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Haemophilus influenzae type b conjugate vaccine use and effectiveness
Review
Haemophilus influenzae type b conjugate vaccine use and effectiveness Shaun K Morris, William J Moss, Neal Halsey
Haemophilus influenzae type b (Hib) is an important cause of invasive bacterial disease in children, including meningitis and pneumonia. The introduction of Hib conjugate vaccines into routine vaccination schedules has contributed to a substantial reduction in the burden of Hib-related disease in many developed countries. However, introduction of Hib conjugate vaccines in developing countries has progressed more slowly. We review the worldwide use and effectiveness of Hib conjugate vaccines. At present, 119 countries have programmes for routine Hib immunisation. WHO estimates that in the developed world 92% of the eligible population is vaccinated against Hib; however, average coverage is 42% in developing countries and only 8% in the poorest countries. Africa and southeast Asia have the lowest rates of Hib vaccine introduction. Vaccine costs and debate about the burden of disease are obstacles to the global use of Hib conjugate vaccine. Even with new funding support, there are many ongoing challenges and vaccine use remains suboptimal, particularly in developing countries.
Introduction Haemophilus influenzae type b (Hib) is an encapsulated, Gram-negative coccobacillus, and is an important cause of invasive bacterial disease in children. The peak incidence of invasive disease among unvaccinated children in developing countries usually occurs between 6 and 7 months of age. Before the routine use of Hib conjugate vaccine in more developed countries, the peak incidence of invasive disease occurred several months later. For example, in the Scandinavian countries most cases occurred after 12 months of age.1 Most cases of Hib-related morbidity and mortality are due to meningitis and pneumonia, but other severe invasive infections caused by Hib include epiglottitis, osteomyelitis, septic arthritis, septicaemia, cellulitis, and pericarditis. Routine use of Hib vaccines began in 1985 when polyribosylribitol phosphate (PRP) polysaccharide vaccines were first licensed. These vaccines were effective in adults and children above 2 years of age, but did not provide adequate protection to infants because young children have poor immune responses to T-cell-independent antigens such as polysaccharides. Conjugation of capsular polysaccharides to protein carriers greatly improved the immunogenicity of Hib vaccines in young children. Hib conjugate vaccines used in early trials were based on conjugation of PRP to diphtheria toxoid (PRP-D), CRM197 (a modified non-toxic fragment of diphtheria toxin; PRP-HbOC), or to the outer membrane protein of Neisseria meningitidis (PRP-OMP).2 PRP conjugated to tetanus toxoid (PRP-T) was licensed on the basis of the demonstration of equivalent serum antibody responses to PRP-OMP and PRP-HbOC. Since the technology used to conjugate PRP to tetanus toxoid was not protected by patent laws, this formulation became the most commonly used protein Hib conjugate vaccine worldwide. PRP-D proved to be less efficacious in populations with high levels of disease and is no longer commonly used.2,3 Vaccine effectiveness, by contrast with efficacy, is a measure of both the direct and indirect effects of vaccination and is calculated as one minus the ratio of the http://infection.thelancet.com Vol 8 July 2008
incidence of disease in vaccinated and unvaccinated individuals. Vaccine effectiveness can be lower than the vaccine efficacy measured in clinical trials because of incomplete acceptance and delivery of vaccines as well as programmatic problems with transport, storage, and delivery of vaccines.4 However, for Hib disease, vaccine effectiveness is often greater than efficacy because of the reduction in nasopharyngeal Hib carriage, the reservoir of Hib in a population. In an unvaccinated population, Hib carriage rates are low in the first 6 months of life and peak between the ages of 3 and 5 years. Carriage rates as determined by throat cultures range between 3% and 5% in young children. In crowded situations, such as in day-care centres, carriage is much higher and rates of 50% have been reported.5–7 Studies have shown that children vaccinated with Hib conjugate vaccine have lower carriage rates, thus providing a level of herd immunity.8,9 Herd immunity is a consequence of unvaccinated children deriving benefit from lower carriage rates in the community and hence reduced risk of exposure to Hib. Following the introduction of Hib conjugate vaccine in Denmark, an indirect protective effect was noted in unvaccinated children that was similar to a vaccine effectiveness of approximately 94%,10 and similar effects have been documented in other settings.11–14 Hib vaccine effectiveness is most commonly measured as a reduction in invasive disease by culturing Hib from blood or cerebrospinal fluid (CSF). However, this underestimates the true incidence of invasive Hib disease because only a small proportion of children with pneumonia caused by Hib are bacteraemic at the time of evaluation and culturing Hib can be difficult. Furthermore, treatment with antibiotics before a sample is obtained for culture (common in many settings) decreases the likelihood of culturing Hib from blood or CSF. These limitations are found in most studies of Hib vaccine effectiveness. Attempts to overcome them include Hib antigen detection assays using urine15 and CSF,16 and vaccine-probe studies in which children are randomised to receive Hib vaccine or a placebo vaccine and the differences in disease incidence are attributed to Hib.17
Lancet Infect Dis 2008; 8: 435–43 Division of Infectious Diseases, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada (S K Morris MD); and Department of Epidemiology (W J Moss MD) and Department of International Health (W J Moss, Prof N Halsey MD), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Correspondence to: Prof Neal Halsey, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21210, USA [email protected]
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WHO region
Number of member states
Number of member states with Hib in routine immunisation schedule (%)
Africa
46
19 (41%)
Americas
35
34 (97%)
Eastern Mediterranean
21
14 (67%)
Europe
52
38 (73%)
Southeast Asia
11
1 (9%)
Western Pacific
27
13 (48%)
192
119 (62%)
Total
Table 1: WHO member states that have introduced Hib conjugate vaccines into the routine immunisation schedule by WHO region, 200624
A recent Cochrane review of randomised trials concluded that Hib vaccines, when compared with placebo, resulted in a large reduction in the risk of disease in multiple settings.18–22 Nevertheless, despite documented efficacy of the Hib conjugate vaccine in randomised, placebo-controlled trials, in 2005 WHO estimated that there were approximately 3 million serious illnesses and 400 000 deaths per year as a result of invasive Hib disease.23 Because the disease burden and the effectiveness of Hib vaccine might vary by geographical region, we review the literature to assess regional data on Hib vaccine effectiveness and progress in the control of invasive Hib disease through the introduction of Hib conjugate vaccine into routine childhood immunisation programmes.
Worldwide Hib vaccination programmes As of December, 2007, 119 countries had programmes for the routine administration of Hib vaccine in infants (table 1 and figure 1).24 However, the success of these programmes, as measured by estimated vaccine coverage, varied. Hib conjugate vaccine coverage in 2007 ranged from less than 40% to 99%. In 2003, WHO estimated that in the developed world, 92% of the eligible population was vaccinated against Hib, but coverage in developing countries was 42%, and only 8% for the poorest countries.26 Countries in Africa and southeast Asia had the lowest levels of Hib vaccine use. The immunisation schedules for selected countries that have introduced the Hib conjugate vaccine into their routine schedule are shown in table 2.
