5. Additional schedules and strategies

The main priority for the EPI has been to establish immunization programmes that can deliver the primary immunization series to over 90% of infants, and hence reduce the public health burden of the EPI diseases. The elimination of target diseases, however, will usually require supplementary activities that involve the administration of additional doses of vaccine. Additional doses may be given in a routine programme as boosters, where the main purpose is to increase the duration of protection from the different vaccines, especially in the absence of “natural” boosting from exposure to the infectious agent. Extra doses may also be given via special delivery strategies such as nationwide or localized campaigns, where the combination of the additional dose and the method of delivery is important to increase the immunogenicity of the vaccine (e.g. polio), to attempt to interrupt transmission of the agent by immunizing a large proportion of the population simultaneously (e.g. polio and measles), and/or to conduct “catch-up” immunization of older age groups who were missed as infants in the years when the coverage of the basic immunization programme was lower (eg measles). Lastly, special strategies may be needed to respond to outbreaks of the EPI diseases.

5.1 Booster doses

Until recently, the EPI has not addressed the issue of booster doses of EPI vaccines (EPI 1993e). The first priority has been to ensure that infants are completely immunized against target diseases at the youngest age possible. Where resources were limited, the EPI suggested that booster doses should not be considered until coverage levels for fully immunized infants was above 80% (EPI 1986).

Today, many countries have achieved coverage levels above 80% and are administering booster doses of various vaccines. The number and frequency of such booster doses depends on the epidemiological patterns of diseases in a particular country, the level of health services infrastructure, the ability to sustain high coverage of infants, and the availability of resources to buy vaccines.

BCG. There is much controversy over the effectiveness of repeated doses of BCG vaccine. Several European countries conduct routine tuberculin tests in immunized children and repeat BCG immunization in children until they develop a BCG scar and/or become tuberculin-positive. However, there is no evidence that the degree of protection from BCG is related to scar formation or to tuberculin conversion (Comstock 1971). On the other hand, there is evidence from some BCG trials that the protection afforded by BCG decreases with time after immunization, and some authors believe that repeating BCG immunization increases its efficacy (Kubit et al. 1983, Lugosi 1987), and revaccination is not associated with adverse events. The EPI recommends that research be conducted on the long-term effectiveness of BCG given in infancy, including the prevention of tuberculosis in adults who acquire HIV infection; the efficacy of different seed lot vaccines, and the safety and efficacy of BCG in HIV infected infants (EPI 1991a).

DPT or DT vaccine. Booster doses of DPT vaccine may be considered on the basis of maintaining immunity against each of the three component antigens of the vaccine.

Table 9. Percentage of countries using different immunization schedules for DPT vaccine by WHO region (Galazka 1992)

Region	Primary three doses in weeks (w) or months (m) of age					Booster doses
	6, 10, 14 w or 2, 3, 4 m	3, 4, 5 m or 4, 5, 6 m	2, 4, 6 m	3, 5-6, 7-15 m	12-24 m	3-6 yrs
African	64	36	-	-	31	-
American	19	10	57	14	57	33
Eastern Mediterranean	30	25	30	15	45	5
European*	11	48	15	18	63	11
S. East Asian	64	36	-	-	36	9
W. Pacific**	23	35	23	16	48	35

* No pertussis vaccine is used in Sweden. In Denmark, monovalent pertussis vaccine is used at 5 and 9 weeks and 10 months.

** In 5 countries, the DPT booster dose given at school entry is the fourth dose of DPT, since no dose is given one year after completing the primary series of DPT.

Diphtheria component. The duration of diphtheria immunity after a primary series of three diphtheria-toxoid-containing vaccines has varied widely in different studies. Studies in England and Italy showed that over 95% of children immunized with three doses of DPT or DT still had protective levels of diphtheria antibody 4-8 years later (Cellesi et al. 1989, Tones et al. 1989), and antitoxin levels were not related to the length of the interval between doses of DPT (Tones et al. 1989, Ramsay et al. 1991). Hence the UK does not administer a booster dose of DPT in the second year of life, but gives DT at school entry. However, studies in other countries have shown that antibody levels may fall below the “protective level” in a substantial proportion of children after the primary series, and also that immunity levels in schoolchildren appear to be lower in recent years (Crossley et al. 1979, Pichichero et al. 1987).

The duration of immunity against diphtheria may depend on the likelihood of exposure to diphtheria organisms (Simonsen et al. 1987, 1989) and thus may be different in developing countries than in developed countries. Data on persistence of immunity in developing countries are scarce, but recent outbreaks show that as immunization coverage increases, immunity gaps may arise in older age groups.

