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Research into Haemophilus influenzae, a commensal and pathogen of humans, has resulted in major scientific contributions to biology. The first endonucleases (restriction enzymes), which paved the way for the new genetics, and the DNA used to obtain the first complete genome sequence of a free-living organism were obtained from H. influenzae. Prevention of invasive bacterial infections of infants, such as meningitis, has been achieved using a novel class of vaccines, of which the glycoconjugates of H. influenzae were the first to be licensed. Originally fallaciously proposed to be the aetiological agent of epidemic influenza, now known to be caused by a virus, H. influenzae is a pathogen of global public health importance. Research into the pathogenesis of the infections it causes (for example, meningitis, septicaemia, pneumonia and otitis media) are case studies in understanding the molecular basis of the variation in gene expression and gene sequences that are critical to its commensal and virulence behaviour and for the strategies that can be pursued to prevent H. influenzae diseases through vaccines.

Protein-polysaccharide conjugate vaccines that protect against Haemophilus influenzae type b (Hib), serogroup C Neisseria meningitids, and multiple capsular serotypes of Stretocoiccus pneumoniae have had a major impact on invasive bacterial disease in childhood when incorporated into routine. However, effectiveness data from the UK suggest that primary infant immunization alone might not be associated with long-term protection.

ABBREVIATIONS. BCG, Bacillus calmette guerin; DTP, diphtheriatetanus-pertussis; Ig, immunoglobulin; Hib, Haemophilus influenzae type b; PS, capsular polysaccharide; Hib PS, Hib capsular polysaccharide vaccine; PRP-T, Hib PS tetanus toxoid conugate vaccine; [...]

Haemophilus influenzae type b (Hib) vaccination coverage and disease incidence were measured among preschool-aged children residing in inner-city Los Angeles. Among children 1.5 to 14 months of age, vaccination coverage of at least one dose increased from 0% in 1990 to 82% (95% confidence interval [CI] = 73%, 91%) in 1992. Among children 15 to 59 months old, vaccination coverage of at least one Hib dose administered at or after age 15 months increased from 35% (95% CI = 29%, 41%) in 1990 to 63% (95% CI = 56%, 70%) in 1992. Although Hib vaccination has reduced disease incidence in this population, greater use of vaccine can result in further reductions. (Am J Public Health. 1994;84:1154-1157), The number of infants younger than 15 months vaccinated against Hemophilus influenzae type B (Hib) appears to have increased significantly between 1990 and 1992 in Los Angeles. Hib infection can lead to bacterial meningitis which may cause death or permanent injury. Hib vaccines for children younger than 18 months only became available in 1987. Households within a 53-census-tract area were sampled in 1990, 1991 and 1992. Adult members of the households provided written records of infants' vaccinations. The proportion of infants between 1.5 and 14 months of age vaccinated with at least one dose of Hib vaccine increased from 0% in 1990 to 82% in 1992. At the time of the 1992 survey, significantly larger numbers of children had been vaccinated with second and third doses of the vaccine before they were 15 months old. Additionally, the incidence of Hib disease in children younger than five years decreased by 69% between 1986 and 1992.

Although Haemophilus influenzae type b (Hib) vaccines are effective in preventing the disease in most children, they sometimes fails to prevent infection. When H. influenzae type b polysaccharide (Hib PS) unconjugated vaccine was licensed in 1985, the vaccine was less effective than had been expected based on a study in Finland. At the end of 1987 a conjugate vaccine (combined with a protein to enhance the immune response) combined with diphtheria toxoid (Hib PS-D) was brought to market. Although the new vaccine is highly effective, some children have developed Hib disease in spite of vaccination. To discover why this occurred, 23 patients who developed Hib disease two weeks or more after vaccination were studied. The findings were compared with those from 149 patients who became infected with Hib after vaccination with the unconjugated vaccine, and from 90 unvaccinated patients who also developed the disease. Every one of the children who developed the disease after vaccination with the Hib conjugate vaccine had abnormally low immunoglobulin (Ig) levels, specifically IgG2. From a practical standpoint, this indicates that Ig concentrations, including IgG2, should be measured in all patients, even though they do not have recurrent infections. In addition, children with deficient immune responses should be revaccinated with conjugate vaccine, because they are at increased risk of having a recurrence of the disease. Most children respond to revaccination, and those who do not should be evaluated for therapy for immunodeficiency. (Consumer Summary produced by Reliance Medical Information, Inc.)

There are three conjugate vaccines licensed by the US Food and Drug Administration (FDA) for use against Haemophilus influenzae type b. The American Academy of Pediatrics (AAP) has reviewed and revised its recommendations regarding use of these vaccines based upon two recent studies. The new recommendations suggest that either the HbOC vaccine or the PRP-OMP vaccine (two of the three Haemophilus influenzae vaccines) be given intramuscularly at about two months of age. Either a three-dose series of HbOC or a two-dose series of PRP-OMP should be given with two-month intervals between doses. The same vaccine given initially should be given throughout the period of immunization. A booster dose of HbOC should be given at 15 months of age, or a booster dose of PRP-OMP should be given at 12 months of age. Infants with immunization started between the ages of 7 and 11 months should be given either vaccine in two doses two months apart, and a third dose of the same vaccine at 15 to 18 months. Children between 12 and 14 months of age should be given two doses at two- to three-month intervals. A single dose is sufficient for any child between 15 months and five years of age, and any unimmunized children over five years of age at risk for H. influenzae type b disease should receive a single dose. Any child that had the disease when younger than 24 months of age should be immunized to prevent recurrence. The AAP will release further statements and guidelines regarding this issue in the future. (Consumer Summary produced by Reliance Medical Information, Inc.)