North America Before the routine use of Hib vaccine in the USA, the annual incidence of invasive Hib disease in children younger than 5 years of age was 88 per 100 000 population.28,29 Incidence rates in Canada were similar. However, these national rates masked regional and ethnic variability. High incidence rates of disease were found in Native Americans, Native Alaskans, and the Inuit population in Canada, where rates of invasive Hib disease exceeded 150 per 100 000 population younger than 5 years. In Native Alaskans, the documented rate of invasive Hib disease in children younger than 5 years was more than 700 per 100 000 children.30,31 436
The first Hib conjugate vaccine was licensed for use in the USA in 1987 and was initially recommended for children 18–59 months of age. In 1991, the vaccine was recommended for all infants beginning at 2 months of age.32 Vaccine coverage in the USA is 94% for three doses by 2 years of age. National33 and regional (Minnesota34 and California35) studies documented a decrease in invasive Hib disease of 85–99% from 1983 to 1995. However, the disease has not been eliminated in the USA. In 2006, the incidence of Hib disease was 0·21 per 100 000 population younger than 5 years, there were 29 confirmed cases of Hib disease in children younger than 5 years, and an additional 179 cases of unknown subtypes of H influenzae.36,37 Most cases of invasive Hib disease occurred in unvaccinated children. Although the Hib conjugate vaccine has proven to be very successful in the USA, there have been notable setbacks—for example, an increase in apparent vaccine failures from 1996 to 2000 in Native Alaskan children. In 1992–95, the incidence per year of invasive Hib disease in Native Alaskan children under the age of 2 years and 5 years was 35·8 and 18·3 per 100 000 population, respectively.38 However, following a change from PRP-OMP to PRP-HbOC combined with diphtheria, pertussis, and tetanus vaccine (DPT) in January, 1996, there was an increase in the incidence of invasive disease in under 2 and under 5-year-olds to 96·6 and 47·6 per 100 000 population per year, respectively. This increase was attributed to a lower antibody response after the first dose of PRP-HbOC compared with PRP-OMP and increased complexity of the schedule. The schedule was revised again in 2001 to include PRP-OMP for all doses and disease rates subsequently decreased below those recorded in 1991–95.38 Routine vaccination of Canadian infants with Hib conjugate vaccine began in 1992. In 1985 (before routine vaccination), 485 children were identified with invasive Hib disease at ten major paediatric centres.39 An active surveillance programme, done between 2001 and 2003 at the same ten centres plus two additional centres (covering an estimated 45% of Canadian children), identified only 29 cases of invasive Hib disease, half of which were meningitis.40 The annual number of cases identified decreased from 16 in 2001 to ten in 2002 and three in 2003.41 As in the USA, failure to vaccinate rather than vaccine failure was the major risk factor associated with invasive disease. 20 of the 29 cases involved children who were unvaccinated or who had not completed the primary series (ie, vaccine recommended at 2, 4, and 6 months of age).41
Europe At the end of 2007, Hib conjugate vaccine was part of the routine immunisation schedule in 38 of 52 countries in the WHO European region (table 1). Hib conjugate vaccine was introduced into the UK in 1992 and given to children at 2, 3, and 4 months of age, with an initial catch-up phase during which children aged 1–4 years received a single dose.42 The annual incidence of invasive Hib disease http://infection.thelancet.com Vol 8 July 2008
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(108 countries introduced infant immunisation schedule) Hib3 ≥80% (92 countries or 48%) Hib3 <80% (16 countries or 8%) Hib vaccine not introduced (85 countries or 44%)
Figure 1: Countries that have introduced Hib vaccine and infant Hib coverage, 2006 Adapted from reference 25. Hib3=three dose of Hib vaccine.
decreased to a low of 0·65 cases per 100 000 children aged under 5 years in 1998.42 However, beginning in 1999, the annual incidence of invasive disease increased to more than 4 per 100 000 children aged under 5 years in 2002.42,43 To investigate this resurgence, Ramsay and colleagues42 estimated Hib vaccine effectiveness in the UK and Wales between October, 1993, and December, 2002, and found it to be only 57% (95% CI 42–67%) following primary immunisation with the 2, 3, and 4-month schedule.42 After adjusting for the probable underestimation of vaccine coverage, the reported effectiveness was 72% (95% CI 62–79%). In 2003, a second catch-up campaign was launched to provide Hib vaccine to all children between 6 months and 4 years of age resulting in a reduction in the number of cases within 12 months in the age-groups targeted for the booster.43–45 Thus, the initial decline in the incidence of invasive Hib disease between 1992 and 1998 was mainly caused by the catch-up vaccination of older children. In the absence of a booster dose to maintain antibody concentrations, the primary series was inadequate to provide long-term protection.46 The initial decision to omit booster doses was based upon increased antibody concentrations following primary immunisation and the false assumptions that they would persist or that immunological memory would protect children against invasive disease. In Finland a three-dose schedule of 4, 6, and 14–18 months has been used with continued high efficacy over a 20-year period.47 The longer interval between the first two doses apparently induces sufficient protection against disease and the third dose serves as a booster dose. The UK has recently introduced a routine booster dose in the second year of life.48 The findings from the UK have potential implications for other countries that are introducing Hib vaccines under the generally recommended WHO schedule of 6, 10, and 14 weeks. http://infection.thelancet.com Vol 8 July 2008
Longer follow-up is required in countries using this schedule to determine if a decrease in circulating Hib will result in a loss of natural boosting and a subsequent increase in vaccine failure rates. Before the introduction of Hib conjugate vaccine, the annual incidence of invasive Hib disease in Scandinavian children younger than 4 years of age was 49 per 100 000 population.10 Although the five Scandinavian countries have implemented immunisation policies that differ in terms of age of vaccination and the type of vaccine used, each has seen a substantial reduction in Hib disease. In 2002, no cases of invasive Hib disease were recorded in children under 5 years of age in Denmark and Finland, Norway recorded only two cases (0·66 per 100 000 children aged under 5 years per year), and Sweden recorded seven cases (1·35 per 100 000 children aged under 5 years per year).49 Between 1992 and 1994, and before the use of Hib vaccine, the annual incidence of Hib meningitis in the Veneto region of Italy was 17·9 per 100 000 children aged under 2 years.50 In 1997, routine immunisation with three doses of PRP-HbOC vaccine was initiated at 3, 5, and 11 months, with a single dose for children over 11 months of age. Although this programme achieved only 26% and 31–53% coverage rates in children aged 1 year and 1–4 years, respectively, the annual incidence of invasive Hib disease in the region decreased from 11·3 per 100 000 children aged under 5 years in 1997 to 1·0 per 100 000 children under 5 years in 2000—a 91% reduction over 3 years.51 This reduction in invasive Hib disease despite low coverage rates could be explained by the use of the single dose in older children, similar to the catch-up dose used in the UK, or the effects of herd immunity. In the Val-de-Marne region of France, a 90% decrease in invasive Hib disease was reported after the introduction of Hib conjugate vaccine.52 Vaccine effectiveness against 437
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Schedule (months of age) North America Canada
2, 4, 6, 18
USA
2, 4, 6, 12–15
Europe Czech Republic
2, 3, 4, 18
Denmark
3, 5, 12
Finland
4, 6, 14–18
France
2, 3, 4, 16–18
Germany
2, 3, 4, 11–14
Iceland
3, 5, 12
Ireland
2, 4, 6, 12–15
Italy
3, 5, 11–12
Norway
3, 5, 12
Spain
2, 4, 6, 15–18
Sweden
3, 5, 12
UK
2, 3, 4, 12
South and Central America Argentina
2, 4, 6, 18
Brazil
2, 4, 6
Chile
2, 4, 6
Colombia
2, 4, 6
Costa Rica
2, 4, 6, 15
Uruguay
2, 4, 6, 12
Pacific and Asia Australia
2, 4, 6, 12
Fiji
2, 3, 4
Malaysia
2, 3, 5
New Zealand
1·5, 3, 15
Middle east Israel
2, 4, 6, 12
Kuwait
2, 4, 6, 18
Qatar
2, 4, 6, 18
Saudi Arabia
2, 4, 6, 18
Africa Kenya
1·5, 2·5, 3·5
South Africa
1·5, 2·5, 3·5
The Gambia
2, 3, 4
Uganda
1·5, 2·5, 3·5
Table 2: Hib conjugate vaccine immunisation schedules for selected countries27
invasive Hib disease in Germany was 90% (95% CI 67–97%) for an incomplete primary series (2, 3, and 4 months), 97% (95% CI 88–99%) for a full primary series, and 98·5% (95% CI 94·5–99·6%) for a booster dose.53 Hib conjugate vaccine was included in the routine vaccination schedule in the Valencia region of Spain in 1997 and the incidence per year of invasive Hib disease in children less than 15 years of age declined from 3·6 per 100 000 population in 1996 to 0·3 per 100 000 population in 1998, and has remained low.54 In eastern Europe, the Czech Republic introduced routine Hib vaccination in July, 2001. The annual incidence of invasive Hib disease in children aged less than 1 year decreased from 438
17·1 per 100 000 population to 3·3 per 100 000 population (an 81% decrease) 2 years after introduction, and to 1·1 per 100 000 population (a 94% decrease) after 3 years.55 The need for a booster dose of Hib vaccine in the second year of life remains controversial in western Europe. In 2002, the two European Union countries with the highest incidence per year of invasive Hib disease were the UK (4·3 per 100 000 children under 5 years) and Ireland (2·6 per 100 000 children under 5 years),49 neither of which routinely provided a booster dose. In response, Ireland began a temporary programme in November, 2005, where a booster dose of Hib vaccine was offered to children between the ages of 1 year and 4 years, and a fourth dose of Hib vaccine is now recommended for all children at 12 months. A summary of the changes in Hib conjugate vaccine schedules and coverage rates, and incidence rates of invasive Hib disease was published by the European Union Invasive Bacterial Infections Surveillance Network49 and WHO.56
