Development, evaluation and implementation of Haemophilus influenzae type b vaccines for young children in developing countries: current status and priority actions.

Abstract

Haemophilus influenzae is an important cause of morbidity and mortality from pneumonia, meningitis and other invasive infections among infants and young children in developing countries. Virtually all episodes of H. influenzae meningitis and most episodes of severe H. influenzae pneumonia are caused by serotype b (Hib), and these 2 entities together are estimated to cause >375 000 deaths annually in children <5 years old.1, 2 Invasive diseases caused by Hib now can be prevented by immunization with polysaccharide-protein conjugate vaccines that were developed in the 1980s and have proved to be safe, immunogenic and highly effective when given to infants.3 In the industrialized countries Hib meningitis and other invasive Hib diseases have been virtually eliminated through widespread use of the vaccines.4, 5 Until now, however, the vaccines have not been added to the routine immunization schedules of developing countries. The aims of this article are to review the epidemiology and burden of Hib disease among infants and young children, especially in developing countries, describe the status of Hib conjugate vaccines, identify factors that will affect the introduction and routine use of Hib conjugate vaccines in developing countries and recommend priority actions to facilitate such use. BURDEN OF HIB DISEASE Strains of H. influenzae are either encapsulated or nonencapsulated. The encapsulated strains are differentiated into six serotypes (a through f) based on the antigenic structure of the capsular polysaccharide; nonencapsulated strains are classified as nontypable. Although all serotypes of H. influenzae and the nonencapsulated strains may cause invasive disease, Hib is responsible for most episodes of severe disease among children <5 years of age. Hib pneumonia.Diagnostic methods. Efforts to define the burden of morbidity and mortality resulting from Hib pneumonia have been hindered by a lack of sensitive and specific tests to determine the etiology of pneumonia. Problems in the use of culture depend on the type of specimen being evaluated. Culture of fluid aspirated from the lung is sensitive and specific, but lung aspirates are performed rarely, may be dangerous and can be done only in hospitalized children with lobar disease. Blood cultures are more widely available and are highly specific but are insensitive. Secretions from the lower respiratory tract are difficult to obtain from children and often are contaminated with upper respiratory tract flora, making interpretation of culture results difficult. Nasopharyngeal (NP) swab specimens are easy to obtain, but there is no evidence that culture results reliably predict the etiology of pneumonia. The sensitivity of tests to detect Hib capsular antigen from urine or cerebrospinal fluid has varied between studies but frequently has been <50% for culture-documented invasive infection. Specificity also may be reduced by upper respiratory carriage of Hib, which may cause positive antigen assays in urine samples. Attempts to detect Hib infection by detecting antibody responses to the type b capsular antigen have been reported from several developing countries,6-8 but the sensitivity and specificity of this method are unknown. The practical value of this approach also is limited by difficulties in obtaining acute and convalescent sera from young children. These difficulties also limit the use of culture, antigen detection and serologic methods for diagnosing other causes of pneumonia. Nevertheless studies that use a combination of culture and nonculture methods have identified a bacterial or viral pathogen in one-fourth to three-fourths of children with pneumonia, with higher yields of bacteria in children with severe disease.6-8 Multiple pathogens are identified in almost one-third of thoroughly studied cases, which may reflect poor specificity of the tests or the occurrence of true mixed infections. When evidence of infection with Hib and a viral pathogen is obtained, it is possible that the viral respiratory infection occurred first and facilitated secondary invasion of the lower respiratory tract by Hib. When death results from mixed infection, however, it is likely that the bacterial agent is largely responsible. This conclusion is based in part on the more frequent isolation of bacteria from children with severe disease and on evidence that providing antimicrobials early to children with pneumonia substantially reduces their risk of death. Role of Hib in pneumonia. Because the etiology of most episodes of pneumonia cannot be determined, models have been developed to estimate the contribution of specific pathogens to the total burden of pneumonia morbidity and mortality. One approach has been to assume that results from lung aspirate studies apply to all pneumonias.9 This is probably inappropriate, however, because