Editorial: The Gambian pneumococcal vaccine trial – implications for control of childhood pneumonia (2005)

Publication of the results of the Gambian pneumococcal vaccine trial focuses international attention once again on the problem of childhood pneumonia. In an era when public health is increasingly being practiced through the implementation of high budget, disease-based approaches, the lack of international attention devoted to childhood pneumonia is surprising, even incredible. In recent years, attention has been focused on malaria, measles, tuberculosis, yet the combined total of child deaths attributable to these three causes does not equal the number of deaths due to childhood pneumonia (Bryce et al. 2005). Early in the 20th century pneumonia was recognized as the main cause of child death throughout the world. In crowded cities with high infant and child mortality rates, pneumonia was the main killer of children (Linder & Grove 1943; Woods 1997). In the early days of microbiology, Streptococcus pneumoniae (pneumococcus) was recognized as a major cause of pneumonia in all age groups (Lyon 1922). The prospect of serum therapy stimulated the rapid development of pneumococcal microbiology. It was quickly recognized that protective immunity was derived from antibodies directed at the polysaccharide capsule, but the diversity of serotypes posed a challenge for vaccine developers. The first trial of a polysaccharide-based pneumococcal vaccine was undertaken in 1911 (Wright & Morgan 1914) and there was a lot of progress in the field up to the time of the Second World War. The late 1930s saw the development of the first antibiotics, the sulphonamides, which were followed by penicillin and chloramphenicol (King 1944; Greengard et al. 1941). For the first time pneumococcal pneumonia was easily treatable, and as a result vaccine development virtually ceased. After another 30 years the work of Robert Austrian drew the world's attention to the fact that, despite the availability of antibiotic therapy, pneumococcal pneumonia remained a major cause of illness and death in both children and adults (Austrian 1980). Pivotal efficacy trials conducted by Austrian and others on South African miners who had a high incidence of pneumococcal pneumonia, ushered in the development of modern pneumococcal polysaccharide vaccines, initially covering 14 serotypes (14-valent) (Smit et al. 1977). The vaccine was developed further and the present 23-valent pneumococcal polysaccharide vaccine was licensed in 1983. During the 1980s, the vaccine was trialled in infants in the USA and Australia, with minimal impact on otitis media rates (Douglas & Douglas 1984; Sloyer et al. 1981). A trial from Papua New Guinea showed a reduction in pneumonia rates and pneumonia mortality (Riley et al. 1986). This exciting finding was to be tested in a study in the Gambia scheduled to start in 1989. Around the same time the dramatic success of the polysaccharide–protein conjugate Haemophilus influenzae type b (Hib) vaccine in young infants convinced authorities that a pneumococcal conjugate vaccine could be manufactured easily and would be greatly superior to the polysaccharide vaccine (Adams et al. 1993). Consequently, the Gambian pneumococcal polysaccharide vaccine trial was never undertaken, and plans were developed to undertake a trial of a conjugate vaccine in the Gambia when it became available. Now, almost 16 years later, the results of that trial have been published. The 1980s also saw the development of the WHO case management approach to prevent death from childhood pneumonia by effective management of acute respiratory infections (ARI). This approach assumed that most potentially fatal pneumonia cases could be successfully treated with simple antibiotics administered by a health worker based on the recognition of simple clinical signs (Pio 1988). This was supported by a large body of research including several large field trials demonstrating an impact of community based case management on overall survival (Sazawal & Black 1992). While most workers involved in ARI case management did not believe that vaccination could ever offer an effective means of preventing a condition caused by such a diverse array of organisms as pneumonia, officials from US Government agencies had the foresight to contract a biotechnology company to construct a pneumococcal conjugate vaccine suitable for use in developing countries, especially Africa. That company had been at the forefront of Hib vaccine development and was ideally placed to take on the more difficult task of developing a pneumococcal conjugate vaccine. At that time no-one would have anticipated that the vaccine would not be licensed until 2000, that the vaccine licensed would lack the two most important serotypes for developing countries (1 and 5), or that the vaccine would be marketed by a large multinational company as a ‘blockbuster’ product, aimed at rich western countries (Anonymous 2003). As the new vaccine was being launched, three large trials of pneumococcal conjugate vaccines were about to start or underway. To support these trials WHO developed a standardized approach to the production and interpretation of chest radiographs (Cherian et al. 2005). All trials used the same methods and were supported by a WHO radiology panel. The trial conducted on the Philippines island of Bohol used an 11-valent vaccine produced by Aventis Pasteur. Sadly the company decided to abandon the product while the trial was underway. That trial is now nearing completion. The other two trials used a 9-valent vaccine produced by Wyeth Vaccines (and including serotypes 1 and 5). The South African trial showed that the vaccine was effective at preventing invasive pneumococcal disease in both HIV positive and negative South African infants. It also showed a modest (20–25%) reduction in radiological pneumonia by WHO's definition (Klugman et al. 2003). Opinions differed as to whether this constituted a successful result. Some felt that this impact was consistent with what was known about the contribution of pneumococcus to the burden of pneumonia and the range of serotypes covered. Others were disappointed, as they had taken the view that vaccine trials would uncover a greater than expected burden of pneumococcal disease, as a contribution to the burden of childhood pneumonia, as they had done with Hib vaccine, where the proportion of cases prevented was substantially greater than the proportion of pneumonia cases that had been previously attributed to Hib (Mulholland et al. 1997). The most important use for a pneumococcal vaccine would be the prevention of death. Thus, if a vaccine could be shown to improve child survival by a significant amount, that would be a major impetus to promote its use in the developing world. The South African trial was conducted in a low mortality setting, where most child deaths were due to HIV. Only the Gambian trial was to be in a setting where the impact on child survival could be evaluated. The trial was originally powered to evaluate this