8. Other vaccines that can be used as a part of EPI

There are several other vaccines available which are used in different countries but are not yet recommended for use worldwide by the EPI. Some vaccines, such as Japanese encephalitis and Pig bel vaccines, are against diseases which are prevalent only in limited geographical areas; others such as Haemophilus influenzae type b (Hib) vaccine are used in industrialized countries but data on their cost-effectiveness in developing countries are not yet available; others such as pneumococcal vaccines are effective in adults but preparations for use in infants under 2 years of age have not yet been developed. This section provides a summary of information on vaccines currently available that certain countries may choose to include in their immunization programmes, and references to useful review papers. Factors that affect the decision to incorporate a new vaccine into a national vaccination schedule are summarized in Table 12.

Table 12. Factors affecting inclusion of a vaccine in a national programme (EPI 1993g)

8.1 Rubella vaccine

In childhood, rubella is a mild infectious disease in both industrialized and developing countries. The public health importance of the disease relates to congenital rubella syndrome (CRS) (EPI 1991d, EPI 1992f, Galazka 1991). When maternal rubella infection occurs during the first 3 months of pregnancy, foetal infection results in 90% of cases, with severe permanent consequences including blindness, deafness, and congenital heart defects. Spontaneous abortions and stillbirths are common. In the absence of immunization, rubella is endemic, and most children acquire the infection before they reach childbearing age. The proportion of women of childbearing age that are susceptible to rubella varies widely between and within regions, and there are few data on the incidence of CRS in developing countries.

Most industrialized countries include rubella vaccine in their national immunization programmes, most commonly as a combined measles-mumps-rubella (MMR) vaccine which is administered instead of single antigen measles vaccine in the second year of life. Some countries give a second dose at school age. Other countries conduct selective immunization of adolescent female children with single antigen rubella vaccine. Universal rubella immunization has not been recommended by WHO to date, because of the need for very high coverage to avoid the potential for an increase in the risk of CRS in the presence of an immunization programme. As discussed in section 4, immunization acts to increase the average age at infection, and if coverage is not high enough to reduce rubella transmission close to zero, there could thus be a paradoxical increase in CRS incidence in the presence of an immunization programme. The cost of MMR vaccine is also approximately twice that of single antigen measles vaccine. Now that many developing countries are sustaining coverage of measles vaccine above 85%, there is a need for research on the burden of CRS in developing countries and for cost-benefit analysis of rubella immunization.

8.2 Japanese encephalitis vaccine

Japanese B encephalitis (JE) is caused by an arthropod-borne virus (arbovirus). JE occurs in Southeast Asia and the Western Pacific countries (ACIP 1993a; EPI 1994b; Igarashi 1992). It is estimated that 2.4 billion persons are at risk and 20 000 cases occur each year with a case fatality rate of 25% and residual disease in about 30% of the survivors. In areas where JE is endemic, the annual incidence ranges from 1-10 per 10 000. Children younger than 15 years of age are mainly affected.

At present, two types of formalin-inactivated JE vaccine are in use, one derived from mouse brain and the other from primary hamster tissue culture. The vaccine produced in mouse brain is purified to remove myelin basic protein and is not associated with central nervous system damage in recipients. For primary immunization two doses of mouse brain JE vaccine are administered subcutaneously at an interval of 1 - 2 weeks. One additional dose is recommended a month after the primary immunization. A booster dose is recommended every 1 to 4 years. The vaccine has been shown to be highly effective and safe. The vaccine is produced in Japan, Republic of Korea, Taiwan, Thailand, and Vietnam. Purified JE vaccine is also produced and used in India (Rao Bhau 1992). An inactivated JE vaccine produced in baby hamster kidney cell culture was developed in China. It has been used since 1967 on a massive scale among children between 1 and 10 years of age in China.

Given the severity of the disease, particularly in young children, and the effectiveness of the available inactivated vaccines, countries where JE is endemic should consider its inclusion in their immunization programmes. There are no data on whether JE vaccine can be given simultaneously with measles or other EPI vaccines.

Issues that need to be resolved in further studies include: (1) the earliest age for immunization; (2) the need for booster doses; (3) whether JE vaccine can be given simultaneously with other EPI antigens, and (4) ways to decrease the cost of JE vaccine.

