Summary and conclusions
Wherever thorough studies have been performed, Haemophilus influenzae
type b (Hib) has been shown to be an important cause of childhood meningitis and a major
cause of bacterial pneumonia in children. Although little population-based incidence data
are available from most of Asia and the newly independent States of the former Soviet
Union, Hib is estimated to cause at least 3 million cases of serious disease and hundreds
of thousands of deaths annually, worldwide. The most important manifestations of Hib
disease, namely pneumonia and meningitis, are seen mainly in children under five years of
age, particularly infants. Currently, several different Hib vaccines, all conjugate
vaccines, are on the market. These vaccines have shown protective efficacy in early
infancy. Hib vaccines are now used as part of routine childhood vaccination programmes in
more than 20 countries including Australia, Canada, New Zealand, the United States, and
many countries of western Europe, and have proved to be highly efficacious and virtually
free from serious side-effects. Also, excellent results of trials or national introduction
in Chile, Uruguay, and the Gambia show that Hib conjugate vaccines are effective in
developing country settings. Because these vaccines significantly reduce nasopharyngeal
carriage, a herd effect is achieved through Hib vaccination.
In view of the demonstrated safety and efficacy of the Hib conjugate
vaccines, Hib vaccine should be included, as appropriate to national capacities and
priorities, in routine infant immunization programmes. In geographical regions where the
burden of Hib disease is unclear, efforts should be made to evaluate the magnitude of the
problem.
Public health impact
H. influenzae type b (Hib) is estimated to cause at least 3 million cases of serious
disease and 400 000700 000 deaths each year in young children. Rarely
occurring in infants under three months, and after the age of six years, the disease
burden is highest at 418 months of age. In both developed and developing countries
Hib is the dominant cause of non-epidemic bacterial meningitis in this age group, and is
frequently associated with severe neurological sequelae despite prompt and adequate
antibiotic treatment. In economically developed countries meningitis accounts for the
majority of invasive Hib disease, whereas in developing countries acute respiratory
infection, particularly the estimated 23 million cases of Hib pneumonia occurring
each year, represents an even heavier disease burden. Other important, but less frequent,
manifestations of Hib disease include epiglottitis, osteomyelitis, septic arthritis, and
septicaemia.
Following introduction of Hib conjugate vaccines into routine childhood
immunization programmes in the 1990s, Hib disease has largely disappeared in Australia,
Canada, New Zealand, the United States and Western Europe.
The pathogen
H. influenzae is a Gram-negative bacterium. Serious infection is
usually caused by strains carrying a polysaccharide capsule. Of the six capsular types,
type b (Hib) causes almost all systemic infections. This polysaccharide is a polymer of
D-ribose-ribitol-phosphate (PRP) and is an essential virulence factor. Up to 15% of
children in non-immunized populations may harbour Hib in their nasopharynx. However, only
a fraction of those acquiring the microorganism will subsequently develop clinical
disease. Transmission of Hib is by droplets originating from colonized persons and hence,
asymptomatic carriers are important disseminators of the organism. The non-encapsulated
strains that are more frequently isolated from naso-pharyngeal secretions are mainly
associated with mucosal infections such as bronchitis and otitis.
Facilities for reliable cultivation of Hib and identification of the
capsular polysaccharide by immunological techniques are found in laboratories
well-equipped for clinical microbiology, but are not easily available throughout the
world.
Immune response
In older children and adults the Hib polysaccharide induces production
of bactericidal antibodies. However, this polysaccharide does not reliably elicit
protective levels of antibodies in children less than 18 months of age. Furthermore, it
does not induce immunological memory and consequently no booster response with subsequent
exposure to the polysaccharide. For these reasons, a new generation of vaccines was
developed by conjugating a T-cell dependent protein antigen to the Hib polysaccharide.
These Hib conjugate vaccines not only induce protective circulating antibodies and
immunological memory in infants, but also result in decreased nasopharyngeal colonization
of Hib. Thus, a herd effect is achieved through reduced transmission of the microorganism.
Justification for vaccine control of Hib disease
Hib disease, mainly meningitis and pneumonia in young children, is a
significant public health concern in both developed and developing countries. In developed
countries meningitis is the most important manifestation, whereas in developing countries
pneumonia is more common. However, due to inherent problems regarding etiological
diagnosis, especially of pneumonia, the true burden of Hib may be seen only by a reduction
in the incidence of pneumonia and meningitis following vaccination. Antibiotics are
essential for treatment, but have only a minor role in control, and development of
bacterial resistance to some of the most efficient antibiotics underlines the need for
prevention. Vaccines are the only public health tool available to prevent the vast
majority of Hib disease.
The safety, efficacy and effectiveness of the Hib conjugate vaccines
are clearly demonstrated in developed countries, where rapid declines in disease incidence
have been documented in every country in which the vaccine has been used routinely in
childhood immunization programmes. Furthermore, several studies demonstrate high efficacy
of the vaccines against invasive disease in high-incidence and developing country
settings, including studies in Chile, in the Gambia and in a Native American population in
the United States. In the Gambian trial, vaccinated infants were protected against
laboratory-confirmed Hib pneumonia, and the incidence of all X-ray documented pneumonia
was reduced by approximately 20%.
A series of cost-benefit analyses in industrialized countries
underscores the value of routine immunization against Hib disease. Substantially more
disease could be prevented in the developing world, where the burden of disease and death
is many times higher. An assessment of the situation in representative countries of most
geographical regions was recently made by the Children's Vaccine Initiative. This
study showed that inclusion of Hib vaccine into the respective childhood immunization
schedules may be cost-effective, even in the lowest income strata.