outcome. However, when the trial was underway, Wyeth Vaccines, who provided all the vaccines for the trial, decided to cease production of the DTP-Hib combination vaccine that had been used as the diluent for the trial. This necessitated a revision of the trial design, which in turn led to a re-evaluation of the ethical basis of the design of the trial on the part of the US sponsoring agencies (Anonymous 2005). It was then decided not to proceed with the revised trial design, but to reduce the sample size instead. As completed, the trial sample size was defined by the availability of the DTP-Hib vaccine, and it finished up with less than half the original sample size (Lucero & Williams 2005). To accommodate this, the primary endpoint was revised to become radiological pneumonia (by the WHO definition). Despite this the results have been eagerly awaited. The results, now published, were certainly worth the wait (Cutts et al. 2005). The efficacy of the vaccine against invasive pneumococcal disease was good, with no hint of the problem of serotype replacement that many had predicted, but with somewhat lower efficacy than previous studies. The efficacy against the new primary endpoint of radiological pneumonia (35–37%) was as good as the most optimistic had hoped for, supporting the view that, as with Hib, the true contribution of the organism to the burden of pneumonia has been underestimated by prospective pneumonia aetiology studies (Adegbola et al. 1994). Most surprising, and most encouraging, was the finding that the impact on child survival was considerable and statistically significant, although the confidence intervals were so wide that all one can really say about this is that the vaccine had some impact (vaccine efficacy was 16%, 95% CI 3–28%). Had the original sample size been completed, the point estimate of the impact on survival would have been much more precise. The Gambian trial demonstrates the validity of the WHO definition of radiological pneumonia. There was significant protection against this outcome, and virtually no protection against clinical pneumonia that did not achieve the required degree of consolidation to fulfil the WHO definition. The results are presented as rates allowing the reader to see that the burden of radiological pneumonia prevented, the burden of clinical pneumonia prevented and the burden of hospital admissions prevented are all rather similar (about 15/1000 child years). This is a very important finding as it indicates that in the Gambia, most pneumococcal pneumonia was captured by the WHO definition, and that epidemiological measurement of this endpoint is the logical way to conduct disease burden studies designed to predict the impact of pneumococcal vaccine introduction. Microbiological studies will only detect a small and variable fraction of this burden. The Philippines study is the last of the current round of pneumococcal vaccine trials remaining to be completed. Like the Gambian study, this also uses the WHO definition of radiological pneumonia as the primary endpoint. The only disappointing aspect of the results of the Gambian trial was the lack of impact on invasive disease caused by serotype 1. As the only other trial of a serotype 1 containing vaccine (South Africa) did not have enough cases of serotype 1 disease to evaluate efficacy, this trial raises doubts about whether this type of vaccine is effective against disease caused by serotype 1, which in other respects behaves differently to other pneumococcal serotypes. Serotype 1 is rarely found as a carriage isolate, but is an important cause of invasive disease (Brueggemann & Spratt 2003). Concerns have been voiced that the use of a 7-valent vaccine (lacking serotype 1) in a country where serotype 1 disease is prevalent may result in an increase in serotype 1 disease as a manifestation of serotype replacement, with unpleasant consequences. In this trial, a vaccine containing serotype 1 was used, yet there was still a small increase in serotype 1 disease. It is interesting to speculate what would have happened to serotype 1 disease had the 7-valent vaccine been used for the trial. Clearly, if the 7-valent vaccine is introduced into the Gambia or another African country, surveillance for an increase in invasive disease, particularly serotype 1, is essential. One of the surprising findings was that the efficacy against both invasive disease and pneumonia was not dependent on age, and was evident well into the second year. For reasons that are not clear the investigators chose to terminate surveillance at 30 months, although many participants had passed this age by the time the trial was completed. This leaves the critical question of duration of protection unanswered. Follow-up of the children enrolled in this study to address this issue is now essential. An analysis was performed to see if the impact of the vaccine on mortality was more marked in remote areas, as would be expected. In fact the reverse was found with the impact on mortality most marked in those children who were registered at health centres that were themselves located less than 1 hour from a hospital. This approach is not optimal for addressing access to health services, as it is more likely to be the distance from the child's house to the health centre or hospital that better defines geographical access. Further analyses of the data will be undertaken to address this issue. Publication of the Gambian pneumococcal trial should give new impetus to efforts to control ARI, both by vaccination and by other methods. The period since 1990 has seen a drought in ARI research that is in some ways analogous to the drought in vaccine research that followed the discovery of antibiotics. It seems that this time the international community has sat back, waiting for a vaccine that will control the ARI problem, just as following the discovery of antibiotics vaccine research was stopped as it was widely believed that antibiotics would control the problem. In The Gambia the 9-valent pneumococcal conjugate vaccine reduced radiographic pneumonia by 35%. Because of the major public health importance of childhood pneumonia this will be regarded as a success and should open the way to the vaccine's use in developing countries, if the major issues of supply, price and serotype coverage can be overcome. Yet we must also acknowledge that the problem of childhood pneumonia will not be solved by vaccines alone. Just as Robert Austrian's work in the 1960s reminded the world that pneumococcal disease was alive and well in the era of penicillin, we now need a new body of ARI research that acknowledges the limitations of immunization. Great improvements are needed in the field of case management, particularly in the use of oxygen, and the potential benefits of measures to improve nutrition or reduce indoor air pollution for reducing pneumonia morbidity and mortality need to be evaluated. It is time for the international community to wake up to the importance of childhood pneumonia, the leading cause of child death throughout the world.