Causes and Epidemiology of Diseases Prevented by Vaccines Used in National Immunization Programs
The epidemiology and burden of vaccine-preventable diseases vary by country and region partly because of differences in vaccine uptake. Numerous other factors that contribute to the disease burden include geography, seasonal patterns, crowding, nutritional status, travel to and from other countries, and possibly genetic differences in populations that affect disease severity. Table 20.1 summarizes the features of selected vaccines in use in childhood immunization programs throughout the world.
[Table .]
Burden of Vaccine-preventable Diseases
A number of vaccine-preventable diseases are not reportable events in many countries. The estimates of the burden of disease by the World Health Organization (WHO) are based on a combination of often incomplete vital registration data, mortality survey data, and mathematical models using numerous assumptions. Most models of vaccine-preventable diseases are derived from the susceptible fraction of the population (calculated from natural immunity from presumed historical infections in regions without previous vaccination and historical immunization coverage rates), infectivity rates of disease, sequelae of diseases, and estimates of local CFRs. The degree of accuracy of these models is only as good as the data supporting the assumptions. The disease burden is most appropriately represented by a range of values reflecting uncertainty. In this chapter, we estimate the burden of disease as the number of deaths and DALYs per World Bank region in 2001. The following description draws in part on discussion of methods for burden of disease calculations reflected in the Global Immunization and Vision Strategy of WHO and the United Nations Children's Fund (UNICEF) (Wolfson and Lydon 2005).
Diphtheria
Diphtheria is caused by a toxin-producing strain of the bacterium Corynebacterium diphtheriae, which is transmitted by means of respiratory droplets. The 2001 WHO estimates of diphtheria mortality are extrapolations from reported deaths in countries with full or partial vital registration systems.
Before the widespread use of immunization, more than 5 percent of people living in temperate climates suffered from clinical diphtheria at some point during their lifetimes (Griffith 1979). Rates exceeding 100 cases per 100,000 population were seen in Europe during World War II (Galazka, Robertson, and Oblapenko 1995). The CFRs from respiratory tract diphtheria have been 2 to 20 percent, with an average of 10 percent for patients receiving good medical care (Feigin, Stechenberg, and Hertel 2004). To estimate diphtheria deaths in the absence of vaccination and to project future deaths with and without vaccination, we assumed an average incidence rate of 15 per 100,000 and CFRs of 2.5 percent in developed countries,5.0 percent in Europe and Central Asia, and 10.0 percent elsewhere (Birmingham and Stein 2003; Galazka and Robertson forthcoming).
Tetanus
Clostridium tetani is maintained in nature and is found in all countries. Spores remain viable for many years in soil and dust, especially in areas contaminated by animal feces (Cherry and Harrison 2004). The organism is usually transmitted through burns, cuts, and other penetrating injuries. Neonatal tetanus is the most common presentation in developing countries. The portal of entry is usually the umbilical stump but has been associated with circumcision and other surgical procedures (Birmingham and others 2004; Stanfield and Galazka 1984). Children born to women who do not have protective levels of tetanus antibody are susceptible to neonatal tetanus.
The estimated burden of neonatal tetanus assumes that in areas with low rates of skilled delivery, all births not protected by the immunization of pregnant women are subject to a preimmunization era neonatal tetanus mortality rate expressed as deaths per 1,000 live births (Birmingham and others 2004; Griffiths and others 2004). In other areas, we assume that births not protected through immunization or skilled delivery are subject to an incidence and CFR equal to 25 percent of the preimmunization era neonatal tetanus mortality rate.1
CFRs are directly associated with the quality of medical care available. With the availability of secondary and tertiary care, CFRs have declined to 25 percent or less (Cherry and Harrison 2004; Wassilak and others 2004). The CFRs used to derive cases from estimated deaths range from 40 percent in developed countries to 80 percent in the poorest developing countries. We estimate the tetanus burden other than for neonates by applying an estimated age distribution of total tetanus to the estimated neonatal tetanus deaths (Galazka and others forthcoming) and region-specific CFRs, which indicate a range of from 27 percent among children age one to four in developed countries to 65 percent among those age 80 or older in developing countries.
Pertussis
Bordetella pertussis is transmitted through respiratory excretions and occurs throughout the world. Most pertussis in developing countries occurs in school-age children. In developed countries, mild or asymptomatic infections in adults are believed to be common sources of transmission to very young infants (Edwards and Decker 2004). Clinical manifestations include an initial 7 to 10 days of rhinorrhea progressing to a cough that becomes paroxysmal or spasmodic, usually associated with profuse rhinorrhea (Cherry and Heininger 2004). Clinical pneumonia is seen in approximately 10 percent of infants.
Our estimates for the burden of pertussis followed the model described in Crowcroft and others (2003). We estimated that the proportion of susceptible children becoming infected in countries with vaccination coverage of less than 70 percent over the previous five years was 30 percent by age 1, 80 percent by age 5, and 100 percent by age 15. For countries with coverage of more than 70 percent in the past five years, we assumed that 10 percent of susceptible children were infected by age 1, 60 percent by age 5, and 100 percent by age 15. A vaccine efficacy of 80 percent was assumed for preventing infection and 95 percent for preventing deaths. The CFR was 0.20 percent in infants, 0.04 percent in children age one to four, and 0 percent in those older than five in low-mortality countries; and 3.7 percent among infants, 1 percent among children age one to four, and 0 percent in those older than five in high-mortality countries.