aspirates are performed only on children with lobar pneumonia, a syndrome caused predominantly by bacterial infection, whereas viruses play a more important role in causing nonlobar pneumonia, especially episodes that are not clinically severe. Another approach, used in this review, is to estimate the contribution of specific etiologic agents by characterizing the overall burden of pneumonia and its age distribution, categorizing infection and mortality as bacterial or viral and apportioning cases and deaths in each group based on the relative frequency of different pathogens as determined by review of the available literature. Because serotyping of H. influenzae isolates is not reported in all studies and because of the likelihood that bacteremic disease may differ for type b and other H. influenzae infections, calculations first estimate pneumonia deaths caused by all H. influenzae types, after which the contribution of type b is determined. By this method all H. influenzae (including all serotypes and nontypable strains) are estimated to cause 482 000 pneumonia deaths each year among children <5 years old in the developing world, which is 16% of all pneumonia deaths not associated with measles or pertussis. Although 67% of these deaths occur in infants, only ∼5% occur at <2 months of age, when maternal antibodies protect most infants. Morbidity from H. influenzae pneumonia also is more common among infants, but the age shift is less marked than for deaths, because of the higher case fatality rate in the very young. Sequelae from pneumonia are estimated to occur in ∼1% of cases, bronchiectasis and reactive airway disease being most common. The proportions of H. influenzae pneumonia cases and deaths caused by Hib are not precisely defined. The proportion of cases caused by Hib can be estimated from studies with cultures of fluid obtained by lung puncture in children with lobar pneumonia. In three such studies Hib accounted for a trimmed mean of 35% of all H. influenzae pneumonias (range, 16 to 63%). In contrast the proportion of Hib was 71% (trimmed mean; range, 29 to 100%) in eight studies based on isolates from children with bacteremic H. influenzae pneumonia. These data suggest that most nonbacteremic cases of H. influenzae pneumonia are caused by strains other than Hib, whereas most cases of bacteremic H. influenzae pneumonia are caused by Hib. For all H. influenzae irrespective of serotype, pneumonia probably is caused by descending infection from the upper respiratory tract. Once they reach the lung, however, Hib organisms are more likely to cause bacteremia, probably because the type b capsule protects the organism from phagocytosis. There are no data from industrialized or developing countries on the proportion of deaths among all H. influenzae pneumonias that is caused by Hib. It may be reasonable to assume, however, that this proportion is similar to the proportion of Hib among bacteremic pneumonias, in which the risk of death is known to be highest. This would suggest that about 71% of deaths among children <5 from H. influenzae pneumonia, or 342 000 annual pneumonia deaths in the developing world, are caused by Hib. The above estimates are for the entire developing world and differences between countries are likely. It is reported, for example, that the proportion of all deaths caused by pneumonia (and probably also by Hib pneumonia) is greatest in countries with the highest rates of infant mortality.10 It also is believed that in countries with lower infant mortality rates and better standards of living, viruses are a relatively more frequent cause of pneumonia than are bacteria, including Hib. Hib meningitis. About 200 000 cases and 37 000 deaths occur annually from H. influenzae meningitis among children <5 years of age in developing countries.2 Most studies show that >97% of H. influenzae meningitis is caused by Hib.11-13 Two exceptions are reports from Papua New Guinea14 and the White Mountain Apaches,15 where 78 to 82% of H. influenzae meningitis was caused by Hib. Incidence in industrialized countries.Table 1 summarizes the rates of Hib meningitis from 13 studies in industrialized countries. Before the use of Hib vaccines the reported incidences among children <5 years old of Hib meningitis and of all invasive Hib diseases were 8 to 60 (median, 25) and 21 to 100 (median, 41) cases per 100 000 per year, respectively. The decision to use Hib vaccines routinely in these countries was based on these data.TABLE 1: Reported incidence of Hib meningitis and invasive Hib disease among children <5 years old in industrialized countries before the widespread use of Hib vaccines Incidence in developing countries. Available data are summarized in Table 2 and median disease rates by region are shown in Figure 1. These vary widely, from a median of 109 cases per 100 000 children <5 years in the Western Pacific and Oceania, to 6 per 100 000 children in Asia. Variations usually were smaller within than between regions. In