Facilitating the WHO Expanded Program of Immunization: the

Original Report

Facilitating the WHO Expanded Program of Immunization: the clinical profile of a combined diphtheria, tetanus, pertussis, hepatitis B and Haemophilus intuenzae type b vaccine Javier Aristegui, 0) Vytautas Usonis, c2) Hoosen Coovadia,(3) Stella Riedemann,c4) Khin Maung Win,c5) Salvation Gatchalian(@ and Hans L. Back(7)

Background: Vaccines are important weapons in the fight against infectious diseases. The World Health Organization (WHO) Expanded Program on Immunization (EPI) has been extended to include recommendations for hepatitis B and Haemophilus influenzae type b (Hib) vaccinations. The WHO has recommended that combined vaccines be used where possible, to reduce the logistic costs of vaccine delivery. This paper reviews the efficacy, safety and cost- effectiveness of Tritanrix-HB/Hib, the only commercially available combined diphtheria, tetanus, whole cell pertussis, hepatitis B and conjugated Hib vaccine.

Methods: The immunogenicity and reactogenicity results of five published clinical trials involving Tritanrix-HB/Hib in a variety of immunization schedules and countries were reviewed. Based on these data and cost-effectiveness studies, an assessment of its suitability for use in national immunization programs was made.

Results: Tritanrix-HBiHib has shown excellent immunogenicity in clinical trials using a variety of schedules, with no reduced immunogenicity observed for any of the components of the combined vaccine. It has similar reactogenicity to DTPw vaccines alone. Pharmacoeconomic analyses have shown combined DTP-HB/Hib vaccines to be cost- effective compared to separate vaccines.

Conclusions: Replacement of DTPw vaccination by Tritanrix-HB/Hib can be done without modifying the existing national immunization programs. This should facilitate widespread coverage of hepatitis B and Hib vaccinations and their rapid incorporation into the EPI.

Int J Infect Dis 2003; 7: 143-151

INTRODUCTION

Infectious diseases constitute the leading cause of mortality and morbidity worldwide. Their impact varies widely among countries: in 1997, infectious and parasitic diseases were responsible for 43% of deaths in developing countries, but just 1% of fatalities in industrialized c0untries.l Vaccines are among the most effective weapons against infectious diseases, and effective vaccination programs can lead to dramatic decreases in mortality.2 One of the most spectacular

(‘)Department of Pediatrics, Basurto Hospital, Bilbao, Spain; (2)Vilnius University Center of Pediatrics, Vilnius, Lithuania; c3)Department of Pediatrics and Child Health, University of Natal, Durban, South Africa; (4)Universidad Austral de Chile, Valdivia, Chile; (S)Experimental Medi- cine Division, Department of Medical Research, Yangon, Myanmar; @Department of Pediatrics, University of the Philippines, Philippines General Hospital, Manila, Philippines; (‘)GlaxoSmithKline Biologicals, Rixensart, Belgium.

Address correspondence to H. L. Bock, GlaxoSmithKline Biologicals, Rue de l’Institut, 89,133O Rixensart, Belgium.

E-mail: [email protected]

Corresponding Editor: Jane Zuckerman, London, UK

successes of vaccination was the global eradication of smallpox in 1980, after a campaign that began in 1967. However, there is still much to be done in implementing effective vaccination programs. The WHO has estimated that at least 2 million deaths among children under 5 years old could be prevented each year, using existing vaccines.l

A potential drawback of vaccination programs covering a wide range of diseases is that such programs could comprise large numbers of injections. A common strategy to reduce the number of injections needed is the use of combined vaccines, in which a single injection contains more than one antigen.3,4 Combined vaccines in widespread use include diphtheria, tetanus and pertussis (DTP) vaccine, and measles, mumps and rubella (MMR) vaccine. There are many advantages of combining vaccines in this way, as not only does it reduce discomfort for patients by sparing them multiple injections, but it also reduces some logistic costs linked to factors such as fewer clinic visits, syringes and needles, and a reduced requirement for cold storage of vaccines.5 Moreover, when vaccinations are given separately, there is greater scope for missed doses6 so combined vaccines can also increase compliance, and hence the overall effectiveness of vaccination programs.

brought to you by COREView metadata, citation and similar papers at core.ac.uk

provided by Elsevier - Publisher Connector

https://core.ac.uk/display/82403127?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v1

144 International Journal of Znfectious Diseases I Volume 7, Number 2,2003

Combined DTP vaccines have been in widespread use since the 1940s. Today, global DTP coverage is estimated to exceed 8O%;7 this is a consequence of the fact that DTP is a mandatory component of most immunization programs. DTPw has been shown to be the most cost-effective means of pertussis prevention, provided that an effective whole cell vaccine is used with high coverage.8 Combining new vaccinations with DTP vaccine would therefore facilitate their inclusion in vaccination programs. However, before vaccines can be combined in the same injection, it is essential to demonstrate that the new combined vaccine does not adversely affect the immunogenicity of any of the components or lead to increased reactogenicity.

