Haemophilus influenzae type b conjugate vaccine use and effectiveness

Haemophilus influenzae type b (Hib) is an important cause of invasive bacterial disease in children, including meningitis and pneumonia. The introduction of Hib conjugate vaccines into routine vaccination schedules has contributed to a substantial reduction in the burden of Hib-related disease in many developed countries. However, introduction of Hib conjugate vaccines in developing countries has progressed more slowly. We review the worldwide use and effectiveness of Hib conjugate vaccines. At present, 119 countries have programmes for routine Hib immunisation. WHO estimates that in the developed world 92% of the eligible population is vaccinated against Hib; however, average coverage is 42% in developing countries and only 8% in the poorest countries. Africa and southeast Asia have the lowest rates of Hib vaccine introduction. Vaccine costs and debate about the burden of disease are obstacles to the global use of Hib conjugate vaccine. Even with new funding support, there are many ongoing challenges and vaccine use remains suboptimal, particularly in developing countries.     

Efficacy of pneumococcal conjugate vaccines and their effect on carriage and antimicrobial resistance

Pneumococcal conjugate vaccines have shown a high degree of success in preventing pneumococcal bacteraemia in children. They also reduce the acquisition of carriage of vaccine serotypes in the nasopharynx, and reduce otitis media caused by those serotypes. Non-vaccine serotypes, which can colonise vaccinated infants, are associated with otitis media in these children and lower the overall effectiveness of the vaccine to this disorder. Longer term studies, however, could show that immunised children develop immunity to a broad range of pneumococcal serotypes at a younger age than non-immunised children. Preliminary data suggest that these vaccines could reduce the burden of radiologically confirmed pneumonia. Pneumococcal conjugate vaccines interrupt the transmission of antibiotic-resistant pneumococci and thus decrease the burden of antibiotic resistance in immunised children and in their contacts. Studies are underway to assess conjugate vaccine efficacy against invasive disease, pneumonia, and all-cause mortality in developing countries, and to assess the potential use of these vaccines in adults.     

Antibiotic resistant infections due to Streptococcus pneumoniae: impact on therapeutic options and clinical outcome

PURPOSE OF REVIEW: Streptococcus pneumoniae is a major cause of morbidity and mortality in the pediatric population. The development of increasing resistance to multiple classes of antibiotics is making treatment of infections due to this organism much more difficult. The ultimate impact of high-level antibiotic resistance on therapeutic options and clinical outcomes of various pneumococcal infections is unclear and remains to be determined. Use of the conjugate pneumococcal vaccine has markedly decreased invasive pneumococcal disease in children under 5 years of age; however, its impact on decreasing antibiotic resistance is currently unknown. RECENT FINDINGS: Studies suggest that response to therapy and clinical outcome of infections due to pneumococcal isolates with intermediate resistance to the beta-lactam antibiotics is no different from that of infections due to susceptible isolates. However, evidence is accumulating that infections caused by highly resistant pneumococcal isolates are associated with higher rates of treatment failure and mortality than infections due to susceptible strains. SUMMARY: Use of a conjugate pneumococcal vaccine in conjunction with educational intervention programs that promote appropriate and judicious antibiotic use is a safe and effective means of decreasing the prevalence of pneumococcal disease in the pediatric population, decreasing the use of broad-spectrum antibiotic agents and potentially decreasing the amount of antibiotic resistance currently being seen.     

The expanding spectrum of disease due to Salmonella: An international perspective

Human disease due to Salmonella infections appears to be on the rise worldwide. Despite the availability of vaccines and generally effective antibiotic therapy, salmonellosis, in the forms of gastroenteritis and enteric fever, remains a major cause of morbidity and mortality in many developing countries, especially in young children and immunocompromised hosts. In certain highly endemic areas of South and Southeast Asia, the emergence of quinolone-resistant and multidrug-resistant strains of Salmonella contribute to the magnitude of the problem. In the United States and Europe, a low but consistent rate of disease appears to be primarily related to ingestion of contaminated poultry, lapses in sanitary agricultural practices, and importation of tainted vegetable products. An improved understanding of the molecular basis of bacterial resistance and improved design and expanded use of vaccines provide hope for containing the spread and reducing morbidity of the international spectrum of disease due to Salmonella pathogens.     