The appearance of diphtheria in older age groups in developing countries indicates the need to consider introduction of booster doses.

Routine use of booster doses of diphtheria toxoid in adults remains a controversial issue. Routine booster doses of Td vaccine are recommended every 10 years in many countries including Australia (National Health 1991), Canada (Health and Welfare 1984), Luxemburg and Switzerland (Bytchenko 1990), and the USA (ACIP 1991b, American Academy of Pediatrics 1991). Routine decennial booster doses of Td vaccine are difficult to monitor and usually this strategy is marginally effective. Td vaccine can be used instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated e.g. in treating wounds in emergency rooms.

In many recent diphtheria outbreaks in Europe, adolescents and young adults were mainly affected. In Poland, additional routine booster doses of Td vaccine for adolescents at the age of 19 years have been introduced to prevent the spread of the diphtheria epidemic in young adults (EPI 1995). Serological investigations performed in several countries have shown a low level of diphtheria immunity among adults aged 20 to 50 years. A study in Denmark suggested that long-term protection against diphtheria may be assured by a booster dose of Td vaccine administered 20 years after the primary immunization (Simonsen et al. 1986b). The introduction of Td immunization of high risk groups in the adult population should be considered in industrialized countries. Td vaccine can be used in military service personnel and in other high-risk adults including medical service staff, kindergarten and creche personnel, teachers, students, alcohol and drug abusers and persons travelling to areas where diphtheria is endemic. In the face of a diphtheria epidemic, emergency immunization should involve mass immunization of affected age-groups or regions with high diphtheria incidence.

Pertussis component. The duration of immunity following pertussis immunization is also unresolved. Epidemiological investigations suggest that the efficacy of pertussis vaccine falls with time after immunization (Blennow et al. 1988, Jenkinson 1988). Serological studies show a steep decline of postvaccination antibody levels against various pertussis antigens (EPI 1993c) and one study suggested that the rate of decline may be more rapid after schedules with one month rather than longer intervals between doses (Booy et al. 1992). Antibody levels increase significantly after booster doses in the second year of life and/or at school entry, and may help to decrease pertussis infection during the school years. The pertussis component is not recommended after the age of school entry.

Recently, there have been several reports of pertussis in adults in industrialized countries. Decreased immunity among adults may be related to the reduced circulation of pertussis organisms in the community and less natural boosting. It has been suggested that acellular pertussis vaccines should be used to boost antibody levels in adults in an effort to reduce transmission of pertussis infection (Cherry 1992, 1993). This policy has not yet been evaluated, however.

Tetanus component. The expected duration of immunity against tetanus after the primary series of DPT is 5 years (see Fig 1). Administering additional doses in the second year of life and at school entry will prolong protection for at least 15 years, and in the long term may be an important part of the overall strategy for neonatal tetanus elimination (see section 3.6).

Current practice regarding DPT boosters. Questions about the duration of immunity after a primary series of three doses of DPT are reflected by differences in the immunization schedules used in different countries. Figure 2 depicts schedules used in European countries and Table 9 shows DPT immunization schedules in six WHO regions. Some countries, mostly in the African and South East Asia Regions use only the primary series of three doses of DPT vaccine. Many countries recommend a booster dose of DPT vaccine one year after the primary series; upwards of 31% of countries in the African Region to 63% of countries in the European Region recommend a fourth dose of DPT vaccine at 12-24 months of age. Finally, in the USA and in about one third of countries in the American and Western Pacific Regions, an additional booster dose is administered at 4 to 6 years of age.

Figure 2: DPT immunization schedules for European countries

Issued January 1996

The policy recommended by EPI is: · In all countries, and particularly where pertussis is still an endemic disease and poses a serious health problem in infants and young children, the priority should be to reach at least 90% coverage with a primary series of three doses of DPT vaccine in infants in all districts. · In countries where pertussis incidence has been considerably reduced by successful immunization programmes, a booster dose administered approximately one year after the primary series (at the middle or the end of the second year of life) is warranted. A booster dose of DPT will also help to maintain immunity against diphtheria, and will form part of the long-term strategy for neonatal tetanus control. The need for additional booster doses of DPT or DT and their efficacy should be assessed by individual national programmes.

