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This time, a vaccine for everyone?
With hopes running high for
a new vaccine against the major killer pneumococcus, the Alliance
partners are tackling the tough challenge of making sure it
will be promptly available and affordable in
developing countries. Phyllida Brown reports
FEW other microbes are as deadly.
Pneumococcus kills at least 1 million people a year, according
to WHO estimates mainly young children in the worlds
poorest countries. Most die of pneumonia, while some develop
fatal meningitis or septicaemia. And even those who survive
meningitis often suffer long-lasting disabilities.
Given its huge toll on life and
health equal to or greater than either malaria or measles
pneumococcus has managed to keep a relatively low profile
in the public consciousness. But it may not do so for much
longer. In 2002, this microbe is finally beginning to attract
the concerted global attention required to tackle a major
killer, for two reasons.
a sick Iraqi girl with pneumonia is examined with a stethoscope
First, a new tool to protect children from the disease is within
sight. A pneumococcal conjugate vaccine (see Box
1) is now on trial in South Africa and the Gambia, with the
results of the first trials in South Africa due later this spring.
Most researchers are hopeful. If the vaccine proves as effective
as its close cousin, licensed two years ago in the United States,
it could potentially save hundreds of thousands of childrens
lives each year. "This could have a major impact on child survival,
which is why GAVI has selected pneumococcal vaccines as a development
priority," says Thomas Cherian, a paediatrician from the Christian
Medical College, Vellore, India, who currently works at WHOs
Geneva headquarters coordinating global research activities on pneumococcal
| 1: Pneumococcus: the disease
- The bacterium, properly known as
Streptococcus pneumoniae, causes acute respiratory
disease, ear infections, meningitis and septicaemia. Pneumonia
is the biggest cause of death. Of those who develop meningitis,
studies in the Gambia and elsewhere suggest half will die
and most of the remainder suffer longterm disabilities(1).
- Conservative estimates suggest that pneumococcus
is responsible for at least 1 million of the 4 million deaths
that occur worldwide each year in under-fives from acute
- Pneumococcal disease can be treated with
antibiotics, but an increasing number of strains in circulation
are antibiotic-resistant. Vaccines are the only effective
way to control the disease and effective, globally available
vaccines would be among the most useful tools in public
health for decades.
- Although there are at least 90 known
serotypes, or strains, of S. pneumoniae, 9-11 serotypes
appear to account for up to 80% of disease cases, with the
prevalence of different serotypes varying from region to
Vaccines licensed and in trial
- Since February 2000 a pneumococcal
conjugate vaccine made by Wyeth Vaccines has been licensed
in the US and is routinely administered to infants there(4).
Seven pneumoccocal serotypes are conjugated to a protein
carrier, a mutated nontoxic form of the diphtheria toxoid
called CRM197; the vaccine is known as 7-valent. The conjugation
technology first developed for vaccines against Haemophilus
influenzae type B (Hib) is a feat in itself. For the
pneumococcal vaccine, the bacterial polysaccharide from
each different serotype is separately joined to a protein
carrier in a laborious process.
- Unlike an earlier polysaccharide vaccine,
the conjugate vaccine protects infants, the most vulnerable
group. In trials, the vaccine reduced the incidence of invasive
pneumococcal disease by more than 90 per cent, and also
reduced pneumonia and ear infections.
- The vaccine on trial in Africa, also made
by Wyeth, is 9-valent: in addition to the 7 original serotypes
it includes two prevalent outside the US. If trials go well,
a licence could be granted by about 2006. Additonal vaccines
are at earlier stages (Box 2).
- Early evidence suggests that children immunized
against S. pneumoniae are not only protected themselves,
but are also less likely to pass the infection on to others.
So a vaccine may protect unvaccinated as well as vaccinated
children in a population and may also reduce the spread
of antibiotic-resistant strains(6).
But a vaccine can only save
lives if it is accessible and this is the second reason
why pneumococcus is coming under the spotlight now. 2002 sees
the birth of an ambitious plan, probably the first of its
kind in international health, to make sure that the vaccine
will actually reach those who need it most within five years
of its licensure.
Well aware that the field trials
are not even finished, the key players which include
the Vaccine Fund and the manufacturers, governments and other
key GAVI partners are pressing ahead with the plan
because if the vaccine works, there is no time to lose.
babies in the Gambia, where a vaccine is on trial
Breaking a vicious circle
Too often in the past, new vaccines developed
against major diseases such as hepatitis B have waited 10 or even
20 years after their initial licensure to reach those in low-income
countries where disease burden tends to be highest. We have
always got caught in a vicious circle, says Orin Levine, a
researcher at the National Institutes of Health in Bethesda, Maryland.
Together with Jay Wenger and Thomas Cherian at WHO, Levine is charged
by GAVI with the task of developing an agenda to rapidly evaluate
and introduce pneumococcoal vaccines for developing countries. Typically
with new vaccines, the price is high, says Levine, so
there is no demand from the low-income countries, and the industry
has no incentive to invest in increased capacity and supply. We
are trying to break that vicious circle, and we have to break it
at multiple points.
