2. Vaccines used in the EPI

2.1 The target diseases

The EPI recommends that all countries immunize against poliomyelitis, diphtheria, pertussis, tetanus and measles, and that countries with a high incidence of tuberculosis (TB) infection should immunize against TB. Hepatitis B vaccine should be integrated into national immunization programmes in all countries by 1997 (EPI 1992c). Immunization against yellow fever is recommended in endemic countries. Table 1 summarises the information on the EPI target diseases which is most relevant to the design of control programmes.

Tuberculosis, caused by Mycobacterium tuberculosis, caused an estimated 2.6 million deaths worldwide in 1990. The pandemic of HIV infection and an increase in multi-drug-resistant tuberculosis bacteria have profoundly worsened the public health burden of tuberculosis.

Diphtheria is a bacterial infection caused by Corynebacterium diphtheriae (C. diphtheriae), transmitted person to person through close physical and respiratory contact. Like other respiratory infections, transmission is increased in overcrowded and poor socio-economic conditions. In temperate climates, prior to vaccination, respiratory diphtheria commonly affected preschool and school-age children, and deaths occurred from exotoxin-induced damage to other organs. Large epidemics occurred in Europe during and after the second world war, with an estimated one million cases and 50 000 deaths in 1943 (Stowman 1945). Nasal diphtheria may be mild and chronic carriage of the organism frequently occurs; asymptomatic infections are common. A cutaneous form of diphtheria is common in tropical countries, and may be important in transmission. Recently, large epidemics have occurred in Russia and the Ukraine (see section 4).

Tetanus is caused by the action of a potent neurotoxin produced during the growth of the anaerobic bacterium, Clostridium tetani (Cl. tetani), in necrosed tissues such as occur in dirty wounds, or the umbilical cord if delivery has not been clean. Tetanus has an environmental reservoir, and is not a transmissible disease. In developed countries, it affects mainly elderly persons, because younger age groups have been immunized. In developing countries, neonatal tetanus is an important cause of infant mortality. Maternal tetanus can occur by postpartum contamination of the uterus. In addition to vaccination, improving delivery care and the care of wounds are important interventions to reduce tetanus.

Table 1. Epidemiology of the EPI target diseases

Pertussis (whooping cough) is a bacterial respiratory infection caused by Bordetella pertussis (B. pertussis). It causes a severe cough of several weeks duration, with a characteristic whoop, often with cyanosis and vomiting. In young infants the cough may be absent and disease may manifest with spells of apnoea. Many of the symptoms are thought to be caused by toxins released by B. pertussis, in particular the pertussis toxin (PT; also known as lymphocyte promoting factor, LPF). The role of different antigens of B. pertussis is relevant to the development of new vaccines, and interested readers are referred to Cherry (1992), Edwards (1993) and EPI (1993c).

Poliomyelitis is an acute viral infection spread via the faecal-oral route, thus transmission is higher in areas of poor sanitation. Where sanitation is good, pharyngeal spread becomes more important. The majority of wild poliovirus infections are asymptomatic; the risk of paralysis is approximately 1 in 200 infections among infants <1 year old, and 1 in 100 infections among children aged 1-14 years. Factors increasing the likelihood of paralysis include the administration of injections or tonsillectomy during the incubation period of poliovirus infection, pregnancy, stress and trauma.

Measles is an acute viral infection that is transmitted by close respiratory contact, and may also spread via aerosolized droplets. Most deaths occur through secondary infections of the respiratory and/or gastrointestinal tract.

Yellow fever is a viral haemorrhagic fever that causes an estimated 30 000 deaths each year (EPI 1992d). In the forest pattern of yellow fever, the most common in the Americas, the main host is the monkey, and man is an accidental host. In the urban pattern, man is the host and the virus is transmitted via Aedes aegypti mosquitoes from person to person. The mosquito vector breeds in small stagnant water collections and hence transmission is facilitated by poor environmental hygiene. Thirty-three countries in Africa are considered at risk of yellow fever.