South America and the Middle East incidence varied from 17 to 25 and 16 to 31 cases per 100 000 children, whereas in Africa it was 50 to 60 cases per 100 000 per year. The incidences in Hong Kong and Malaysia were similar and substantially lower than elsewhere. In the Western Pacific the incidence appeared to vary, being substantially higher in New Caledonia and Vanuatu than Fiji.TABLE 2: Reported incidence of Hib meningitis and invasive Hib disease among children <5 years old in low and middle income countries, by geographic region Fig. 1: Geographic variations in the median reported incidence of Hib or H. influenzae meningitis among children <5 years old, by region.No estimates of incidence are available from India or China (apart from the reports in this supplement) or from the newly independent states of the former Soviet Union. In the Middle East and South America, data are available only from wealthier countries; estimates of incidence in lower income countries of these regions are needed. In Africa the only incidence estimates are from the neighboring West African countries Senegal, The Gambia and Niger and from South Africa. Although hospital-based studies have shown that Hib is a common cause of bacterial meningitis in Central and East Africa, data on incidence are lacking. Incidence in native Americans. Navajo and Apache Indians and Native Alaskans have the highest reported incidence of Hib meningitis and other invasive Hib diseases.15, 29, 43 The incidence of Hib meningitis is 152 to 282 cases per 100 000 children <5 years old. Geographic and population differences in the reported incidence of Hib meningitis are unexplained. Possible explanations include the sensitivity of diagnostic methods, the proportion of patients given antibiotics before admission, socioeconomic and environmental conditions and genetic factors. The latter almost certainly play a role in the high incidence observed in American Indians and Native Alaskans. Isolation of H. influenzae is not difficult but does require the use of appropriate culture media. Because many of the reported studies do not indicate the type of media and reagents used, it is not possible to assess the effect of diagnostic technique on reported incidence. Assessing the independent effects of socioeconomic or environmental conditions and genetic factors on the incidence of Hib meningitis is difficult. For example the incidence of Hib meningitis among Melanesians in New Caledonia is substantially greater than that among Caucasian residents (70 vs. 10 cases per 100 000 children <5 years old).36 However, the socioeconomic level of the Melanesians is lower than that of the Caucasians, making it impossible to distinguish the relative importance of genetic or environmental and socioeconomic factors, such as crowding. Age distribution of Hib meningitis. In developing countries the incidence of Hib meningitis typically peaks earlier than in industrialized countries. Figure 2 illustrates this point with data from The Gambia, the United States and Finland.20, 44, 46 In the Gambia 45% of cases occurred in the first 6 months of life and 83% by age 1 year. By contrast in Finland, only 5% of cases occurred among infants <6 months old and only 35% by age 1 year. The US showed an intermediate pattern.Fig. 2: Cumulative proportion of H. influenzae meningitis cases, by age, from The Gambia, United States and Finland. Data adapted from References 20, 45 and 46.The earlier peak of meningitis in developing areas might reduce the benefit of immunization, because infants are not fully immunized before 4 to 6 months of age. It is possible, however, that herd immunity would minimize this problem. By eliminating carriage of Hib immunization could reduce the incidence of meningitis in all ages, including those not yet fully immunized. In the US widespread use of Hib vaccine caused a 40% reduction in the incidence of meningitis in unimmunized infants <2 months old.4 Mortality resulting from Hib meningitis. The case fatality rate (CFR) for Hib meningitis also varies among countries, with rates in some up to 40%.11, 12 In general the CFR for bacterial meningitis varies inversely with measures of health status or development, with countries with higher per capita health expenditures having a lower CFR. Long term disability after Hib meningitis is common, even where the CFR is low. Up to 30% of survivors develop sequelae that range in severity from mild hearing loss to severe neurologic damage and mental retardation. In poor countries up to 20% of these children die within 4 months after the episode of meningitis.47 Other invasive Hib disease. In industrialized countries meningitis accounts for 40 to 60% of all invasive Hib disease. Other invasive diseases caused by Hib, in addition to bacteremic pneumonia and meningitis, include cellulitis, septic arthritis and, among children >2 years, epiglottitis. The incidence of all invasive Hib disease in various developed countries is summarized in Table 1. Few data exist on