Haemophilus influenzae type b
conjugate vaccines (Hib-vaccines)
The vaccines currently licensed for use against Hib disease are based
on Hib-polysaccharide conjugated to a protein carrier, such as diphtheria toxoid (PRP-D),
a diphtheria toxoid-like protein (PRP-HbOC), tetanus toxoid (PRP-T), or meningococcal
outer membrane protein (PRP-OMP). The conjugation of PRP to the protein induces a T-cell
dependent immune response to the Hib-polysaccharide. The conjugate vaccines differ in
their carrier protein, method of chemical conjugation and by polysaccharide size, giving
them somewhat different immunological properties.
The vaccine is usually given in infancy as repeated doses together with
diphtheria/tetanus/pertussis (DTP) and other vaccines of the national childhood
immunization programmes. A booster dose is recommended in most countries at 1218
months of age, but may not be necessary, especially in developing countries where most of
the Hib disease occurs before this age. In adults and children over 18 months of age a
single dose is sufficient to induce immunity.
All conjugate Hib vaccines are given by the intramuscular route. No
serious side-effects are recorded, and no contraindications known, except for
hypersensitivity to the vaccine components. The Hib vaccine may safely be administered
concurrently with any vaccine of the EPI or corresponding national childhood vaccination
programmes, as well as with pneumococcal and meningococcal vaccines.
WHO position on Hib vaccines
The commercially available Hib conjugate vaccines are all of known good
quality. The indication for the use of these vaccines is protection of children below five
years of age, particularly infants. WHO encourages the introduction of Hib vaccines
worldwide. However, because of differences in epidemiology, health priorities and economic
capacity, Hib vaccines will in practice be introduced at different speeds into national
immunization programmes. The emphasis is on introduction in countries with the highest
disease burden.
The efficacy and effectiveness of the Hib conjugate vaccines have been
clearly demonstrated in developed countries, where rapid declines in disease incidence
have been documented in every country in which the vaccine has been used routinely.
Several studies also demonstrate the efficacy in high-incidence and developing-country
settings.
Three out of the four currently-licensed Hib conjugate vaccines
(PRP-HbOC, PRP-OMP, PRP-T) have proven to be comparably efficacious in infancy, provided a
complete primary series is given. Furthermore, these vaccines are easily adapted to the
routine schedule of the national immunization programmes. One of the vaccines (PRP-D)
performs less well in children below 18 months of age, and is therefore not licensed for
use in infants in many countries. All conjugate vaccines have an excellent safety record,
and, where tested, do not interfere substantially with the immunogenicity of
simultaneously given vaccines.
Unfortunately, in large areas of Asia as well as in the Newly
Independent States, population-based data on the burden of Hib disease are largely
missing, and so far, no Asian country has adopted Hib vaccine as part of its routine
immunization programme. Data from additional surveillance studies are needed to assist
public health planners in these areas. A WHO-sponsored protocol to evaluate Hib disease
burden is available on request. However, the lack of simple, rapid and reliable techniques
for etiological diagnosis of pneumonia is a challenge to future research.
Other issues which must be faced as the vaccine is introduced into developing countries
include combination with other antigens such as locally produced DTP, and conceivably with
pneumococcal and/or meningococcal vaccines. Also, questions of appropriate formulation
including multidose vials, and liquid versus lyophilized vaccine preparations, will have
to be addressed.
This chapter was last published as a WHO position paper: The WHO position paper on
Haemophilus influenzae type b conjugate vaccines. Weekly Epidemiological Record, 1998,
73:6468. It is also available on the Internet http://www.who.int/wer/pdf/1998/wer7310.pdf.
Administration summary
Haemophilus influenzae b immunization. Introducing Haemophilus influenzae b conjugate
vaccine into national immunization services (Fact sheet). Geneva, 2001 (unpublished
document WHO/V&B/01.29; available from Vaccines and Biologicals, World Health
Organization, 1211 Geneva 27, Switzerland and on the Internet at www.who.int/vaccines-documents/DocsPDF01/www599.pdf.
Eskola J, Peltola H, Takala AK, et al. Efficacy of Haemophilus influenzae type b
polysaccharide-diphtheria toxoid conjugate vaccine in infancy. New England Journal of
Medicine, 1987, 317:717722.
Estimating the local burden of Hib disease preventable by vaccination: a rapid
assessment tool. Geneva, 2001, unpublished document WHO/V&B/01.27; available from
Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland and on
the Internet at http://www.who.int/vaccines-documents/DocsPDF01/www625.pdf.
Estimating the potential cost-effectiveness of using Hib vaccine. Field test version 1.
Geneva, 2001, unpublished document WHO/V&B/01.36; available from Vaccines and
Biologicals, World Health Organization, 1211 Geneva 27, Switzerland and on the Internet at
http://www.who.int/vaccines-documents/DocsPDF01/www654.pdf.
Expert review of a tool for rapidly assessing Hib disease burden. Geneva, 2001
(unpublished document WHO/V&B/01.25; available from Vaccines and Biologicals, World
Health Organization, 1211 Geneva 27, Switzerland and on the Internet at http://www.who.int/vaccines-documents/DocsPDF01/www604.pdf.
Introduction of Haemophilus influenzae type b (Hib) vaccine into immunization
programmes. Geneva: World Health Organization; 2000 (unpublished document
WHO/V&B/00/05; available from Vaccines and Biologicals, World Health Organization,
1211 Geneva 27, Switzerland and on the Internet at http://www.who.int/vaccines-documents/DocsPDF99/www9940.pdf.
Mulholland EK, Hilton S, Adegbola R, et al. Randomized trial of Haemophilus influenzae
type b tetanus protein conjugate vaccine for prevention of pneumonia and meningitis in
Gambian infants. Lancet, 1997, 349:11911197.