Haemophilus influenzae type b: Epidemiology and Prevention

INTRODUCTION

The existence of safe and effective vaccines to combat Haemophilus influenzae type b (Hib) and the enormous impact of vaccine on the control of diseases caused by Hib in the industrialized countries has led to its acceptance as a possible vaccine for inclusion in immunization programs in the Region. Some countries in the Region, such as Uruguay, Chile, and the Netherlands Antilles, have used the H. influenzae type b vaccine, and it has been possible to confirm a similar impact. Medical professionals and parents alike recognize the seriousness of meningitis and pneumonias and are anxiously awaiting the inclusion of this vaccine in regular immunization programs. It is important to point out that since this microorganism is a major cause of mortality and morbidity from pneumonias, as well as meningitis and other invasive diseases, it is hoped that Hib vaccination will have a significant impact on the health of children in the Americas.

MICROBIOLOGY

Haemophilus influenzae is a Gram negative coccobacillus that has been identified as an important pathogen in human beings and has become a serious public health problem. Although the information is incomplete in this regard, it is estimated that at least 3 million serious cases of disease worldwide are caused by Haemophilus influenzae type b each year, with mortality in children under 5 ranging from 380,000 to 700,000.

This bacterium is very difficult to culture and requires the X (hemin) and V (NAD: nicotinamide-adenine dinucleotide) factors. The use of inadequate culture media is probably one of the primary reasons for the low reported incidence of this microorganism. On the basis of three biochemical reactions it is possible to differentiate 8 biovars among the capsular or noncapsular strains of H. influenzae. The former may be differentiated into six serovars or types (a to f), based on the antigenic structure of the capsular polysaccharides. Although both the capsular and noncapsular (nontypable) strains can cause disease, the type b varieties are responsible for more than 90% of serious disease in children under 5 years of age. The type b polysaccharide is a polymer of D-ribose-ribosyl-phosphate, also known as PRP. The capsular polysaccharide is the principal virulence factor in the capsular strains, but others also exist, such as the lipopolysaccharides, the proteases for IgA, and some of the outer membrane proteins.

PATHOGENESIS

Haemophilus influenzae is part of the indigenous flora of the upper respiratory tract. Various percentages have been reported for asymptomatic carriers of H. influenzae, which vary from country to country. In the industrialized countries, for example, the range is between 1% and 5% of the population, possibly attaining levels of more than 40% in the developing countries. These percentages vary even within a country itself, depending on the populations and/or areas analyzed, and are generally lower in adults than in children of preschool age. Colonization with nontypifiable strains is much more common. Colonization may persist in the oropharynx for many months. Transmission takes place from person-to-person through air droplets and/or oral secretions. The factors that influence the effectiveness of transmission and the ability to colonize are unknown. Usually, a prolonged carrier state with colonization of the respiratory mucosae is the rule for subsequent invasive disease. Propagation `through the mucosae leads to infections such as bronchitis, sinusitis, otitis, and conjunctivitis, in addition to dissemination toward the lower respiratory tract, causing pneumonia. Alteration of the anatomical barriers permits passage of the microorganism to the meninges, causing meningitis, or to the blood (bacteremia) with subsequent dissemination, causing infections where the microorganism establishes itself, for example, meningitis, arthritis, sepsis, abscesses, cellulitis, etc.

EPIDEMIOLOGY

Incidence:

  1. Industrialized countries. Most of these studies focus on invasive infections, including meningitis, sepsis, bacteremic pneumonias, and other syndromes such as epiglotitis that are accompanied by the presence of organisms in normally sterile sites such as the blood, cerebrospinal fluid (CSF), and pleural fluid. These studies indicate that the incidence of H. influenzae type b in meningitis may range from 8 to 60 cases per 100,000 children under 5 and from 21 to 100 cases per 100,000 children under 5 for all invasive diseases.
  2. Developing countries. Studies of the Hib incidence in meningitis and invasive diseases in these countries are very limited. Estimating the incidence would require surveillance to be conducted in defined populations of known size, whereas much of the available data is usually from a particular hospital or health center where neither the population served nor the incidence of the disease can be estimated. It may therefore be said that the incidence varies from region to region and that in Asia it is estimated at 6 cases per 100,000 children under 5; in South America, 17 to 25 per 100,000; in the Middle East, 16 to 31 per 100,000; and in Africa, 50 to 60 per 100,000.

The accuracy of these studies is influenced by a number of factors, and these results are usually documented when an organism is isolated from a normally sterile site, and this is influenced by the isolation techniques and culture media employed, in addition to the prior use of antibiotics. In many cases, moreover, specimens have not been taken from all patients with invasive disease, leading to an inevitable underestimation of the true incidence.

Efforts to calculate the incidence of Hib in pneumonias are hindered by the low sensitivity and specificity of the tests used to determine the etiology of pneumonias. Nevertheless, the results of recent field trials with Hib vaccine conjugate in Gambia have shown a 20% reduction in radiologically confirmed cases of pneumonia, making it possible to assert that at least in the developing countries, most of the serious disease caused by Hib occurs in the form of pneumonias.

Age distribution: Even though Hib disease occurs in children under 2, the highest incidence occurs in infants under 1 year of age in the developing countries and over 1 in the industrialized countries. Table 1 shows the differences between Gambia, Chile, the United States, and Finland.

