Prevention of invasive Haemophilus influenzae type b disease: lessons from vaccine efficacy trials (original) (raw)
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Effectiveness of Haemophilus influenzae type b vaccines
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 1990
To determine the clinical effectiveness of Haemophilus influenzae type b (Hib) vaccines. STUDY IDENTIFICATION AND SELECTION: Computerized searches of MEDLINE, EMBASE and SCISEARCH databases were performed, and the reference list of each retrieved article was reviewed. Two prospective clinical trials of Hib polyribosyl ribitol phosphate conjugated with diphtheria toxoid (PRP-D) were identified. In addition, one cohort study of the PRP-D vaccine, two trials of the PRP vaccine, five case-control studies of the PRP vaccine and 10 randomized controlled trials of the immunogenicity of the PRP-D vaccine were identified. Study quality was assessed and descriptive information concerning the study populations, the interventions and the outcome measurements was extracted. The difference in the effectiveness of the PRP-D vaccine between the prospective trials, in which a three-dose schedule had been used beginning at 2 to 3 months of age, was clinically important (37% v. 83%) but not statistica...
Safety and immunogenicity of two Haemophilus influenzae type b conjugate vaccines
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 2004
OBJECTIVES Haemophilus influenzae type b (Hib) infection remains a major public health problem in the developing world. We evaluated the safety and immunogenicity of a new PRP-CRM197 conjugate Hib vaccine (Vaxem Hib, Chiron Vaccines), compared with the HibTITER vaccine (Wyeth-Lederle Vaccines), following the World Health Organisation (WHO)'s accelerated schedule which allows 4-week intervals between doses. STUDY DESIGN A phase II, observer-blind, multicentre, randomised, controlled, non-inferiority study. METHODS In total, 331 babies were immunised with either Vaxem Hib (N = 167) or HibTITER (N = 164) vaccine at 6, 10 and 14 weeks of age, in parallel with oral polio, diphtheriatetanus-pertussis and hepatitis B vaccines. Post-immunisation reactions were recorded after each immunisation and at follow-up visits. Anti-polyribosylribitol phosphate (PRP) antibodies were measured using enzyme-linked immunosorbent assays (ELISAs) before and 1 month after the third immunisation. RESULTS ...
Human Vaccines, 2009
Hib is estimated to cause at least 3 million cases of serious disease every year as well as approximately 386,000 deaths. 2 The burden of Hib disease is proved in large studies conducted in Africa, Asia and Latin America where the vaccine was found to be useful in reducing childhood infections. 3-5 In view of demonstrated safety and efficacy, World Health Organization (WHO) recommends that conjugate Hib vaccines should be included in all routine infant immunization program. 2 Hib vaccination also reduces nasopharyngeal colonization with the organism, leading to substantial reduction in disease incidence than can be directly attributed to the effects of the vaccine. This indirect effect (herd immunity) has been amply demonstrated in several post-introduction efficacy studies in which near-elimination of Hib disease occurred even when vaccine coverage was sub-optimal. 2,6-8 The successful reduction of Hib disease including pneumonia and meningitis has been observed in Hib vaccine recipients in developing countries like Gambia, Uganda, Kenya and Bangladesh. 9-12 In these countries, the Hib conjugate vaccine was made available from vaccine manufacturers and/or global organizations aiming at improved immunization services. The actual number of children receiving a third dose of the vaccine globally has increased from 8% of the world's surviving infants in 1999 to 22% in 2006. 13 The epidemiology of Hib infections in India has revealed that the infection is prevalent, even in India. Hib is a leading cause of bacterial childhood meningitis and important cause of severe pneumonia, in India. Approximately, 19% (410,000) of under 5 deaths in India are due to pneumonia. 14 India accounts for almost 40% of worldwide childhood pneumonia cases. However, experts opine that these estimates are underestimated. The case-fatality rate for Hib meningitis was 11% overall, in a study conducted in India. 15 A study showed that about 30% of Indian children who survived Hib meningitis, suffered from major disabilities. 