UPDATE - July 2002
Call for intensified research after pneumococcus trial surprises
AS a key component of the plan to accelerate vaccines against pneumococcus, partners and scientists are calling for research to be urgently stepped up to provide better data on the burden of the disease and the efficacy of current candidate vaccines. Their calls come after trials of the most advanced candidate vaccine against pneumococcus produced unexpected results, answering some important questions but raising as many new ones.
Around 2 million children under five years old die from pneumonia each year in developing countries, according to the latest estimates (1) . The bacterium Streptococcus pneumoniae, known commonly as pneumococcus, is thought to cause 50% or more of these deaths and a similar proportion of severe cases. A pneumococcal conjugate vaccine is licensed in the US and Europe and has proven efficacy against invasive pneumococcal disease (infections of the bloodstream). But trials are still ongoing to find out whether the vaccine can prevent pneumonia in children in developing countries: if the answer is yes, it could sharply reduce child deaths, alongside vaccines against the other major microbe responsible for pneumonia, Haemophilus influenzae type b (Hib).
Waiting in line: pneumococcal vaccines could save many lives but better data are urgently needed on just how many
Assuming that around half of all cases of severe pneumonia are caused by pneumococcus, and assuming that the vaccine has less than 100% efficacy, researchers had hoped that the vaccine could reduce the total number of pneumonia cases by around 30%. Some even hoped that the figure could be as high as 40%. But at the Third International Symposium on Pneumococci and Pneumococcal Diseases in Alaska in May, Professor Keith Klugman of Emory University, Atlanta, presented the results of a trial (2) from Soweto, South Africa, involving 40,000 children in which the vaccine reduced total pneumonia cases by around 22%. This figure is lower than expected and only marginally statistically significant.
However, the trial did confirm that the vaccine, made by Wyeth, reduced the incidence of invasive pneumococcal disease by more than 80%. Even in children infected with HIV, for whom invasive pneumococcal disease is a serious threat, the vaccine halved the incidence. In addition, separate data from studies in the US, also presented in Alaska, showed that the vaccine may help to reduce the spread of pneumococcal infections, as well as protecting those who are vaccinated. When infants in the US are vaccinated, the number of infections in people aged 20-39 and over 60 also drops suggesting that parents and grandparents benefit.
Klugman is upbeat. If the Soweto findings are borne out elsewhere, then combined use of pneumococcal vaccine and Hib vaccine could cut the overall burden of pneumonia in children by some 40%, as well as offering specific benefits to children with HIV, he says. However, like other researchers, he believes that the pneumococcal vaccines lower-than-expected efficacy against pneumonia needs to be better understood.
"These results are forcing researchers to rethink their expectations about the vaccine, and strongly reinforce the need for continuing with other efficacy trials," says Dr Orin Levine, of the US National Institutes of Health, one of a team charged by GAVI with the task of developing an agenda to rapidly evaluate and introduce pneumococcal vaccines into developing countries.
At present, researchers are missing key pieces of information. First, it is still not clear exactly how big the burden of pneumococcal pneumonia is. Doctors rely on chest x-rays rather than laboratory cultures to diagnose pneumonia, and chest x-rays cannot distinguish between pneumonia caused by Hib, pneumonia caused by pneumococcus or other microbes. The estimate that pneumococcus causes half of all severe cases of pneumonia is based on a handful of studies from developing countries where bacteria have been cultured from patients lung fluid or blood, but those studies may not be representative. One purpose of vaccine trials is to get a better estimate of the burden.
Another problem is that, to measure a vaccines efficacy, there must be clearly defined "endpoints" to the trial, such as comparing the number of cases of pneumonia in those children who have been immunized with the number of cases in those who have not. However, with x-ray as the main tool for diagnosing pneumonia, doctors in different settings may disagree over whether some individual cases should be defined as pneumonia or not. This may affect the numbers, and so the estimated efficacy of the vaccine.