Table 1, Distribution by age

Risk factors: The factors that increase the risk of Hib infection can be divided into those associated with: a) greater susceptibility to Hib infections; and b) greater exposure to the microorganism. It is sometimes difficult to distinguish clearly between the two.

Among the factors related to greater susceptibility are:

Among the factors associated with greater exposure are:

PREVENTION

Chemoprophylaxis: The use of antibiotics such as rifampicin makes it possible to attain high concentrations of antimicrobial agents intracellularly, in saliva and other secretions, thereby providing an efficient means of eliminating colonization and, consequently, possible spread and secondary infections.

Natural immunity: Natural immunity to Hib involves many factors and components of the immune system, e.g., immunity of mucous membranes, humoral immunity, activation of inflammatory responses, phagocytosis, and cellular immunity. It is difficult to determine which of these mechanisms is the most important in protecting the individual. Most people acquire a natural immunity to Hib in the first years of life without having developed disease. This immunity arises from pharyngeal colonization and/or asymptomatic enteric colonization of microorganisms that have an antigenic cross-reactivity with H. influenzae type b. The importance of antibodies as one of the elements that provide protection is demonstrated by a gradual increase in their concentration in blood with age and by a concomitant reduction in the risk of contracting disease. It is also observed that in newborns, as the maternal antibodies acquired through the placenta decline, the risk of contracting invasive diseases from Hib increase. Functional analyses of the specific antibodies to the capsular polysaccharide of Hib demonstrate their bactericidal and opsonophagocytic capacity. Other surface antigens also stimulate the production of protective antibodies. Antibody levels above 0.15m g/ml, specifically IgG, are considered to protect against Hib; to ensure long-term protection, a value of 1.0m g/ml is necessary.

Active immunity: Based on the demonstrated importance of the specific antibodies for the capsular polysaccharide (PRP), a first-generation vaccine consisting of purified polysaccharide was developed. This vaccine, as well as others based on polysaccharide against pneumococcus and meningococcus, stimulate the specific B cell clones; however, since they are not identified by the T cells and/or macrophages, they generate a poor response. They are known as T-independent antigens and, as such, have the following characteristics: a) the antibody response is age-dependent, and antibodies are not detected below the age of 18 months, are variable between 18 and 23 months, and immunogenic over age 2; b) no memory response is generated and consequently there is no booster effect; and c) a high percentage of the antibodies generated are IgM, whereas the IgG are more protective.

The antigenic characteristics of these polysaccharides are changed once they are conjugated chemically to carrier proteins. These new antigens can now be recognized by the T cells and macrophages, eliciting the characteristic immune response forT-dependent antigens that consists of: a) stimulation of antibodies in children under 2 years of age; b) a booster effect, which makes it possible to attain high antibody concentrations; and c) a more mature immune response characterized by IgG and IgA.

There are three aspects to be considered in the preparation of these new semisynthetic vaccines: a) the form of the polysaccharide; b) the carrier protein; and c) the method of conjugation. The conjugates may be divided into two types depending on the conjugation model: neoglycoproteins and macromolecular complexes. In the neoglycoproteins, the protein has a central position and the polysaccharides­­or rather oligosaccharides­spread out radially (Wyeth-Lederle and Biocine vaccines), while in the macromolecular complexes the random activation of the polysaccharide and/or the protein with subsequent conjugation forms macromolecular networks with both linked components (Pasteur-Merieux-Connaught, MSL, SmithKline Beecham vaccines).

This second generation of Hib vaccines has proven safe, immunogenic, and highly effective in several field trials, and more recently, after the introduction of these vaccines in immunization programs, with the enormous impact in reducing diseases caused by Hib. The available vaccines vary chemically and structurally (see Table 2) and appear to generate immune responses with varying characteristics (see Table 3 3).

It is important to point out the following with regard to the available vaccines:

characteristics of Hib vaccines

Immunogenicity of three Hib vaccines

As previously mentioned, the introduction of Hib conjugate vaccines in the industrialized countries has had a dramatic impact. In the United States, a more than 90% reduction in the incidence of invasive Hib diseases has been observed, and in Finland and Iceland Hib disease seems to have disappeared. As an example of a developing country in the Region we have Uruguay, which subsequent to the introduction of vaccination in 1994, has almost succeeded in eliminating reports of invasive Hib. Immunization with Hib prevents colonization and carriers, and this may be the mechanism for the observed herd immunity.

The various vaccination schedules adopted by the countries are shown in Table 4. The introduction of vaccination into the EPI regimen may also be done gradually by beginning vaccination of children when they reach the age of 2 months and administering the second dose at the appropriate time; or alternatively, immunizing the entire population of children under 2, 3, or 4 years of age, depending on the available resources and the objectives. This strategy was employed in Great Britain and Uruguay.

Table 4
Latin America Countries Primary Schedule Booster
Argentina2,4,6m16m
Chile2,4,6m 
Cuba2,4,6m12-15m
Uruguay2,4,6m 
Other CountriesPrimary ScheduleBooster
Austria3,4,5m14-18m
Bahrain2,4,6m 
Belgium3,4,5m13m
Denmark5,6m16m
Finland4,6m14-18m
France2,3,4m15m
Germany3,5m15m
Iceland3,4 6m14m
Ireland2,4,6m6m
Kuwait3,4,6m18m
Luxembourg3,5m15m
Netherlands3,4,5m11m
Norway3,5m10m
Qatar2,4 6m 
Sweden3,5m12m
Switzerland2,4,6m15m
USA2,4,6m12-15m
UK2,3,4m