EPIDEMIOLOGY

Diphtheria was responsible for a substantial burden of disease before the introduction of routine vaccination against it. Large epidemics occurred in Europe during and after World War II, with an estimated 1 million cases and 50 000 deaths in 1943. Even recently, epidemics have occurred where vaccination coverage has been poor, particularly in eastern Europe.9 However, the incidence of diphtheria has fallen dramatically since routine vaccination was introduced in the 1940s and 195Os.lO

Tetanus is more common in developing countries, where immunization is less widespread than in industrialized countries, and is a significant cause of mortality and morbidity. The WHO has estimated that there were 410 000 deaths due to tetanus in 1998, of which only 1000 occurred in countries classified as having high income.‘l

Worldwide, Bordetella pertussis causes some 20-40 million cases of pertussis, 90% of which occur in developing countries, and an estimated 200 000-300 000 deaths each year. Although pertussis may occur at any age, most cases of serious disease and the majority of deaths are observed in early infancy. The introduction of routine vaccination against pertussis has dramatically reduced its public health impact.12,i3 When routine vaccination was withdrawn in the UK, Sweden and Japan because of concerns about the reactogenicity of the vaccine, a resurgence of the disease was seen.14-i6

Hepatitis B (HB) is a widespread disease. More than 2 billion people worldwide have evidence of past or current HB virus (HBV) infection, and more than 350 million are chronic carriers of the virus.] Many chronic carriers of HBV develop cirrhosis and hepatocellular carcinoma, leading to substantial mortality.17-lg Overall, about 1 million people die each year as a result of HBV infectionzO HBV can be transmitted by a variety of routes, such as from mother to child (perinatal transmission), household contact with highly infectious individuals (horizontal transmission), sexual contact, or blood contact (e.g. needle sharing by intravenous drug users, or needlestick injuries to health care workers). The most important mode of transmission depends to

some extent on prevalence rates. In countries with high HBV seroprevalence, perinatal transmission is common, whereas sexual transmission tends to be more important in countries with low HBV seroprevalence.21.22

When HB vaccination was first introduced, it tended to be used only for individuals considered to be at high risk. However, that strategy has failed to control the disease in countries where it has been practiced,20 so it is now recommended that all infants be vaccinated against HBV. It has been clearly demonstrated that mass HB vaccination programs can dramatically reduce carrier rates. In Taiwan, where a nationwide program of HB vaccination began in 1984, the seroprevalence of HBV surface antigen (HBsAg) in children fell from 9.8% in 1984 to only 1.3% in 1994.23 Moreover, there is evidence from Taiwan that such vaccination can be effective in reducing the incidence of hepatocellular carcinoma.“4,25 Similar beneficial effects have been observed in Italy.26

Haemophilus injluenzae type b (Hib) is a Gram- negative bacterium responsible for a substantial burden of disease in industrialized and developing countries, causing about 3 million cases of serious disease and 400 000-700 000 deaths annually in young children.27 It can cause various diseases, including meningitis and pneumonia. 28 Meningitis caused by Hib can have severe neurologic sequelae, even when promptly treated with appropriate antibiotics. 2g The burden of Hib disease in Latin America30 and Asia31,32 has recently been reviewed. In Latin America, the overall annual incidence of Hib meningitis in children under 5 years old was 35/100 000, which is similar to that in industrialized countries before the routine use of Hib vaccination, and translates into about 20 000 cases of Hib meningitis annually in the region. Overall, Hib disease was responsible for an annual burden of about 5000 deaths and 4800 children with serious sequelae in the region.30 In Asia, Hib was the most commonly isolated pathogen in children with bacterial meningitis. 31 Using a hypothetical model, it was estimated that 87% of cases of Hib deaths could be prevented by vaccination.33

Because of the high burden of disease caused by Hib, even with the availability of antibiotic treatment, it is highly desirable that children be protected against Hib infection by vaccination. Vaccination programs can be extremely effective in preventing Hib infection. The incidence of invasive H. influenzae infection in children aged less than 5 years fell by 97% during the period 1987-97 in the USA, where routine vaccination with Hib conjugate vaccines was introduced in 1988.34 There is also evidence that Hib vaccination can be effective in preventing invasive disease in developing countries.35,36