South and Central America and the Caribbean Before the introduction of Hib vaccine into Latin America, data supporting the effectiveness of the Hib conjugate vaccine came from high-income countries with strong health infrastructures. The experience with Hib vaccine in South and Central America provided the first evidence of the effectiveness of the Hib conjugate vaccine in lowincome and middle-income countries. As of the end of 2007, 31 of 32 countries in South and Central America had introduced Hib conjugate vaccine into their routine immunisation schedules.23 In 1992, PRP-HbOC and PRP-T were licensed in Chile to be given to children at 2, 4, and 6 months of age. A study in Santiago showed a vaccine effectiveness of 92% (95% CI 65–100%) under programmatic conditions.19 Hib vaccine was introduced into the routine Chilean immunisation schedule in 199657 and the annual incidence of Hib meningitis in children under 5 years decreased from 40 per 100 000 population to less than 2 per 100 000 population 2 years later. In the 30 months following introduction of vaccine, vaccine effectiveness against invasive Hib disease was 90% (95% CI 75–100%).19 In 1994, Uruguay introduced Hib conjugate vaccine into the routine immunisation schedule, consisting of a primary series at 2, 4, and 6 months of age and a booster dose at 12–15 months of age.58 The incidence of Hib meningitis per year decreased from 17 per 100 000 children aged under 5 years in 1992–94 to 1 per 100 000 children under 5 years in 1995–96.58 In Central America, Hib-related hospital admissions decreased by 57% at a tertiary-care facility in Costa Rica following the routine use of Hib conjugate vaccine. Monovalent Hib conjugate vaccine was introduced into Argentina’s national immunisation programme in 1997, followed by tetravalent vaccine in 1998 as a three-dose schedule. A review of hospital records at two major http://infection.thelancet.com Vol 8 July 2008
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paediatric hospitals in or near Buenos Aires reported a decrease in the number of cases of culture-confirmed Hib meningitis from 1996 to 2001.59 Colombia introduced Hib vaccination of infants in May, 1998, and a 40% decrease in the number of cases of Hib meningitis was recorded the following year.60 Before the introduction of Hib vaccine, the average annual incidence of Hib meningitis in Brazilian children aged less than 1 year and between 1 and 4 years of age was 22·3 and 8·8 per 100 000 population, respectively.61 Although Hib vaccine was used in the private sector throughout the 1990s, it was made publicly available as part of the national immunisation programme in 1999 in a 2, 4, and 6-month vaccination schedule without a booster dose. For children who received fewer than three doses in the first year of life, an additional dose was recommended in the second year of life. In Salvador, Brazil, 5 years after the introduction of Hib conjugate vaccine, the annual incidence of Hib meningitis had decreased from 60·9 to 3·1 per 100 000 children aged under 1 year and from 2·39 to 0·6 per 100 000 population for all ages.62 Additional evidence for the effect of Hib vaccine in Brazil comes from a study showing a decrease in the frequency of Hib strains recovered from CSF, blood, and bronchial secretions from diverse locations around the country in 2001–03 compared with 1990–99.61 A 31% (95% CI –9% to 57%) reduction in radiologically confirmed pneumonia was seen in Goiania, central Brazil,63 and decreases in the frequency of Hib meningitis and in meningitis of unknown aetiology were reported in Salvador.64
The Pacific region and Asia The reduction in invasive Hib disease in Australia and New Zealand following the introduction of Hib vaccine was similar to that observed in North America and western Europe. However, in other countries in Asia and the Pacific region, uncertainty persists about the magnitude of the burden of disease caused by Hib and whether or not Hib vaccination is cost effective. Australia initiated Hib conjugate immunisation in 1992 and the annual incidence of invasive Hib disease in children less than 4 years of age declined from 15 per 100 000 children to 1·2 per 100 000 children between 1993 and 2000.65 Vaccine effectiveness was estimated to be 83% (95% CI 71–91%), and 90% (95% CI 83–94%) after adjusting for under-reporting.66 A substantial reduction in Hib meningitis was seen in indigenous Australian children, who before vaccination had the highest documented incidence of invasive Hib disease in the world.66,67 Hospital admissions resulting from Hib meningitis in children less than 5 years of age decreased by 92% (95% CI 89–94%) in New Zealand following the introduction of Hib vaccine in 1994.68 Fiji introduced a primary series of Hib vaccine at 2, 3, and 4 months of age in 1995, but shortage of vaccine led to inconsistent use until 1999 when coverage reached 76%.69 Comparing the period from 1992 to 1993 with 1999, the rate ratio for hospital http://infection.thelancet.com Vol 8 July 2008
UK/Wales42 UK/Wales (adjusted for probable underestimation of vaccine coverage)42 Germany53 Santiago, Chile19 Australia65 Australia (adjusted for probable underestimation of vaccine coverage)65 *The Gambia12 Kenya84 0
20
40
60
80
100
Vaccine effectiveness (%)
Figure 2: Effectiveness of full primary Hib vaccine series in protecting against all invasive Hib disease in children aged under 5 years in selected countries Error bars represent 95% CIs. Vaccine schedules used in studies were UK/Wales 2, 3, and 4 months; Germany 2, 3, and 4 months; Santiago, Chile 2, 4, and 6 months; Australia 2, 3, and 4 months; The Gambia 2, 3, and 4 months; Kenya 6, 10, and 14 months.*Vaccine efficacy is shown for The Gambia.
admissions due to meningitis in children younger than 5 years of age was 0·68 (95% CI 0·52–0·72), and 0·44 (95% CI 0·27–0·72) in children 6–18 months of age.69 The burden of Hib disease was thought to be lower in Asia than elsewhere in the world on the basis of infrequent isolation of Hib from diagnostic specimens. However, several recent studies suggest that the incidence of invasive Hib disease might be higher than previously reported.70–75 Hib conjugate vaccine use in national immunisation programmes in Asia has been limited. In 2002, Malaysia became the first country in the region to introduce Hib conjugate vaccine into its national immunisation schedule; however, published data on vaccine effectiveness are not available. In a randomised, placebo-controlled, vaccine-probe study undertaken on Lombok Island, Indonesia, more than 55 000 children were enrolled between 1998 and 2002.76 Hib conjugate vaccine was given at 6, 10, and 14 weeks of age and children were followed until 2 years of age, death, or the end of the study. In the first 2 years of life, the vaccinated group had 1561 (95% CI 270–2853) fewer cases of clinical pneumonia per 100 000 child-years following at least one dose of Hib vaccine, and 1467 (95% CI –6 to 2994) fewer cases per 100 000 child-years following three doses. Hib vaccine, however, did not prevent radiologically confirmed pnemonia in the first 2 years of life: the vaccine-preventable Hib incidence was –89 (95% CI –248 to 71) cases per 100 000 child-years. The absence of a decrease in radiologically confirmed pneumonia in the Lombok study differs from results of other Hib vaccine studies.20,63 The investigators propose that their intensive case finding led to the identification of a large number of children with viral and other non-bacterial pneumonias and that the identification of such cases might have obscured the effect on Hib pneumonia.76 They 439
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also propose that the proportion of pneumonia caused by Hib might be lower in Asia than in other settings.76 After receipt of at least one dose of vaccine, the incidence of microbiologically confirmed Hib meningitis in the first 2 years of life decreased from 19 to 2·6 per 100 000 child-years, representing a vaccine-preventable incidence of 16 (95% CI 1·4–31) per 100 000 child-years (86% reduction). At least one dose of vaccine prevented 22% of cases of clinical meningitis, for a vaccine-preventable incidence of 158 (95% CI 42–273) per 100 000 child-years. There are limited data on Hib vaccine effectiveness from other countries in Asia. An incident case-control study in Dhaka, Bangladesh, with a birth cohort of approximately 68 000 infants, allocated 25 high patientvolume and six low patient-volume immunisation clinics to provide Hib-DPT vaccine, while other clinics continued to provide routine DPT vaccine.77 Vaccine coverage was measured in the study area using standard WHO cluster survey methodology. This study found that in children receiving at least two doses of Hib conjugate vaccine, the incidences of radiologically confirmed pneumonia and microbiologically confirmed Hib meningitis were 34% (95% CI 6–53%) and 89% (95% CI 28–100%) lower than in community controls over the approximately 3-year period of case ascertainment.77 The incident case-control methodology avoids many of the inherent biases of typical case-control studies because new cases are identified prospectively, and thus provides strong evidence for a substantial burden of Hib disease in Dhaka and a high degree of effectiveness of the vaccine.77