Prevention of Pneumococcal Meningitis

With the success of the conjugated Haemophilus influenzae type b vaccines, Streptococcus pneumoniae has become one of the most important causes of bacterial meningitis worldwide, causing significant morbidity and mortality. Additionally, the increasing amount of resistance that this organism is developing to multiple classes of antimicrobial agents has made the treatment of pneumococcal infections, especially meningitis, much more difficult. Immunization has been shown to be one of most effective methods for preventing pneumococcal meningitis, resulting not only in a decrease in disease burden, but also a decrease in antimicrobial resistance. Currently, a 23-valent pneumococcal polysaccharide vaccine and a heptavalent protein conjugate vaccine are licensed for use. However, the 23-valent polysaccharide vaccine is poorly immunogenic in infants and young children. The continued development, licensing, and use of pneumococcal conjugate vaccines have the best potential to both prevent disease and decrease the prevalence of pneumococcal meningitis.     

Study on the possible use of Vi polysaccharide typhoid fever vaccine to control endemic typhoid fever in Nepal

This review of literature was conducted to explore the various aspects of typhoid fever in Nepal and to identify the factors concerned in the possible use of the Vi polysaccharide typhoid fever vaccine in Nepal as the tool for prevention and control. There are hotspots of Typhoid fever in developing countries, urban areas and slums, where poor conditions of safe drinking water and sanitation prevail. The use of currently available typhoid fever vaccines, especially the Vi polysaccharide vaccine has been recommended by World Health Organization to control typhoid fever in endemic areas. However, factors like, the burden and the changing epidemiological pattern of the disease, efficacy of the vaccines, ease for intervention, cost effectiveness, financing, and programmatic issues should be considered in local settings before the introduction of vaccines as a public health tool for prevention. We concluded that the possible use of currently available Vi polysaccharide vaccine to control endemic typhoid fever in Nepal might not have the same positive impact as reported in trials from different Asian countries. The major issues to be considered are emergence of Salmonella Paratyphi A as a major cause of enteric fever, no difference in prevalence of typhoid fever in preschool and school children, similar clinical profiles and severity of typhoid and paratyphoid fever. So, an ideal vaccine that can provide the protection both to typhoid and paratyphoid fever, and the vaccination programs that also includes preschool children would be the best option for Nepal.     

Typhoid and paratyphoid fever

Typhoid fever is estimated to have caused 21.6 million illnesses and 216,500 deaths globally in 2000, affecting all ages. There is also one case of paratyphoid fever for every four of typhoid. The global emergence of multidrug-resistant strains and of strains with reduced susceptibility to fluoroquinolones is of great concern. We discuss the occurrence of poor clinical response to fluoroquinolones despite disc sensitivity. Developments are being made in our understanding of the molecular pathogenesis, and genomic and proteomic studies reveal the possibility of new targets for diagnosis and treatment. Further, we review guidelines for use of diagnostic tests and for selection of antimicrobials in varying clinical situations. The importance of safe water, sanitation, and immunisation in the presence of increasing antibiotic resistance is paramount. Routine immunisation of school-age children with Vi or Ty21a vaccine is recommended for countries endemic for typhoid. Vi vaccine should be used for 2-5 year-old children in highly endemic settings.     

The emergence of antibiotic resistance in typhoid fever

Typhoid fever, caused by Salmonella typhi, causes over 20 million cases annually, with at least 700,000 deaths. The main burden of disease is in developing countries, particularly the Indian Subcontinent and South East Asia. However, cases in returning travellers, immigrants and refugees in developed countries are not uncommon. Drug resistance is fast becoming a major problem in the management of this infection. Chloramphenicol resistance became established globally in the S.Typhi population after 1972 on plasmids of incompatibility group IncH. Multi-drug resistance defined as resistance to the three first-line agents used to treat typhoid fever, namely chloramphenicol, ampicillin and co-trimoxazole, and acquired on the same plasmid type, has been endemic in most of South East Asia and the Indian Subcontinent for many years. Resistance data from many endemic areas are sparse and with the increasing problem of reduced sensitivity to the fluoroquinolone antibiotics, empirical choice of antibiotics may be difficult. We review the historical aspects of the development of resistance and the current data available on the epidemiology of antibiotic resistance in S.Typhi.     