Poliomyelitis vaccine. The immunization schedule recommended by EPI calls for four doses of OPV given by 14 weeks of age. The importance of a birth dose of OPV has been discussed in section 3.1. If a dose of OPV is not given at birth, the fourth dose should be given at the time of the measles contact, or at any other contact with the health system in the first year of life. There should be an interval of at least 4 weeks between any two doses. The rationale for providing several doses of OPV is to assure initial seroconversion against all types of poliovirus, rather than to boost waning immunity.

In a number of countries where the circulation of wild polioviruses has been greatly reduced, if not eliminated, booster doses of OPV are commonly given at the second year of age and again before entering school.

Measles vaccine. Although measles can be controlled by achieving and sustaining coverage of over 90% of infants with a single dose, measles elimination is unlikely to be possible with the existing strategy. Recently measles epidemics have occurred in countries after prolonged periods of low disease incidence due to high immunization coverage (EPI 1989, EPI 1992e) - see section 4. Many countries have therefore introduced supplementary doses of measles vaccine. Industrialized countries that have low drop-out rates and high coverage through routine services have tended to adopt a routine two-dose schedule (Rosenthal and Clements 1992), but this has not been endorsed by WHO. On the other hand, countries in the Americas have adopted a mass campaign approach, as described in the next section. Drawing from this experience, WHO has adopted a policy of supplementary immunizations through mass campaigns (EPI 1994c).

Countries with a routine two-dose schedule usually administer the first dose between 12-15 months of age and the second dose between 6 and 12 years of age. The second dose of vaccine is given to provide a second opportunity to immunize persons who were missed at the age for the first dose, and to immunize those who were immunized but failed to respond to the first dose (“primary vaccine failures”). Most persons who respond to measles immunization will have long-term or lifelong immunity, although studies have documented incidence of measles among persons who previously seroconverted after immunization (Mathias et al 1988, Reyes et al 1987). Revaccination of persons whose antibody levels have waned to low or undetectable levels appears to offer only transient benefit. In such persons, although antibody levels boost after revaccination, they subsequently fall to previous levels (Deseda-Tous et al 1978; Markowitz et al 1992). Therefore, decreasing the incidence of secondary vaccine failure is not a major objective of two-dose schedules.

It is not clear whether a two-dose schedule will improve measles control and more data on the cost-effectiveness and impact and of this strategy are needed. The challenge for most countries remains that of covering over 95% of each new birth cohort and administering the measles vaccine on time.

Hepatitis B vaccine. After the primary course of HB vaccine, surface antibody decays at a rate which is similar in all infants. Those who have high initial antibody levels will remain positive for antibody much longer than those who have a low post-vaccination antibody level. A significant proportion of immunized children have no detectable antibody 5-10 years following immunization, and subclinical infection, as demonstrated by detection of antibodies to HBV core antigen, has been reported. However, because such infections do not lead to clinical disease or to chronic carriage of HBsAg (Hall 1994), current thinking is that booster doses of HB vaccine are not needed (ACIP 1991a).

The longest follow-up of immunized children is still less than 15 years, however, and continuing study is important to assess the future need for booster immunization, particularly when persons immunized in infancy enter the sexually-active period of life (Hall 1993).

Yellow fever vaccine. The International Health Regulations require reimmunization at intervals of 10 years. Revaccination boosts antibody titre; however, evidence from several studies (Groot and Ribeiro 1962, Poland et al 1981; Rosenzweig et al 1963) suggests that yellow fever vaccine immunity persists for at least 30-35 years and probably for life.

5.2 Campaigns

Mass immunization campaigns are an integral part of the global polio eradication strategy, and are now recommended by WHO for use in measles elimination programmes (EPI 1994c, Global Programme for Vaccines 1994).

Polio eradication includes the following activities:

· The use of OPV in national and subnational immunization days aiming at the administration of two doses of OPV 4-8 weeks apart to all children under 5 years of age, regardless of their previous immunization status. Campaigns are best conducted during the low season for polio transmission, which is usually the cool, dry season.

· “Mopping up” immunization activities

· In selected high risk areas conducted on a house-to-house basis. High-risk areas are those with polio cases at any time in the preceding 3 years, with low immunization coverage, or with epidemiologically defined risk factors such as urban slums. Two doses of OPV one month apart are administered to all children under age 5 years.

· Surveillance and investigation of cases of acute flaccid paralysis, followed by rapid outbreak response immunization where suspected cases are detected (see section 5.3).