WHO VACCINATION RECOMMENDATIONS

Because vaccines represent an extremely effective and even cost-effective method of reducing the burden of disease, the World Health Organization (WHO) takes

Facilitating the WHO Expanded Program of Immunization / Aristegui et al 145

an active role in encouraging their use. The WHO Expanded Program on Immunization (EPI) was founded in 1974, and originally included vaccinations against polio, diphtheria, tetanus, pertussis, tuberculosis, and measles. The EPI has made substantial progress in increasing global vaccine coverage, and all six of the original EPI vaccines had a global coverage of at least 80% by 1997.7 However, that global figure masks substantial inequalities among countries. For example, coverage with BCG vaccine in 1997 was 90% worldwide, but only 66% in the WHO African region.7 There is therefore still substantial room for improvement in vaccination coverage, particularly in developing countries.

Because of the substantial burden of disease caused by HBV, and because of the dramatic reduction in that burden that can result from mass vaccination programs, the WHO recommended adding HB to the EPI vaccines in 1992.37 They stressed that it was important to implement routine vaccination, because of the failure of the strategy of vaccinating only those considered at high risk, stating ‘Only by mass vaccination of infants with HB vaccine as part of the EPI would the burden of HB infection be significantly reduced globally.‘38 Their original targets were to introduce routine vaccination against HBV in countries with carrier rates of 8% or greater by 1995, and in all countries, irrespective of HBV prevalence, by 1997. Although those targets were not met in full, substantial progress has been made towards them. The number of countries practicing routine HB vaccination increased from 20 in 1990 to 80 in 1996,20 and was over 13.5 by the end of 2001.37 HBV can be transmitted perinatally, and in countries where this is a common mode of transmission, such as in Asia, the WHO recommends that the first dose of HB vaccine be given as soon after birth as possible, and within 12 h at the latest. This dose can then be followed by a second HB vaccination dose between months 1 and 2.“g

The US Centers for Disease Control have also recommended routine childhood vaccination against HBV40 The recommendation has been successfully implemented with coverage of three or more doses of HB of vaccine administered to infants in the USA increased from 8% in 1992 to 82% in 1996.41

The WHO issued further recommendations for HB vaccination in 1996;42 these noted that combined vaccines lead to fewer clinic visits, fewer injections, and reduced logistic requirements. The WHO therefore recommended that the combined DTP-HB vaccine was an excellent choice for the inclusion of HB vaccine in vaccination programs.

More recently, the WHO has recommended that vaccination against Hib should be included in routine infant immunization programs, as appropriate to national capacities and priorities. 27 Those recommendations noted that Hib conjugate vaccines given in infancy are effective in reducing the burden of Hib disease, and also that Hib vaccination may safely be given concurrently with other EPI vaccines.

A COMBINED DTPW-HB/Hib VACCINE

To facilitate the incorporation of Hib into immunization schedules, GlaxoSmithKline Biologicals has developed a combined diphtheria, tetanus, whole cell pertussis, HB and Hib vaccine from two vaccines that were already licensed: Tritanrix-HB, a quadrivalent DTPw-HB vaccine; and Hiberix, a monovalent Hib conjugate vaccine. Both products have been reviewed by the WHO and found to be acceptable for purchase by UN agencies.

The vaccine is prepared by extemporaneously mixing Tritanrix-HB and Hiberix vaccines in the same syringe. The clinical development program of the vaccine has included a number of trials comparing the combined vaccine with separate administration of its two constituent vaccines, over a range of schedules.

Tritanrix-HB was first licensed in 1996, and is currently approved in over 70 countries. It has a proven track record of good immunogenicity and reactogenicity, as has been shown by many clinical studies. Those studies were done with a variety of schedules: 3 4 and 5 months,43 2, 4 and 6 months,44 3, 4.5 and 6’months4’ and 1.5,3.5 and 6 months, following a dose of HB vaccine at birth.46 In all those studies, the seroprotection rates for HBV exceeded 95%, as recommended by the WH0,s7 and immune responses to the other three components were also excellent. Reacto- genicity was similar to that seen for DTPw vaccines alone.47%48 Although mild fever was common, fever >39.5”C was rare. The range of different schedules used in the clinical studies shows that Tritanrix-HB can be used without having to modify the schedules routinely used in different national immunization programs.

Hiberix was first approved in 1997, and is now licensed in over 60 countries. It has good immunogenicity, and a good reactogenicity profile.49

Tritanrix-HB/Hib is the only commercially available combined vaccine against diphtheria, tetanus, pertussis, HB and Hib.

