Invasive Haemophilus influenzae Infections after 3 Decades of Hib Protein Conjugate Vaccine Use.

Haemophilus influenzae serotype b (Hib) was previously the most common cause of bacterial meningitis and an important etiologic agent of pneumonia in children aged <5 years. Its major virulence factor is the polyribosyl ribitol phosphate (PRP) polysaccharide capsule. In the 1980s, PRP-protein conjugate Hib vaccines were developed and are now included in almost all national immunization programs, achieving a sustained decline in invasive Hib infections. However, invasive Hib disease has not yet been eliminated in countries with low vaccine coverage, and sporadic outbreaks of Hib infection still occur occasionally in countries with high vaccine coverage. Over the past 2 decades, other capsulated serotypes have been recognized increasingly as causing invasive infections. H. influenzae serotype a (Hia) is now a major cause of invasive infection in Indigenous communities of North America, prompting a possible requirement for an Hia conjugate vaccine. H. influenzae serotypes e and f are now more common than serotype b in Europe. Significant year-to-year increases in nontypeable H. influenzae invasive infections have occurred in many regions of the world. Invasive H. influenzae infections are now seen predominantly in patients at the extremes of life and those with underlying comorbidities. This review provides a comprehensive and critical overview of the current global epidemiology of invasive H. influenzae infections in different geographic regions of the world. It discusses those now at risk of invasive Hib disease, describes the emergence of other severe invasive H. influenzae infections, and emphasizes the importance of long-term, comprehensive, clinical and microbiologic surveillance to monitor a vaccine's impact.

An explosive outbreak of Streptococcus pneumoniae serotype-8 infection in a highly vaccinated residential care home, England, summer 2012.

In August 2012, an explosive outbreak of severe lower respiratory tract infection (LRTI) due to Streptococcus pneumoniae serotype-8 occurred in a highly vaccinated elderly institutionalized population in England. Fifteen of 23 residents developed LRTI over 4 days (attack rate 65%); 11 had confirmed S. pneumoniae serotype-8 disease, and two died. Following amoxicillin chemoprophylaxis and pneumococcal polysaccharide vaccine (PPV) re-vaccination no further cases occurred in the following 2 months. No association was found between being an outbreak-associated case and age (P = 0.36), underlying comorbidities [relative risk (RR) 0.84 95% confidence interval (CI) 0.34-2.09], or prior receipt of PPV (RR 1.4, 95% CI 0.60-3.33). However, the median number of years since PPV was significantly higher for cases (n = 15, 10.2 years, range 7.3-17.9 years) than non-cases (n = 8, 7.2 years, range 6.8-12.8 years) (P = 0.045), provided evidence of waning immunity. Alternative vaccination strategies should be considered to prevent future S. pneumoniae outbreaks in institutionalized elderly populations.

Haemophilus influenzae serotype b conjugate vaccine failure in twelve countries with established national childhood immunization programmes.

The present study describes the clinical and immunological features of children with Hib vaccine failure, who were identified through national surveillance between 1996 and 2001 in Europe, Israel and Australia. True vaccine failure was defined as invasive Hib disease occurring ≥2 weeks after one dose, given after the first birthday, or ≥1 week after ≥2 doses, given at <1 year of age. Of the 423 cases (representing 0.2 cases per 100,000 child-years at risk) reported, 330 (78%) had received three doses in the first year of life and developed disease at a median age of 28 months. Of the remaining 93, 48 had received two doses in infancy, 34 had received four doses including a booster, and 11 had received a single dose after 12 months of age. These children developed disease at a median age of 12, 33 and 71 months, respectively. In total, 47 out of 258 children (18%) with available information had an underlying medical problem (including prematurity) and 53 out of 161 (33%) had immunoglobulin deficiency. Convalescent Hib antibody concentrations were above the putative protective concentration of 1.0 mg/L in 147/194 (76%) children; low concentrations were associated with both the presence of an underlying medical problem and young age at the time of Hib disease. Almost all children who received an additional vaccine dose developed antibodies at protective concentrations. Thus, Hib vaccine failure is rare, but can occur with any immunization schedule. Children with Hib vaccine failure should have immunoglobulin and convalescent Hib antibody concentrations measured after infection and receive additional vaccination, if required.

Genetic characteristics of pneumococcal disease in elderly patients before introducing the pneumococcal conjugate vaccine.

Streptococcus pneumoniae strains causing invasive pneumococcal disease (IPD) in the elderly population of England and Wales during the winter of 2003/2004 (1 November 2003 to 30 April 2004) were characterized by serotyping and genotyping in order to determine their population structure in the elderly. Serotyping and multilocus sequence typing (MLST) were carried out on 542 invasive isolates referred to the Respiratory and Systemic Infection Laboratory. Pneumococci were distributed among 32 serotypes and 144 MLST sequence types. A high genetic diversity was observed within the major serotypes. Genetic relatedness varied with regard to serotype. Isolates within serotypes 3, 7F and 8 were the most genetically related whereas serotypes 6A and 19F comprised isolates originating from unrelated ancestors. There was indirect evidence that some pneumococci were derived from clones that had undergone capsular switching in the past. Interestingly one case of IPD was caused by a pneumococcus originating from a clone that had undergone capsular switching from serotype 18C, a serotype included in 7-valent pneumococcal conjugate vaccine (PCV) to serotype 1 (serotype not included in PCV) suggesting that virulent clones with the potential ability to evade PCV existed in the pneumococcal population prior to the routine introduction of this vaccine. Isolates from 28 cases of apparent 23-valent pneumococcal polysaccharide vaccine (PPV) failure were included but there was no evidence of the emergence of particular clones associated with vaccine failures. Longitudinal studies based on serotypic and genetic characterization of pneumococci are fundamental to understanding the impact of both PPV and PCV on the genetic structure of pneumococcal populations.

