Memorandum submitted by Professor Douglas
Young and Professor Glyn Hewinson
Douglas Young is chair of VPAG (Vaccine Programme
Advisory Group), a group of academic, industrial and government
scientists who provide advice to Defra on the development of vaccines
for control of bovine tuberculosis (bTB). Glyn Hewinson is a member
of VPAG and leads the bTB research group at the Veterinary Laboratories
Agency (VLA). VLA is a major contractor for Defra-funded research
on bTB vaccines.
Tuberculosis—in people, cows and badgers—involves
a fine balance between a virulent bacterium and the host immune
system. In human TB, the outcome of this encounter is generally
in favour of the host (only 10% of infected people actually show
signs of disease) and tilting this further towards the host by
vaccination has been a major research objective since the time
of Robert Koch. Progress towards a vaccine for human TB was made
in the early years of the 20th century with development of the
BCG vaccine (a live attenuated TB bacterium originally isolated
from a cow), but BCG has proved inadequate for global TB control.
There has been a major renewal of human TB vaccine research over
the last decade, fuelled by new opportunities arising from genome
science. The Global Plan to Stop TB[1]
envisages that an improved vaccine for human TB will be available
for use by 2015. It is estimated that a budget of the order of
$3 billion over the next 10 years is required to reach this goal.
The bacteria responsible for bTB are very closely
related to the major human pathogen,[2]
and fundamental features of the immune response to TB are shared
across all mammalian species. It may therefore be possible to
exploit advances in human TB vaccine science to develop tools
for control of bTB. Vaccination could be applied for bTB control
in wildlife or directly in cattle. Research in this area is underpinned
by strong collaborative projects across the UK, Republic of Ireland
and New Zealand.
VACCINATION
OF BADGERS
"Vaccination more effective than culling?"
Although the BCG vaccine has had limited impact
on human TB, decades of experimental research have shown it to
be very effective in guinea pigs. Would BCG vaccination provide
a tool to control bTB in badgers, at least to the extent that
it would reduce transmission to cattle? In 1997 the Krebs Report
on Bovine Tuberculosis in Cattle and Badgers viewed this as a
potential back-up plan, though it was considered that the partial
effect of vaccination—perhaps reducing disease by 70 or
80%—would always be lower than the 100% reduction achieved
by culling. The potential role of badger vaccination has to be
re-evaluated in light of two findings in the recent ISG Report.
Firstly, the Report presents definitive evidence that badgers
do make a significant contribution to the incidence of bTB in
cattle. Secondly, the ISG identified a detrimental "perturbation"
effect associated with culling; vaccination may provide an alternative
strategy that avoids this.
To obtain a licence to use BCG in badgers it
is necessary to show that the vaccine protects animals against
bTB in a controlled experimental setting, and that it is safe
for use in a natural setting. Experiments to test this are underway,
including a controlled trial of BCG vaccination in over 300 badgers
in the Cirencester area. If successful, it is expected that BCG
would be available for use in 2010. The current vaccine has to
be delivered by injection and therefore requires trapping of badgers.
This may have application in targeted trials—as a ring-vaccination
strategy in combination with trap-based culling, for example—but
large scale use will require a vaccine that can be delivered in
the form of an oral bait. Several oral formulations of BCG are
currently under development, and it is anticipated that an oral
vaccine could be available from 2012.
The impact of badger vaccination has to be assessed
in terms of reduced transmission to cattle. Monitoring the effect
of badger vaccination in defined geographic regions may provide
a mechanism to achieve this. Figure 1 illustrates the VPAG timeline
for badger vaccine development.
VACCINATION OF
CATTLE
BCG vaccination has been assessed in cattle.
The results are similar to trials of BCG against human TB, with
widely varying outcome in different countries, though with some
of the most encouraging results being seen in the UK. Can we develop
improved cattle vaccination protocols analogous to those now going
forward in human trials? A range of new vaccines have been tested
in cattle exposed to experimental infection. Again the results
parallel findings in human TB, with the best protection obtained
using BCG combined with a second booster vaccine. BCG itself was
found to be particularly effective when administered as a neonatal
vaccine to calves under 6 weeks of age.
In addition to its variable efficacy, BCG has
the drawback that vaccination primes animals to respond to the
tuberculin skin test used for diagnosis, and its use is therefore
incompatible with the standard test-and-slaughter policy for disease
control and contravenes EU legislation. It was necessary to develop
diagnostic tests that distinguish bTB infection from BCG vaccination.
This has been achieved by taking advantage of genetic differences
specific to the vaccine strain. Differential diagnostic tests
are also important in the context of wildlife vaccination programmes
using oral baits that may inadvertently be taken up by cattle.
"How good is good enough?"
In the experimental challenge model used to
compare new vaccines, all of the animals receive a high dose of
infection which leads to rapid progression of disease. To get
a better idea of how a vaccine might perform in the field, a natural
transmission model has been set up. This involves housing vaccinated
and control animals together with diseased cows; monitoring infection
using blood tests, with a final disease assessment port-mortem.
At the current stage of the VPAG timeline (see Figure 2), a comparative
trial of the best new candidate with BCG has been initiated in
the natural transmission model; first results will be available
by the end of 2008.
To assess new vaccines we have to consider the
performance characteristics required in a vaccination programme.
Would vaccination be introduced as a national policy, or in defined
local circumstances? To prevent infection, or just to reduce transmission?
What are the national and international trade implications? Who
would pay for vaccination? As part of the vaccine development
programme, Defra has initiated work to address these questions.
The availability of vaccines does not necessarily equate to use;
the balance of cost and benefits will remain a question for policy
makers.
"Cattle vaccines for global development?"
The expense of test-and-slaughter policies precludes
general use in developing countries, many of which have no programme
for control of bovine TB. Cost-benefit assessments of cattle vaccination
are therefore significantly different from the UK. In a parallel
project supported by the Wellcome Trust, cattle vaccines are being
tested in a natural transmission model in Addis Ababa, with results
fed into an economic model of the impact of bovine TB in Ethiopia.
SUMMARY
Research is underway to develop and test vaccines
to control bovine TB in badgers and cattle. It is anticipated
that the earliest date an injectable vaccine for badgers could
be licensed is 2010, followed by neonatal BCG for cattle in 2012.
Oral BCG for badgers is expected to be available from 2012, and
a cattle vaccine that improves on BCG from 2015. The timeframe
for moving from the availability of a vaccine to its use in practice
will depend on assessment of its performance in the broader context
of control policy. Outside of its potential role in the UK, an
effective cattle vaccine could have important health and economic
benefits in developing countries.
October 2007
1 http://www.stoptb.org/globalplan/ Back
2
The DNA sequence of Mycobacterium tuberculosis, the human pathogen,
is 99.95% identical to that of the Mycobacterium bovis, the pathogen
responsible for TB in cows and badgers. This is roughly the same
level of genetic identity shared between two human individuals. Back
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