition for Pnc CAP, and to estimate its incidence., Methods: We prospectively enrolled patients with clinical and radiological findings compatible with CAP at municipal on-call clinics serving an elderly population (age ≥ 65 y) of approximately 29,500. Sputum, urine, nasopharyngeal swab (NPS), and blood samples were analyzed using diverse methods for the identification of Pnc (culture, PCR, antigen tests, serology) and of other pathogens. The following case definition for Pnc CAP was derived: encapsulated Pnc in blood culture or in high-quality sputum culture or at least 2 of the following: positive urine Pnc antigen; ≥ 2-fold increase in serum anti-PsaA or anti-CbpA antibodies; encapsulated Pnc culture or LytA PCR in either sputum or NPS., Results: We enrolled 490 clinical CAP patients during the 2-y follow-up, 53% of all clinical CAP patients in the source population; 323 were radiologically confirmed. The incidence of radiologically confirmed CAP was 5.5/1000 person-y (95% confidence interval (CI) 4.9-6.1) and 10.5/1000 person-y when adjusted for non-captured patients. The proportion of radiologically confirmed CAP caused by Pnc was estimated at 17%; i.e. 0.95/1000 person-y (95% CI 0.7-1.2) and 1.8 when adjusted for non-captured patients., Conclusions: We developed and documented a feasible methodology for capturing endpoints in a vaccine trial for the prevention of pneumonia. CAP incidence in the elderly population remains considerable and Streptococcus pneumoniae was one of the most commonly detected causative agents.
- Published
- 2014
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50. Bacterial etiology of empyema thoracis and parapneumonic pleural effusion in Thai children aged less than 16 years.
- Author
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Lochindarat S, Teeratakulpisarn J, Warachit B, Chanta C, Thapa K, Gilbert GL, Wangroongsarb Y, Pirçon JY, Van Dyke MK, Liu Y, and Hausdorff WP
- Subjects
- Adolescent, Anti-Bacterial Agents therapeutic use, Child, Drainage, Empyema epidemiology, Empyema therapy, Female, Humans, Male, Paracentesis, Pleural Effusion epidemiology, Pleural Effusion therapy, Pneumococcal Infections epidemiology, Pneumococcal Infections therapy, Polymerase Chain Reaction, Serotyping, Staphylococcal Infections epidemiology, Staphylococcal Infections therapy, Thailand epidemiology, Thoracic Diseases epidemiology, Thoracic Diseases therapy, Empyema microbiology, Pleural Effusion microbiology, Pneumococcal Infections microbiology, Staphylococcal Infections microbiology, Thoracic Diseases microbiology
- Abstract
This study aimed to identify the bacterial etiology of empyema thoracis or parapneumonic pleural effusions in Thai children, with a focus on pneumococcus. This hospital-based, descriptive study included children aged < or = 16 years, diagnosed with empyema thoracis or parapneumonic pleural effusion, from whom a pleural fluid (PF) sample was taken between January 2008 and November 2009. PF and blood samples were cultured and PF samples were also tested by polymerase chain reaction (PCR) to assess whether evidence of an infection might be identified among culture-negative samples. Serotyping of Streptococcus pneumoniae-positive samples was performed by molecular techniques and Quellung reaction. In this study, 29 children with empyema thoracis and 42 children with parapneumonic pleural effusion were enrolled. Potentially pathogenic bacteria were cultured in 13/71 samples at local or central laboratories; the most common bacteria were Staphylococcus aureus (8 children) and S. pneumoniae (2 children). Molecular techniques detected one or more targeted respiratory pathogens in 18/71 PF samples. S. pneumoniae and Haemophilus influenzae were identified by PCR in 13 and 6 children, respectively; PCR for S. aureus was not performed. The pneumococcal serotypes identified were 1, 3, 5, 6A/B, 9A/V, 14, 15A, 19F and 23A. This study shows that among Thai children with empyema thoracis and parapneumonic pleural effusions, S. aureus and S. pneumoniae were the most common pathogens identified by culture and PCR, respectively. These findings confirmed that molecular techniques are more sensitive for identification of S. pneumoniae and H. influenzae and enhance detection of important bacterial causes of empyema.
- Published
- 2014
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