In many ways The Gambia is typical of much of sub-Saharan Africa. The majority of the country's one million people live in rural areas and survive on subsistence agriculture. As in many African countries, infrastructure is poor, literacy rates are low and access to care is limited. Unlike some other countries, however, there is a relatively strong government program of infant immunization. Another key difference is the strong presence of the Medical Research Council (MRC) Laboratories based in The Gambia.
The MRC began working in The Gambia in 1949. Since that time they have worked closely with The Gambia Government to conduct several large-scale studies of potentially-life saving interventions, including studies of vaccines against hepatitis B, bacterial meningitis and pneumonia, and malaria.
The Problem of Infant and Child Mortality
Worldwide Incidence
In developing countries, Streptococcus pneumoniae is a major cause of mortality in children under 5 years of age, accounting for 20-25% of the total mortality in this age group. See WHO Report.
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Beginning in 1988, the Medical Research Council Laboratories in The Gambia began a series of carefully planned surveillance studies to determine the patterns of childhood mortality in the Upper River Division (URD) of The Gambia. These studies involved identifying all the births and childhood deaths in over 360 villages of URD for a period of 5 ½ years. During this period, the surveillance system indicated that the infant mortality rate was 80 per 1000 live births; in other words, approximately 8% of all children died in the first year of life. This rate is more than 10 times higher than the rates in the United Kingdom. the United States or other industrialized countries.
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Acute Respiratory Infections are a Major Killer
Under the best of circumstances it is often difficult to determine the primary cause of death in a young child. Determining the cause of death is even harder in an area where most childhood deaths occur at home, in children who had little or no medical attention immediately prior to death, and where there are few or no laboratory resources to make an accurate diagnosis. To determine the causes of childhood death in The Gambia, researchers use a method for interviewing family members and caretakers following a child's death — a technique called the "verbal autopsy" method. This approach provides a rough estimate of the relative contribution of various causes of childhood death. However, this method does not distinguish between illnesses that cause similar signs and symptoms. For example, using this method it is often difficult to distinguish deaths due to malaria from those due to pneumonia or sepsis. Also, the cause of a high proportion of infant deaths simply cannot be determined.
Using the verbal autopsy method, researchers from MRC were able to demonstrate that acute respiratory infections (ARI) are the leading cause of infant mortality and the second leading cause of mortality among children aged 2-4 years old. From studies done in The Gambia and elsewhere we know that the overwhelming majority of ARI deaths are due to bacterial pneumonia.
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Streptococcus pneumoniae is the Leading Cause of Bacterial Pneumonia
Globally, the WHO estimates that pneumococcal infections may kill more than 1 million children each year, almost entirely children who live in poor countries. A number of studies done in The Gambia show that the pneumococcus (Streptococcus pneumoniae) is consistently identified as the most common cause of bacterial pneumonia. This finding is consistent with observations from many other countries where similar studies have been done.
The pneumococcus also causes several other important diseases including bacterial meningitis, bloodstream infections (also called sepsis, septicemia, or bacteremia), and ear infections. More than half of all children in The Gambia who develop pneumococcal meningitis will die, and the majority of survivors will have some long-term disability. Although ear infections are not life threatening, repeated ear infections can lead to hearing loss and to delays in learning and child development.
(See Cause of infant mortality chart above.)
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The Case for Preventing Pneumococcal Disease
In a pattern typical of many developing areas, infant and child mortality rates in The Gambia are high, acute respiratory infections are a leading cause of death, and pneumococcus is the most common cause of these infections. Preventing diseases caused by Streptococcus pneumoniae is therefore one strategy to improving child survival in these areas.
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Estimating the Burden of Pneumonia Preventable by Vaccination: the Example of Hib Vaccine in The Gambia
Vaccine trials can provide the most accurate measure of the burden of a disease. Based on observational studies of patients with pneumonia conducted in The Gambia it was expected that about 5-10% of severe pneumonia episodes in infants and young children were likely due to the bacterium, Haemophilus influenzae type B (Hib). Between 1993 and 1995, a randomized controlled trial was conducted in the Western Division of The Gambia in which nearly 40,000 infants were given either Hib conjugate vaccine or placebo. This study design was able to show that vaccination with Hib conjugate vaccine reduced the incidence of radiographic pneumonia by 21%. This reduction in pneumonia cases was substantially greater (21%) than expected (5-10%) on the basis of the observational studies that preceded it. The results of this study were important in The Gambia and elsewhere because they provide a firm basis of evidence that supports the use of this vaccine as a routine immunization. The results of the pneumococcal vaccine trial are expected to be equally or more influential for the decision of whether to use pneumococcal vaccine in the future. |
Pneumococcal Conjugate Vaccine: A Possible Solution to the Problem of Pneumococcal Mortality?
- Formulation of the new vaccine
There are over 90 different serotypes of S. pneumoniae and immunity to one serotype does not protect a person against infection from another. Fortunately, not all 90 serotypes are equally common and most cases of serious disease (ie, 60-80%) in any area are typically due to a relatively limited number of serotypes (ie, 7-11 serotypes). Thus, vaccines to prevent pneumococcal disease are designed to protect against a mix of the most common serotypes.
To make the vaccine protective in young infants, the polysaccharide (ie, sugar) capsules from each of the serotypes included in the vaccine is linked to a protein carrier. This is the technology that was used to create the safe and highly effective Hib conjugate vaccine that has been in routine use in the United States, the United Kingdom and other industrialized countries since 1990 and in The Gambia since 1997. The vaccine being evaluated in The Gambia PVT will include 9 of the pneumococcal serotypes that are most common in The Gambia. The vaccine that we are using was developed by Wyeth-Lederle Vaccines.
- Safety and immune response: Experience in Gambian infants with a 9-valent pneumococcal conjugate vaccine
Previous studies involving approximately 200 Gambian infants have shown that the vaccine can be combined with DTP-Hib conjugate vaccines without increasing the risk of severe side effects. Receiving the vaccine was associated with an increase in the frequency of minor side effects such as tenderness and/or swelling at the injection site, but these resolved quickly. Infants who received the pneumococcal vaccine developed a high level of antibody to the serotypes included in the vaccine. Combining the pneumococcal conjugate vaccine with the DTP-Hib vaccine did not interfere with the response to the DTP-Hib vaccines and makes it possible to deliver all 13 antigen (D+T+P+Hib+9 pneumococcal serotypes) with a single syringe. This is important because it makes administration easier, reduces the number of shots that a child must receive, and reduces the chances of unsafe injections.
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Other Pneumoccocal Vaccine Trials: What Makes this Trial Unique?
The efficacy of a similar pneumococcal conjugate vaccine was established in trials conducted in the United States and in Finland. These were carried out in the San Francisco area of California and in urban areas of Finland, where virtually all cases of pneumococcal disease get treatment and few children die. The success of the vaccine in low mortality, industrialized settings does not assure that the vaccine will be equally effective in places like The Gambia.
Other trials of pneumococcal vaccines are ongoing in South Africa and the Philippines and others are planned. These trials are important in their own right but the successful completion of these trials does not eliminate the need for the trial in The Gambia. The Gambia trial is the only one being conducted in an area of high infant mortality, where malaria is common, and access to care is limited. In many ways, the setting is typical of many areas of the developing world where children die. Furthermore, it will be the only study capable of answering the fundamental question of how many lives can be saved by the use of the vaccine — the ultimate measure of the vaccine's public health benefit and the results most likely to convince decision-makers to introduce the vaccine
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