The middle east In January, 1994, the Israel Ministry of Health introduced Hib conjugate vaccine (PRP-OMP) into the national immunisation schedule at 2, 4, and 12 months and achieved greater than 90% coverage. Prospective surveillance, including all 25 centres in the country offering paediatric services, estimated that vaccine effectiveness was 95% (95% CI 92–96%) and 97% (95% CI 93–98%) against invasive Hib disease and Hib meningitis, respectively.11 This study also showed a decrease in Hib infection in infants too young to be vaccinated, indicative of a herd immunity effect. In another study,78 no cases of invasive Hib disease were identified in vaccinated children among a cohort of 1444 Israeli children followed prospectively from 1992 to 1999. In 1997, Israel adopted a four-dose Hib vaccination schedule at 2, 4, 6, and 12 months. Qatar introduced Hib conjugate vaccine in 1993 with a schedule of 2, 4, 6, and 15 months. In 1992, 14 cases of Hib meningitis were documented in the country, but, after the vaccine’s introduction, only one case was reported in 1995, and one in 1996.57 Kuwait introduced Hib conjugate vaccine into the routine national immunisation schedule in 199757 and in 2000 WHO estimated that the country had achieved 98% coverage.56 The King Fahad National Guard Hospital, in Riyadh, Saudi Arabia, began using Hib conjugate vaccine in 1998 440
and a retrospective review of cases of Hib meningitis showed a decrease in the number of cases after vaccination at this institution.79
Africa As of Dec 31, 2007, only 19 of 46 countries in the WHO African region included Hib conjugate vaccine in their national immunisation schedule.25,80 These countries were Angola, Benin, Burkina Faso, Burundi, The Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Malawi, Mali, Mauritius, Rwanda, Senegal, Sierra Leone, South Africa, Togo, Uganda, and Zambia. Before the introduction of Hib vaccine in The Gambia, the annual incidence of invasive Hib disease was 274 cases per 100 000 children aged under 1 year.12 In a vaccine-probe study done from 1993 to 1995 to estimate the burden of disease caused by Hib, nearly 43 000 Gambian children were randomised to receive either DTP alone or PRP-T combined with DTP at 2, 3, and 4 months of age.20 Vaccine efficacy against culture-confirmed invasive Hib disease following three doses was 95% (95% CI 67–100%). Vaccine efficacy against radiologically confirmed pneumonia was 21% (95% CI 5–44%) in all study children, and 22% (95% CI 2–39%) in fully vaccinated children, showing the large but unrecognised burden of disease caused by Hib pneumonia in this country. PRP-T Hib vaccine was introduced in 1997 into The Gambia’s routine immunisation schedule at 2, 3, and 4 months. A prospective, case-control study measured the effectiveness of the Hib conjugate vaccine delivered through the routine programme.12 The median age at vaccination was 3·4 months, 6·5 months, and 8 months for one, two, and three doses, respectively. The adjusted vaccine efficacy against invasive Hib disease was 38% (95% CI –58% to 75%), 94% (95% CI 62–99%), and 94% (95% CI 62–99%) for one, two, and three doses, respectively. The adjusted vaccine efficacy for Hib meningitis was 35% (95% CI –84% to 77%), 93% (95% CI 42–99%), and 96% (95% CI 47–100%) for one, two, and three doses, respectively. Despite difficulties with vaccine supply, the national incidence per year of Hib meningitis decreased from 60 cases per 100 000 children aged under 5 years to no cases 5 years after the introduction of the vaccine. An equally impressive effect was seen in the subset of children under 1 year of age, in whom the incidence per year of Hib meningitis decreased from over 200 per 100 000 children to none.81 Formal Hib disease surveillance was stopped in The Gambia in 2007; however, between July, 2005, and April, 2006, five cases of invasive Hib disease (including three cases of meningitis) were identified in the country. Four of these children had received three doses of vaccine and one had received two doses, reinforcing the need to reinstitute surveillance to fully understand the effectiveness of Hib vaccine in this setting.81 PRP-T Hib vaccine was first used in South Africa in July, 1999, and WHO estimated the national coverage to be 92% in 2004.24 A hospital-based study found no effect of http://infection.thelancet.com Vol 8 July 2008
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Hib conjugate vaccine on all-cause or Hib cultureconfirmed bacterial meningitis, or surrogate markers of meningitis (CSF white blood cell count, protein level, glucose level, and turbidity) at Kalafong Hospital near Pretoria.59 However, the same study found a decrease in the same surrogate markers of bacterial meningitis at Chris Hani Baragwanath Hospital in Soweto.59 The investigators suggest that increasing rates of pneumococcal meningitis in the community served by Kalafong Hospital, particularly among HIV-1-infected children, might have masked the benefits of Hib vaccine. Clearly, the effect of HIV-1 infection on vaccine effectiveness is of particular importance in sub-Saharan Africa. In a cohort of nearly 40 000 children who received Hib conjugate vaccine, HIV-1-infected children had a 35 times greater (95% CI 15–85) risk of vaccine failure compared with HIV-1-uninfected children.82 Although most vaccine failures occurred in the first year following vaccination, there was a second peak among children aged 2–4 years. The relative importance of primary and secondary vaccine failure in HIV-1-infected children is not known; however, the second peak suggests that HIV-1-infected children might benefit from a booster dose at 2 years of age. The first population-based data to document the effectiveness of Hib vaccine in South Africa showed a 65% decrease in laboratory-confirmed invasive Hib cases in the first 5 years after the introduction of Hib vaccine. Notably, an increase in non-type b H influenzae infections was also reported, particularly among HIV-1-infected children.83 Additional data on the benefits of Hib vaccine in east Africa come from studies in Kenya and Uganda where Hib vaccine was introduced in 2001 and 2002, respectively. In Kenya, 3 years after vaccine introduction, prospective surveillance for culture-confirmed invasive Hib disease showed a vaccine effectiveness of 88% (95% CI 73–96%) among children younger than 5 years of age, and 87% (95% CI 66–96%) among children younger than 2 years of age.84 In Uganda, a hospital-based surveillance study showed a decrease in Hib meningitis from 88 to 13 cases per 100 000 children under 5 years per year 4 years after the introduction of the vaccine.80 This study calculated a vaccine effectiveness of 93% (95% CI 69–99%) for two or more doses, and estimated that 28 000 cases of Hib pneumonia and meningitis and 5000 Hib-related deaths are now prevented in Uganda every year.80
Conclusions Hib conjugate vaccines are highly effective in reducing the incidence of invasive Hib disease, with similar effectiveness seen across geographical regions and different levels of socioeconomic development (figure 2). Invasive Hib disease has gone from a major cause of childhood illness to a rare disease in every country where conjugate vaccine has been introduced into the routine immunisation schedule. However, despite nearly two decades of documented success and many deaths averted, less than two-thirds of all countries have incorporated Hib http://infection.thelancet.com Vol 8 July 2008
Search strategy and selection criteria PubMed and Medline databases were searched for articles published in the English language between January, 1985, and December, 2007, with the keywords “haemophilus”, “influenzae”, “type b”, “Hib”, “conjugate”, “vaccine”, “effectiveness”, “incidence”, “meningitis”, “pneumonia”, “North America”, “Europe”, “Asia”, “Africa”, “Pacific Region”, “South America”, “Central America”, and specific country names. Additional articles were obtained by searching the citations within retrieved papers. Internet searches were done to obtain data from WHO and the US Centers for Disease Control and Prevention, as well as for national immunisation schedules. Additional country level immunisation coverage data, and data describing vaccine effectiveness and the effect on the burden of Hib disease, were obtained from WHO tables and national ministry of health websites.
conjugate vaccines into their routine immunisation schedules. In 2006, only 26% of the world’s children received Hib vaccine.85 Vaccine costs and debate about the burden of disease remain obstacles to the global use of Hib conjugate vaccine. Recent data from Asia suggest that the burden of disease is higher than previously thought. Innovative funding schemes from the Global Alliance for Vaccines and Immunization (GAVI), other international health groups, and public–private partnerships, with continued documentation of the disease burden, have the potential to overcome barriers and increase the number of children benefiting from Hib vaccine. Local manufacturers, such as those in India, should be able to provide Hib vaccines at lower cost. However, even with new funding support, it is clear that many obstacles remain and vaccine use remains at a substandard level, particularly in developing countries. According to the Hib Initiative, at the end of 2007, only one-third of countries eligible for GAVI funding were using Hib vaccines.85 However, progress is being made. In 2008, it is expected that six countries that received conditional approval for GAVI funding in 2007 will reapply, eight new countries will make their initial application to the fund, and three countries that received funding approval in 2006 will actually introduce Hib conjugate vaccine into their national programmes.86 In 2006, the WHO Strategic Advisory Group of Experts recommended worldwide implementation of Hib vaccination unless “robust epidemiologic evidence exists of low disease burden, lack of benefit, or overwhelming impediments to implementation”.87 Although there is much work to be done before this recommendation is fully realised, all children should be protected against invasive Hib disease. Conflicts of interest NH has a research grant that provides a portion of his university salary from Wyeth, a manufacturer of Hib vaccine, and he has served on a data and safety monitoring board for an unrelated vaccine for Merck, a manufacturer of Hib vaccine. SKM and WJM declare that they have no conflicts of interest.