Selective primary health care: strategies for control of disease in the developing world. XX. Typhoid fever

The incidence of typhoid fever remains unacceptably high in developing countries. Because Salmonella typhi is disseminated by carriers, there is an urgent need to increase the rate of detection of carriers and to decrease the risk they pose to their communities. In urban areas where sewage disposal is lacking or inadequate, public water supplies are contaminated and typhoid fever is common. The contamination of food by carriers is the second commonest route of infection. Water purification processes lead to a rapid decline in the incidence of the disease; thus, many developing countries hope to develop pure water supplies for all citizens by the end of this century. Until this important public health goal is achieved, the use of vaccine, especially in children, could cause a significant decrease in the incidence of typhoid fever. A new oral attenuated vaccine promises to be effective and safe.     

Prospects for pneumococcal vaccination in African children

Streptococcus pneumoniae (pneumococcus) remains a major cause of morbidity and mortality in both developed and undeveloped countries. Accurate disease burden estimates for developing countries and Africa in particular, where diagnostic facilities are less adequate and a disease surveillance system virtually non-existent, is difficult. However, from conservative estimates, the pneumococcus is probably responsible for at least 1 million of the 4 million deaths that occur from acute lower respiratory infections in children aged less than 5 years. The global burden of disease has been accentuated by the rising menace of multi-drug resistant strains, which defy geographic and racial borders. Thus, now more than ever before, there is an urgent need to identify and implement preventive measures to avert this problem. The currently licensed pneumococcal polysaccharide vaccine, comprises 23 capsular polysaccharides of the pneumococcus, many of which are poorly immunogenic in the very vulnerable age group of under-fives. A possible solution to the problem of poor immunogenicity is to use a protein/polysaccharide conjugate vaccine similar to that recently introduced successfully for Haemophilus influenzae type b (Hib) and using this approach, several workers have reported promising results from safety and immunogenicity studies. However, unlike Hib, the development of conjugate vaccine against pneumococcal disease is complicated by the existence of more serotypes than can be feasibly incorporated in a single conjugate vaccine formulation. Whilst this challenge has been taken on by some vaccine manufacturers, novel approaches such as the identification or construction of protective protein antigen, common to all clinically important strains are being explored. Novel application of the pneumococcal polysaccharide vaccines in pregnancy for protection of disease in early infancy is an approach that has not been evaluated. For maximum impact, the ultimate vaccine formulation should be affordable and available to resource poor countries where the burden of disease is highest. Establishing disease surveillance systems in such countries now will greatly facilitate the introduction of the vaccines.     

HIV and pneumococcal disease

PURPOSE OF REVIEW: To describe the impact of highly active antiretroviral therapy on the burden of pneumococcal disease and advances in our understanding of the impact of HIV on this disease. RECENT FINDINGS: Although highly active antiretroviral therapy has reduced the burden of pneumococcal disease among HIV-infected adults, these infections remain far more common than in HIV uninfected adults. HIV-infected adults who smoke or have comorbidities are at particular risk. In the absence of highly active antiretroviral therapy, pneumococcal meningitis has emerged in Africa as a major disease burden with a high mortality among HIV-infected children and adults. Conjugate pneumococcal vaccine protects HIV-infected infants from pneumococcal pneumonia. In the United States, where conjugate vaccine is given to children, herd immunity has reduced the burden of invasive pneumococcal disease among HIV-infected adults. SUMMARY: The pneumococcus remains a significant cause of morbidity and mortality among HIV-infected children and adults, both in developed and in developing countries.     

Drug-resistant Mycobacterium tuberculosis in Korean isolates

Tuberculosis is a common disease in developing countries. An increasing incidence of resistance to isoniazid (INH) and streptomycin in organisms isolated from patients who contracted their disease in these countries, particularly in the Far East, is well recognized. This drug resistance has led to the recommendation of empirically beginning a regimen in patients with tuberculosis from the Far East of INH, ethambutol, and rifampin. This report documents the increasing incidence of resistance in isolates from Korea to ethambutol and rifampin in addition to INH and streptomycin. It suggests that the empiric use of INH, ethambutol, and rifampin in this group of patients could potentially lead to resistance to all of these drugs because of a significant amount of multidrug resistance. A regimen of INH, rifampin, pyrazinamide, and capreomycin is suggested as appropriate initial therapy in these patients based on the in vitro sensitivity data presented and initial clinical experience.     

