Vaccination against bluetongue serotype 8 –a
proposal for discussion
by Dr Ruth Watkins 14 10 2007 (third draft)
INTRODUCTION
The ideal would be to have limitless supplies of vaccine so that
all domestic ruminants in Northern Europe can be vaccinated.
Unfortunately this will not happen until perhaps late 2009 or
2010, when both Merial and Intervet are in full production. It is also likely
that 2 doses of an inactivated vaccine will be required to prime immunity and an
annual booster, also cattle will need a bigger antigen dose than sheep as they
are larger animals.
Until then vaccine will come on line slowly from about
Springtime 2008. Merial awaits inspections and the go ahead from DEFRA, and this
is not likely before January as inspection is to be made in December. I don’t
have a timeline for Intervet.
Vaccination would have to be done by farmers with the help of
their vets and a witness method validated.
Goal for 2008- Damp down the BTV-8 infection and disease in
the endemic areas of N Europe and prevent further outward spread.
I will divide the infected areas as the French (see page 2 of
their most recent report):
A = Hyper endemic area. Almost all holdings have infected
ruminants, and most have been infected ( the areas of dense red dots)
B = Recently infected area. Some holdings have infected
ruminants and the % infected in each holding is low, below 10 – 20 % (zone
‘jaune pale’ with scattered outbreaks, also as in the eastern fringe of East
Anglia at present)
C = The zone where infection is imminent or has occurred but
unrecognised as animal disease (the zone ‘bleu’)
D = The zone of surveillance comprising the French zone beyond
the zone bleu, in which active surveillance is carried out as shown by numbers
of holdings or ‘foyers’ sampled on white county areas.
Demarcate each infected country into these areas at the
end of December 2007.
Vaccine starts becoming available during the first half of
2008.
During the first 6 months of 2008
Zone A Vaccinate all calves lambs and kids born after the
1st August 2007 through to July 2008. This should be done promptly as
a priority. Each will need two doses of inactivated vaccine about 2 to 4 weeks
apart to gain full immunity.
-
The objective is that >80% of all domestic ruminants in
zone A are immune from the 1st July. It is said that >80%
vaccination of susceptible domestic animals in the case of BTV-2 and BTV-4
using inactivated vaccine has been sufficient to control infection with the
BTV vaccine serotype.
-
The young each year add almost 50% of new susceptibles to an
already immune adult population, quite enough to keep the BTV-8 virus in
circulation. By choosing a date such as the 1st of August it is
hoped to capture all young animals including those whose maternal antibody
might have protected them against infection in the 2007 season so that all
susceptible young are rendered immune.
-
The vaccination course should be given between 2 and 8 weeks
old so that there is not a gap where there is no protective
immunity.
It is assumed that the greater majority of adult animals have
already been infected in the hyper-endemic areas. It would be ideal if there
were some antibody sampling to check this is the case. These infected
animals that have recovered are immune for life against reinfection, or any
significant reinfection, with BTV-8 so will never need vaccination with BTV-8
vaccine. It would be a waste of vaccine to vaccinate them unnecessarily when
there is likely to be insufficient vaccine. They will also pass on passive
antibody to their offspring. This should not interfere with vaccination,
normally neonatal and very young animals (including humans) respond very well to
virus antigen vaccines (the presence of maternal antibody does interfere with
live vaccines hence the wait until this is lost).
If adult animals are screened for antibody in zone
A and found to be seronegative then they too should be vaccinated at this
time. Any lacunae of susceptible (uninfected) animals in the
hyperendemic area in 2008 will act as amplifiers of infected female midges and
it is large numbers of these that the vaccine programme is designed to prohibit.
The Authorities should be encouraged to provide such antibody screening tests.
Otherwise if laboratory tests are done privately vaccine should be made
available to vaccinate the non-immune (the uninfected).
Zones B and C Vaccinate all cattle young and old, of any
age, male and female: cows calves heifers steers and bulls.
They will all need two doses of the inactivated
vaccine.
When this is completed and there is enough vaccine then
vaccinate all cattle as above in zone D.
The purpose of this is
-
To prevent cattle acting as the amplifiers of infected female
midges, as cattle are the most important amplifiers. They seem to be infected
first when the virus arrives and they are bitten by more midges than sheep
because of their larger surface area.
-
There are less cattle than sheep, in Wales the ratio is at
least 10 :1 sheep:cattle. When the vaccine is in short supply this will give
the greatest benefit over the great area in N Europe that needs action to
prevent BTV-8 infection.