Poliomyelitis
Before the availability of polio vaccines, as many as 90 percent of children in the developing world were infected with all three types of the polio virus in the first two or three years of life (Sutter and Kew 2004). In developed countries, transmission occurred primarily in school-age children and more than 90 percent of infections were asymptomatic; 4 to 8 percent of children had nonspecific febrile illness and less than 1 percent developed acute flaccid paralysis (Sutter and Kew 2004).
Children with residual paralysis require rehabilitation. Surgical intervention is necessary if contractures develop because of the lack of rehabilitative services following the acute illness. These children are at increased risk of premature death because of late onset postpolio muscle atrophy (postpolio syndrome), which occurs 20 to 40 or more years after acute illness.
Disease burden estimates are based on actual active surveillance. The estimated 1,000 deaths a year caused by polio reflect past infections and current deaths. Following Robertson (1993), we obtained the number of cases and deaths in the absence of immunization by applying an incidence rate of 1 per 1,000 population under age five and CFRs of from 2.5 percent in developed countries to 10.0 percent in Sub-Saharan Africa. To determine current cases, we applied an estimate of notification efficiency to reported cases.
Measles
Measles is an acute respiratory viral infection. Children born to immune mothers are protected against clinical measles from passively acquired maternal antibodies until they are five to nine months of age. More than 90 percent of infections are associated with clinical disease (Krugman 1963). Complications include pneumonia, diarrhea, encephalitis, and blindness, especially in children with vitamin A deficiency. In recent years, CFRs have been estimated at 3 percent in many developing countries, but historically they have been as high as 30 percent in some community-based studies (Aaby 1988; Aaby and Clements 1989; Moss, Clements, and Halsey 2003; Perry and Halsey 2004).
For a disease such as measles in which infection is almost universal in the absence of immunity, small changes in the CFR result in large changes in estimates of total mortality. Increased complication and mortality rates occur in children who are younger than five, vitamin A deficient, or infected with HIV or who have acquired measles from a household contact (Perry and Halsey 2004). Declines in CFRs in the past two decades are associated with the tendency of the disease to infect older children, decreased crowding, and improved nutritional status in many developing countries (Perry and Halsey 2004). At the same time, recent studies indicate CFRs of 0.4 to 9.7 percent in Sub-Saharan African countries with low immunization coverage (Perry forthcoming).
Considerable controversy is associated with the number of deaths resulting from measles, because of difficulty in accurately specifying the cause of death in children afflicted with measles and in separating complications of measles from those of other conditions. In addition, CFRs, which have decreased rapidly in many countries, vary significantly. The natural history model used in this chapter is based on Stein and others (2003), modified to account for the effect of supplementary immunization activities.
We derived estimates of the burden of disease in countries with high-quality surveillance data and high sustained coverage of measles vaccine by adjusting the number of reported cases by a reporting efficiency factor ranging from 5 to 40 percent. In estimating the future burden of disease, the averted burden of disease, and the burden in countries without both adequate surveillance and sustained high coverage, we assumed that the average number of cases per year is equal to the number of children in the current birth cohort who are not protected by either routine or supplemental vaccination. WHO (2005a) estimates that in 2001, 611,000 deaths (approximately 5 percent of all childhood mortality) were attributable to measles.
An alternative proportional mortality approach, which is based on retrospective verbal autopsy studies in 18 countries to derive the proportional causes of child deaths in 42 high-mortality countries, also has appeared in the literature (Morris, Black, and Tomaskovic 2003). This model suggests that measles may have accounted for approximately 3 percent of all childhood deaths in 2000.
In countries with a high disease burden, the true number of measles deaths may be somewhere between the proportional mortality and natural history estimates. WHO (2005b) uses a hybrid method that estimates that measles was responsible for an average of 4 percent of mortality among children under five between 2000 and 2003, or approximately 400,000 deaths per year. If the actual number of deaths in 2001 was 400,000, then the cost per death averted will be lower than what has been estimated for this chapter, and the effect of increasing coverage will be overestimated because fewer deaths could be prevented.
Both of the approaches described have strengths and limitations. We adopt the natural history approach for this analysis because the chapter includes deaths at all ages and the model can adapt to recent changes in CFRs and coverage rates. However, the natural history method is sensitive to the accuracy of parameter inputs such as CFRs and may underestimate the effect of herd immunity. Further modeling efforts would need to incorporate sensitivity testing around a range of parameter estimates.
In the absence of vaccination, the measles virus would infect almost 100 percent of the population, including most of the 688 million children under five in the developing world. Using the methods described here, approximately 125 million cases and 1.8 million to 2.0 million deaths per year would be expected in the absence of vaccination.