16 There is an increase in consensus among experts that estimates of Hib pneumonia rates in India are underestimated. A large percent of Indian children are thought to be at a high risk due to increasing resistance to antibiotics as well as to limited access to health care facilities. As per hospital data, 30-45% cases of meningitis and 8-12% cases of pneumonitis in India are due to Hib. It is estimated that annual incidence of Hib In view of the need for a cost effective Haemophilus influenzae type b (Hib) conjugate vaccine, a lyophilized vaccine as capsular polysaccharide (PRP) conjugated to tetanus toxoid (Sii HibPRO) was indigenously developed by Serum Institute of India Ltd., Pune (SIIL). From 2004-07, this new vaccine underwent a series of clinical studies before its licensure by National Regulatory Authority (NRA). This paper discusses the results obtained during the clinical development of this vaccine. On finding the vaccine to be safe in animal toxicity studies, a Phase I single dose study was carried out to assess the safety profile of Sii HibPRO in healthy adult male volunteers. Subsequently, in Phase III pre-licensure study, immunogenicity and safety of Sii HibPRO was assessed and compared with Hib tetanus conjugate vaccine (Act-HIB) of Aventis, France. Immunogenicity was evaluated based upon serum anti-PRP IgG antibody concentrations by ELISA at prevaccination and one month each after the second and third dose. Safety was evaluated by recording details of adverse events after each dose of the vaccine. Postvaccination after the third dose, there was 100% seroprotection (anti PRP IgG titre ≥ 0.15 μg/ml) in both the groups. Long term protection (≥1 μg/ml) was achieved in 95.2% and 98.06% infants in Sii HibPRO and Act-HIB groups, respectively. At 15 months, prior to booster dose, 30 children in each group were evaluated and all were found to be seroprotected. Post booster, all of them responded with a strong boost response. Safety of Sii HibPRO was re-established in the post marketing surveillance in which 2,739 doses were administered to 1,029 infants, in 23 cities across India.
Haemophilus influenzae type b conjugate vaccine trial in Oxford: implications for the United Kingdom
Archives of Disease in Childhood, 1989
Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection in young children worldwide. During childhood, acquisition of antibody directed against the polysaccharide capsule of the organism, presumably as a result of asymptomatic carriage, confers protection and disease is much less common after the age of 4 years. Like other polysaccharides, the polyribosyl ribitol phosphate (PRP) of the Hib capsule is a T-independent antigen and not immunogenic when administered as a vaccine in infancy. Because the highest rates of disease occur in the first 2 years of life, efficacious Hib vaccines have been designed by covalently linking the PRP capsule to a carrier protein that recruits T-cell help for the polysaccharide immune response and induces anti-PRP antibody production even in the first 6 months of life. Introduction of Hib protein-polysaccharide conjugate vaccines into many industrialized countries over the past 15 years has resulted in the virtual elimination of invasive Hib disease. However, despite the success of the vaccine programme several factors may interfere with the effectiveness of the vaccine in the routine programme, as observed in the UK recently. Such factors may include interference with other concomitant vaccines, waning immunity in the absence of booster doses of vaccine, and reduced natural boosting as a result of decreased transmission of the organism. However, the burden of disease remains highest in resource-poor countries and urgent efforts are needed to provide the benefits of this vaccine for children living in regions where it cannot be used for economic and logistical reasons.
Vaccine, 2010
The use of the highly effective Haemophilus influenzae type b (Hib) conjugate vaccine has increased globally. We review the benefits and limitations of studies measuring Hib vaccine effectiveness (VE). We critically examine the case-control approach by assessing the similarities and differences in methodology and findings and discuss the need for future Hib VE studies. In the absence of good surveillance data, vaccine effectiveness studies can play an important role, particularly with the increasing use of pneumococcal vaccine that has not been well tested under field conditions in less developed countries. However, the effectiveness of Hib vaccine has been well documented so the need for future VE Hib studies is minimal.
Strategies for immunization against invasive Haemophilus influenzae type b infection
Vaccine, 1991
Available data on the immunogenicity, safety and efficacy of Hib conjugate vaccines are encouraging and the prospects for having a means to control invasive Hib disease are good. Most of the third generation Hib vaccines seem to prevent invasive Hib disease at a level of efficacy that motivates worldwide mass immunization of infants. The peak incidence of Hib meningitis occurs before the age of 1 year in most industrialized countries and the most desirable time to start vaccination against Hib is at 2-3 months of age. In many countries a Hib conjugate vaccine may ideally be coordinated with the DTP immunization programme. In non-industrialized countries the peak incidence of Hib meningitis occurs earlier than in industrialized countries, which means that in these areas immunization against Hib meningitis should start earlier, for instance at 6 weeks when the first DTP vaccine injection is given in many countries.