CLINICAL STUDIES OF THE DTP-HB/Hib VACCINE

Tritanrix-HB and Hiberix have proven immunogenicity and tolerability when given separately, but it cannot automatically be assumed that the combined vaccine will therefore be immunogenic and have acceptable reactogenicity. Although combining vaccines has many advantages, such as reduced costs and increased convenience for patients and health care workers, there is always a possibility that the vaccine components will interact in such a way that the immunogenicity is reduced or the reactogenicity is increased. A program of clinical trials was therefore undertaken to investigate whether the combined DTPw-HB/Hib vaccine produced by combining the vaccines in the same syringe would also be immunogenic and well tolerated.

146 International Journal of Infectious Diseases I Volume 7, Number 2,2003

In general, the studies found that the combined vaccine was indeed immunogenic for all five components, with no increase in reactogenicity compared with the separate components. As with Tritanrix-HB, there was already a good immune response after the second dose, with the advantages that this brings to areas where rates of partial non-compliance are high. The combined vaccine was also compatible with a single dose of HB vaccine given at birth (in this case, subjects received a total of four doses of HB vaccine), as recommended by the WHO for areas of high seroprevalence. The results of the studies are described in detail below.

IMMUNOGENICITY OF TRITANRIX-HB/Hib

Two studies have compared primary vaccination courses of the combined DTPw-HB/Hib vaccine, prepared by reconstituting Hiberix with Tritanrix-HB, with the same vaccines given separately. Coovadia et also vaccinated 120 healthy South African infants with Tritanrix-HB and Hiberix, either as separate injections or as a combined injection, with a schedule of 2,4 and 6 months of age. Riedemann et a151 studied 120 Chilean infants in a study with a similar design, but with the addition of a booster dose at 18 months. Neither study showed any difference between the two modes of administration, and both studies showed seroconversion rates of 100% for all five vaccine components (some seroconversion rates in the Chilean study were less than 100% after the third dose, but all were 100% after the booster). The studies therefore convincingly demonstrated that Hiberix and Tritanrix-HB could be combined in the same syringe without any loss of immunogenicity for any of the vaccine components. Again, both studies showed high seroconversion rates as early as after the second dose. The booster dose in the Chilean study led to dramatic increases in antibody titers, demonstrating that the immune system had been suitably primed by the earlier doses, which is likely to be indicative of long-term protection. Figure 1 shows the rates of seroprotection in

i i 60 s

40

0 PII Pill Pil Pill

(m5) 0-W 0-W WI

Schedules 3, 4 ,!? and 2, 4, 6b

Figure 1. Responses to hepatitis B vaccination at two different schedules. %SP, percentage of seroprotected subjects. “Prikasky and Bock.43 bRiedemann et aL5’ m, month. P, post dose.

response to the HB component of the vaccine, in comparison with the rates obtained in a separate study using separate and combined DTPw and HB vaccinations. A seroprotection rate of almost 95% was observed in the group who received the combined vaccine after two doses, compared to 66% when DTPw and Hiberix vaccines were administered separately.52

In a study conducted in Lithuania, 120 healthy infants received Tritanrix-HB combined with one of two production lots of Hiberix. Vaccinations were given at 3, 4.5 and 6 months of age. The study found no difference between the subjects receiving either of the two lots of Hiberix mixed with DTPw-HB, with seroconversion rates of 100% or close to 100% for all five components.52

The DTPw-HBiHib combined vaccine is also compatible with a separate HB vaccination at birth. Win et a153 compared combined and separate administration of Tritanrix-HB and Hiberix in 269 healthy infants in Myanmar at a schedule of 1.5,3 and 5 months of age, after a single dose of HB vaccine at birth. Both modes of administration had excellent immunogenicity, with no significant difference between them. A similar study in the Philippiness4 included 148 healthy infants, and used a vaccination schedule of 6,10 and 14 weeks, following a single HB vaccination at birth. Again, the proportion of subjects with seroprotective titers after three doses was lOO%, or close to 100%) for all components, and did not differ significantly between the two modes of administration.

The geometric mean antibody titers after vaccination at the various schedules described above are shown in Figures 2-6. The seroconversion rates observed in the studies are shown in Table 1. They demonstrated that no reduced immunogenicity was observed for any of the components of the combined vaccine when Hiberix was added to Tritanrix-HB. There is also little difference in the immunogenicity of the vaccine among the schedules. Therefore, the vaccine is likely to be suitable for inclusion in national immunization programs without having to modify their existing immunization schedules..

