Serum bactericidal antibody assays - The role of complement in infection and immunity.

Complement is an essential component of the immune system and human pathogenic organisms have developed various mechanisms for evading complement mediated serum killing. The "gold standard" for measuring the ability of vaccine-induced antibody to kill Neisseria meningitidis is the serum bactericidal antibody (SBA) assay which measures complement mediated killing via antibody. This assay requires active complement, either intrinsic from the serum being tested or the addition of exogenous complement, either from a human or from another species such as rabbit. For serogroup C, an SBA titre of ≥4 was established as the correlate of protection when using human complement and ≥8 as the threshold when using rabbit complement, based on comparative assay results. Licensure of meningococcal vaccines, including polysaccharide protein conjugate vaccines and serogroup B vaccines has been based on the immune responses measured with the SBA assay, thus on a surrogate of vaccine efficacy. This review examines the use of complement and the SBA assay to assess immunity to meningococcal infection, and provides examples of vaccine trials in different age groups where various assays have been used.

Influenza A and respiratory syncytial virus hospital burden in young children in East London.

Epidemiological studies have demonstrated high hospitalization rates attributable to influenza and RSV in children aged 6 months and those aged <12 months, respectively (43 and 92.5/10 000 person-months, respectively). In conclusion, these high paediatric RSV and influenza incidence rates can be used to inform UK policy on childhood influenza immunization and subsequent RSV immunization in the future.

Burden of paediatric invasive pneumococcal disease in Europe, 2005.

Within the European Union (EU), documenting the burden of invasive pneumococcal disease (IPD) in infants and children is important for coordinating effective pneumococcal immunization policies. Our objective was to document the burden of IPD in countries of the EU plus Switzerland and Norway. European affiliates of Wyeth Vaccines made available recent epidemiological data on IPD from local disease surveillance programmes, including unpublished sources. Recent literature and websites were also searched to provide as wide a representation as possible. This included OVID and abstracts from a number of international meetings, dating from the year 2000. The reported rates of paediatric IPD per 100000 (age) ranged from a low of 1.7 (<2 years) to 4.2 (2-15 years) in Sweden to a high of 93.5 to 174 (<2 years) to 56.2 (<5 years) in Spain. The percentage of circulating serotypes causing IPD that are covered by 7-valent pneumococcal conjugate vaccine (PCV) IPD serotype coverage ranged from 60% to 80% for European children aged <2 years. Under reporting, differences in reporting methods, antibiotic prescribing and disparities in blood-culturing practices may explain the differences in reported disease incidence. Because of the excellent clinical efficacy of the PCV against IPD, national pneumococcal vaccination programmes in Europe have the potential to prevent much morbidity and mortality.

Controlling invasive pneumococcal disease: is vaccination of at-risk groups sufficient?

Risk factors for invasive pneumococcal disease (IPD) include young and old age, comorbidities (such as splenic dysfunction, immunodeficiencies, chronic renal disease, chronic heart or lung disease or cerebral spinal fluid leak), crowded environments or poor socioeconomic conditions. Universal use of the 7-valent pneumococcal conjugate (7vPncCRM) vaccine for infants and young children has led to significant decreases in IPD in the vaccinated population (direct protection), and there has also been a decrease in the incidence of IPD among the nonvaccinated population (indirect immunity; herd protection). While 7vPncCRM vaccine is administered universally to children in USA, many countries of the European Union have chosen to target children with comorbidities. This review aims to highlight individual risk factors for IPD, describe studies that evaluated pneumococcal conjugate vaccines in at-risk groups and estimate the proportion of at-risk children who may have been vaccinated in the European Union since the 7vPncCRM vaccine was introduced, using UK as an example. Although immunisation targeting only children with comorbidities may achieve satisfactory results for a few, many otherwise healthy children at risk simply because of their age will be neglected, and herd protection might not be established.

Pneumococcal pneumonia in the UK--how herd immunity affects the cost-effectiveness of 7-valent pneumococcal conjugate vaccine (PCV).

This study examines the potential clinical and economic benefits for adults arising from paediatric pneumococcal vaccination in the UK. A UK birth cohort model with a 10-year horizon and using a primary 4-dose paediatric 7-valent pneumococcal conjugate vaccine (PCV) schedule was populated with 1999 morbidity and mortality data scaled up to the UK population. Herd immunity effects on adult pneumococcal hospital-treated pneumonia, meningitis and septicaemia, but not on community-treated pneumonia, were calculated using the lower end of the confidence intervals published for the effects in the US. Universal paediatric pneumococcal immunisation would prevent 1168 deaths (1141 adults) and 7147 cases (1791 adults constituted by 32 meningitis, 37 septicaemia and 1722 pneumonia) of serious pneumococcal infection (meningitis, septicaemia, pneumonia) with a resultant direct (payor) cost per life year gained of 4360 pounds. The 7-valent PCV appears to be highly cost effective.

