Helena Käyhty

Efficacy of a Pneumococcal Conjugate Vaccine against Acute Otitis Media

BACKGROUND Ear infections are a common cause of illness during the first two years of life. New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae. METHODS We enrolled 1662 infants in a randomized, double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197. The children received either the study vaccine or a hepatitis B vaccine as a control at 2, 4, 6, and 12 months of age. The clinical diagnosis of acute otitis media was based on predefined criteria, and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy. RESULTS Of the children who were enrolled, 95.1 percent completed the trial. With the pneumococcal vaccine, there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously. There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age. The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent (95 percent confidence interval, -4 to 16 percent [the negative number indicates a possible increase in the number of episodes]), culture-confirmed pneumococcal episodes by 34 percent (95 percent confidence interval, 21 to 45 percent), and the number of episodes due to the serotypes contained in the vaccine by 57 percent (95 percent confidence interval, 44 to 67 percent). The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent, whereas the number of episodes due to all other serotypes increased by 33 percent. CONCLUSIONS The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine.

A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease.

BACKGROUND Haemophilus influenzae type b is the leading cause of invasive bacterial disease in young children. The capsular polysaccharide vaccine does not protect children at greatest risk (those under the age of 18 months), but a polysaccharide-protein conjugate vaccine has proved to be more immunogenic in this age group. METHODS We enrolled 114,000 infants in Finland in an open, prospective, randomized trial of a H. influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]). Children born on odd-numbered days were vaccinated at the ages of 3, 4, 6, and 14 to 18 months; those born on even-numbered days formed the control group and received the same vaccine at the age of 24 months. RESULTS After three doses of the vaccine there were 4 cases of verified bacteremic H. influenzae type b disease in the group receiving early vaccination, as compared with 64 cases in the control group, between the ages of approximately 7 and 24 months. The protective efficacy of the vaccine was thus 94 percent (95 percent confidence interval, 83 to 98). No serious adverse effects were reported. The immune response to the conjugate vaccine was characteristic of a T-cell-dependent response when studied in a cohort of 120 infants. The primary immunization series resulted in a geometric mean concentration of anticapsular antibody of 0.53 micrograms per milliliter at the age of seven months, and the fourth dose evoked an anamnestic response, with a mean antibody concentration of 45.22 micrograms per milliliter. CONCLUSIONS A new conjugate vaccine consisting of the capsular polysaccharide of H. influenzae type b covalently linked to a protein carrier (PRP-D), administered to infants beginning at the age of 3 months, is highly effective in protecting young Finnish children (7 to 24 months old) against invasive H. influenzae type b infections.

Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants

The World Health Organization (WHO) is undertaking a series of consultations on serological criteria for the evaluation and licensure of new formulations/combinations or different vaccination schedules of pneumococcal conjugate vaccines. The lack of a definitive serological correlate of protection and the multiplicity of antigens involved, especially since the clinical efficacy of most of the individual serotypes represented in the only licensed vaccine has not been established, are hindering the formulation of criteria for licensure of new formulations or combinations of the vaccine. This report analyses the various options with their relative merits and drawbacks and provides preliminary recommendations as guidance to regulatory agencies in evaluating these vaccines for the purposes of licensure. More detailed recommendations for production and control of pneumococcal conjugate vaccines, including criteria for evaluation for licensure, are currently being drafted.

Prevention of Hemophilus influenzae Type B Bacteremic Infections with the Capsular Polysaccharide Vaccine

A long-term follow-up of approximately 50,000 children who received the Hemophilus influenzae type b capsular polysaccharide vaccine in 1974 at three months to five years of age has shown good protective efficacy in those who received the vaccine at 18 months or older. No adverse effects were observed. Analysis of paired serum samples from 514 vaccinated children showed that effective immunization with this vaccine could be performed after but not before the age of 16 to 20 months. An analysis of 956 bacteremic H. influenzae infections occurring in Finland over a period of five years showed that 94 per cent of all cases were in children under 10 years of age. Of these, 40 per cent occurred in children under 18 months, and 60 per cent in children between the ages of 1 1/2 and 9 years. These 60 per cent are potentially preventable with the capsular polysaccharide vaccine.