REACTOGENICITY OF TRITANRIX-HB/Hib

The reactogenicity of Tritanrix-HB/Hib has been compared, in a per dose analysis, with that of Tritanrix- HB and Hiberix injections given separately in two studies.50,51 Both studies found no difference between modes of administration in the incidence of systemic reactions (which were mostly mild or moderate). There was a trend towards a higher incidence of local reactions for the combined vaccine, which was statistically significant for redness in one study. However, since giving the Hib vaccine separately requires twice as many injections as giving the combined vaccine, the overall burden of local reactions was lower for the combined vaccine. This is well demonstrated by the study of Win et a1,53 where the overall incidence of injection site reactions was 38.5% in the group receiving the


IO

3 E I 3 = g 0.1

Anti-D GMTs 1.5-3-5 (Myanmar)

q 2-4-6 (South Africa)

0 2-4-6 (Chile)

q 6-10-14 (Philippines)

n 3-4.5-6 lot (Lithuania OOlA44)

3-4.5-6 (Lithuania lot 0012A41)

Mixed Separate

Figure 2. Geometric mean titers (with 95% confidence intervals) of antidiphtheria antibody (anti-D GMT in IU/mL) at different schedules of DTPw-HB and Hiberix, separately and combined.

Anti-T GMTs 1.5-3-5 (Myanmar)

2-4-6 (South Africa)

2 q 2-4-6 (Chile) E 5 1 q 6-10-14 (Philippines) =

g

n 3-4.5-6 (Lithuania lot OOlA44)

8 0.1 3-4.5-6 (Lithuania lot 0012A41)

0.01 Mixed Separate

Figure 3. Geometric mean titers (with 95% confidence intervals) of antitetanus antibody (anti-T GMT in IUlmL) at different schedules of DTPw-HB and Hiberix, separately and combined.

Anti-pertussis GMTs

Mixed Separate

1.5-3-5 (Myanmar)


0 2-4-6 (Chile)

0 6-10-14 (Philippines)



Figure 4. Geometric mean titers (with 95% confidence intervals) of antipertussis antibody (GMT in EL.U/mL) at different schedules of DTPw-HB and Hiberix, separately and combined.


Anti-HBs GMTs 1 Z-3-5 (MyanmaF)


0 2-4-6 (Chile)

0 6-10-14 (Philippinesa)



Mixed Separate

Figure 5. Geometric mean titers (with 95% confidence intervals) of anti-hepatitis B antibody (anti-HBs GMT in mlU/mL) at different schedules of DTPw-HB and Hiberix, separately and combined. alncluded a single dose of HBV at birth.

1.5-3-5 (Myanmar)


0 2-4-6 (Chile)

0 6-10-14 (Philippines)

W 3-4.5-6 (Lithuania lot OOlA44)


Anti-PRP GMTs

Mixed Separate

Figure 6. Geometric mean titers (with 95% confidence intervals) of anti-H. influenzae antibody (anti-PRP GMT in mg/L) at different schedules of DTPw-HB and Hiberix, separately and combined.

combined DTPw-HB/Hib vaccine, but was 41.3% at the DTPw-HB site and 19.7% at the Hiberix site. Therefore, as the DTPw-HB and DTPw-HB/Hib injection sites account for a similar incidence of local reactions, having a separate Hiberix injection site is clearly an additional burden. In any case, local tolerability was good for both treatments, with a low incidence of severe injection site reactions.

Usonis et a152 also found that the overwhelming majority of reactions after 358 doses of combined Tritanrix-HB/Hib vaccination were mild or moderate. There were no reports of fever higher than 39.5”C, and all symptoms resolved without major medical inter- vention.

Other studies have compared the reactogenicity of the Tritanrix-HB/Hib combined vaccine with Tritanrix- HB and Hiberix given separately, after a single dose of HB vaccine at birth. At schedules of 1.5,3 and 5 months

of age,53 and 6,10 and 14 weeks of age,54 there were no significant differences in reactogenicity between the different modes of administration, except for a higher incidence of fever (>37.5”C) in one study in the group receiving separate injections (65%) than in those receiving the combined injections (49%). Again, in both studies, the vaccine was generally well tolerated.