Acute hepatitis B is caused by the hepatitis B virus (HBV). Three of the antigens of the HBV are crucial in sero-epidemiology. These are the hepatitis B surface antigen (HBsAg) which is part of the coat of the virus, the core antigen (HBcAg), and the e antigen, a product of the breakdown of the core antigen which indicates high infectivity (HBeAg). Acute infection may be subclinical, especially in infants and young children, or may present with malaise, nausea and jaundice. The main public health consequences of HBV infection are the chronic liver disease and liver cancer which arise in carriers of the HBV virus, who are identifiable through detection of HBsAg. The younger the age at infection, the higher the chance of becoming a carrier: as many as 95% of infected infants, but only around 10% of adults, become long term carriers. In developing countries, the main route of transmission is perinatally (vertical transmission) from a carrier mother to her baby, which is more likely if the mother is positive for HBVe antigen, and “horizontal” transmission between young children. In industrialized countries, the main routes of transmission are sexual intercourse (which also plays a role in central and east Africa and much of Asia), blood to blood contact (eg transfusion, needle sharing among intravenous drug users as well as mother to baby (Hall 1994)).

2.2 Vaccine preparations available

Table 2 presents general information on the nature of EPI vaccines, their potency, form and route of administration, and Table 3 summarizes information on their immunogenicity and efficacy. Bacterial vaccines include Bacille Calmette Guerin (BCG) that contains live attenuated Mycobacterium bovis (M. bovis), and pertussis vaccine that contains killed pertussis bacteria. Vaccines against diphtheria and tetanus are toxoids (detoxified bacterial toxins). Viral vaccines include measles, yellow fever and oral polio vaccine which are all live attenuated viruses. Hepatitis B vaccines are produced from the surface antigen. Some vaccines are available in a fluid form, ready for use, while others are in a freeze-dried (lyophilized) form that must be reconstituted with cool diluent prior to administration. Detailed information on the immunological basis for the use of these vaccines is provided in the EPI series of modules on the Immunological Basis for Immunization (EPI 1993c).

Table 2. Characteristics of EPI vaccines

U: International units of potency as determined in animal tests

Infectious units: CCID₅₀ - cell culture infective dose 50%: the quantity of a virus suspension that will Infect 50% of cell cultures

PFU - plaque forming units: the smallest quantity of a virus suspension that will produce a plaque in monolayer cell cultures

* Number of doses In EPI-recommended primary schedule (see section 3); I/D: intradermal; I/M: intramuscular (some countries use deep subcutaneous injections);

S/C: subcutaneous

Table 3. Vaccine efficacy and vaccine-induced immunity

* Best estimate of protective level of antibody when measured by neutralization tests; may not correlate well with other assays

BCG. Although BCG is the most widely used vaccine in the world (85% of infants received a dose of BCG in 1993), estimates of efficacy vary widely and there are no reliable immunological markers of protection against tuberculosis. Clinical efficacy in preventing pulmonary TB has ranged from zero protection in the southern United States and in Southern India/Chingleput, to approximately 80% in the UK (Fine and Rodrigues 1990). There is no consensus on the reasons for this variation. Efficacy does not depend on BCG strain or manufacturer (Milstien and Gibson 1990). Some studies suggest that efficacy is reduced if there has been prior sensitization by environmental mycobacteria, but the evidence is not consistent. The degree of protection has not correlated with the degree of tuberculin test sensitivity induced by immunization, nor with BCG scar size. Data showing that BCG protects against tuberculous meningitis and against miliary tuberculosis (estimated 75-86% protection (Rodrigues et al 1993)) have led to a hypothesis that BCG protects against bloodborne dissemination of the bacteria, but does not limit the growth of localized foci that occurs in pulmonary TB. BCG also protects against leprosy, although the estimated efficacy has varied from 20% in Burma to 80% in Uganda (Fine 1989). Because efficacy against pulmonary tuberculosis is doubtful, the mainstay of the tuberculosis control programme is case-finding and treatment. BCG immunization at birth, however, will reduce the morbidity and mortality from tuberculosis among children.

Diphtheria toxoid. Diphtheria toxoid is a formaldehyde-inactivated preparation of diphtheria toxin, adsorbed onto aluminium salts to increase its antigenicity. This toxoid protects against the action of the toxin. Immunized persons can be infected by toxin-producing strains of diphtheria, but the systemic manifestations of diphtheria do not occur. Although the public health burden of diphtheria has been low in most developing countries, because most children acquired immunity through subclinical or cutaneous infection, recent outbreaks of diphtheria have been observed in Algeria, China, Jordan, Lesotho, Sudan, and Yemen Arab Republic, showing the importance of immunizing children in all countries (Galazka et al 1995a, 1995b). Diphtheria outbreaks in adults in Europe show the need to maintain immunity against the disease throughout life (see section 5). There are no data from randomized controlled trials of the clinical efficacy of diphtheria toxoid, but outbreak investigations have shown efficacies of over 87% (Jones et al 1985).

