Elsevier

The Lancet

Volume 349, Issue 9060, 26 April 1997, Pages 1191-1197
The Lancet

Articles
Randomised trial of Haemophilus influenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants

https://doi.org/10.1016/S0140-6736(96)09267-7Get rights and content

Summary

Background

In developing countries, pneumonia and meningitis due to Haemophilus influenzae type b (Hib) are common in children under age 12 months and the mortality from meningitis is high. Protein-polysaccharide conjugate vaccines have brought Hib disease under control in industrialised countries. We did a double-blind randomised trial in The Gambia to assess the efficacy of a Hib conjugate vaccine for the prevention of meningitis, pneumonia, and other invasive diseases due to Hib.

Methods

Between March, 1993, and October, 1995, 42 848 infants were randomly allocated the conjugate vaccine Hib polysaccharide tetanus protein (PRP-T) mixed with diphtheria-tetanus-pertussis vaccine (DTP), or DTP alone at age 2 months, 3 months, and 4 months. Children who presented with signs of invasive Hib were investigated by blood culture and, where appropriate, by lumbar puncture, chest radiograph, or percutaneous lung aspirate. Children were followed up for between 5 and 36 months.

Findings

The median ages at which children received the study vaccine were 11 weeks, 18 weeks, and 24 weeks. 83% of children enrolled received all three doses of vaccine. 17 cases of culture-positive Hib pneumonia, 28 of Hib meningitis, and five of other forms of invasive Hib disease were detected amongst the study children. The efficacy of the vaccine for the prevention of all invasive disease after three doses was 95% (PRP-T vaccinees 1, controls 19 [95% Cl 67–100]), for the prevention of Hib pneumonia after two or three doses, 100% (vaccinees 0, controls 10 [55–100]), and for the prevention of radiologically defined pneumonia at any time after enrolment, 21·1% (PRP-T vaccinees 198, controls 251 [4·6–34·9]).

Interpretation

PRP-T conjugate Hib vaccine prevented most cases of meningitis and pneumonia due to Hib in Gambian infants. The reduction in the overall incidence of radiologically defined pneumonia in PRP-T vaccinees suggests that about 20% of episodes of pneumonia in young Gambian children are due to Hib. The introduction of Hib vaccines into developing countries should substantially reduce childhood mortality due to pneumonia and meningitis.

Introduction

Invasive disease due to Haemophilus influenzae type b (Hib) remains a major problem in developing countries, where the epidemiology of the disease differs from that seen in industrialised countries in several important respects. In developing countries, the incidence of Hib disease is greater than in industrialised countries, and the disease occurs in younger children, with most cases occurring before 12 months of age and almost half before the age of 6 months.1, 2 The clinical pattern of disease also differs; in developing countries, pneumonia is commoner than meningitis, whereas epiglottitis is not seen.3 The outcome of Hib meningitis in developing countries is poor. In sub-Saharan Africa, 20–40% of patients who reach health-care facilities die from the disease and neurological sequelae occur in a significant proportion of survivors.2 Nasopharyngeal carriage of Hib is commoner and occurs in younger children in developing than in industrialised countries.4, 5, 6

Protein-polysaccharide conjugate vaccines against Hib have been highly effective in reducing Hib disease and carriage in industrialised countries.7, 8 Although, before the present study, no randomised double-blind efficacy study of the Hib polysaccharide-tetanus protein conjugate vaccine (PRP-T) had been done, the vaccine was effective in preventing Hib meningitis in British infants in an open study.9 Two randomised trials of other Hib conjugate vaccines in American communities whose living conditions resemble those of developing countries produced differing results. Hib polysaccharide-Neisseria meningitidis group B outer membrane protein complex conjugate vaccine (PRP-OMPC) proved effective in Navajo Indians,10 whereas Hib polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) did not in Alaskan natives.11

Before this study, no efficacy studies of any Hib vaccines had been done in developing countries, although an effectiveness study was done in Santiago, Chile, where PRP-T was shown to prevent invasive Hib disease.12 However, the epidemiology of Hib disease in Santiago is more similar to that in the USA than to that in poorer developing countries. For example, the proportions of cases of Hib disease in infants younger than 12 months in Chile, the USA (before vaccination), and The Gambia were 60%, 51%, and 84%, respectively.13, 14 Furthermore, no studies have evaluated the efficacy of vaccination against Hib pneumonia, which is probably the most common manifestation of invasive Hib disease in developing countries. The study reported here was designed to assess the efficacy of an Hib conjugate given to infants in a poor developing country for the prevention of pneumonia and other invasive disease due to Hib. As selection of pneumonia cases for investigation is subjective, a double-blind study design was used.

Section snippets

Methods

The study was done in the Western Region of The Gambia, an area where the epidemiology of Hib disease has been well studied and where most cases of invasive Hib disease are likely to reach medical attention.14, 15 During the 3 years before the study, the incidence of invasive Hib disease in children under age 12 months living in the study area was estimated to be 274 per 100 000 children each year.15 The study area, which is populated by about half of the one million people who live in The

Results

Between March 8, 1993, and Oct 1, 1995, 42 848 infants were enrolled into the study, of whom 21 490 received the PRP-T mixed with DTP and 21 358 received DTP alone (figure). Study vaccines were available until March 1, 1996, for partly vaccinated children who presented for later doses. Of the 42 848 children enrolled, 40 366 (94%) received a second dose of vaccine and 35 713 (83%) received all three doses. The median ages of administration for doses one, two, and three were 11 weeks, 18 weeks,

Discussion

Murray and Lopez estimated that over 200 000 cases of Hib meningitis occur in the developing world every year.23 The mortality and morbidity amongst those who get medical attention is substantial; a significant proportion die without getting any medical attention. Our study showed that PRP-T Hib conjugate vaccine was highly effective in preventing pneumonia and meningitis due to Hib after three doses given in infancy, and offered 75% protection from the time the first dose was given. As has

References (24)

  • AK Takala et al.

    Reduction of oropharyngeal carriage of Haemophilus influenzae type b (Hib) in children immunized with an Hib conjugate vaccine

    J Infect Dis

    (1991)
  • M Santosham et al.

    The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type b polysaccharide and Neisseria meningitidis outer-membrane protein complex

    N Engl J Med

    (1991)
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