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Haemophilus influenzae type b conjugate vaccine use and effectiveness Shaun K Morris, William J Moss, Neal Halsey
Haemophilus influenzae type b (Hib) is an important cause of invasive bacterial disease in children, including meningitis and pneumonia. The introduction of Hib conjugate vaccines into routine vaccination schedules has contributed to a substantial reduction in the burden of Hib-related disease in many developed countries. However, introduction of Hib conjugate vaccines in developing countries has progressed more slowly. We review the worldwide use and effectiveness of Hib conjugate vaccines. At present, 119 countries have programmes for routine Hib immunisation. WHO estimates that in the developed world 92% of the eligible population is vaccinated against Hib; however, average coverage is 42% in developing countries and only 8% in the poorest countries. Africa and southeast Asia have the lowest rates of Hib vaccine introduction. Vaccine costs and debate about the burden of disease are obstacles to the global use of Hib conjugate vaccine. Even with new funding support, there are many ongoing challenges and vaccine use remains suboptimal, particularly in developing countries.
Introduction Haemophilus influenzae type b (Hib) is an encapsulated, Gram-negative coccobacillus, and is an important cause of invasive bacterial disease in children. The peak incidence of invasive disease among unvaccinated children in developing countries usually occurs between 6 and 7 months of age. Before the routine use of Hib conjugate vaccine in more developed countries, the peak incidence of invasive disease occurred several months later. For example, in the Scandinavian countries most cases occurred after 12 months of age.1 Most cases of Hib-related morbidity and mortality are due to meningitis and pneumonia, but other severe invasive infections caused by Hib include epiglottitis, osteomyelitis, septic arthritis, septicaemia, cellulitis, and pericarditis. Routine use of Hib vaccines began in 1985 when polyribosylribitol phosphate (PRP) polysaccharide vaccines were first licensed. These vaccines were effective in adults and children above 2 years of age, but did not provide adequate protection to infants because young children have poor immune responses to T-cell-independent antigens such as polysaccharides. Conjugation of capsular polysaccharides to protein carriers greatly improved the immunogenicity of Hib vaccines in young children. Hib conjugate vaccines used in early trials were based on conjugation of PRP to diphtheria toxoid (PRP-D), CRM197 (a modified non-toxic fragment of diphtheria toxin; PRP-HbOC), or to the outer membrane protein of Neisseria meningitidis (PRP-OMP).2 PRP conjugated to tetanus toxoid (PRP-T) was licensed on the basis of the demonstration of equivalent serum antibody responses to PRP-OMP and PRP-HbOC. Since the technology used to conjugate PRP to tetanus toxoid was not protected by patent laws, this formulation became the most commonly used protein Hib conjugate vaccine worldwide. PRP-D proved to be less efficacious in populations with high levels of disease and is no longer commonly used.2,3 Vaccine effectiveness, by contrast with efficacy, is a measure of both the direct and indirect effects of vaccination and is calculated as one minus the ratio of the http://infection.thelancet.com Vol 8 July 2008
incidence of disease in vaccinated and unvaccinated individuals. Vaccine effectiveness can be lower than the vaccine efficacy measured in clinical trials because of incomplete acceptance and delivery of vaccines as well as programmatic problems with transport, storage, and delivery of vaccines.4 However, for Hib disease, vaccine effectiveness is often greater than efficacy because of the reduction in nasopharyngeal Hib carriage, the reservoir of Hib in a population. In an unvaccinated population, Hib carriage rates are low in the first 6 months of life and peak between the ages of 3 and 5 years. Carriage rates as determined by throat cultures range between 3% and 5% in young children. In crowded situations, such as in day-care centres, carriage is much higher and rates of 50% have been reported.5–7 Studies have shown that children vaccinated with Hib conjugate vaccine have lower carriage rates, thus providing a level of herd immunity.8,9 Herd immunity is a consequence of unvaccinated children deriving benefit from lower carriage rates in the community and hence reduced risk of exposure to Hib. Following the introduction of Hib conjugate vaccine in Denmark, an indirect protective effect was noted in unvaccinated children that was similar to a vaccine effectiveness of approximately 94%,10 and similar effects have been documented in other settings.11–14 Hib vaccine effectiveness is most commonly measured as a reduction in invasive disease by culturing Hib from blood or cerebrospinal fluid (CSF). However, this underestimates the true incidence of invasive Hib disease because only a small proportion of children with pneumonia caused by Hib are bacteraemic at the time of evaluation and culturing Hib can be difficult. Furthermore, treatment with antibiotics before a sample is obtained for culture (common in many settings) decreases the likelihood of culturing Hib from blood or CSF. These limitations are found in most studies of Hib vaccine effectiveness. Attempts to overcome them include Hib antigen detection assays using urine15 and CSF,16 and vaccine-probe studies in which children are randomised to receive Hib vaccine or a placebo vaccine and the differences in disease incidence are attributed to Hib.17
Lancet Infect Dis 2008; 8: 435–43 Division of Infectious Diseases, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada (S K Morris MD); and Department of Epidemiology (W J Moss MD) and Department of International Health (W J Moss, Prof N Halsey MD), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Correspondence to: Prof Neal Halsey, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD 21210, USA [email protected]
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WHO region
Number of member states
Number of member states with Hib in routine immunisation schedule (%)
Africa
46
19 (41%)
Americas
35
34 (97%)
Eastern Mediterranean
21
14 (67%)
Europe
52
38 (73%)
Southeast Asia
11
1 (9%)
Western Pacific
27
13 (48%)
192
119 (62%)
Total
Table 1: WHO member states that have introduced Hib conjugate vaccines into the routine immunisation schedule by WHO region, 200624
A recent Cochrane review of randomised trials concluded that Hib vaccines, when compared with placebo, resulted in a large reduction in the risk of disease in multiple settings.18–22 Nevertheless, despite documented efficacy of the Hib conjugate vaccine in randomised, placebo-controlled trials, in 2005 WHO estimated that there were approximately 3 million serious illnesses and 400 000 deaths per year as a result of invasive Hib disease.23 Because the disease burden and the effectiveness of Hib vaccine might vary by geographical region, we review the literature to assess regional data on Hib vaccine effectiveness and progress in the control of invasive Hib disease through the introduction of Hib conjugate vaccine into routine childhood immunisation programmes.
Worldwide Hib vaccination programmes As of December, 2007, 119 countries had programmes for the routine administration of Hib vaccine in infants (table 1 and figure 1).24 However, the success of these programmes, as measured by estimated vaccine coverage, varied. Hib conjugate vaccine coverage in 2007 ranged from less than 40% to 99%. In 2003, WHO estimated that in the developed world, 92% of the eligible population was vaccinated against Hib, but coverage in developing countries was 42%, and only 8% for the poorest countries.26 Countries in Africa and southeast Asia had the lowest levels of Hib vaccine use. The immunisation schedules for selected countries that have introduced the Hib conjugate vaccine into their routine schedule are shown in table 2.