The burden of severe pneumococcal infection in Ireland: potential effectiveness and indirect benefits of the 7-valent pneumococcal conjugate vaccine.

This study attempts to overcome the problem of under-reporting of serious pneumococcal infection in the Republic of Ireland by adding a proportion of 'unspecified' disease to pneumococcal disease reports. ICD-9 data for all age groups was collected on meningitis (from the National Disease Surveillance Centre), and septicaemia and pneumonia (from the Hospital In-Patient Enquiry system) for the year 1999. A 7-valent pneumococcal conjugate vaccine (PCV) has been shown to have significant effectiveness in the target paediatric age group and also indirect herd effects on the US adult population. The implications of these direct and indirect effects were applied to the epidemiology of serious pneumococcal infection in Ireland. The annual reported incidence rates for laboratory confirmed severe pneumococcal disease in Ireland in 1999 may underestimate both the morbidity and mortality of disease by 21% and 28% respectively. In all age groups 1,183 cases and 132 deaths may be prevented annually by the introduction of the vaccine. In addition, the vaccine provides an effective new tool for reducing disease caused by antibiotic resistant pneumococci thus assisting in the control of anti-microbial resistance in humans.

How many episodes of hospital care might be prevented by widespread uptake of pneumococcal conjugate vaccine?

BACKGROUND: It is likely that disease specific infectious morbidity is under-reported. Microbiologically identifiable diseases may be "hidden" in ICD-10 code as "unspecified" disease. AIMS: To estimate the proportion of "unspecified" morbidity of infectious cause in infants and young children reported by Hospital Episode Statistics (HES) in England in 1999 that could reasonably be attributed to Streptococcus pneumoniae, and to calculate what number and proportion of diseases could potentially be prevented by a programme of pneumococcal conjugate vaccination. METHODS: Proportions of HES "unspecified" septicaemia, meningitis, and pneumonia attributable to pneumococcal infection were estimated by applying theoretical rates obtained from studies using highly sensitive diagnostic tests. The numbers obtained were added to those coded as pneumococcal in origin. The vaccine preventable proportion was then calculated using serogroup coverage, disease specific efficacy, and vaccine uptake. RESULTS: For infants and children 3 months to 5 years of age in 1999, HES reported 134, 245, and 216 episodes of pneumococcal septicaemia, meningitis, and pneumonia respectively. In addition, 68, 36, and 2548 episodes of "unspecified" disease respectively are probably pneumococcal in origin. For hospitalisations in England in this age group, 157/202 (78%) cases of pneumococcal septicaemia, 218/281 (76%) cases of pneumococcal meningitis, and 452/2764 (16%) cases of pneumococcal pneumonia may be preventable annually by means of pneumococcal conjugate vaccination. CONCLUSIONS: Paediatric hospital morbidity in England due to pneumococcal septicaemia, meningitis, and pneumonia is under-reported by 34%, 13% and 92% respectively. A larger proportion of morbidity is preventable than implied by ICD-10 code alone.

Invasive pneumococcal disease in England and Wales: what is the true burden and what is the potential for prevention using 7 valent pneumococcal conjugate vaccine?

BACKGROUND: The annual reported incidence rates for laboratory confirmed invasive pneumococcal disease (IPD) underestimate the true burden of invasive disease attributable to pneumococcal infection. AIMS: To estimate the proportion of "unspecified" mortality of infectious cause in infants and young children aged 1 month to 4 years reported by the Office for National Statistics (ONS) in England and Wales that could reasonably be attributed to IPD, thereby revising the total number of deaths per year potentially attributable to IPD, and producing a more accurate figure for the number of deaths that may be prevented by a programme of pneumococcal conjugate vaccination. METHODS: Polymerase chain reaction, latex agglutination, and other alternate methodologies to microbiological culture have been applied in various studies to the detection of Streptococcus pneumoniae. Some of these tests have been shown to be more sensitive indicators of pneumococcal infection. In our analysis the implications of these tests were applied theoretically to the "unspecified" clinical deaths caused by septicaemia, meningitis, and pneumonia reported by the ONS, with a 20% correction/reduction factor for nasopharyngeal carriage which these sensitive tests may coincidentally detect. RESULTS: The ONS reported an average of 13 deaths per year (1989-99) in infants and children aged 1 month to 4 years caused by pneumococcal septicaemia, meningitis, or pneumonia. By applying the rates for the more sensitive tests to the most recent ONS "unspecified" mortality data available (1999), the actual annual number of deaths caused by IPD in the age group 1 month to 4 years is shown to be at least as high as 43. CONCLUSIONS: The mortality as a result of IPD in infants and young children may be at least three times the reported rate. The 7 valent pneumococcal conjugate vaccine may have the potential to prevent up to 26 (61%) of the IPD deaths per year in infants and young children in England and Wales alone.