Serotype and antimicrobial susceptibility patterns of isolates of Streptococcus pneumoniae causing invasive disease in The Gambia 1996-2003

OBJECTIVES: To describe the characteristics of pneumococcal isolates obtained from patients with invasive pneumococcal disease in The Gambia. METHODS: Pneumococcal isolates were obtained from children aged < or =6 years with invasive pneumococcal disease during a Haemophilus influenzae vaccine effectiveness study (1997-2002) and from patients with invasive pneumococcal disease admitted to the MRC hospital, Fajara, for routine care (1996-2003). Isolates were identified, serotyped and tested for antibiotic susceptibility. RESULTS: Five hundred and thirty one pneumococcal isolates were obtained from 518 patients; 55 (10.6%) patients died; 415 isolates (79%) were from blood culture, 84 (16%) from CSF, and 42 (8%) from lung aspirates. Forty serogroups and serotypes were identified; six accounted for 64% and 16 for 86% of all episodes; 33.7% were of serotypes 1 and 5. 23.5% were of a 7-valent vaccine serotype, 57.1% were of a 9-valent vaccine serotype; 56% were of a 7-valent serogroup and 78% were of a 9-valent serogroup. There was a significant increase in the proportion of isolates of non-vaccine serogroup with increasing age (P < 0.0001). Antibiotic resistance had not significantly increased over time; but intermediate non-susceptibility to penicillin had risen and resistance to chloramphenicol had fallen in isolates of vaccine serotype compared with those of non-vaccine serotype. CONCLUSIONS: The majority of invasive pneumococcal disease in The Gambia is caused by pneumococci of relatively few serogroups. A conjugate vaccine would be expected to reduce the pneumococcal disease burden substantially and to have a beneficial effect on pneumococcal antibiotic resistance to penicillins.     

Epidemiology of pneumococcal diseases in Spain after the introduction of pneumococcal conjugate vaccines

In Spain, the use of pneumococcal conjugate vaccines (PCVs) has led to a decrease in the incidence of vaccine serotypes causing invasive and non-invasive disease in vaccinated and unvaccinated children and adults. Further, the coverage of most of the resistant serotypes by vaccines resulted in an overall decline in antibiotic resistance.As an undesirable effect, there was an increase in the non-vaccine serotypes causing infection, especially serotypes 1, 7F and 19A after PCV7 and serotype 8 after PCV13 approval, this making the beneficial effect of vaccination less apparent.The inclusion of PCVs in childhood vaccination schedules, its approval for use in healthy adults and the increasing number of serotypes covered by the vaccines in development are strong strategies in the fight against pneumococcal disease. Nonetheless, the epidemiology of Streptococcus pneumoniae infections must be still under surveillance to detect new changes, given the high capacity for recombination and adaptability of this always-surprising microorganism.     

Vaccine development for capsulate bacteria causing pneumonia

Pneumonia strikes the extremes of the age spectrum, causing maximal death and disability in children and the elderly. Despite its worldwide impact, there is a paucity of epidemiologic data regarding its incidence and the causative organisms. The two leading causes of bacterial pneumonia in childhood are Streptococcus pneumoniae (SP) and Haemophilus influenzae type b (Hib). SP is the major cause of pneumonia beyond the newborn period. In neonates, Group B Streptococcus (GBS) remains a major cause of sepsis and pneumonia despite recent reductions due to targeted perinatal antibiotic prophylaxis. Hib vaccine can prevent pneumonia in developing countries. SP conjugate vaccine prevents X-ray confirmed pneumonia in low incident populations, but protection appears more marginal in high incident populations. Non-vaccine SP serotypes have demonstrated increased carriage and mucosal disease, but not invasive disease following vaccination. GBS vaccines are in the early stages of clinical development as prenatal or antenatal vaccines.     

The epidemiology of childhood pneumococcal disease in the United States in the era of conjugate vaccine use

In 2000, a heptavalent pneumococcal conjugate vaccine was licensed and included in the schedule of routine childhood immunizations in the United States. The vaccine contains the serotypes most commonly associated with invasive and noninvasive pneumococcal infection in children and the serotypes most commonly expressing antibiotic resistance. Since the introduction of the vaccine, the incidence of invasive pneumococcal disease has declined dramatically in the United States, particularly among children younger than 2 years of age. The incidences of pneumonia and acute otitis media also have declined, but less substantially. Several factors may blunt the future effectiveness of the vaccine, however, particularly the emergence of noninvaccine pneumococcal serotypes and the propensity for pathogenic pneumococci to switch their capsular types, evading vaccine-conferred immunity.     