North America Before the routine use of Hib vaccine in the USA, the annual incidence of invasive Hib disease in children younger than 5 years of age was 88 per 100 000 population.28,29 Incidence rates in Canada were similar. However, these national rates masked regional and ethnic variability. High incidence rates of disease were found in Native Americans, Native Alaskans, and the Inuit population in Canada, where rates of invasive Hib disease exceeded 150 per 100 000 population younger than 5 years. In Native Alaskans, the documented rate of invasive Hib disease in children younger than 5 years was more than 700 per 100 000 children.30,31 436
The first Hib conjugate vaccine was licensed for use in the USA in 1987 and was initially recommended for children 18–59 months of age. In 1991, the vaccine was recommended for all infants beginning at 2 months of age.32 Vaccine coverage in the USA is 94% for three doses by 2 years of age. National33 and regional (Minnesota34 and California35) studies documented a decrease in invasive Hib disease of 85–99% from 1983 to 1995. However, the disease has not been eliminated in the USA. In 2006, the incidence of Hib disease was 0·21 per 100 000 population younger than 5 years, there were 29 confirmed cases of Hib disease in children younger than 5 years, and an additional 179 cases of unknown subtypes of H influenzae.36,37 Most cases of invasive Hib disease occurred in unvaccinated children. Although the Hib conjugate vaccine has proven to be very successful in the USA, there have been notable setbacks—for example, an increase in apparent vaccine failures from 1996 to 2000 in Native Alaskan children. In 1992–95, the incidence per year of invasive Hib disease in Native Alaskan children under the age of 2 years and 5 years was 35·8 and 18·3 per 100 000 population, respectively.38 However, following a change from PRP-OMP to PRP-HbOC combined with diphtheria, pertussis, and tetanus vaccine (DPT) in January, 1996, there was an increase in the incidence of invasive disease in under 2 and under 5-year-olds to 96·6 and 47·6 per 100 000 population per year, respectively. This increase was attributed to a lower antibody response after the first dose of PRP-HbOC compared with PRP-OMP and increased complexity of the schedule. The schedule was revised again in 2001 to include PRP-OMP for all doses and disease rates subsequently decreased below those recorded in 1991–95.38 Routine vaccination of Canadian infants with Hib conjugate vaccine began in 1992. In 1985 (before routine vaccination), 485 children were identified with invasive Hib disease at ten major paediatric centres.39 An active surveillance programme, done between 2001 and 2003 at the same ten centres plus two additional centres (covering an estimated 45% of Canadian children), identified only 29 cases of invasive Hib disease, half of which were meningitis.40 The annual number of cases identified decreased from 16 in 2001 to ten in 2002 and three in 2003.41 As in the USA, failure to vaccinate rather than vaccine failure was the major risk factor associated with invasive disease. 20 of the 29 cases involved children who were unvaccinated or who had not completed the primary series (ie, vaccine recommended at 2, 4, and 6 months of age).41
Europe At the end of 2007, Hib conjugate vaccine was part of the routine immunisation schedule in 38 of 52 countries in the WHO European region (table 1). Hib conjugate vaccine was introduced into the UK in 1992 and given to children at 2, 3, and 4 months of age, with an initial catch-up phase during which children aged 1–4 years received a single dose.42 The annual incidence of invasive Hib disease http://infection.thelancet.com Vol 8 July 2008
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(108 countries introduced infant immunisation schedule) Hib3 ≥80% (92 countries or 48%) Hib3 <80% (16 countries or 8%) Hib vaccine not introduced (85 countries or 44%)
Figure 1: Countries that have introduced Hib vaccine and infant Hib coverage, 2006 Adapted from reference 25. Hib3=three dose of Hib vaccine.
decreased to a low of 0·65 cases per 100 000 children aged under 5 years in 1998.42 However, beginning in 1999, the annual incidence of invasive disease increased to more than 4 per 100 000 children aged under 5 years in 2002.42,43 To investigate this resurgence, Ramsay and colleagues42 estimated Hib vaccine effectiveness in the UK and Wales between October, 1993, and December, 2002, and found it to be only 57% (95% CI 42–67%) following primary immunisation with the 2, 3, and 4-month schedule.42 After adjusting for the probable underestimation of vaccine coverage, the reported effectiveness was 72% (95% CI 62–79%). In 2003, a second catch-up campaign was launched to provide Hib vaccine to all children between 6 months and 4 years of age resulting in a reduction in the number of cases within 12 months in the age-groups targeted for the booster.43–45 Thus, the initial decline in the incidence of invasive Hib disease between 1992 and 1998 was mainly caused by the catch-up vaccination of older children. In the absence of a booster dose to maintain antibody concentrations, the primary series was inadequate to provide long-term protection.46 The initial decision to omit booster doses was based upon increased antibody concentrations following primary immunisation and the false assumptions that they would persist or that immunological memory would protect children against invasive disease. In Finland a three-dose schedule of 4, 6, and 14–18 months has been used with continued high efficacy over a 20-year period.47 The longer interval between the first two doses apparently induces sufficient protection against disease and the third dose serves as a booster dose. The UK has recently introduced a routine booster dose in the second year of life.48 The findings from the UK have potential implications for other countries that are introducing Hib vaccines under the generally recommended WHO schedule of 6, 10, and 14 weeks. http://infection.thelancet.com Vol 8 July 2008
Longer follow-up is required in countries using this schedule to determine if a decrease in circulating Hib will result in a loss of natural boosting and a subsequent increase in vaccine failure rates. Before the introduction of Hib conjugate vaccine, the annual incidence of invasive Hib disease in Scandinavian children younger than 4 years of age was 49 per 100 000 population.10 Although the five Scandinavian countries have implemented immunisation policies that differ in terms of age of vaccination and the type of vaccine used, each has seen a substantial reduction in Hib disease. In 2002, no cases of invasive Hib disease were recorded in children under 5 years of age in Denmark and Finland, Norway recorded only two cases (0·66 per 100 000 children aged under 5 years per year), and Sweden recorded seven cases (1·35 per 100 000 children aged under 5 years per year).49 Between 1992 and 1994, and before the use of Hib vaccine, the annual incidence of Hib meningitis in the Veneto region of Italy was 17·9 per 100 000 children aged under 2 years.50 In 1997, routine immunisation with three doses of PRP-HbOC vaccine was initiated at 3, 5, and 11 months, with a single dose for children over 11 months of age. Although this programme achieved only 26% and 31–53% coverage rates in children aged 1 year and 1–4 years, respectively, the annual incidence of invasive Hib disease in the region decreased from 11·3 per 100 000 children aged under 5 years in 1997 to 1·0 per 100 000 children under 5 years in 2000—a 91% reduction over 3 years.51 This reduction in invasive Hib disease despite low coverage rates could be explained by the use of the single dose in older children, similar to the catch-up dose used in the UK, or the effects of herd immunity. In the Val-de-Marne region of France, a 90% decrease in invasive Hib disease was reported after the introduction of Hib conjugate vaccine.52 Vaccine effectiveness against 437
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Schedule (months of age) North America Canada
2, 4, 6, 18
USA
2, 4, 6, 12–15
Europe Czech Republic
2, 3, 4, 18
Denmark
3, 5, 12
Finland
4, 6, 14–18
France
2, 3, 4, 16–18
Germany
2, 3, 4, 11–14
Iceland
3, 5, 12
Ireland
2, 4, 6, 12–15
Italy
3, 5, 11–12
Norway
3, 5, 12
Spain
2, 4, 6, 15–18
Sweden
3, 5, 12
UK
2, 3, 4, 12
South and Central America Argentina
2, 4, 6, 18
Brazil
2, 4, 6
Chile
2, 4, 6
Colombia
2, 4, 6
Costa Rica
2, 4, 6, 15
Uruguay
2, 4, 6, 12
Pacific and Asia Australia
2, 4, 6, 12
Fiji
2, 3, 4
Malaysia
2, 3, 5
New Zealand
1·5, 3, 15
Middle east Israel
2, 4, 6, 12
Kuwait
2, 4, 6, 18
Qatar
2, 4, 6, 18
Saudi Arabia
2, 4, 6, 18
Africa Kenya
1·5, 2·5, 3·5
South Africa
1·5, 2·5, 3·5
The Gambia
2, 3, 4
Uganda
1·5, 2·5, 3·5
Table 2: Hib conjugate vaccine immunisation schedules for selected countries27
invasive Hib disease in Germany was 90% (95% CI 67–97%) for an incomplete primary series (2, 3, and 4 months), 97% (95% CI 88–99%) for a full primary series, and 98·5% (95% CI 94·5–99·6%) for a booster dose.53 Hib conjugate vaccine was included in the routine vaccination schedule in the Valencia region of Spain in 1997 and the incidence per year of invasive Hib disease in children less than 15 years of age declined from 3·6 per 100 000 population in 1996 to 0·3 per 100 000 population in 1998, and has remained low.54 In eastern Europe, the Czech Republic introduced routine Hib vaccination in July, 2001. The annual incidence of invasive Hib disease in children aged less than 1 year decreased from 438
17·1 per 100 000 population to 3·3 per 100 000 population (an 81% decrease) 2 years after introduction, and to 1·1 per 100 000 population (a 94% decrease) after 3 years.55 The need for a booster dose of Hib vaccine in the second year of life remains controversial in western Europe. In 2002, the two European Union countries with the highest incidence per year of invasive Hib disease were the UK (4·3 per 100 000 children under 5 years) and Ireland (2·6 per 100 000 children under 5 years),49 neither of which routinely provided a booster dose. In response, Ireland began a temporary programme in November, 2005, where a booster dose of Hib vaccine was offered to children between the ages of 1 year and 4 years, and a fourth dose of Hib vaccine is now recommended for all children at 12 months. A summary of the changes in Hib conjugate vaccine schedules and coverage rates, and incidence rates of invasive Hib disease was published by the European Union Invasive Bacterial Infections Surveillance Network49 and WHO.56