Infection by Haemophilus influenzae type b bacteria can lead to a variety of serious complications, including meningitis, in which the membranes that surround the brain and spinal cord become inflamed. Some population groups, including certain Native American tribes, have infection rates several times higher than the general population. To evaluate the effectiveness of a new vaccine among Navajo infants, a controlled study was carried out. Infants aged between 42 and 90 days were randomly assigned to receive either the vaccine (2,588 subjects), a conjugate of H. influenzae type b capsular polysaccharide and parts of the outer-membrane protein complex (OMPC) of Neisseria meningitidis serogroup B, or a placebo (2,602 subjects), an inactive substance. Second injections were given between the ages of 70 and 146 days. Blood samples were obtained at different points during the study and analyzed to determine the infants' levels (titers) of antibodies against H. influenzae; the safety and efficacy of the vaccine were also monitored. The study began in July 1988; by August 1990, after 23 cases of H. influenzae infection had occurred, it was decided to stop the study. The group that had received the vaccine had far fewer cases than the placebo group (1 case versus 22 cases) by the age of 18 months. Thirteen of the 22 placebo cases developed meningitis. No infections occurred in the vaccine group between the first and second doses of vaccine; eight occurred in the placebo group. Antibody levels did not increase noticeably after the second vaccination, but the vaccine was effective up until 18 months of age. The overall efficacy of the H. influenzae type b OMPC vaccine was more than 90 percent in this population. This was much higher than the efficacy reported for another conjugate vaccine in another study of Native Americans in Alaska. Use of this vaccine should eliminate H. influenzae type b infection. (Consumer Summary produced by Reliance Medical Information, Inc.)

The relative efficacy of two vaccines was assessed for use against invasive Haemophilus influenzae type b infection in two groups of vaccinated children. Data used were derived from reports of spontaneous cases of Haemophilus influenzae type b disease that were reported to the Food and Drug Administration (FDA) Spontaneous Reporting System, a computerized database that contains information on adverse drug episodes reported by health professionals and pharmaceutical manufacturers. Additional data were obtained from investigators at Washington University School of Medicine, St. Louis, MO. The two vaccines examined were H influenzae type b polysaccharide (PRP) and PRP-diphtheria toxoid-conjugate (PRP-D) vaccine. H influenzae type b disease results in respiratory infection. It was previously considered to be the cause of influenza (flu), but is now believed to be a primary or secondary invader. The children were followed-up for 13 months after receiving PRP or PRP-D vaccine. A total of 127 cases of invasive H influenzae were reported in the group given the PRP vaccination; 17 cases were noted in the PRP-D group. The results of the data were limited by a number of variables within the subject population groups. The proportion of H influenzae cases that occurred 14 days or more after vaccination was significantly greater for the PRP vaccine group (106 of 127 cases) than for the group who received PRP-D vaccine (7 of 17 cases). Only seven failures occurred with the PRP-D vaccine; this was fewer than the 86 percent that was expected. The findings demonstrated that the PRP-D vaccine was more effective than the PRP vaccine in preventing infection by H. influenzae type b 14 days or more after immunization. (Consumer Summary produced by Reliance Medical Information, Inc.)

COMMENTARY The introduction and widespread use of Haemophilus influenzae type b (Hib) vaccine has drastically reduced the incidence of bacterial meningitis in children and other invasive infections caused by this [...], One hundred forty-one children of 5 to 59 months of age were immunized with a single intramuscular dose of 0.67, 3.3, 17, or 67 jig polyribophosphate (PRP), the capsular antigen of Hemophilus influenzae, type b. The immunizations were well tolerated, particularly at doses of .67 to 17 µ g. Antibody activity was measured by radioactive antigen binding, using ³H-labelled PRP. Doses of 3.3 and 17 µ g produced significant antibody rises in nearly 90% of recipients; 0.67 and 67 µ g in approximately half. The geometric mean titers were similar at three and six weeks after immunization and were greater with the middle doses. The net antibody increase in responding children was strongly age dependent, but was not related to the pre-immunization antibody concentration. Rises in serum bactericidal activity against H. influenzae type b generally accompanied rises in antibody concentration as measured by the antigen-binding assay. A recently developed Haemophilus influenzae type b capsular polysaccharide vaccine was given to 48 977 children 3 months to 5 years of age; an equal number of children receiving group A meningococcal vaccine served as,controls. The protection as well as serum antibody response was strongly age dependent. Among children who had received the H. influenzae type b vaccine when 18 months of age or older, there were no cases of bacteremic disease caused by H. influenzae type b in the first year after vaccination. At the same time 11 such cases were seen in the control group of the same age, a highly significant difference. In the second year after vaccination two cases occurred in the H. influenzae type b-vaccinated group, five in the meningococcal-group A vaccinated group. No protection was seen among children who had been younger than 18 months when vaccinated, even if they received a booster dose of the vaccine. The serum antibody response to the H. influenzae type b polysaccharide, measured by radioimmunoassay, was poor in children below 18 months of age and good in those above it. No effect of the vaccine could be seen on the nasopharyngeal carriage of H. influenzae type b, which was approximately 6% in this age group. Adverse effects of the vaccine were mild.