In all studies, the reactogenicity of the combined DTPw-HB/Hib vaccine was similar to that seen for the DTPw-HB vaccine alone (Table 2). Indeed, the reactogenicity of the combined DTPw-HB/Hib vaccine com- pares favorably with that reported for DTPw vaccine alone.47,48

COST-EFFECTIVENESS

An important consideration in vaccination programs, particularly in the developing world, is the cost-

Facilitating the WHO Expanded Program of Immunization i Aristegui et al 149

Table 1. Seroconversiona rates (%) after vaccination at various schedules

n Diphtheria Tetanus Pertussis HB Hib

3,4 and 5 months Prikazsky and Bock43 (Tritanrix-HB) 44 100.0 100.0 97.7 97.7

2,4 and 6 months Aristegui et al44

(Tritanrix-HB) 167 100.0 100.0 92.2 100.0 Coovadia et a150

(DTPw-HBIHib) 49 100.0 100.0 100.0 100.0 100.0 Riedemann et a15’

(DTPw-HB/Hib) 41 97.6 100.0 97.6 97.6 100.0

3, 4.5 and 6 months Usonis et al45

(Tritanrix-HB) 91 98.9 100.0 100.0 100.0 - Usonis et al53

(DTPw-HB-Hib) 113 99.1 100.0 99.1 100.0 100.0

1.5, 3.5 and 6 months+ HBV at birth

Chiu et al46 (Tritanrix-HB) 50 100.0 100.0 98.0 98.0

1.5, 3 and 5 months+ HBV at birth

Win et aIS (DTPw-HB/Hib) 127 89.7 100.0 100.0 100.0 98.4

6, 10 and 14 weeks+ HBV at birth

Bravo et al54 (DTPw-HB/Hib) 50 94.0 100.0 95.9 96.0 100.0

aSeroconversion was defined as seroprotective antibody titers for diphtheria (~0.1 IU/mL), tetanus (20.1 IU/mL), hepatitis B (>I0 mlU/mL), and H. influenzae (~0.15 mg/L), and as 2 15 ELISA Units/mL for pertussis.

Table 2. Reactogenicity of DTPw-HB, DTPw-HB/Hib, and DTPw vaccines

Vaccines

Pain severe

Swelling >2cm

Redness >2cm

Fever >39.5”C

DTPw-HB DTPw-HBIHib pooled data pooled data

n=2161 n=2241

46.0 46.0 3.0 3.7

38.0 29.0 9.0 6.0

44.0 32.0 5.0 3.8

40.0 43.0 0.6 1.0

DTPw Cody et aF7

n= 15 752

51.0 -

41 .o -

38.0

47.0

DTPw Gustafsson et a148

n =2000

81.0

78.0 22.0

67.0 15.0

90.0 1.3

effectiveness of vaccines. In general, vaccines constitute an extremely cost-effective method of reducing the burden of disease. Combined vaccines lead to lower costs of vaccination programs than separate vaccinations. This has been borne out by pharmacoeconomic analysis. For example, Hadler55 calculated that adding HB and Hib vaccine to the US childhood immunization schedule would cost $440-500 million if separate vaccinations were given, but only $280 million if a combined DTP-HB/Hib vaccine was used. Fendrick et als6 have also found combined vaccines to be more attractive economically, using a decision analysis model, and that they are more cost-effective than many commonly used medical interventions. A recent model

evaluated the costs of a combined DTPw-HB versus separate DTPw + HB vaccination strategy if implemented in three countries of intermediate to high endemicity. The results showed that there are significant benefits to be gained from a combined DTPw-HB vaccination strategy in terms of economic savings and averted chronic carriers in each of the three countries studied (Van Damme and Maes, personal communi- cation).

CONCLUSIONS

Despite the substantial progress that the EPI has made in improving health, there is no room for complacency.


Many deaths are still potentially preventable by vaccination. One of the ways in which the goal of routine infant vaccination against vaccine-preventable diseases can be achieved is the use of combined vaccines, which protect against several diseases in a single injection, thereby saving considerable resources when compared with separate injections. Tritanrix-HB/Hib is a valuable weapon in the fight against infectious diseases, as it provides simultaneous vaccine coverage against diphtheria, tetanus, pertussis, HBV, and Hib. Many studies have shown it to have excellent immunogenicity when used in a variety of schedules, together with reactogenicity similar to that of DTPw vaccine alone. Replacing standard DTP vaccines, which already have high coverage, with Tritanrix-HB/Hib would therefore help to increase coverage against HBV and Hib diseases, both of which are responsible for substantial mortality and morbidity worldwide.

ACKNOWLEDGEMENTS

The authors would like to express their thanks to Drs Adam Jacobs and Vkronique Delpire for their editorial assistance in preparing this manuscript.

REFERENCES

1. World Health Organization. The World Health Report 1998: life in the 21st century-a vision for all. Geneva: WHO, 1998.

2. Hinman AR. Global progress in infectious disease control. Vaccine 1998; 16:1116-1121.

3. Choo S, Finn A. Pediatric combination vaccines. Curr Opin Pediatr 1999; 11:14-20.

4. Centers for Disease Control and Prevention. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). MMWR 1999; 48(No. RR-5):1-16.