South and Central America and the Caribbean Before the introduction of Hib vaccine into Latin America, data supporting the effectiveness of the Hib conjugate vaccine came from high-income countries with strong health infrastructures. The experience with Hib vaccine in South and Central America provided the first evidence of the effectiveness of the Hib conjugate vaccine in lowincome and middle-income countries. As of the end of 2007, 31 of 32 countries in South and Central America had introduced Hib conjugate vaccine into their routine immunisation schedules.23 In 1992, PRP-HbOC and PRP-T were licensed in Chile to be given to children at 2, 4, and 6 months of age. A study in Santiago showed a vaccine effectiveness of 92% (95% CI 65–100%) under programmatic conditions.19 Hib vaccine was introduced into the routine Chilean immunisation schedule in 199657 and the annual incidence of Hib meningitis in children under 5 years decreased from 40 per 100 000 population to less than 2 per 100 000 population 2 years later. In the 30 months following introduction of vaccine, vaccine effectiveness against invasive Hib disease was 90% (95% CI 75–100%).19 In 1994, Uruguay introduced Hib conjugate vaccine into the routine immunisation schedule, consisting of a primary series at 2, 4, and 6 months of age and a booster dose at 12–15 months of age.58 The incidence of Hib meningitis per year decreased from 17 per 100 000 children aged under 5 years in 1992–94 to 1 per 100 000 children under 5 years in 1995–96.58 In Central America, Hib-related hospital admissions decreased by 57% at a tertiary-care facility in Costa Rica following the routine use of Hib conjugate vaccine. Monovalent Hib conjugate vaccine was introduced into Argentina’s national immunisation programme in 1997, followed by tetravalent vaccine in 1998 as a three-dose schedule. A review of hospital records at two major http://infection.thelancet.com Vol 8 July 2008
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paediatric hospitals in or near Buenos Aires reported a decrease in the number of cases of culture-confirmed Hib meningitis from 1996 to 2001.59 Colombia introduced Hib vaccination of infants in May, 1998, and a 40% decrease in the number of cases of Hib meningitis was recorded the following year.60 Before the introduction of Hib vaccine, the average annual incidence of Hib meningitis in Brazilian children aged less than 1 year and between 1 and 4 years of age was 22·3 and 8·8 per 100 000 population, respectively.61 Although Hib vaccine was used in the private sector throughout the 1990s, it was made publicly available as part of the national immunisation programme in 1999 in a 2, 4, and 6-month vaccination schedule without a booster dose. For children who received fewer than three doses in the first year of life, an additional dose was recommended in the second year of life. In Salvador, Brazil, 5 years after the introduction of Hib conjugate vaccine, the annual incidence of Hib meningitis had decreased from 60·9 to 3·1 per 100 000 children aged under 1 year and from 2·39 to 0·6 per 100 000 population for all ages.62 Additional evidence for the effect of Hib vaccine in Brazil comes from a study showing a decrease in the frequency of Hib strains recovered from CSF, blood, and bronchial secretions from diverse locations around the country in 2001–03 compared with 1990–99.61 A 31% (95% CI –9% to 57%) reduction in radiologically confirmed pneumonia was seen in Goiania, central Brazil,63 and decreases in the frequency of Hib meningitis and in meningitis of unknown aetiology were reported in Salvador.64
The Pacific region and Asia The reduction in invasive Hib disease in Australia and New Zealand following the introduction of Hib vaccine was similar to that observed in North America and western Europe. However, in other countries in Asia and the Pacific region, uncertainty persists about the magnitude of the burden of disease caused by Hib and whether or not Hib vaccination is cost effective. Australia initiated Hib conjugate immunisation in 1992 and the annual incidence of invasive Hib disease in children less than 4 years of age declined from 15 per 100 000 children to 1·2 per 100 000 children between 1993 and 2000.65 Vaccine effectiveness was estimated to be 83% (95% CI 71–91%), and 90% (95% CI 83–94%) after adjusting for under-reporting.66 A substantial reduction in Hib meningitis was seen in indigenous Australian children, who before vaccination had the highest documented incidence of invasive Hib disease in the world.66,67 Hospital admissions resulting from Hib meningitis in children less than 5 years of age decreased by 92% (95% CI 89–94%) in New Zealand following the introduction of Hib vaccine in 1994.68 Fiji introduced a primary series of Hib vaccine at 2, 3, and 4 months of age in 1995, but shortage of vaccine led to inconsistent use until 1999 when coverage reached 76%.69 Comparing the period from 1992 to 1993 with 1999, the rate ratio for hospital http://infection.thelancet.com Vol 8 July 2008
UK/Wales42 UK/Wales (adjusted for probable underestimation of vaccine coverage)42 Germany53 Santiago, Chile19 Australia65 Australia (adjusted for probable underestimation of vaccine coverage)65 *The Gambia12 Kenya84 0
20
40
60
80
100
Vaccine effectiveness (%)
Figure 2: Effectiveness of full primary Hib vaccine series in protecting against all invasive Hib disease in children aged under 5 years in selected countries Error bars represent 95% CIs. Vaccine schedules used in studies were UK/Wales 2, 3, and 4 months; Germany 2, 3, and 4 months; Santiago, Chile 2, 4, and 6 months; Australia 2, 3, and 4 months; The Gambia 2, 3, and 4 months; Kenya 6, 10, and 14 months.*Vaccine efficacy is shown for The Gambia.
admissions due to meningitis in children younger than 5 years of age was 0·68 (95% CI 0·52–0·72), and 0·44 (95% CI 0·27–0·72) in children 6–18 months of age.69 The burden of Hib disease was thought to be lower in Asia than elsewhere in the world on the basis of infrequent isolation of Hib from diagnostic specimens. However, several recent studies suggest that the incidence of invasive Hib disease might be higher than previously reported.70–75 Hib conjugate vaccine use in national immunisation programmes in Asia has been limited. In 2002, Malaysia became the first country in the region to introduce Hib conjugate vaccine into its national immunisation schedule; however, published data on vaccine effectiveness are not available. In a randomised, placebo-controlled, vaccine-probe study undertaken on Lombok Island, Indonesia, more than 55 000 children were enrolled between 1998 and 2002.76 Hib conjugate vaccine was given at 6, 10, and 14 weeks of age and children were followed until 2 years of age, death, or the end of the study. In the first 2 years of life, the vaccinated group had 1561 (95% CI 270–2853) fewer cases of clinical pneumonia per 100 000 child-years following at least one dose of Hib vaccine, and 1467 (95% CI –6 to 2994) fewer cases per 100 000 child-years following three doses. Hib vaccine, however, did not prevent radiologically confirmed pnemonia in the first 2 years of life: the vaccine-preventable Hib incidence was –89 (95% CI –248 to 71) cases per 100 000 child-years. The absence of a decrease in radiologically confirmed pneumonia in the Lombok study differs from results of other Hib vaccine studies.20,63 The investigators propose that their intensive case finding led to the identification of a large number of children with viral and other non-bacterial pneumonias and that the identification of such cases might have obscured the effect on Hib pneumonia.76 They 439
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also propose that the proportion of pneumonia caused by Hib might be lower in Asia than in other settings.76 After receipt of at least one dose of vaccine, the incidence of microbiologically confirmed Hib meningitis in the first 2 years of life decreased from 19 to 2·6 per 100 000 child-years, representing a vaccine-preventable incidence of 16 (95% CI 1·4–31) per 100 000 child-years (86% reduction). At least one dose of vaccine prevented 22% of cases of clinical meningitis, for a vaccine-preventable incidence of 158 (95% CI 42–273) per 100 000 child-years. There are limited data on Hib vaccine effectiveness from other countries in Asia. An incident case-control study in Dhaka, Bangladesh, with a birth cohort of approximately 68 000 infants, allocated 25 high patientvolume and six low patient-volume immunisation clinics to provide Hib-DPT vaccine, while other clinics continued to provide routine DPT vaccine.77 Vaccine coverage was measured in the study area using standard WHO cluster survey methodology. This study found that in children receiving at least two doses of Hib conjugate vaccine, the incidences of radiologically confirmed pneumonia and microbiologically confirmed Hib meningitis were 34% (95% CI 6–53%) and 89% (95% CI 28–100%) lower than in community controls over the approximately 3-year period of case ascertainment.77 The incident case-control methodology avoids many of the inherent biases of typical case-control studies because new cases are identified prospectively, and thus provides strong evidence for a substantial burden of Hib disease in Dhaka and a high degree of effectiveness of the vaccine.77