8.3 Meningococcal vaccine

Neisseria meningitidis causes both endemic and epidemic disease, principally meningitis and meningococcaemia (Wright 1989). Case fatality ratios reach 10-20% despite treatment in industrialized countries, and may be higher in developing countries. Most meningococcal diseases are caused by meningococci of serogroups A, B and C. Serogroup A is mostly responsible for large epidemics. Meningococcal disease is an important epidemic and endemic cause of morbidity and mortality, particularly in the sub-Sahelian meningitis belt of Africa. In epidemics, attack rates are higher than 500 cases per 100 000 population and about half of all cases are reported in children aged 0-4 years.

Safe and effective vaccines composed of monovalent groups A and C, bivalent A + C or quadrivalent A, C, W-135 and Y capsular polysaccharides are currently in use. A single dose of group A polysaccharide given to persons over 2 years of age will protect for 1 to 3 years. For children less than 2 years of age, two doses of group A polysaccharide vaccine are required 3 months apart to achieve protective levels of immunity. The vaccine has a clinical efficacy of 85-95% against serogroup A disease and is of use in controlling epidemics. Group C polysaccharide vaccine is effective in adults, but fails to elicit protective levels of antibodies in children less than two years of age. The linkage of a carrier protein to the polysaccharide (conjugate vaccine) allows the polysaccharide (PS) to provide long lasting immunity. Progress in development of conjugate PS-protein vaccines for invasive Haemophilus influenzae type b disease suggested that the same approach could be taken to prepare meningococcal A/C conjugate vaccines. Progress is ongoing to reach this goal.

Serogroup B is responsible for approximately 50% of endemic meningococcal infections in developed countries, but the group B polysaccharide is a poor antigen. Because some of the molecular structure is identical between meningococcal B polysaccharide and human brain tissue, safety concerns were raised on this cross-reactivity and a new approach has been taken using outer membrane protein (OMP) as potential candidate vaccine. OMP based vaccines have been developed in Norway (protective efficacy, PE, 57%) and in Cuba (PE in Cuba 80%, in Brazil 74% in infants 4 years old, 47% in children between 2 and 4 years of age, and no protection in children less than 2 years of age).

Currently available meningococcal polysaccharide vaccine is not recommended for routine infant immunization because of the short duration of immunity and the failure to protect against endemic serogroup B infections. However, widespread emergency immunization can control meningococcal A/C disease if implemented early in the course of an epidemic. Therefore, an effective meningitis surveillance is needed to detect the emergence of an epidemic in order to institute immunization at the earliest possible time. Studies in Burkina Faso showed that meningitis incidence rate of 15 per 100 000 averaged over 2 weeks is a specific and predictive threshold for an epidemic and for initiating emergency immunization (Moore et al. 1990, 1992).

8.4 Haemophilus influenzae type b vaccine

H. influenzae type b (Hib) is a common cause of bacterial meningitis and a variety of serious and potentially life-threatening infections, including pneumonia, epiglottitis and sepsis in infants and older children (ACIP 1993b; Pediatrics, supplement 1990; Wright 1989). A polysaccharide vaccine has been available for several years but was not immunogenic in infants. Recently, however, safe and effective conjugated Hib vaccines have been developed and licensed for use in several industrialized countries, where they have dramatically reduced the incidence of Hib meningitis. They contain Hib polysaccharide conjugated to diphtheria or tetanus toxoid, to a CRM₁₉₇ mutant C. diphtheriae toxin protein, or to an outer-membrane protein complex of Neisseria meningitis group B. Vaccines are given in a schedule of three doses in infancy (together with DPT), with (eg USA) or without (eg UK) a booster dose at age 12-18 months. A combination DPT-Hib conjugate vaccine is now available (ACIP 1993b). It would be premature to recommend the wide-scale use of conjugated Hib vaccine in developing countries until cost-effectiveness of such immunization is known. However, the high case fatality rate due to Hib meningitis and H. Influenzae - pneumonia in developing countries warrants thorough testing of the efficacy of conjugated Hib vaccines given in infancy, and a large efficacy study is in progress in the Gambia.