No one pretends that breaking that vicious circle
will be easy. The price for pneumococcal conjugates is indeed high
at least relative to most childrens vaccines. The product
licensed in the US, made by Wyeth Vaccines, is sold there at around
$50 a dose, and with three doses required, it costs $150 to protect
each child. The candidate vaccine now on trial in Africa is designed
to protect against a wider range of serotypes, or strains, of pneumococcus
than those found in the US; its price might be expected to be at
least as high. But, while the era of vaccines costing just a few
cents a dose is clearly over, few believe that a vaccine costing
fully $150 per child will be attractive to developing countries,
given that many of these countries governments spend under
$20 on health per person each year. This is a global issue,
says Keith Klugman, of Emory University, Atlanta, the principal
investigator on the South Africa trial. The price is clearly
Putting real numbers on future demand
Wyeth appears willing to discuss
a different price for the poorest countries, although no one is
ready to start quoting figures at this stage. The price is
going to have to reach what is do-able and affordable, says
Peter Paradiso, vice-president for scientific affairs and research
strategy at Wyeths Rochester, New York, base. It is
incumbent upon all of us to figure out how to do that, and to come
up with a financial solution that can be acceptable to everybody,
But no manufacturer is going to invest
in producing more vaccine unless it knows that it has a buyer. Vaccine
companies need to know that there is a credible demand for their
product, and gauge the size of that demand, before they will move
ahead. We need to have some hard numbers put into the system
so that people can proceed, says Paradiso. The last
thing we want is to build up capacity and have a vaccine that is
Which is where the new plan comes in.
Sponsored by the World Bank, the Vaccine Fund and the Gates Foundation,
the plan is an Alliance initiative to be agreed between public agencies,
foundations, and vaccine manufacturers with products in development
(See Box 2). It will set out a detailed road
map for achieving the introduction of an agreed supply of an effective
pneumococcal vaccine at an acceptable price, starting between 2006
2: A dwindling set of vaccine
Wyeths 9-valent vaccine
is the most advanced of the candidate pneumococcal conjugate
vaccines. While many had hoped that, if trials proved successful,
it could be licensed and used exactly as it is, the company
favours developing the 9-valent vaccine as a combination product
with meningococcus C.
Some researchers have argued against
this combination, saying it would be inappropriate for developing
countries as meningococcus C is a relatively minor pathogen
in many populations, and the extra antigen is likely to add
to the cost and even the time for bringing the product to
market. Paradiso at Wyeth disputes this view and adds that,
since the price of the vaccine in the poorest countries will
be negotiated on different terms from those in industrialised
countries, it will be unaffected by one extra antigen.
Although the rest of the
field is not empty - quite - the alternatives are few. Glaxo
SmithKline has developed an 11-valent candidate vaccine, but
is currently reformulating it and doing additional work to
improve the vaccines consistency, so its journey to market
will be delayed.
Aventis Pasteur had developed
an 11-valent pneumococcal candidate vaccine, currently undergoing
field trials in the Philippines. However, the company has
recently decided not to pursue commercialization of the vaccine.
Dr Juhani Eskola at Aventis Pasteur
says the decision was taken because, although the vaccine
produces a strong immune response when given at the same time
as whole-cell DTP (DTwP) vaccine, it performs disappointingly
when given at the same time as acellular DTP (DTaP). Since
most industrialized countries use DTaP, this presents a serious
problem for the company in gaining regulatory approval and
marketing of the product.
"We asked ourselves whether
we could develop the vaccine for the DTwP environment," says
Dr Eskola. The final conclusion was no, since some further
trials of the vaccine would also be required. "With these
regulatory difficulties, the development time would be extended,"
he says. "Since we also have another pneumococcal candidate,
a protein vaccine, in development that could be used with
both DTaP and DTwP, we decided we would focus on that and
try to get it to the market as quickly as possible." He says
that the projected timelines for the extra work on the conjugate
vaccine would be almost as long as for the new protein vaccine,
so it was a logical choice to go for the newer approach. However,
he says the new vaccine is at a relatively early stage, and
it will be "several years" before development is complete,
assuming of course that it proves protective in trials.
Too little competition
Some researchers are dismayed
that Aventis Pasteur has abandoned a vaccine that could have
been suitable for many developing countries in favour of a
newer approach that is still some distance from market. "While
there may be major practical advantages to the protein vaccine
approach, it is unproven, whereas the conjugate is an established
mechanism," says Kim Mulholland, a paediatrician specialising
in international child health at the University of Melbourne.
Mulholland - and, privately, others
- believe that Aventis Pasteurs withdrawal of its product
will also make it more difficult for the public sector to
negotiate an affordable price for any pneumococcal vaccine
in developing countries because Wyeth now has little competition.