Diphtheria toxoid is almost always administered together with tetanus toxoid and pertussis vaccine as part of DPT vaccine in the primary vaccination series. It is also available as a component of other combined vaccines, or as a monovalent vaccine. DPT vaccine contains 10-20 Lf per dose of diphtheria toxoid, and the potency of diphtheria toxoid is at least 30 IU per dose. A combined diphtheria-tetanus vaccine exists in two forms: DT, with 10 - 30 Lf per dose, intended for children 7 years of age or younger, and Td, which has a reduced amount of diphtheria toxoid (2 to 5 Lf per dose) for use in older children and adults because of hyperreactivity to diphtheria toxoid in persons already sensitized to the antigen. DT is used for children who have contraindications to pertussis vaccine, and Td is used in countries that recommend booster doses of these toxoids throughout life (see section 5.1).

Tetanus toxoid. Tetanus toxoid (TT) is a formaldehyde-inactivated preparation of tetanus toxin, adsorbed onto aluminium salts to increase its antigenicity. TT is stable and can withstand exposure to room temperature for months and to 37°C for a few weeks without a significant loss of potency. TT induces the formation of specific antitoxins, which neutralize the toxin. Antitoxin which passes to the foetus across the placenta following active immunization of the mother prevents neonatal tetanus. In general, a tetanus antitoxin level of 0.01 IU/ml serum, as determined by in vivo assays such as the neutralization assay, is considered the minimum protective level (EPI 1993c). The corresponding level of antibody measured by other assays may be higher, and usually 0.1 IU/ml of antibody measured by in vitro assays such as ELISA or passive haemagglutination is considered a safe estimation. TT is a highly effective vaccine, although as with all vaccines, some cases of disease occur in immunized individuals. In most studies, the efficacy of two doses of TT during pregnancy in preventing NT has ranged from 80-100% (EPI 1993c).

Pertussis vaccine. Two types of pertussis vaccine are available: whole cell vaccines, which contain whole pertussis bacteria killed by chemicals or heat, and acellular vaccines, which have been introduced recently in some industrialized countries. Whole cell vaccines are effective in preventing serious illness, but they do not protect completely against infection with the organism. Efficacy and antibody levels wane with time after vaccination (Fine and Clarkson 1987). The protective level of antibodies against pertussis is not known. The degree of protection against disease has varied widely in different studies, partly because of methodological differences, and there have been very few studies in developing countries. Nonetheless, the importance of pertussis vaccination is demonstrated by the decline in reported incidence in industrialized and developing countries with well established immunization programmes, and the rebound in incidence and recurrence of epidemics that occurred in countries such as Sweden, the UK and Japan when vaccination uptake fell (Galazka 1992). Whole cell vaccine causes frequent local reactions and fever. Rarely, it may cause neurological reactions (see section 7).

Acellular pertussis vaccines contain isolated and purified immunogenic pertussis antigens. Usually they include pertussis toxoid (pertussis toxin treated to destroy its toxicity), filamentous haemagglutinin, agglutinogens and outer membrane protein. Local reactions are much less common following acellular than whole cell pertussis vaccine. The frequency of more serious neurological events in young children has not been determined. Acellular pertussis vaccines have been used routinely in Japan since 1981 in children above two years of age and in December 1991 were licensed in the USA for booster doses of DPT in children aged 15 months through 6 years (ACIP 1992). Several clinical trials are now in progress to compare the efficacy of primary immunization of infants with DPT acellular and whole cell pertussis vaccines (Cherry 1992). Meanwhile, the widespread use of DPT vaccine containing the whole cell pertussis component remains the cornerstone of pertussis control.

Poliomyelitis vaccines. There are two types of vaccine against poliomyelitis: oral and injectable. Oral poliomyelitis vaccine (OPV) is composed of the three types of attenuated polioviruses (1, 2 and 3). Because of its low cost, ease of administration, superiority in conferring intestinal immunity, and the potential to infect household and community contacts secondarily, the EPI recommends trivalent OPV as the vaccine of choice for eradication of poliomyelitis.

In industrialized countries, seroconversion rates after 3 doses of OPV have been demonstrated to be high (>90%) to all 3 types of virus. Seroconversion rates have been lower in developing countries, however: 73% (range 36% to 99%) for type 1, 90% (range 71% to 100%) for type 2, and 70% (range 40% to 99%) for type 3. The efficacy of 3 doses of OPV in preventing paralytic polio in developing countries ranges from 72% to 98% when the cold chain is properly maintained (EPI 1993c). Factors that reduce the immune response in developing countries (other than cold chain problems) include interference from other enteroviruses (that may be related to seasonal differences in response), and interference between the three vaccine viruses (that may be related to the relative doses of each virus type in the vaccine formulation). In many developing countries, routine immunization alone may not be sufficient to stop transmission of wild poliovirus, and supplementary immunization activities are recommended, as described in section 5.