Children who have sickle cell disease have an increased risk of infection by certain types of bacteria, known as encapsulated bacteria. This may result from the reduction or complete absence of spleen function. One of the encapsulated bacteria is Hemophilus influenza type b. A vaccine for this pathogen was approved in 1985 for use by asplenic (lacking a functioning spleen) children with sickle cell disease. Little research has been performed to evaluate the safety and effectiveness of this vaccine. This prompted a study which examined the use of this vaccine in 98 sickle cell patients, aged one and one half to 20 years. Overall, the subjects tolerated the vaccine well. Six of the 98 patients developed mild side effects, and one developed more serious symptoms eight hours after receiving the vaccine. The H influenza type b polysaccharide vaccine reliably stimulated immunity in sickle cell patients over age five. However, the vaccine did not consistently protect children under five years against H influenza type b infection. (Consumer Summary produced by Reliance Medical Information, Inc.)

ABSTRACT: We evaluated the efficacy of Haemophilus b polysaccharide vaccine in children in Minnesota using a case-control study. The vaccine became available in Minnesota in August 1985. During the subsequent 28 months, 88 cases of invasive H influenzae type b disease were identified in children 24 to 71 months of age, the group targeted for vaccination. Of the 88 cases, 36 (41%) occurred in vaccinated children. Fifty-eight (33%) of 176 controls were vaccinated during a similar period. The vaccine's protective efficacy for children with any history of vaccination was -58% (95% confidence interval =-204%to 18%). The vaccine's protective efficacy for children who were most likely to be protected by vaccination was -55% (95% confidence interval =-238% to 29%). Our results indicate that vaccination with Haemophilus b polysaccharide vaccine had no effect in preventing H influenzae type b disease in Minnesota children.

ABSTRACT: To assess the protective efficacy of the Haemophilus b polysaccharide vaccine, a case-control study was conducted in Connecticut, Dallas County, and greater Pittsburgh. Seventy-six children 24 to 72 months of age who had H influenzae type b isolated from normally sterile sites from August 1985 through July 1987 were enrolled. For each case two controls, matched by age and place of residence, were randomly selected from the records of all live births in the area. Antecedent receipt of the Haemophilus b polysaccharide vaccine was ascertained from the records of all physicians and clinics at which the subjects received medical care. Overall, 12% of the cases and 39% of the controls had received the vaccine. The estimate of the protective efficacy of the vaccine was 88% overall (95% confidence interval, 74% of 96%) and 91% (95% confidence interval, 71% to 99%), 92% (95% confidence interval, 76% to 99%), and 81% (95% confidence interval, 45% to 96%) in Connecticut, Dallas County, and greater Pittsburgh, respectively. The estimates were not substantially affected by adjusting with logistic regression for differences between the cases and controls in race and the attendance of group day care. We conclude that the Haemophilus b polysaccharide vaccine is highly effective in these areas among children who receive the vaccine when they are 24 months of age or older.

ABSTRACT: To assess the efficacy of the Haemophilus b polysacchaide vaccine following licensure and to evaluate the risk of Haemophilus influenzae type b (Hib) disease in the week following vaccination, we conducted a day care--based case-control efficacy study using cases of invasive Hib disease ascertained through active surveillance in areas with a total population of 34 million. For each patient 18 to 59 months old, up to three 18- to 59-month-old controls were chosen from the same day care classroom. Using conditional logistic regression, the vaccine efficacy was estimated to be 45% (95% confidence interval = - 1% to 70%) and did not change significantly after accounting for potential biases. In addition, three (3%) of 104 patients vs five (2%) of 207 controls were vaccinated within seven days before the patients' dates of admission (odds ratio = 1.8, 95% confidence interval=0.3 to 10.2), which does not suggest an increased risk of Hib disease in the week following immunization. This study suggests that the efficacy of the currently used HBPV is less than expected from previous studies and points out the usefulness of case-control studies for monitoring vaccine efficacy following licensure.

A SYNTHETIC CONJUGATE POLYSACCHARIDE VACCINE AGAINST HAEMOPHILUS INFLUENZAE TYPE B Verez-Bencomo V, Fernandez-Santana V, Hardy E, et al. Science. 2004;305:522-525 Purpose of the Study. To demonstrate the safety and immunogenicity [...]

The Chief Medical Officer for Northern Ireland Dr Henrietta Campbell has reminded parents again of the importance of ensuring their children are protected against Haemophilus influenza type B (Hib). All [...]