Eskola insists, however, that Aventis Pasteur remains "strongly
committed" to work in the pneumococcus field and that the
potential of the new vaccine is better. "Our plan really is
to provide a vaccine for the whole world."
The plan, being
drawn up with the help of management consultants McKinsey
& Company, will set clear targets for each stage along
the road, and identify key parties such as the manufacturers,
funding agencies and the technical teams that would implement
the plan. All parties will be expected to make commitments
at each stage. The idea sounds obvious, but such a plan is
rare outside the private sector. Its common sense,
as most really good ideas are, says Amie Batson at the
World Bank. But it is a new departure for us.
|Testing time: an enrolment
session for the trial in The Gambia
She hopes that the public sector can
learn from the methods routinely employed by industry to plan the
introduction of their products, and redirect those methods towards
the global objective of achieving a speedy and equitable introduction
of a pneumococcal vaccine. If the approach works, it might eventually
be extended to other new vaccines in future.
The idea for a detailed plan evolved
from an initial decision by the GAVI Board in November 2000 to make
the development of pneumococcal vaccines a priority(5),
since when GAVIs task forces for R&D and financing have
been seeking advice and setting agendas for action. "Were
saying, lets start with our end target a given level
of coverage with a pneumococcal vaccine and work backwards
to say what activities are needed, where, and when, to ensure that
the target is met," says Batson.
Commitments by all parties
So far, the plan is just a framework
to set out the details. "But by the end of 2002 we should have a
good sense of the number of doses that might be needed, what the
price range would be, and by what year," she says. By late 2003
proposals on funding should be drawn up, together with price and
volume agreements with manufacturers. By 2004 the manufacturers
should have clear agreements to scale up production and by 2006-2008,
the vaccine could be purchased and introduced into a first group
of countries. Preliminary discussions with the industry have already
There are many intermediate steps to
be taken before the ultimate goal can be reached. One example is
to measure the burden of pneumococcal disease in different regions
and countries. Governments are more likely to see the value of a
vaccine if they know that it could prevent a significant number
of deaths and cases of illness and disability in their population.
So, to find out the true burden of the disease in each population,
detailed epidemiological studies must be set up now, each of which
must be financed from somebodys budget. The plan will include
details of exactly when such studies will be done and who will pay.
Can it work? Only if all sides
in public and private sectors are prepared to think differently
from before. Wyeth, for its part, is sounding cautiously positive.
"The environment has changed," says Paradiso. "The Alliance is taking
more ownership of this process."
Time for the public sector to take
in the public sector too, there are some signs of a shift. "We [in
the public sector] have to be willing to share the risks with the
industry," says Levine. While industry has traditionally borne risks
such as investing in production only to find that demand for a product
is tiny or delayed for years, the public sector has generally been
able to play safe with its money where vaccines are concerned. Some
in the immunization community now think that, given the small number
of manufacturers and the difficulties of guaranteeing markets in
developing countries, that public-sector habit of playing safe may
need to be rethought.
GAVI may need to commit itself, for
instance, to buying a set number of doses of vaccine upfront
even, says Levine, if that means risking buying too much. "We have
got to be prepared that someone will say, You spent millions
on expensive vaccines that you cannot even use," says Levine.
Without willingess to take such risks, he believes, there might
be no increase in the rate of progress and children in developing
countries could still be waiting for pneumococcal vaccines in 2015.
Does this mean that, to get vaccines
to children in developing countries, the public sector has effectively
to submit to the demands of the vaccine manufacturers? No, says
Batson. "This process is in the public good and has to be controlled
by the public sector. But it is in our interests to involve the
private sector. The only way to accelerate access is for industry
also to accelerate its investment in development and production
capacity, so industry has to be involved." The stakes are high
and the responsibility on all players greater than ever before.
Goetghebuer T., et al. Outcome of meningitis caused by Streptococcus
pneumoniae and Haemophilus influenzae type b in children
in The Gambia. Trop Med Int Health. 2000 Mar;5 (3):207-13.
Obaro SK., et al. Prospects for pneumococcal vaccination
in African children. Acta Tropica 2000. 75 (2);141-53. (Medline:
Hausdorff WP., et al. Which pneumococcal serogroups cause
the most invasive disease: implications for conjugate vaccine formulation
and use, part I. Clin Infect Dis. 2000 Jan;30 (1):100-21.
FDA press release February 2000. http://www.fda.gov/bbs/topics/NEWS/NEW00716.html
GAVI Product Agendas. www.vaccinealliance.org/reference/update_agendas.html
Klugman KP. et al. Efficacy of pneumococcal conjugate vaccines
and their effect on carriage and antimicrobial resistance. Lancet
Infect Dis 2001 Sep;1(2):85-91 and Obaro S., et al., The pneumococcus:
carriage, disease and conjugate vaccines. J. Med. Microbiol
2002 Feb; 51 (2);98-104. (Medline: www.ncbi.nlm.nih.gov/entrez/query.fcgi)
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