-
Sheep flocks will act as sentinels. About 80% of infected
sheep will become ill alerting one to confirm the diagnosis in a virology lab,
thus continued circulation will be detected.
July August September October 2008
Continue to vaccinate all summer born calves in zones
A, B, C and D between 2 and 6 weeks of age. (They will all imbibe passive
antibody with their mothers colostrum. If not vaccinate from neonate)
If any sheep flock has so much as one infected sheep
confirmed in the diagnostic laboratory in zones B, C, and D then
vaccinate the whole flock and the contiguous flocks. This should include all
adult and young animals even animals that are shortly to go to slaughter. The
vaccine is harmless to consume, likewise an infected animal.
If any sheep flock in zone A has so much as one
infected sheep confirmed in the diagnostic laboratory by detection of virus RNA
then it would be desirable to do antibody testing on the whole adult flock. All
antibody negative adult sheep should be vaccinated (the lambs have already been
vaccinated). It is reasonable to assume that vaccination of any sheep incubating
the infection is unlikely to make any difference to the outcome.
The end of October.
It is hoped that this strategy applied to the Netherlands,
Belgium, Luxembourg, France, Germany, Denmark and England and other neighbouring
countries infected in 2007, will prevent the huge amplification of infected
female midges as has occurred in 2007.
It is also hoped that the cattle vaccination over a very large
area combined with a much smaller incursion of infected female midges will have
prevented enlargement of the area infected with BTV-8.
The movement restrictions along the present lines would have to
remain in place to prevent infected ruminants from starting distant foci of
infection. The next year in 2009 movements can become more relaxed see later. A
workable movement to slaughter arrangement should be in place, as in France.
The major midge season is over and most lambs have gone into the
food chain.
The opportunity of November and December
2008.
This is the window when much more vaccine is available and an
opportunity to eliminate infection arises.
The midges implicated in Northern Europe are associated with
animal housing in winter and dung for breeding, namely C dewulfi and C obsoletus
complex. They follow the animals indoors in winter, into the barns, and maintain
the virus by a low rate of midge reproduction or prolonged survival in a torpid
state- thus virus is overwintered by a low level female midge breeding programme
and the availability of susceptible ruminants (see MacLachlan slide show,
overwintering). This is likely to occur in and around barns in the case of BTV-8
in Northern Europe.
The proposal therefore is to ensure that all animals housed in
barns on any farm in zones A, B, C and D are immune to BTV-8. Also all ruminants
grazing on surrounding fields within 2 Km also need to be immune.
It is possible that sheep outwintered on the hill far from
housed animals in barns and dung heaps do not require to be immune as they are
unlikely to play any part in the overwintering of BTV-8 in Northern Europe (see
caveat).
Wild ruminants in other countries are both at a lower latitude
and have different Culicoides species, implicated in the spread of many
serotypes of BTV, with different biological niches for example C
imicola.
Action to be taken:
-
Vaccinate all unvaccinated domestic ruminants that fall
into the housed and surrounding flocks or herds in zones B, C, and D. In
the case of domestic ruminants in Zone A it would be desirable to do an
antibody test on all non-vaccinated animals, with the view of vaccinating only
those without antibody. This would ensure that all domestic ruminants in
zones A, B, C,and D were immune in the barns and on the surrounding
fields.
-
The reason for ensuring immunity by the end of December 2008
is that a few infected animals may remain infectious for some 20 days to
female midges that themselves can live at least 3 weeks (may be longer in the
cool weather). In order to break the cycle before a mild spring or summer all
infected female midges should have died with no newly infected female midges
generated. The virus is not transmitted vertically in ruminants or in the
midge. (current scientific opinion)
Goal for 2009- Eradication of BTV-8
infection
In the first 3 months of 2009
-
All ruminants vaccinated during the first 6 months of 2008 will
need to have a booster dose of vaccine.
-
All outwintered sheep flocks or other animals in zones B, C
and D that have not been vaccinated will need to be vaccinated either when
they are brought in or before lambing or calving on the hill. This should be
within the first 3 months of 2009. Those in Zone A should have antibody
screening if not vaccinated and vaccination of all non-immune or susceptible
animals.
-
Vaccinate all newborn calves, lambs and kids in zones A, B,
C and D.
In the months April, May and June of
2009
-
Continue to vaccinate all newborn calves, lambs and
kids.
In the second half of 2009
-
Continue to vaccinate all newborn calves (lambs and kids if
any born).