Clinical Efficacy of Meningococcus Group A Capsular Polysaccharide Vaccine in Children Three Months to Five Years of Age

We performed field trials in the course of an epidemic in Finland to learn whether Group A memingococcal capsular polysaccharide vaccine protects infants and young children from meningitis. The first trial involved 130,178 children between the ages of three months and five years; 49,295 children received the vaccine, 48,977 received a control Haemophilus influenzae Type b polysaccharide vaccine, and 31.906 remained unvaccinated. No cases of meningitis or sepsis caused by Group A meningococci were seen in the first year of observation among the children vaccinated with meningococcal vaccine whereas six occurred among those vaccinated with the H. influenzae vaccine and 13 among those not vaccinated. In the second trial 21,007 children of the same ages received the meningococcal vaccine. No cases caused by Group A occurred among those vaccinated, although five to seven would have been expected within the year. Meningococcal Group A vaccine appears efficacious in young infants and children.

Enzyme-Linked Immunosorbent Assay for Quantitation of Human Antibodies to Pneumococcal Polysaccharides

Streptococcus pneumoniae is a major human pathogen causing pneumonia, sepsis, meningitis, and otitis media ([12][1]). It causes infections most often in young children ([12][1]) and elderly adults ([1][2]) because their immune systems are either unprepared or unable to respond effectively to

The fundamental link between pneumococcal carriage and disease

Streptococcus pneumoniae (pneumococcus) is a major cause of worldwide mortality and morbidity, and to a large extent is vaccine-preventable. Nasopharyngeal carriage of pneumococcus precedes disease and is the source of pneumococcal spread between people. The use of vaccine effect on carriage as part of the vaccine licensure and post-vaccine introduction evaluation could facilitate and expand the licensure of new, life-saving pneumococcal vaccines and enable a comprehensive estimate of population effects after vaccine introduction. The authors provide a review of the evidence supporting pneumococcal carriage at the individual level as an immediate and necessary precursor to pneumococcal disease. Based on such a causal link between carriage and disease, the authors emphasize the role of information on pneumococcal carriage in vaccine trials and in public health decision-making.

Protective Efficacy of a Second Pneumococcal Conjugate Vaccine against Pneumococcal Acute Otitis Media in Infants and Children: Randomized, Controlled Trial of a 7-Valent Pneumococcal Polysaccharide-Meningococcal Outer Membrane Protein Complex Conjugate Vaccine in 1666 Children

To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PncOMPC) against acute otitis media (AOM), 1666 infants were randomly assigned to receive either PncOMPC or control vaccine (hepatitis B vaccine) at 2, 4, 6, and 12 months of age. Of the 835 children assigned to receive PncOMPC, 187 received a 23-valent pneumococcal polysaccharide vaccine (PncPS) at 12 months of age instead. Whenever AOM was diagnosed, middle ear fluid was aspirated for bacterial culture. In the PncOMPC and control groups, there were 110 and 250 AOM episodes, respectively, in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes, which indicates a vaccine efficacy of 56% (95% confidence interval, 44%-66%). The serotype-specific efficacy ranged from 37% for 19F to 82% for 9V. The 2 boosters seemed to provide equal protection against AOM, but PncPS induced markedly higher antibody concentrations. The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine.

Efficacy of haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy

Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine has recently been shown to be capable of inducing antibodies to H. influenzae in infants. In an evaluation of its clinical efficacy, 60,000 children were enrolled in an open trial in Finland. Children born on odd-numbered days between October 1, 1985, and September 30, 1986, received the vaccine at 3, 4, 6, and 14 months; those born on even-numbered days served as controls. The geometric mean antibody titer measured in a cohort of 99 children rose from a prevaccination level of 0.08 microgram per milliliter at three months of age to 0.42 microgram per milliliter at seven months. Only minor adverse reactions were reported. Up to February 1987, two cases of invasive H. influenzae infection had occurred among the children who had received three doses of vaccine, whereas 12 cases had occurred among the controls (P = 0.0005 by Poisson one-tailed test). The rate of short-term (average follow-up time, five months) protection provided by this conjugate vaccine in infancy was thus 83 percent.

Antibody Responses to Nasopharyngeal Carriage of Streptococcus pneumoniae in Adults: A Longitudinal Household Study

BACKGROUND Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques. METHODS We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members >18 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples. RESULTS Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .006). There was a small (approximately 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA. CONCLUSIONS Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.