the incidence of these syndromes in developing countries. EPIDEMIOLOGY OF HIB DISEASE Spread of infection. Hib is pathogenic only for humans; no animal reservoir exists. Transmission of Hib occurs by spread of respiratory droplets from infected to susceptible persons. Infection typically is established in the oropharynx. This can lead to asymptomatic oropharyngeal carriage, which may persist for months. Invasive disease occurs in a small fraction of infected persons. The reported prevalence of oropharyngeal carriage of Hib varies from country to country. In industrialized countries carriage rates range from 1 to 4%. In developing countries where fewer data are available, carriage rates are sometimes much higher, e.g. 33% in one study from The Gambia.48 Available studies are summarized in Table 3.48-55TABLE 3: Prevalence of oropharyngeal Hib carriage before vaccination in industrialized and developing countries Carriage of Hib is correlated closely with age and the incidence of Hib disease. In industrialized countries carriage is rare in the first year of life and reaches a peak incidence of 3 to 5% during the preschool and school age years.11 Where the peak incidence of Hib disease occurs earlier, as among Navajo Indians, substantial carriage of Hib (prevalence rates of about 3%) occurs as early as 3 months of age.56 Risk factors for Hib infection.Environmental factors. Hib infection is acquired through close contact with a person who is an asymptomatic carrier of Hib or has invasive Hib disease. Most transmission occurs through contact with carriers because they are much more numerous than persons with invasive Hib disease. Risk factors for Hib carriage or disease include an increased number of siblings in a household,57 crowded living conditions,45 day-care attendance45, 57-59 and close contact with a patient with invasive Hib disease.49, 60 Viral upper respiratory tract infections may enhance transmission of Hib by increasing production and spread of respiratory secretions. Exposure to smoke61 and other respiratory irritants may enhance colonization with Hib and increase the risk of developing invasive disease after colonization.58 Host factors. The risk of invasive disease after colonization is related to an individual's level of immunity to Hib, as measured by serum antibodies directed against the capsular polysaccharide. The prevalence of antibody to Hib is high in newborns, as are mean serum titers, owing to passively transferred maternal antibody. Antibodies reach a nadir by age 3 to 4 months and then increase steadily during early childhood as a result of natural exposure to Hib or other organisms with cross-reacting antigens. The incidence of Hib disease shows a reciprocal pattern, being low in newborns, reaching a peak in midinfancy or early childhood and then declining as antibody titers rise.62 The risk of invasive Hib disease is increased in patients with a variety of hematologic and immunologic disorders, including sickle-cell anemia, asplenia, antibody deficiency syndromes, complement deficiencies and malignancies (particularly during chemotherapy).63 American adults with HIV infection have a moderately increased rate of invasive H. influenzae disease (both typable and nontypable), but the full effect of HIV infection on rates of Hib disease is not yet clear.64 Although many studies report equivalent rates for Hib disease in boys and girls, several have reported a 20 to 50% increased incidence among boys.63 There also are variations in the incidence of Hib meningitis across populations that do not seem to be explained by differences in socioeconomic conditions alone, suggesting that genetic factors also may affect susceptibility to invasive Hib disease. For example the incidence of Hib meningitis among Chinese children living in Hong Kong is 10 to 20 times lower34 than that observed in US and European populations. CONTROL OF MORTALITY BY CASE MANAGEMENT The diagnosis of pneumonia in children with cough or difficult breathing can be made using easily discernible signs. Pneumonia cases are classified according to severity and empiric antimicrobial therapy is given.65 The antimicrobials recommended for outpatients (trimethoprim-sulfamethoxazole, amoxicillin and procaine penicillin) and inpatients (penicillin, chloramphenicol) are effective against sensitive strains of S. pneumoniae and H. influenzae. This approach has decreased mortality caused by acute lower respiratory infections, as well as total childhood mortality, in multiple intervention trials.66 A recent metaanalysis of six intervention trials concluded that pneumonia case management interventions can reduce mortality among children <5 years of age by 20 to 25%. The effectiveness of this approach has made case management the key strategy of national acute respiratory infection control programs. Despite its proven effectiveness global implementation of case management is constrained by the need to train and supervise numerous health workers, ensure the availability