5. Weniger BG, Chen RT, Jacobson SH, et al. Addressing the challenges to immunization practice with an economic algorithm for vaccine selection. Vaccine 1998; 16:1885- 1897.

6. Ferson MJ, McKenzie KA, Macartney-Bourne E Fragmen- tation of scheduled visits and missed doses among infants receiving multiple injected vaccines. Aust NZ J Public Health 1997; 21:735-738.

7. World Health Organization. Vaccines and biologicals Annual Report, 1998. Geneva: WHO, 1999.

8. Tormans G, Van Doorslaer E, van Damme P, Clara R, Schmitt HJ. Economic evaluation of pertussis prevention by whole-cell and acellular vaccine in Germany. Eur J Pediatr 1998; 157:395-401.

9. Galazka AM, Robertson SE. Diphtheria: changing patterns in the developing world and the industrialized world. Eur J Epidemiol 1995; 11:107-117.

10. Galazka AM, Robertson SE, Oblapenko GP. Resurgence of diphtheria. Eur J Epidemiol 1995; 11:95-105.

11. World Health Organization. The World Health Report 1999: Making a difference. Geneva: WHO, 1999.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

Cherry JD. The epidemiology of pertussis and pertussis immunization in the United Kingdom and the United States: a comparative study. Curr Probl Pediatr 1984; 14:1-78. Annunziato PW, Pichichero ME. New developments in pertussis vaccines. Clin Immunother 1995; 3:287-296. Gangarosa EJ, Galazka AM, Wolfe CR, et al. Impact of anti-vaccine movements on pertussis control: the untold story. Lancet 1998; 351:356-361. Romanus V, Jonsell R, Bergquist SO. Pertussis in Sweden after the cessation of general immunization in 1979. Pediatr Infect Dis J 1987; 6(4):364-371. Kimura M, Kuno-Sakai H. Current epidemiology of pertussis in Japan. Pediatr Infect Dis J 1990; 9:705-709. Ikeda K, Saitoh S, Suzuki Y, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol 1998; 28:930-938. Kew MC, Yu MC, Kedda MA, Coppin A, Sarkin A, Hodkinson J.The relative roles of hepatitis B and C viruses in the etiology of hepatocellular carcinoma in southern African blacks. Gastroenterology 1997; 112:184-187. Schwabe RF, Stremmel W. The natural course of hepatitis B and hepatitis C virus infection. Schweiz Rundsch Med Prax 1998; 87:1403-1407. World Health Organization. Hepatitis B vaccine-making global progress. EPI Update 1996; 31:1-5. Silveira TR, Da Fonseca JC, Rivera L, et al. Hepatitis B seroprevalence in Latin America. Pan Am J Public Health 1999; 6(6):378-383. Al-Faleh FZ, Al-Jeffri M, Ramia S, et al. Seroepidemiology of hepatitis B virus infection in Saudi children: eight years after a mass hepatitis B vaccination program. J Infect 1999; 38(3):167-170. Chen HL, Chang MH, Ni YH, et al. Seroepidemiology of hepatitis B virus infection in children: ten years of mass vaccination in Taiwan. JAMA 1996; 276:906-908. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997; 336:1855-1859. Lee CL, Ko YC. Hepatitis B vaccination and hepatocellular carcinoma in Taiwan. Pediatrics 1997; 99:351-353. Da Villa G, Piccinino F, Scolastico C, Fusco M, Piccinino R, Sepe A. Long-term epidemiological survey of hepatitis B virus infection in a hyperendemic area (Afragola, southern Italy): results of a pilot vaccination project. Res Viroll998; 149:263-270. World Health Organization. Global Programme for Vaccines and Immunization (GPV): the WHO Position Paper on Haemophilus influenzae type b conjugate vaccines. WER 1998; 73:64-68. Shapiro ED, Ward JI. The epidemiology and prevention of disease caused by Haemophilus influenzae type b. Epidemiol Rev 1991; 13:113-142. Rauter L, Mutz I. Haemophilus influenzae meningitis 1983 to 1992-epidemiology and sequelae of the disease. Wien Klin Wochenschr 1994; 106:187-192. Peltola H. Haemophilus influenzae type b disease and vaccination in Latin America and the Caribbean. Pediatr Infect Dis J 1997; 16:780-787. Peltola H. Need for Haemophilus influenzae type b vaccination in Asia as evidenced by epidemiology of


bacterial meningitis. Pediatr Infect Dis J 1998; 17(suppl): S148-s151.

32. Lee JW. Haemophilus infiuenzae in Asia. Pediatr Infect Dis J 1998; 17:S92.

33. Miller MA. An assessment of the value of Haemophilus injluenzae type b conjugate in Asia. Pediatr Infect Dis J 1998; 17:S152-S159.