-
Carry out the booster vaccination programme in all the
vaccinees.
It is hoped there will not be a season of BTV-8 disease from
July onwards in 2009.
There will be no susceptible domestic ruminants in zones A, B,
C, and D from July onwards in 2009.
Caveat: There is a hypothesis of persistence of
bluetongue virus in gamma/delta cells of the immune system but it has
not yet been proven that this does account for overwintering. If true a female
midge in the next season would be infected from a ruminant infected during the
previous season and who has cleared viraemia and infectivity via blood months
previously. The inflammation from midge bites is hypothesized to facilitate
reactivation of the virus in the gamma/delta cells attracted to the inflamed
skin and so infect further biting midges. If this hypothesis is true then the
virus cannot be eliminated until new infections are terminated and all those
previously infected have died.
Monitoring for infection
Those few that have been missed somehow or who have not
responded to the vaccine (which will happen in a small proportion of vaccinees)
will be insufficient, < 20% of the entire ruminant population, to maintain
circulation of the virus (it is hoped wild ruminants will not be great enough in
number). The reason every effort must be made not to exclude flocks or herds is
that the proportion of non-responders and wild ruminants if too great may make
the vaccine programme unsuccessful at elimination of BTV-8. Surveillance can be
done by laboratory testing so it is preferable not to have unvaccinated
sentinel farms etc within the vaccinated area.
The inactivated vaccine is not a DIVA vaccine. Thus infection
will have to be confirmed by RT-PCR for the virus RNA in whole blood, (usually
an EDTA blood sample) in a vaccinated animal. In an unvaccinated animal either
antibody or/ and the more expensive RT-PCR can be done.
Confirmation of infection by the virology lab should be done in
all herds or flocks suspected of disease. Also surveillance should be carried
out outside zone D.
There should be sufficient vaccine in 2009 to give it
routinely to all domestic ruminants in the affected and surrounding countries
over the winter period to ensure that re-emergence does not occur in summer
2010.
Movement restrictions
These can be relaxed in 2010 and may be relaxed in 2009 in the
affected countries. Movement out of a vaccination zone and into a
non-vaccination zone or country may require an RT-PCR in a vaccinated animal to
prove non-infection., instead of serology as now. Alternatively a DIVA vaccine
may come into use in 2009 or 2010 so that the cheaper test for antibody can be
done to prove non-infection.
Addendum to the proposed bluetongue vaccination policy by Dr
Ruth Watkins
The process of forming a policy is very
important.
The policy should be set out by two groups in the
case of zoonotic epidemics.
One group should be a
panel of professionals in virology and infectious disease.
-
There should be international
professionals on the subject to make sure there is a balanced coverage of
all relevant aspects. A few individuals from one laboratory should not have
control over the policy. Clinical and field experience must be represented by
appropriately chosen vets as well as the science of virology and
epidemiology.
-
Opinions that are held by individuals because of
their research which are at a tangent and not reflected by professional and
peer consensus should not be allowed to derail a best practice policy for
control and eradication of the infection in question. This also rules out
the treatment of the outbreak as an epidemiology experiment.
-
Professionals with disagreement should have that
not only minuted but have their points outlined in an appendix if they so
wish.
-
The possible routes that can be taken towards
control and eradication should be laid out so that the options are clear.
-
The policy should be the best clinical practice
that can be arrived at, peer reviewed and supported by evidence and documented
field experience.
-
The individuals will put their names to the
policy and be held accountable.
-
The policy shall be transparent, fully explained
with explanation clearly set out. The natural history of the infection should
be set out in one appendix and the supporting documentation listed in another
appendix and made available to all.
-
There should be the highest possible ethical
standard applied.
-
No pre-existing rules shall be allowed to
deflect from the best clinical practice.
-
Also as new understanding of the disease, tests
and vaccines become available the policy shall be updated. A regular review
should be carried out.
-
Necessary epidemiology and investigations should
be commissioned during the epidemic so that as much information as possible is
available on which to base analysis. The second group is kept up to date.
The second group should address the practical
issues of carrying out the policy. They might rightly view the first or former
group as their servant to present to them the best possible clinical practice
with regard to the control and eradication of infection.
-
On this group the interests of the stakeholders
are paramount.
-
They should be in regular communication with the
professional group.
-
Civil servants are there to serve the group and
clarify rules and legislation..
-
Issues of trading, politics, economics, etc are
the proper remit.
-
The rules, that may or may not be set in
stone, are accepted or changed.