Changes in the epidemiology of epiglottitis following introduction of Haemophilus influenzae type b (Hib) conjugate vaccines in England: a comparison of two data sources.

Paediatric cases of epiglottitis declined markedly in England following the introduction of safe effective immunization against Haemophilus influenzae type b (Hib). With the recently described resurgence in Hib infections, a corresponding rise in the number of presentations of clinical epiglottitis in children was observed, although numbers were still well below those reported prior to vaccine availability. This was seen both in microbiology reports and hospital admissions data for England. In keeping with the more diverse aetiology of epiglottitis in adults, Hib vaccination had minimal impact on hospital presentations with upper airway infections in those aged 15 years and over, which showed an overall increasing trend over 10 years. The need for a high index of suspicion to allow early diagnosis of this life-threatening clinical presentation is reinforced.

Long-term impact of vaccination on Haemophilus influenzae type b (Hib) carriage in the United Kingdom.

A recent resurgence in serious infections due to Haemophilus influenzae type b (Hib) has been observed in the United Kingdom. More information on Hib transmission in the population is required in order to better understand the mechanism of this increase. The Public Health Laboratory Service (subsumed into the Health Protection Agency since April 2004) conducted four cross-sectional studies of asymptomatic oropharyngeal Hib carriage in children attending day-care nurseries in England and Wales in 1992, 1994, 1997 and 2002. These demonstrated a marked reduction in the prevalence of Hib colonization over time since vaccine introduction (3.98% in 1992; 0.70% in 1994; 0% in 1997; 0% in 2002), which did not explain the increase in invasive disease reports from 1999 onwards. We believe that a reduction in antibody levels over the first 5 years of life in immunized children in recent years has fuelled the rise in reported cases in the absence of an obvious increase in transmission.

Rising incidence of Haemophilus influenzae type b disease in England and Wales indicates a need for a second catch-up vaccination campaign.

The incidence of invasive Haemophilus influenzae type b (Hib) disease in the UK fell rapidly following the introduction of routine vaccination in 1992 and the implementation of a catch-up campaign in children under 4 years old in 1992-93. However, since 1999 the number of cases of Hib has been increasing, and in 2002 there were 134 cases in 0-4 year olds (266 in all ages). While still much less than the prevaccine burden of disease (over 800 cases a year in 0-4 year olds), this increase in incidence is worrying and has sparked a range of detailed investigations. In February 2003, the Department of Health announced a second catch-up campaign offering all children between 6 months and 4 years a further dose of Hib vaccine. The epidemiology of Hib disease in England and Wales between 1990 and 2002 is reviewed here to provide a context for this public health response.

Risk of vaccine failure after Haemophilus influenzae type b (Hib) combination vaccines with acellular pertussis.

An increase in invasive Hib disease incidence in the UK has coincided with the distribution of combination vaccines that contain acellular pertussis (DTaP-Hib). These vaccines have been associated with reduced immunogenicity of the Hib component, although there is little agreement on the clinical relevance of this finding. We retrospectively compared vaccine formulations given to fully vaccinated Hib cases with those administered to fully immunised age-matched controls using conditional logistic regression. More cases than controls received all three doses of their infant primary course as DTaP-Hib, compared with two or three doses of another Hib vaccine (conditional odds ratio 6.77 [95% CI 3.26-14.07]).

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

AIMS: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. METHODS: Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. RESULTS: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). CONCLUSIONS: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.

Hib vaccination in infants born prematurely.

AIMS: To document the immunogenicity and persistence of antibody to polyribosyl-ribitol phosphate (PRP) as well as the clinical protection against invasive Haemophilus influenzae type b (Hib) disease in premature infants immunised at the routine schedule. METHODS: Blood was obtained at 2, 5, 12, and 64 months of age from a cohort of prematurely born infants (

Clinical and microbiological features of Haemophilus influenzae vulvovaginitis in young girls.

AIMS: To define the clinical and microbiological features of vulvovaginitis in prepubertal girls whose genital swabs yielded Haemophilus influenzae. METHODS: Laboratory based study and retrospective collection of clinical data from the requesting doctors. RESULTS: Thirty eight isolates of non-capsulate Haemophilus influenzae and one of H parainfluenzae were isolated from 32 girls aged 18 months to 11 years. No other pathogens, such as beta haemolytic streptococci or yeasts, were present with H influenzae. The most common biotype was biotype II, comprising 57% of the 26 isolates biotyped. Six children had more than one episode of vulvovaginitis caused by H influenzae and a total of 14 children had recurrent vaginal symptoms. CONCLUSION: Children who have H influenzae vulvovaginitis are at risk of recurrent symptoms. Biotype II is the one most commonly associated with this condition.