Haemophilus influenzae Type b (Hib)
Hib is transmitted through the respiratory tract and causes meningitis, pneumonia, septic arthritis, skin infections, epiglottitis, osteomyelitis, and sepsis. Deaths caused by Hib occur primarily from meningitis and pneumonia. In developed countries, approximately half of diagnosed invasive infections are meningitis (Wenger and Ward 2004). In developing countries, a larger proportion of identified cases is meningitis resulting from underdiagnosis of other clinical syndromes (Martin and others 2004; Peltola 2000). Intervention studies have demonstrated significant reductions in pneumonia in vaccinated compared with unvaccinated children (Levine and others 1998; Mulholland and others 1997). Although infections occur throughout the world, the incidence of Hib disease may be lower in some Asian countries than in Africa and the Americas (Gessner and others 2005).
We derived estimates of Hib disease burden from incidence rates and CFRs for meningitis and pneumonia. We derived country-specific estimates of the incidence of Hib meningitis from the literature on incidence in the prevaccine era (Bennett and others 2002). For countries without meningitis incidence data, we used the average incidence in countries with similar epidemiological profiles. Regional averages ranged from 219 cases per 100,000 to 3 per 100,000 population in children under one, and 1 to 15 per 100,000 population in children age one to four. The CFR for meningitis is nearly 100 percent in the absence of intensive antibiotic therapy, but it can be reduced to 5 to 8 percent when appropriate therapy is available (Swartz 2004). We derived CFRs in a manner similar to that used for incidence rates and adjusted them on the basis of country-specific data on access to care. Regional means ranged from 3 to 32 percent.
Estimating the burden of Hib pneumonia is much more complex. A rapid assessment method assumes five pneumonia cases for every meningitis case (WHO 2001). An alternative approach assumes that Hib is responsible for a fixed proportion (about 20 percent) of acute lower respiratory infection deaths in the absence of immunization (Peltola 2000). We derived pneumonia CFRs from a literature review of lower respiratory infections in children (Bennett and others 2002), with average CFRs ranging from 1 percent among infants in developed countries to 12 percent in Sub-Saharan Africa.
Hepatitis B
In many developed countries, most transmission of hepatitis B occurs during or after adolescence, coinciding with the onset of sexual activity and of drug abuse involving unsafe reuse of needles and syringes (McQuillan and others 1999). In many African countries, transmission occurs primarily in early childhood through mucosal contact with infectious body fluids and unsafe injection practices (Margolis, Alter, and Hadler 1997). Some Asian countries have a high rate of chronic carrier states, and the primary mode of transmission is mothers to infants (Beasley 1988; Mast and others 2004). The rate of symptomatic disease is only about 1 percent in infancy and 10 percent in early childhood, but it increases to 30 to 40 percent in adults. Serosurveys for carrier states of hepatitis B are available for almost all nations (WHO 1996).
Models of hepatitis B disease burden are based on estimated ratios between infected and carriage states at various ages or estimates of the percentage of carriers that progress to hepatoma, fulminant hepatitis, or cirrhosis at later stages of life (Miller and McCann 2000). The model we used for estimating hepatitis B mortality estimates the age- and sex-specific progression of hepatitis B surface antigen infection to disease incorporating competing mortality, particularly because individuals infected with HIV are more likely to perish from HIV before the full mortality impact from hepatitis B infection (Gay and others 2001; Griffiths, Hutton, and Pascoal 2005).
Whereas most vaccine-preventable diseases that result in death occur at an early age shortly after the age of vaccination, deaths from hepatitis B occur many years into the future. Countries that introduce hepatitis B vaccines today will not reap most of the benefits for many years. In the absence of vaccination, we estimated approximately 1.4 million future deaths attributable to hepatitis B for the 2001 birth cohort after accounting for competing mortality. Global vaccination of 35 percent would prevent more than 500,000 of those future deaths. Discounting the value of future hepatitis B deaths to their equivalent value in the present to make the burden of disease prevented equivalent to that of other vaccine-preventable diseases results in approximately 87,000 deaths averted.
Yellow Fever
Yellow fever virus is transmitted by mosquitoes, primarily Aedes eqypti, with a three- to six-day incubation period. Patients present with intense headache, fever, chills, and myalgia, among other symptoms. Although once much more widespread, yellow fever is now limited to West and Central Africa, the northern half of South America, and Panama. In approximately 15 to 20 percent of yellow fever patients, severe disease occurs, with liver and kidney failure and cardiovascular collapse. The CFR varies, with increased severity in older adults (Monath 2004). The average CFR in patients in Africa with jaundice is 20 percent (Monath and others 1980; Nasidi and others 1989).
On the basis of surveillance data adjusted for underreporting, WHO (1992) estimates the global burden of yellow fever at 200,000 cases and 30,000 deaths in 1990. Most cases and deaths occur in 33 African countries, where 1 in 80 cases is assumed to be reported. In South American countries, 1 in 10 cases is assumed to be reported. We use the implied incidence rate and a CFR of 15 percent to project future mortality. Between 1990 and 2001, some improvement in routine coverage of yellow fever vaccine occurred, but the overall burden of yellow fever is unlikely to have declined.