8.5 Pneumococcal vaccines

Streptococcus pneumoniae is responsible for three types of disease, pneumonia, otitis and meningitis. It is the leading cause of severe pneumonia in children under 5 years of age, causing over 1 million deaths each year. The current vaccine against S. pneumoniae is composed of capsular antigens to 7, 9 or 23 serotypes, which cause 60% to 90% of the infections in humans, and is immunogenic in persons over 2 years of age (Shann 1990). In some countries, recommendations are to give a dose of vaccine to children over 2 years old who are at high risk (those with sickle cell disease, chronic renal failure, immunosuppression from organ transplantation, leaks of cerebrospinal fluid, and HIV infection) (Feldman 1991), and countries such as the USA also include all persons 65 years of age and older in the target group.

It is difficult to prepare an effective vaccine against S. pneumoniae because protection is serotype specific and there are many (up to 80) different serotypes. Furthermore, like other pure polysaccharide vaccines, pneumococcal vaccine is poorly immunogenic in children, and is not recommended for infant immunization programmes. However, the development of a pneumococcal vaccine effective in infants is a high priority, and efficacy trials of pneumococcal conjugate vaccines will soon be conducted in developing countries. In children the immune response to the 6 serotypes involved in most of the infection, appeared over 4 years of age, and the PS candidate vaccines are unlikely to provide protection for more than 60-70% of invasive disease. An alternative approach has been taken using other components of the bacteria like pneumococcal surface protein (PspA), pneumolysin or protein 37KD.

8.6 Pig bel vaccine

Pig bel is a severe form of food poisoning; it is a necrotizing inflammatory disease of the small bowel (necrotizing enteritis) caused by toxins elaborated by Clostridium perfringens (welchi) type C. This disease is an endemic and an important cause of morbidity and mortality in children in Papua New Guinea. A condition with similar etiology has been reported from the south of China (Shann et al. 1979) and from a refugee camp on the Thai-Cambodian border (Karanth et al. 1986).

A toxoid prepared from Clostridium welchi type C is available and appears to be effective in children aged 1 to 15 years (Lawrence et al. 1979, Murrell 1982) and in infants, when it can be given simultaneously with DPT vaccine (Davis & Walker 1982). Routine immunization of children with Cl. perfringens toxoid was introduced in Papua New Guinea in 1980 in the five highland provinces and since then the incidence of the disease has fallen dramatically. Three intramuscular injections are given at two-monthly intervals to infants, at 2, 4 and 6 months of age, simultaneously with DPT immunization. Protection lasts for 2 to 4 years.

8.7 Typhoid vaccine

Typhoid fever remains an important and underestimated disease in many regions of the world (causing 560, 000 deaths every year globally) and it poses a risk for travellers. In most endemic areas the incidence of typhoid fever is highest in children 5-19 years of age; hence a vaccine is needed that can establish durable immunity prior to school age (Levine 1990, Levine et al 1991, Editorial 1992, Ivanoff et al. 1994).

Existing inactivated, injectable typhoid vaccines prepared from whole cell organisms confer protection after two doses in 51 - 88% of school children, but cause high rates of adverse reactions. The efficacy of killed vaccine has never been shown in controlled trials in children less than 2 years of age.

Live oral typhoid vaccine contains an attenuated strain of Salmonella typhi, Ty21a. The vaccine is safe and its efficacy has been evaluated in field trials in endemic areas. The level of protection is influenced by the formulation of the vaccine, the number of doses given, and the immunization schedule used (Levine 1990). With a liquid formulation, a 67% protective efficacy has been obtained after 7 years of follow up in an endemic area.

Purified Vi antigen, a polysaccharide capsule in the surface of S. typhi, has been used as a one-dose injectable vaccine in Nepal and South Africa, where the vaccine provided, respectively, 72% protection at 17 months, 64% protection at 21 months and 55% protection after 5 years of follow-up.

Both Ty21a and Vi polysaccharide are currently licensed and available, and offer an alternative to the poorly tolerated whole cell typhoid vaccine (Levine 1990). There is, however, insufficient information on the efficacy of these vaccines in children below 2 years to recommend them for use in infant immunization programmes at this time. Because of the current increased resistance against antibiotics, immunization should be considered as an alternative strategy in combatting typhoid fever.