Campaigns have also been used for measles elimination by countries in the American region and are being introduced in some countries of South-East Asia, combined with the polio eradication campaigns. The first phase of the elimination strategy is a mass campaign to immunize every child between the ages of 9 months and 15 years, irrespective of previous immunization or disease history (Anonymous 1994, Hospedales 1993). This strategy was based on the experience of Cuba, which had interrupted measles transmission by immunizing over 95 percent of children under age 15 years in 1988 (PAHO 1992). By the end of 1994, all countries in Latin America and the Caribbean will have implemented such campaigns. The short term impact of this strategy is dramatic, but in the longer term it is important to set up active measles surveillance to detect any suspected cases, which will trigger timely measles control measures. Additionally, high coverage of new birth cohorts must be achieved and maintained, and catch-up mass immunization in a narrower age range undertaken. Deciding on which age group to target for catch-up immunization will be dependent on the number of susceptibles who have accumulated in the respective age groups.

The policy recommended by EPI is: Mass campaigns should be used in certain circumstances, especially in countries whose health infrastructure is inadequate to achieve high coverage through routine services. Such campaigns should be targeted to age groups identified through analysis of epidemiological data on age-specific attack rates of the disease. Urban areas, particularly those with low coverage and high measles incidence, may be operational targets in measles immunization campaigns. School- children or other age groups may be considered target groups in emergency diphtheria immunization campaigns in the face of diphtheria epidemics. Such campaigns should not be isolated events but should be part of a comprehensive, long-term strategy for polio eradication and measles control and elimination, and may include catch-up campaigns. Where possible, campaigns should include different EPI vaccines (EPI 1994c).

5.3 Outbreak response

Outbreak response immunization is localized mass immunization conducted rapidly in response to detection of an outbreak of an EPI disease.

The degree to which a country responds to an outbreak of measles is variable, and depends on: the availability of resources; the stage of development of the surveillance system; current measles coverage; measles incidence, and programme objectives. Countries with low measles vaccine coverage and high measles incidence should focus on developing and improving routine service. When an outbreak is observed, it is usually too late to intervene successfully. However, the opportunity should be taken to better understand why the outbreak occurred and to adjust strategies to reduce the chance of another outbreak occurring. In the event of an outbreak, countries may choose to increase access to case management services and to provide public information to increase knowledge about measles treatment and prevention through immunization. Sometimes political necessity over-rides these criteria and alters the degree of response. An area experiencing a measles outbreak may be identified as high risk and subsequently be targeted for supplementary immunization activities.

Countries having high measles immunization coverage (e.g. 80% or more for at least three years), low incidence of disease, or both, may decide to provide a greater range of activities in the event of an outbreak. In addition to case management and public information, these include: supplementary immunization activities; case (or outbreak) investigation, ie the collection of information on the age, immunization status, date of onset of the rash, and other details about each case to use in analysing the cause of the outbreak, and intensive measles surveillance (an active searching by health workers for unreported or unexpected cases).

All countries should respond to outbreaks in refugee and other emergency relief settlements, with special emphasis on rapid supplementary immunization. Susceptible individuals should be immunized upon arrival at the settlement. If, despite this, a child in the settlement develops measles, all children between six months and five years of age should be immunized regardless of previous immunization history.

Transmission of measles in hospital must be prevented by immunization of all eligible children seen by health staff for any reason. An outbreak in a hospital setting should be responded to immediately with immunization of all in-patients aged between six months and fourteen years of age - they should be immunized regardless of previous immunization history.

A single case of diphtheria warrants a rapid and widespread immunization response covering affected age groups. Special attention should be given to close contacts of diphtheria cases; they should be monitored for signs/symptoms of diphtheria, bacteriologically tested for carriage of diphtheria organisms, and immunized against diphtheria. Previously immunized contacts should receive a booster dose of diphtheria-toxoid-containing vaccine, and a primary series should be initiated in unimmunized contacts using DPT, DT or Td vaccines, depending on age. Useful guidelines on response to diphtheria outbreaks, including use of antibiotics, have been published (Benenson 1990, Farizo et al 1993, WHO 1994).

The detection of cases of polio should generate an outbreak immunization response with OPV. A single case of paralytic polio suggests a community with a low level of immunity. Even though many children will already be infected with the outbreak strain, others may be uninfected and the current recommendation is that if a case of suspected poliomyelitis is detected, one dose of OPV should be administered to all children less than 5 years of age living in the vicinity of a case, regardless of immunization status. The number of children, the distance, and the area to be targeted will depend on local resources and epidemiology (Hull et al 1994). Guidelines on the management of polio outbreak response activities have been published (EPI 1991c).