Concern over low seroconversion after 3 doses of OPV led to a revival of interest in inactivated polio vaccine (IPV) in some countries, either as the sole vaccine against polio or in schedules combined with OPV. An improved IPV (e-IPV, enhanced potency vaccine) has been developed and used in several European countries. A schedule of two doses of combined IPV/DPT has been used in Africa and Israel, with high seroconversion rates to polio. However, pertussis agglutinin level waned faster in a two-dose schedule group than in a three-dose group (Muller et al 1984, Swartz et al. 1986, Rumke et al 1993). Although IPV suppresses pharyngeal excretion of wild poliovirus, this vaccine has only limited effects on intestinal excretion of poliovirus. The ability of IPV to eradicate poliovirus in developing countries, where faecal-oral transmission predominates, is doubtful.

Measles vaccine. Measles vaccines are live, further attenuated virus preparations derived from various measles virus strains isolated in the 1950s. Standard titre vaccines contain about but not less than 3 log₁₀ (i.e. 1000) infectious units per dose; higher potency vaccines do not increase seroresponse when administered to children aged 9 months or above. In developing countries, seroresponse rates and clinical efficacy have usually exceeded 85% (Diaz-Ortega et al 1994).

Yellow fever vaccine. Freeze-dried yellow fever vaccine contains the live attenuated 17D virus strain. It is highly immunogenic, over 92% of immunized children develop neutralizing antibodies that persist for at least 10 years and often 30 years or more (EPI 1993c). In 1990, the EPI Global Advisory Group recommended that all countries at risk of yellow fever should incorporate the vaccine into their EPI schedules on a routine basis (EPI 1991a). The vaccine is recommended for use from 6 months of age and is most easily integrated into the EPI by administering it at the same time as measles vaccine (usually 9 months). As of 1992, 16 of 33 countries at risk in Africa included yellow fever vaccine routinely in their immunization programmes.

Hepatitis B vaccine. Two types of hepatitis B vaccine containing HBsAg are available: plasma-derived vaccine and recombinant vaccine. Both vaccines are safe and immunogenic even when administered at birth (maternal anti-HBsAg antibody does not interfere with the response to the vaccine), and highly efficacious. Over 90% of susceptible children develop a protective antibody response (over 10 mIU/ml) following three doses of vaccine, and the efficacy of the vaccine in preventing chronic carriage in most cohorts of children studied for more than 10 years exceeds 90%.

Infants of HBsAg-positive carrier mothers respond less well to the vaccine since it is often delivered after infection has occurred. The vaccine efficacy in preventing chronic HBV carriage in these infants ranges from 75% to 95%. Addition of one dose of hepatitis B immune globulin (HBIG) at birth to the vaccine schedule may improve efficacy somewhat, but use of HBIG is not feasible in most developing countries.

2.3 Administration of vaccines

Table 2 shows number of doses and route of administration of EPI vaccines.

Vaccines containing aluminium adjuvants (DPT, DT, TT, Td and hepatitis B vaccine) should be injected intramuscularly. Some Scandinavian and Eastern Europe countries practise deep subcutaneous injections of aluminium-adjuvanted vaccines, claiming a low rate of local reactions. The preferred site for intramuscular injection in infants and young children is the anterolateral aspect of the upper thigh since it provides the largest muscular mass. In older children, the deltoid muscle has achieved sufficient size to offer a convenient site for intramuscular injection. Similarly, in adult women, the deltoid is recommended for routine intramuscular administration of TT.

The buttock should not be used routinely as an immunization site for infants, children, or adults because of the risk of injury to the sciatic nerve. Since the depth of gluteal fat in adult women is usually more than 3.5 cm, which is typically the length of the injection needle, injecting vaccines into the buttock may result in depositing the vaccine in the deep gluteal fat tissue. Gluteal administration of hepatitis B and rabies vaccine in adults has been associated with an impaired immune response possibly because of inadvertent deposition into, and poor adsorption of the vaccine from, fatty tissue.

Since hepatitis B vaccine is still expensive, some authors advocate the intradermal injection of a reduced dose of this vaccine. The adequacy and reliability of this practice has not been clearly established, and the EPI does not recommend this route. The immune response following a lower dose, especially of recombinant hepatitis B vaccine, may be reduced.