of recommended antimicrobials and educate mothers on appropriate care-seeking for children with respiratory illness. Moreover antimicrobial resistance, which is increasing rapidly in many countries, may reduce the efficacy of empiric antimicrobial therapy. For example surveillance in Pakistan found that more than one-half of H. influenzae isolated from blood in children with pneumonia had decreased susceptibility to trimethoprim-sulfamethoxazole,67 the treatment recommended by the National ARI Control Program. Studies in other countries (Thailand, Central African Republic) also found resistance to this antimicrobial, but at lower rates. Hib strains also have developed resistance to beta-lactam antibiotics, such as penicillin and amoxicillin, most often by production of beta-lactamase, but sometimes through alterations in penicillin-binding proteins. Rates of beta-lactam resistance in developing countries generally have been lower than in developed countries, where use of this class of agents is more common. Increasing resistance is likely in developing countries, however, owing to the wide availability and indiscriminate use of antimicrobials. PREVENTION OF HIB DISEASE Breast-feeding. Breast-feeding provides >90% protection from invasive Hib disease in infants <6 months of age,45 probably reflecting a protective effect of breast milk antibodies on NP colonization by Hib. Antimicrobial prophylaxis. Antimicrobial treatment can eradicate oropharyngeal carriage of Hib organisms. In the US and elsewhere rifampin (20 mg/kg orally once daily for 4 days, maximal dose 600 mg/day) has been used to prevent secondary cases among close contacts of children with invasive Hib disease. Passive immunization. The protective role of passively transferred maternal antibodies is discussed above. Passive immunoprophylaxis with hyperimmune globulin preparations also provides up to 4 months of protection against invasive Hib disease in high risk infants.68-71 In a randomized, double blind, placebo-controlled trial conducted among Apache infants, passive immunization with bacterial polysaccharide hyperimmune globulin (BPIG; 0.5 mg/kg) at ages 2, 6 and 10 months provided 100% protection against invasive Hib disease for 3 months and 88% protection for 4 months.68, 69 It also showed that one dose of BPIG (0.5 ml/kg) ensured a serum anti-polyribosylribitol phosphate (PRP) concentration of >0.15 μg/ml for up to 4 months.70 In addition simultaneous administration of BPIG and oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine produced higher anti-PRP titers between the first and second doses of HbOC and did not interfere with responses to the second and third doses of HbOC.69 Drawbacks to the routine use of BPIG are high cost and the risk of contamination with unintended blood products. Active immunization. That antibodies to PRP were protective against invasive Hib disease was first suggested by the inverse relationship observed between the age-specific incidence of Hib meningitis and the prevalence of serum antibodies to PRP (the incidence of Hib meningitis decreases as the prevalence of anti-PRP antibodies increases). The protective role of anti-PRP was confirmed by the studies of passive immunization with BPIG, described above. These observations underlie efforts to immunize against Hib disease by evoking antibodies to the capsular polysaccharide PRP. Thus an ideal Hib vaccine should evoke high levels of anti-PRP. After immunization protection should be longlasting, and the vaccine should be effective when given to young infants. The first generation of Hib vaccines consisted of purified PRP. The efficacy of one PRP vaccine was evaluated in Finnish children ages 3 to 71 months.72 Two doses of vaccine (12.7 μg of purified PRP/dose) provided 90% protection for children ≥18 months old but did not protect children <18 months old. Immunogenicity results paralleled protective efficacy. After two doses 95% of children ≥18 months old had ≥0.15 μg/ml of anti-PRP antibody; in contrast, only 10 to 80% of those <18 months reached this level of antibody. In addition the antibodies produced by children <18 months were primarily of the IgM class, whereas children ≥18 months produced IgG and IgA antibodies. A different PRP vaccine was evaluated among children 18 to 59 months old in the US.74-77 Estimates of vaccine efficacy ranged from −69 to 88%, but most were on the order of 50%. Thus unconjugated PRP vaccines protected children ≥18 months old but were neither efficacious nor immunogenic in children <18 months of age.72 Moreover they did not prevent asymptomatic carriage of Hib.72 The poor immunogenicity of PRP in young infants is typical of polysaccharide antigens, most of which are T cell-independent. The capacity to respond reliably to T cell-independent antigens is not established until the second year of life. These results led to efforts to develop T cell-dependent Hib vaccines that would be immunogenic and efficacious in young infants. This was achieved by