The Soweto trial was the first to use standardised criteria for x-ray confirmed pneumonia, developed by WHO, says Klugman. "It may be that the criteria need to be reworked," he says.
Given these problems, says Levine, it is difficult to know what the impact of the vaccine is. The results from Soweto could be interpreted in a range of different ways, he says. At one extreme, we might hypothesise that pneumococcus is as big a problem as we expected but we need better vaccines. At the other extreme, the hypothesis would be that the vaccines are highly effective, but pneumococcus is not as big a problem as we thought. Its essential to find out where between these two extremes the truth lies, says Levine. "As long as vaccines remain expensive, we are going to have to have very convincing data of their impact."
"This opens up a whole bunch of questions," agrees Professor Kim Mulholland, a paediatrician specialising in international health at the University of Melbourne, Australia. First, what will other trials show? All eyes are now a major trial of the same vaccine in The Gambia, which is due to end in late 2004. Conditions there may be more representative of Sub-Saharan Africa as a whole than Soweto. Although children in Soweto are disadvantaged in many respects, they have better access to hospital care than in most of rural Africa.
Key research questions
The Soweto trial was not designed to measure the impact of the vaccine on mortality, so no one knows how many deaths it could prevent. "It is entirely possible that the vaccine may have a higher impact on the more severe forms of pneumonia," says Dr Thomas Cherian, of the Christian Medical College, Vellore, India, who has been at WHO coordinating pneumococcal vaccine research.
Attention is also turning to other candidates. GlaxoSmithKline has developed a conjugate vaccine that is intended to protect against 11 different strains, or serotypes, of pneumococcus, compared with the 9 serotypes in the Wyeth product. Walter Vandersmissen of GSK told Immunization Focus that, following some technical delays, the vaccine is now due to start Phase II clinical trials in Europe and Latin America before the end of the year.
Soweto: despite these tough living conditions, children are more likely to get hospital treatment here than in most of rural Africa
Another candidate pneumococcal conjugate vaccine was developed by Aventis Pasteur. The company recently decided to abandon the vaccine in order to develop a protein pneumococcal vaccine instead (see "This time, a vaccine for everyone?", Immunization Focus, March 2002 ), but trials of the conjugate vaccine are still continuing in the Philippines. Even if the vaccine produces promising results, there are no known plans to develop it commercially. But scientists say the results of the trial will still be very important in providing information about the efficacy of this type of vaccine.
Another important question is to find out whether vaccines against pneumococcus simply move the goalposts for the microbe. Scientists have been concerned that, in theory, even if a vaccine protects children against the serotypes of pneumococcus included in it, other serotypes may simply take their place and cause disease. The actual findings on this phenomenon, known as serotype replacement, have been mixed. In most studies, there is no evidence that it has happened. In Finland, however, researchers have found that vaccinated children do develop ear infections with different serotypes but the most severe infections are still prevented and the number of children needing to have ear tubes inserted has been reduced.
Levine says it will be important to find out whether the more severe infections are prevented in pneumonia too, and to monitor carefully for serotype replacement, in the remaining clinical trials.
Dr Tore Godal, executive secretary of GAVI, says the surprise results from Soweto are good for the field. "They force us to answer the important questions about disease burden and vaccine efficacy," he says. Researchers are hopeful that the GAVI decision to back an accelerated development and introduction plan for pneumococcal vaccines (see above) will now help to kick-start precisely the kind of studies needed to answer these questions.
1. Williams, B.G. et al. Estimates of worldwide distribution of child deaths from acute respiratory diseases. Lancet Infectious Diseases 2, January 2002. www.thelancet.com
2. Klugman, K. Presentation to 3rd International Symposium on Pneumococci and Pneumococcal Diseases, Anchorage, Alaska, May 2002. www.emory.edu/WHSC/HSNEWS/releases/may02/klugman.html
Immunization Focus July 2002 - Contents