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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).
in line: pneumococcal vaccines could save many lives but better data are urgently
needed on just how many|
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.
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
"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
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
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.
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.
despite these tough living conditions, children are more likely to get hospital
treatment here than in most of rural Africa|
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.
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
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