34. Centers for Disease Control and Prevention. Progress towards eliminating Haemophilus influenzae type b disease among infants and children-United States, 1987-1997. MMWR 1998; 47:993-998.

3.5. Lagos R, Horwitz 1,Toro J, et al. Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus in@enzae type b infections. Pediatr Infect Dis J 1996; 15216-222.

36. Mulholland K, Hilton S, Adegbola R, et al. Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants. Lancet 1997; 349:1191-1197.

37. World Health Organization. Expanded Programme on Immunization: Global Advisory Group-Part 1. WER 1992; 67:11-15.

38. World Health Organization. Informal consultation on quadrivalent diphtheria-tetanus-pertussis-hepatitis B vaccine. Final report. Geneva: WHO, 1992.

39. Andre FE, Zuckerman AJ. Protective efficacy of hepatitis B vaccines in neonates. J Med Virol 1994; 44:144-151.

40. Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991; 40(RR-13): 1-19.

41. Centers for Disease Control and Prevention. Status report on the childhood immunization initiative: national, state, and urban area vaccination coverage levels among children aged 19-35 months-United States, 1996. MMWR 1997; 46:657-664.

42. World Health Organization. The children’s vaccine initiative and the global programme for vaccines and immunization: recommendations from the special advisory group of experts, Part I. WER 1996; 71:261-266.

43. Prikazsky V, Bock HL. Higher anti-hepatitis B response with combined DTPLw-HB vaccine compared with separate administration in healthy infants at 3, 4 and 5 months of age in Slovakia. IJCP 2001; 55(3):156-161.

44. Aristegui J, Garrote E, Gonzalez A, Arrate JP, Perez A, Vandepapelibre P. Immune response to a combined hepatitis B, diphtheria, tetanus and whole-cell pertussis vaccine administered to infants at 2,4 and 6 months of age. Vaccine 1997; 15:7-g.

45. Usonis V, Bakasenas V, Taylor D, Vandepapeliitre P Immunogenicity and reactogenicity of a combined DTPw- hepatitis B vaccine in Lithuanian infants. Em J Pediatr 1996; 155:189-193.

46. Chiu HH, Huang LM, Lee PI, Safary A, Lee CY. Diphtheria, tetanus and whole cell pertussis vaccine combined with hepatitis B vaccines: a comparison of two doses (10 ug and 5 ug). Pediatr Infect Dis J 1998; 17:206-211.

47. Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 1981; 68:650-660.

48. Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J,A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996; 334~349-355.

49. Usonis V, Bakasenas V. Does concomitant injection of a combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio virus vaccine influence the reactogenicity and immunogenicity of commercial Haemo- philus influenzae type b conjugate vaccines? Eur J Pediatr 1999; 158:398-402.

50. Coovadia HM, Ramkissoon A, Jugnundan P, Willems P, Clemens R. A new combined DTP-HBV-Hib vaccine: strategy for incorporation of Hib vaccination into childhood immunization programs. S Afr Med J 2001; 91(10): 864869.

51. Riedemann S, Reinhardt G, Jara J, et al. Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV and Hib vaccines given to healthy infants at 2, 4: and 6 months of age, with a booster at 18 months. Int J Infect Dis 2002; 6:215-222.

52. Usonis V, Bakasenas V, Willems P, Bock HL. Evaluation of the immunogenicity and reactogenicity of a new combined diphtheria, tetanus, whole-cell B pertussis and hepatitis B vaccine and Haemophilus influenzae type b (DTPw-HBVI Hib) vaccine in children at 3,4.5 and 6 months of age. Acta Med Lithuanica 1999; 6(3):187-191.

53. Win KM, Aye M, Htay-Htay H, Safary A, Bock HL. Comparison of separate and mixed administration of DTPw-HBV and Hib vaccines: immunogenicity and reactogenicity profiles. Int J Infect Dis 1997; 2:79-84.

54. Bravo L, Carlos J, Gatchalian S, et al. The new DTPw- HBV-Hib combination vaccine can be used at the WHO schedule with a monovalent dose of hepatitis B vaccine at birth. SE Asian J Trop Med Pub Health 1998; 29:772-778.

55. Hadler SC. Cost benefit of combining antigens. Biologicals 1994; 22:415-418.

56. Fendrick AM, Lee JH, LaBarge C, Glick HA. Clinical and economic impact of a combination Haemophilus influenzae and hepatitis B vaccine: estimating cost-effectiveness using decision analysis. Arch Pediatr Adolesc Med 1999; 153: 126-136.

Documents

Facilitating the WHO Expanded Program of Immunization: the