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2000 contents page
R&D briefing: news from the Third
Annual Conference on Vaccine Research
LEADERS in public health and industry
told researchers that they were entering a new era for vaccine
development as they met earlier this month at the Third Annual
Conference on Vaccine Research in Washington, DC to hear updates
in strategies against HIV, malaria and other diseases.
Michel De Wilde, deputy executive
vice-president for R&D for Aventis Pasteur, warned that the
industry must set priorities. Despite expansion in recent years
the vaccine market accounts for just US $5 billion, or 1.6 per
cent, of the pharmaceuticals market overall.
On the one hand, the time for vaccine
development has never been better, said Sir Gustav Nossal,
of the University of Melbourne, Australia. Knowledge of
the genomes of major microbes and parasites is increasing
rapidly, enabling new approaches to design. Policy-makers
and new donors are also recognizing the value of vaccines
as cost-effective tools in the fight against poverty. On
the other hand, the industry is facing spiralling costs
for product development. And in some societies, from Asia
to North America, people appear to be more afraid of vaccines
than of the diseases they prevent.
New generation: todays babies are inheriting
a changing world for vaccine development
Four major companies account
for three-quarters of this market. De Wilde said that increased
regulatory pressures and higher technical demands were resulting
in "skyrocketing" development costs.
Four products have been registered with the US
Food and Drug Administration in the past eight years, and development
costs have been estimated to be $300 million to $400 million per
product. "This is becoming an increasingly difficult business to
be in," said De Wilde.
experimental vaccines and vaccine delivery systems were in plentiful
evidence at the conference. Among them:
Scientists in the United States
and Italy are testing an ingenious but relatively simple approach
to immunization that stimulates an aggressive immune response
against the virus. If the approach proves successful in further
studies, it might eventually be used both to control HIV in people
who are already infected and also to prevent the virus from establishing
infection in the first place. In animals, the prototype vaccine
is stable at room temperature and can been given without needles
simply by painting it onto shaven skin.
Julianna Lisziewicz of the Research
Institute for Genetic and Human Therapy in Washington, DC, and
colleagues, made an artificial construct of HIV genes, a plasmid
DNA, that cannot integrate itself into cells or replicate. The
researchers then attached this gene construct to a chemical called
polyethylenimine mannose, a mix of a polymer and a sugar, which
has a unique ability to dock onto dendritic cells, a key group
of cells of the immune system whose job is to introduce other
defence cells to microbial antigens. Unlike other cell types,
dendritic cells have a specific receptor for mannose. Once docked
on this receptor, mannose activates the dendritic cells, which
start to alert other defence cells. In the laboratory, the team
found that dendritic cells were activated by exposure to the solution,
and that when the dendritic cells were cultured with T cells,
these made strong responses against the virus.
Just as important, they found,
very large numbers of dendritic cells in the skin of mice and
pigtail macaques were activated when the solution was painted
onto shaven skin. The activated cells have been shown to travel
to the animals lymph nodes where they trigger strong T-cell responses
against HIV. Lisziewicz and her colleagues now plan to test whether
their potential vaccine can protect rhesus macaques against deliberate
challenge with an HIV-like experimental virus, SHIV. The team
is also discussing with the Italian regulatory authorities a small
trial of the experimental vaccine as an immune therapy in people
with HIV in Italy. Nossal, of the University of Melbourne, said
the approach was interesting and warranted further study and support,
particularly to find out how the solution penetrates the skin.
Vaccines are urgently needed to protect
young children and mothers from malaria
For years, scientists have recognized
an antigen known as MSP-1 (merozoite surface protein 1)
on the surface of the blood stage of the malaria parasite,
Plasmodium falciparum, which they have hoped could
form part of an effective vaccine. However, the antigen
on its own has triggered only disappointingly weak immune
responses and researchers have argued that adjuvants stronger
than most of those licensed for human use will be needed
to make a successful vaccine (see, for example, 1).
Now researchers may have a way around the problem.
They are using a natural human protein, C3d, part of the complement
system of the immune system, which coats invading microbes and helps
to stimulate defence cells known as B cells to produce antibodies
Two or more copies of the C3d protein
can increase the antibody response by up to four orders of
magnitude, explained Vivienne Cox of AdProTech, the small
company based near Cambridge, UK, that makes the C3d under
the name of Immudaptin(TM).
The idea of using C3d as a kind of
natural adjuvant was first described in 1996 (2). But
now the team has successfully applied the idea in a mouse
malaria model. Using the mouse equivalent of C3d and the
comparable MSP from a rodent malaria, P. yoelii,
the team found that three-quarters of all the mice immunized
were protected from a lethal challenge with the parasite.
The team includes Louis Miller at the National Institutes
of Health in Bethesda, Maryland, USA, Anthony Holder at
the National Institute for Medical Research in London,
and Douglas Fearon at the University of Cambridge, UK.
"The results are very exciting
and we are moving immediately into generating the
equivalent protein for human immunization against
P. falciparum and P. vivax [the two
main human forms of malaria worldwide]," said Cox
of AdProTech. The team have contacted WHO and are
discussing a collaboration with researchers at the
Pasteur Institute in France for these studies
"This is an interesting and
original approach," says Howard Engers, who coordinates
malaria vaccine research for TDR, the multisponsor
tropical disease research programme based at WHO
(1) Holder, A. (1999).
Malaria vaccines. Proceedings of the
National Academy of Sciences, 96:
P.W. and others. (1996). C3d of Complement
as a Molecular Adjuvant: Bridging
Innate and Acquired Immunity. Science
Needles might be redundant in immunization
programmes sooner than some suspect, judging from the
studies presented at the meeting. Several groups reported
early work on vaccines delivered nasally, for example
against pneumococcus. Meanwhile PowderJect Vaccines Inc
of Madison, Wisconsin, USA, has developed a needle-less
syringe for single use that uses helium gas to drive powdered
vaccines at high speed into the epidermis without causing
pain. In mice the existing hepatitis B vaccine, in powdered
form, stimulated strong immune responses to the virus
when delivered by this route. The small cylinder costs
about US$1, says Kathleen Weis of PowderJect. This is
clearly more expensive than the conventional equipment
used in low-income countries, but may reduce costs in
other components, for example in the amount of vaccine
used. Weis says that less antigen may be needed with epidermal
immunization than with conventional vaccines, as the trans-skin
approach may target dendritic cells in the skin (see above).
"We are projecting to start a clinical trial next year,"
(Abstracts P 41, 43, 44)
approach to combination vaccines:
Luciana Leite from the Instituto Butantan in Sao Paulo,
Brazil and her colleagues are attempting a tough challenge:
to persuade the familiar Bacille Calmette-Guérin,
or BCG, a live microbe used to vaccinate against TB,
to express antigens against diphtheria, tetanus and
pertussis. The advantages are obvious: a single immunization
would protect infants against all four diseases, and
BCG is an inexpensive vector, already well established
for use in humans.
Keeping it all cold: todays vaccines
fill up the cold stores in many low-income countries.
Combination vaccines would help save space.