Serotype distribution and antibiotic susceptibility of invasive and nasopharyngeal isolates of Streptococcus pneumoniae among children in rural Mozambique

Objective To describe and compare serotype distribution and antibiotic susceptibility of invasive and nasopharyngeal isolates of Streptococcus pneumoniae from children in rural Mozambique. Methods From August 2002 to July 2003, we prospectively obtained invasive pneumococcal isolates from children <15 years of age admitted to the paediatric ward of Manhiça District Hospital. During a cross‐sectional study of children <5 years of age with mild illnesses, attending the outpatient department of the hospital in March and April 2003, we collected nasopharyngeal isolates. Serotypes and antibiotic susceptibilities were determined using standardized methods. Results The two most common pneumococcal serotypes among invasive isolates were types 1 (40% of 88 isolates serotyped) and 5 (10%), but these types were rare among nasopharyngeal isolates. Compared with invasive isolates, nasopharyngeal isolates were more likely to be serotypes in the licensed seven‐valent conjugate vaccine (49%vs. 20%, P < 0.01), to have intermediate‐level penicillin resistance (52%vs. 14%, P < 0.01) and to be non‐susceptible to trimethoprim–sulfamethoxazole (61%vs. 45%, P < 0.01). Recent receipt of antibiotics or sulfadoxine/pyrimethamine were associated with carriage of antibiotic non‐susceptible isolates. Conclusions These data indicate that a pneumococcal conjugate vaccine containing serotypes 1 and 5 could substantially reduce pneumococcal invasive disease among young children in rural Mozambique. Carriage surveys can overestimate potential coverage of the seven‐valent pneumococcal conjugate vaccine in settings where serotypes 1 and 5 predominate.     

Diversity and antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae carriage isolates in the post-heptavalent conjugate vaccine era

BACKGROUND: In response to the selective pressure of pneumococcal conjugate vaccine, increased asymptomatic carriage of antibiotic-nonsusceptible nonvaccine serotypes (NVTs) has been observed. Possible mechanisms include de novo acquisition of resistance, serotype switching, introduction of new clones, and expansion of existing clones. METHODS: To investigate the process of increased antibiotic nonsusceptibility among replacing serotypes, we applied multilocus sequence typing to samples of 126 and 222 pneumococci collected in 2001 and 2004, respectively, from the nasopharynges of children <7 years of age in 16 Massachusetts communities. RESULTS: We found no evidence of penicillin resistance due to either serotype switching or de novo acquisition. Nonetheless, resistance increased through the expansion of previously recognized clones of NVTs, particularly in serotypes 19A, 15A, and 35B. In 19A, several unrelated clones increased in frequency, whereas, in the other 2 serotypes, single resistant lineages were responsible for the increased prevalence of resistant strains. CONCLUSIONS: The decreased prevalence of antibiotic resistance with the introduction of heptavalent pneumococcal conjugate vaccine is likely to be partially eroded over time as vaccine-included serotypes are replaced by resistant clones of NVTs. The clinical significance of this will depend on the pathogenic potential of replacing clones to cause local (e.g., otitis media) or invasive disease.     

Streptococcus pneumoniae in western Europe: serotype distribution and incidence in children less than 2 years old

We did a systematic search and synthesis of evidence on the incidence of invasive pneumococcal disease, symptomatic disease, and circulating Streptococcus pneumoniae serotypes in western Europe. Using data from studies published between 1992 and 2005 we calculated a weighted mean invasive pneumococcal disease and pneumococcal meningitis incidence rate per 100,000 children aged 2 years or younger within 95% confidence intervals, together with the prevalence of S. pneumoniae serotypes and resistance to penicillin. Invasive pneumococcal disease incidence was 27.03 cases per 100,000 children under 2 years (95% CI 21.85-33.43) [corrected] Heptavalent conjugate vaccine serotypes account for 43.18-75.32% of isolates among people aged under 18 years of age. 11% of isolates in individuals aged under 18 years were penicillin resistant. The incidence of invasive pneumococcal disease appeared consistently lower in western European countries compared with studies from the USA. Thus the use of studies of vaccine effectiveness based on the US population may lead to an overestimation of the benefits of its introduction in Europe.