The middle east In January, 1994, the Israel Ministry of Health introduced Hib conjugate vaccine (PRP-OMP) into the national immunisation schedule at 2, 4, and 12 months and achieved greater than 90% coverage. Prospective surveillance, including all 25 centres in the country offering paediatric services, estimated that vaccine effectiveness was 95% (95% CI 92–96%) and 97% (95% CI 93–98%) against invasive Hib disease and Hib meningitis, respectively.11 This study also showed a decrease in Hib infection in infants too young to be vaccinated, indicative of a herd immunity effect. In another study,78 no cases of invasive Hib disease were identified in vaccinated children among a cohort of 1444 Israeli children followed prospectively from 1992 to 1999. In 1997, Israel adopted a four-dose Hib vaccination schedule at 2, 4, 6, and 12 months. Qatar introduced Hib conjugate vaccine in 1993 with a schedule of 2, 4, 6, and 15 months. In 1992, 14 cases of Hib meningitis were documented in the country, but, after the vaccine’s introduction, only one case was reported in 1995, and one in 1996.57 Kuwait introduced Hib conjugate vaccine into the routine national immunisation schedule in 199757 and in 2000 WHO estimated that the country had achieved 98% coverage.56 The King Fahad National Guard Hospital, in Riyadh, Saudi Arabia, began using Hib conjugate vaccine in 1998 440
and a retrospective review of cases of Hib meningitis showed a decrease in the number of cases after vaccination at this institution.79
Africa As of Dec 31, 2007, only 19 of 46 countries in the WHO African region included Hib conjugate vaccine in their national immunisation schedule.25,80 These countries were Angola, Benin, Burkina Faso, Burundi, The Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Malawi, Mali, Mauritius, Rwanda, Senegal, Sierra Leone, South Africa, Togo, Uganda, and Zambia. Before the introduction of Hib vaccine in The Gambia, the annual incidence of invasive Hib disease was 274 cases per 100 000 children aged under 1 year.12 In a vaccine-probe study done from 1993 to 1995 to estimate the burden of disease caused by Hib, nearly 43 000 Gambian children were randomised to receive either DTP alone or PRP-T combined with DTP at 2, 3, and 4 months of age.20 Vaccine efficacy against culture-confirmed invasive Hib disease following three doses was 95% (95% CI 67–100%). Vaccine efficacy against radiologically confirmed pneumonia was 21% (95% CI 5–44%) in all study children, and 22% (95% CI 2–39%) in fully vaccinated children, showing the large but unrecognised burden of disease caused by Hib pneumonia in this country. PRP-T Hib vaccine was introduced in 1997 into The Gambia’s routine immunisation schedule at 2, 3, and 4 months. A prospective, case-control study measured the effectiveness of the Hib conjugate vaccine delivered through the routine programme.12 The median age at vaccination was 3·4 months, 6·5 months, and 8 months for one, two, and three doses, respectively. The adjusted vaccine efficacy against invasive Hib disease was 38% (95% CI –58% to 75%), 94% (95% CI 62–99%), and 94% (95% CI 62–99%) for one, two, and three doses, respectively. The adjusted vaccine efficacy for Hib meningitis was 35% (95% CI –84% to 77%), 93% (95% CI 42–99%), and 96% (95% CI 47–100%) for one, two, and three doses, respectively. Despite difficulties with vaccine supply, the national incidence per year of Hib meningitis decreased from 60 cases per 100 000 children aged under 5 years to no cases 5 years after the introduction of the vaccine. An equally impressive effect was seen in the subset of children under 1 year of age, in whom the incidence per year of Hib meningitis decreased from over 200 per 100 000 children to none.81 Formal Hib disease surveillance was stopped in The Gambia in 2007; however, between July, 2005, and April, 2006, five cases of invasive Hib disease (including three cases of meningitis) were identified in the country. Four of these children had received three doses of vaccine and one had received two doses, reinforcing the need to reinstitute surveillance to fully understand the effectiveness of Hib vaccine in this setting.81 PRP-T Hib vaccine was first used in South Africa in July, 1999, and WHO estimated the national coverage to be 92% in 2004.24 A hospital-based study found no effect of http://infection.thelancet.com Vol 8 July 2008
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Hib conjugate vaccine on all-cause or Hib cultureconfirmed bacterial meningitis, or surrogate markers of meningitis (CSF white blood cell count, protein level, glucose level, and turbidity) at Kalafong Hospital near Pretoria.59 However, the same study found a decrease in the same surrogate markers of bacterial meningitis at Chris Hani Baragwanath Hospital in Soweto.59 The investigators suggest that increasing rates of pneumococcal meningitis in the community served by Kalafong Hospital, particularly among HIV-1-infected children, might have masked the benefits of Hib vaccine. Clearly, the effect of HIV-1 infection on vaccine effectiveness is of particular importance in sub-Saharan Africa. In a cohort of nearly 40 000 children who received Hib conjugate vaccine, HIV-1-infected children had a 35 times greater (95% CI 15–85) risk of vaccine failure compared with HIV-1-uninfected children.82 Although most vaccine failures occurred in the first year following vaccination, there was a second peak among children aged 2–4 years. The relative importance of primary and secondary vaccine failure in HIV-1-infected children is not known; however, the second peak suggests that HIV-1-infected children might benefit from a booster dose at 2 years of age. The first population-based data to document the effectiveness of Hib vaccine in South Africa showed a 65% decrease in laboratory-confirmed invasive Hib cases in the first 5 years after the introduction of Hib vaccine. Notably, an increase in non-type b H influenzae infections was also reported, particularly among HIV-1-infected children.83 Additional data on the benefits of Hib vaccine in east Africa come from studies in Kenya and Uganda where Hib vaccine was introduced in 2001 and 2002, respectively. In Kenya, 3 years after vaccine introduction, prospective surveillance for culture-confirmed invasive Hib disease showed a vaccine effectiveness of 88% (95% CI 73–96%) among children younger than 5 years of age, and 87% (95% CI 66–96%) among children younger than 2 years of age.84 In Uganda, a hospital-based surveillance study showed a decrease in Hib meningitis from 88 to 13 cases per 100 000 children under 5 years per year 4 years after the introduction of the vaccine.80 This study calculated a vaccine effectiveness of 93% (95% CI 69–99%) for two or more doses, and estimated that 28 000 cases of Hib pneumonia and meningitis and 5000 Hib-related deaths are now prevented in Uganda every year.80
Conclusions Hib conjugate vaccines are highly effective in reducing the incidence of invasive Hib disease, with similar effectiveness seen across geographical regions and different levels of socioeconomic development (figure 2). Invasive Hib disease has gone from a major cause of childhood illness to a rare disease in every country where conjugate vaccine has been introduced into the routine immunisation schedule. However, despite nearly two decades of documented success and many deaths averted, less than two-thirds of all countries have incorporated Hib http://infection.thelancet.com Vol 8 July 2008
Search strategy and selection criteria PubMed and Medline databases were searched for articles published in the English language between January, 1985, and December, 2007, with the keywords “haemophilus”, “influenzae”, “type b”, “Hib”, “conjugate”, “vaccine”, “effectiveness”, “incidence”, “meningitis”, “pneumonia”, “North America”, “Europe”, “Asia”, “Africa”, “Pacific Region”, “South America”, “Central America”, and specific country names. Additional articles were obtained by searching the citations within retrieved papers. Internet searches were done to obtain data from WHO and the US Centers for Disease Control and Prevention, as well as for national immunisation schedules. Additional country level immunisation coverage data, and data describing vaccine effectiveness and the effect on the burden of Hib disease, were obtained from WHO tables and national ministry of health websites.
conjugate vaccines into their routine immunisation schedules. In 2006, only 26% of the world’s children received Hib vaccine.85 Vaccine costs and debate about the burden of disease remain obstacles to the global use of Hib conjugate vaccine. Recent data from Asia suggest that the burden of disease is higher than previously thought. Innovative funding schemes from the Global Alliance for Vaccines and Immunization (GAVI), other international health groups, and public–private partnerships, with continued documentation of the disease burden, have the potential to overcome barriers and increase the number of children benefiting from Hib vaccine. Local manufacturers, such as those in India, should be able to provide Hib vaccines at lower cost. However, even with new funding support, it is clear that many obstacles remain and vaccine use remains at a substandard level, particularly in developing countries. According to the Hib Initiative, at the end of 2007, only one-third of countries eligible for GAVI funding were using Hib vaccines.85 However, progress is being made. In 2008, it is expected that six countries that received conditional approval for GAVI funding in 2007 will reapply, eight new countries will make their initial application to the fund, and three countries that received funding approval in 2006 will actually introduce Hib conjugate vaccine into their national programmes.86 In 2006, the WHO Strategic Advisory Group of Experts recommended worldwide implementation of Hib vaccination unless “robust epidemiologic evidence exists of low disease burden, lack of benefit, or overwhelming impediments to implementation”.87 Although there is much work to be done before this recommendation is fully realised, all children should be protected against invasive Hib disease. Conflicts of interest NH has a research grant that provides a portion of his university salary from Wyeth, a manufacturer of Hib vaccine, and he has served on a data and safety monitoring board for an unrelated vaccine for Merck, a manufacturer of Hib vaccine. SKM and WJM declare that they have no conflicts of interest.
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