covalently bonding the PRP polysaccharide to a carrier protein, a process termed conjugation. The conjugated vaccine was immunogenic in infants, inducing a T-dependent immune response characterized by IgG and IgA antibody and evidence of immunologic memory. The experience with Hib conjugate vaccines is reviewed below. HIB CONJUGATE VACCINES Description and current use. Four Hib conjugate vaccines have been evaluated, each consisting of PRP conjugated to a protein carrier. The vaccines differ in carrier protein, the method of linking the carrier and polysaccharide and the amount and size of polysaccharide in each dose. Table 4 summarizes the characteristics of these vaccines. Synthetic polysaccharide vaccines, reduced dose vaccines and liquid formulations are all under consideration or being developed.TABLE 4: Currently licensed Hib conjugate vaccines Hib conjugate vaccines now are given routinely to infants in most industrialized countries in Western Europe, Scandinavia, North America, Oceania and the Western Pacific. In several countries this has led to the virtual disappearance of invasive Hib disease.4, 5, 77 In the US the primary series for PRP-OMP is two doses, whereas for HbOC and PRP-T three doses are recommended; all doses are given with diphtheria and tetanus toxoids and pertussis vaccine (DTP). PRP-D is not recommended for infants in the US because of poor immunogenicity in this age group. In the developing world Hib conjugate vaccine often is available through the private sector, and a number of countries have added (Uruguay, Chile, Colombia) or are considering adding (South Africa) Hib conjugate vaccines to their Expanded Programme on Immunizations (EPI) programs. Safety. Hib conjugate vaccines sometimes can be given in the same syringe with DTP vaccine and can of course be given as a separate but simultaneous injection.78 Significant adverse reactions are not more common when the vaccines are given by either method than when DTP vaccine is given alone. Immunogenicity.Measuring immunogenicity. Assays for Hib antibodies measure either antibody function or the binding of antibody to PRP antigen.79 Functional assays measure opsonization and complement-dependent serum bactericidal activity. These assays are relatively labor-intensive and difficult to standardize. For these reasons they have not been used routinely to assay all sera in vaccine trials. Binding assays include the radioimmunoassay (RIA) and enzyme immunoassay. Both provide results as micrograms of anti-PRP antibody/ml of serum. RIA measures antibody that binds PRP. It is considered the standard assay for Hib antibodies; RIA antibody determinations were required by the US Food and Drug Administration for licensure of Hib conjugate vaccines in the US. Disadvantages of the RIA include the need to work with radioactive isotopes and its inability to measure immunoglobulin isotype or IgG subclass responses. Enzyme immunoassay, which also measures binding antibody, is inexpensive, does not require radioactive materials and can measure antibody belonging to different immunoglobulin isotypes and IgG subclasses. Efforts have been made to standardize the enzyme immunoassay for anti-PRP; therefore results from different laboratories can be combined or compared. Protective levels of anti-PRP antibody. The risk of invasive Hib disease is inversely related to the level of serum antibodies to PRP.62, 68, 70, 71, 80, 81 The minimum protective concentration of antibody, however, has not been defined precisely. Estimates of the protective threshold of serum anti-PRP have been based on animal challenge studies, seroepidemiologic investigations of naturally acquired immunity, studies of passive immunoprophylaxis and active immunization studies.82, 83 Two serum anti-PRP concentrations, 0.15 μg/ml and 1.0 μg/ml, commonly are used as correlates of short and long term protection, respectively. The threshold of 0.15 μg/ml for short term protection is based on seroepidemiologic and passive immunoglobulin protection studies demonstrating antibody titers above this level in protected individuals. In contrast studies with unconjugated PRP vaccine were used to define the 1.0-μg/ml threshold for long term protection.80 It may be reasonable to use a lower threshold for Hib conjugate vaccines, however, because they stimulate antibodies of higher avidity and greater functional activity.84, 85 In addition because conjugate vaccines induce T cell memory, it is possible that only low levels of circulating antibody are necessary for protection and that the postimmunization level of antibody merely shows how well an individual has been primed. In immunogenicity studies of Hib conjugate vaccines, three outcome measures commonly are used: (1) the geometric mean concentration (GMC) of anti-PRP; (2) the proportion of infants with an anti-PRP concentration ≥1.0 μg/ml; and (3) the proportion of infants with an anti-PRP concentration ≥0.15 μg/ml. Immune response to Hib conjugate vaccines. Each Hib conjugate va