8.8 Cholera vaccine

Cholera is estimated to cause more than 150 000 deaths each year in developing countries (WHO 1991). About one-third of the deaths are in children under 5 years of age, one-quarter in children age 5-14 years, and the remainder in adults. Parenteral immunization with the killed whole-cell vaccine is of no practical value in epidemic control or management of contacts of cases. This vaccine provides only partial protection (50%) of short duration (3-6 months), and is not regarded as a useful public health intervention. Attention has instead turned to the development of oral vaccines that could more efficiently stimulate local immunity (Clemens et al. 1990).

Both inactivated and live oral cholera vaccines have been developed (Levine and Kaper 1993). Two oral inactivated vaccines were evaluated in Bangladesh in the mid-1980’s and three doses provided 68% protection for at least three years in persons above 5 years of age. However, certain limitations were noted: the level of protection was markedly lower and lasted for only 6 months in children less than 5 years of age, and the vaccines provided less protection against the El Tor biotype than the classical biotype, after three years of follow-up. A trial conducted in Peruvian adults showed an 86% protection against El Tor after 6 months of follow-up. Most of those vaccinated were of blood group O.

Significant progress has been made recently towards the development of a one dose live attenuated cholera vaccine, containing the strain CVD-103 HgR, a V. cholerae 01 mutant strain, in which genes encoding cholera toxin have been deleted. In adult volunteers and children over 5 years of age the vaccine is immunogenic. Efficacy studies are now underway in children below 2 years of age. A practical and effective vaccine that can be used in all children is still needed.

New oral one-dose live candidate vaccines against El Tor biotype are under investigation. First results in US volunteers are encouraging (protective efficacy 83%). In March 1993, groups from Calcutta and Dhaka reported an apparently major outbreak of a cholera-like illness caused by a serotypically novel strain of Vibrio cholerae. This strain, which did not react with antisera for any of the 138 recognized serotypes of V. cholerae, has been designated V. cholerae 0139 Bengal. New oral killed and live candidate vaccines against cholera 0139 are under evaluation, as well as combined vaccines (01 and 0139).

8.9 Other vaccines under development

There is an urgent need for development of new vaccines. No successful vaccine against any human parasite has yet been developed. Malaria remains an important public health problem and an effective, safe and cheap vaccine would be a decisive factor in controlling malaria. One vaccine called “SPf66”, a chemically synthesized vaccine, underwent efficacy tests in Africa, having demonstrated immunogenicity in Colombia and Tanzania (WHO 1994). SPf66 is a safe and highly immunogenic vaccine and reduces disease incidence by 31% in Tanzania (Alonso et al. 1994) and 60% in Ecuador (Sempertegui et al. 1994). While these figures fall far short of the 80% and more efficacy of EPI vaccines, malaria’s high death toll means that even a partially effective vaccine could be a valuable weapon. These preliminary results provided a basis for attempts to improve the efficacy of malaria vaccine.

A modern plague - the pandemic caused by HIV - is recognized to be an international health problem of extraordinary scope and unprecedented urgency. A safe and effective vaccine to prevent the acquisition of HIV or to delay or prevent progression of HIV disease in those already infected, would be a vital addition to global AIDS prevention and control efforts. Although considerable progress in the development of HIV vaccines has been made, formidable obstacles remain. Animal models used to test HIV vaccines have several limitations; the genetic diversity of HIV may require an effective vaccine to be based on many viral strains; the immune correlates of protection remain unknown. Notwithstanding their marked genetic variability, the envelope glycoproteins of HIV, gp120 and gp160, have long been the primary foci for vaccine development. However, the degree to which the vaccines might confer protection against homologous or heterologous strains of HIV, or induce cell-mediated cytotoxicity, has remained uncertain.

Infections of the respiratory tract, such as those caused by respiratory syncytial and para-influenza viruses, are another great scourge; vaccines against these infections are under development.

In developing countries, those most at risk of enteric infections and diarrhoeal diseases are infants and young children. If safe, practical and effective vaccines existed against rotaviruses, shigellae, and enterotoxigenic E. coli, the disease burden from enteric infections could be greatly reduced.

The pace of vaccine research and development has quickened with better understanding of the antigens responsible for disease and protection, and with the advent of powerful molecular and cell biological techniques. We are now - as was noted at the first Bellagio Conference - “on the threshold of another major revolution in vaccine research, comparable or even exceeding in its scope the era that began when poliomyelitis virus was first grown in tissue culture” (Nossal 1984).