Seminars in Pediatric Infectious Diseases, 1998
Haemophilus mfluenzae is a small gram-negative pleomorphic coccobacillus. The H influenzaetype b (Hib) strain is especially important because, prior to the advent of effective Hib vaccines, the organism was the cause of 95% to 98% of severs invasive infections, including meningitis, epiglottitis, cellulitis, sepsis, pneumonia, and osteomyelitis, in children less than 5 years of age. An important microbiologic feature of H influenzae is its development of resistance to a wide variety of antibiotics, including sulfonamides, trimethoprim-sulfamethoxazole, erythromycin, tetracycline, and penicillin. Ampicillin resistance is now widespread, ranging between 5% and 40% of all isolates in various parts of the world. The current mainstays of treatment are third-generation cephalosporins, but the potential for increased resistance to them, as well as other factors, has underscored the need for prophylactic measures. Since the early 1970s, when the capsular polysaccharide of Hib was purified, characterized, and shown to be immunogenic, tremendous strides have been made worldwide to immunize children against the organism and to irradicate the bacteria. A steady decline in the incidence of Hib diseases has occurred since the introduction in 1990 of Hib conjugate vaccines for infants. Because of this rapid decline, Hib diseases among children less than 5 years of age is targeted for elimination in the United States. This article provides an overview of the discovery and characterization of the organism and a review of the literature on the impact that the Hib vaccines have had on morbidity and mortality rates among children less than 5 years of age.
Efficacy of Haemophilus influenzae type b vaccination of children: a meta-analysis
European Journal of Clinical Microbiology & Infectious Diseases, 2006
Haemophilus influenzae type b (Hib) infection is a leading cause of meningitis and pneumonia in infants and children in the developing countries, and yet the implementation of routine Hib vaccination is very slow. The aim of the present study was to quantify the protective efficacy of H. influenzae type b vaccination of young children. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials Register were searched. References of selected articles were also reviewed and experts contacted. Eight randomized trials were found that compared the efficacy of H. influenzae type b conjugate vaccine to placebo or no vaccine. Information on study design, patients enrolled, age, vaccine type, cases of invasive H. influenzae type b disease, adverse events, and items to assess potential for bias was recorded. The incidence of invasive H. influenzae type b infection formed the primary outcome. The odds ratio (OR) of developing Hib infection was combined using a random effects model to provide a measure of vaccine efficacy. The protective effect, defined as the relative risk reduction, was estimated as (1-OR). From eight trials, the protective efficacy of the Hib conjugate vaccine was 84% (OR 0.16; 95%CI 0.08-0.30) against invasive Hib disease, 75% (OR 0.25; 95%CI 0.08-0.84) against meningitis, and 69% (OR 0.31; 95%CI 0.10-0.97) against pneumonia. Serious adverse events were rare. The results provide firm evidence that Hib conjugate vaccines are safe and effective in reducing the risk of all forms of invasive Hib disease, further establishing that vaccination of children in developing countries can protect them from a potentially fatal yet preventable disease.
The Journal of Pediatrics, 1995
To evaluate the safety and immunogenicity of differing sequences of heterogeneous Haemophilus influenzae type b (Hib) conjugate vaccines, we randomly assigned 300 infants to one of six vaccination schedules. At 2, 4, and 6 months of age, subjects were given single or heterogeneous vaccines: Hib polysaccharide (PRP) conjugated to mutant diphtheria toxin (HbOC), PRP conjugated to outer-membrane protein of Neisseria meningitidis (PRP-OMP), or PRP conjugated to tetanus toxoid (PRP-T). No serious reactions were attributable to immunization with heterogeneous vaccines, and there were few significant differences in the rates of minor adverse reactions among groups. PRP-OMP was the only vaccine that induced an antibody response after the first dose, but significant booster responses were not seen after the second and third doses. Subjects given PRP-T vaccine responded well after two doses, but three doses of HbOC vaccine were needed for an equivalent antibody response. All the Hib vaccine schedules evaluated were immunogenic, and schedules initiated by PRP-OMP vaccine at 2 months of age, followed by two doses of either HbOC or PRP-T vaccine at 4 and 6 months of age, induced the highest antibody levels after each dose. Such schedules may be the best for protecting infants and children who are at greatest risk of having invasive Hib disease, such as American Indian children. (J PE-DIATR 1995;126:206-11) The widespread use of Haemophilus influenzae type b polysaccharide (polyribosylribitol phosphate) conjugate vaccines has led to a significant (up to 95%) decrease in the incidence of invasive Hib infections in infants and children in the United States and elsewhere.