-
The practicalities of carrying out any policy
recommended are assessed especially in regard to what happens on the farm.
-
Issues of compensation and trading are addressed and sorted.
-
Where any interest is found to over-ride the
recommendation of the professional group to control and eradicate the
infection concerned this should be made clear for all to understand.
-
The professional group can be challenged to
think again and should also make clear the consequences of any proposed course
deviating from best practice.
-
The management policy to be actually put into
practice must again be clearly explained and fully set out-
transparent.
-
The members of this group should put their name
to the management policy and be accountable.
-
This group should meet with members of the
professional group to assess the progress of the management of the epidemic as
it progresses.
-
Members from both groups should be selected and
be responsible for communication of information honestly and fully, and listen
to the response.
You can see that I am trying to change a few
ground rules by separating the professional recommended policy from all the
constraints on carrying it out which in veterinary medicine are caused by
consideration of trading rules and other obstructions of a different nature for
the most part to human medicine. This is one of the reasons why we are so
unprepared now for action, so late to order vaccine against BTV-8 and DEFRA is
unaccountable and the stakeholders do not have a fair representation with regard
to costs etc. In fact I made this point to the room assembled in the parliament
at Brussels when the Animal Health Policy for the EU was presented on the
17th of October.
No policy should be arrived at anonymously,
without responsibility or by one person or interest group eg epidemiology
modellers. Not even myself!
However I do not see why I might not serve as an
expert on the professional group: veterinary medicine has no equivalent to
myself or other types of human medicine professional with higher specialist
training and depth and breadth of experience as a consultant in the field of
clinical virology for instance.
What transpired at the ELA meeting and FMD and
CSF group meeting with regard to BTV-8.
Why is there no vaccine ready for use?
If vaccination against BTV-8 of all domestic
ruminants is compulsory it seems the EU will cover the costs for the vaccine and
50% of the costs of vaccination. Vaccination on a voluntary basis wouldn’t be
funded by Brussels.
However this leads to a chicken and egg situation
as the vaccine companies will not make the vaccine unless an order is firmly
made and the costs underwritten.
Ordering on a voluntary basis has led to
indecision about the number of doses required, further delaying ordering. On
this basis Germany was reckoning on about 3 million which is not very much and
would make the vaccine expensive.
Also how can one country go for compulsory
vaccination with the view of eradicating the infection when none of the
countries around are doing so- they will certainly be reinfected.
Trade rules come into play and as far as I can
gather from COPA-COGECA it has taken
all summer to thrash out trading rules within Europe such as trade to another
country in Europe being allowed 60 days after vaccination. Why should this
agreement have taken precedence over forming a policy to control and eradicate
infection?
What appalls me and I believe many others there,
is that there seems no way in Europe to have a co-ordinated plan to control
BTV-8 infection; to damp down the infection and slow down, if not prevent its
spread, initially, and as soon as there is sufficient vaccine made, to go for
eradication by ensuring immunity of all domestic ruminants, vaccinating all
those not yet infected.
Of course the reason why there is not sufficient
vaccine available is at least in part because the ordering has only just started
now with France for 50 million doses and was not made immediately in the early
summer when BTV-8 infection resurfaced. The vaccine policy should have been
ready for that moment. Issues of trading in the case of vaccination have no
logical reason to hold up vaccination policy.
There seems to be a complete lack of any
transparent well argued and reasoned vaccination policies for bluetongue
serotype 8 control and eradication.
There also seems to have been a dearth of good
epidemiologic information during the summer of 2007 comparable to that
commissioned by EFSA on 2006 and published in Spring 2007. Countries seem to
have been overwhelmed with infected animals and holdings so that the numbers
of these recorded are not truly representative of the situation. There is very
little whole herd and flock testing and work on pathology both of which were not
covered in depth in the Spring report. No work seems to exist on the midges
implicated, C obsoletus complex and C dewulfi, with regard to their
sensitivity to ivermectin or doramectin in the blood or the dung or the efficacy
of any repellent such as deltamethrin. Many animal keepers have used them and
yet it has made no difference overall to the epidemic. The entomological
monitoring has been slight, only 20 traps at different sites in the
Netherlands for example.
The seriousness of the epizootic is being
realised very late as it seems that C obsoletus is very widespread in the
mediterranean and in the palaearctic. For instance in Italy C obsoletus is
universally present except at coastal and low lying sites where C imicola is
present (Sardinia, coastal parts of Sicily and a few places on the mainland),
the two species are not apparently overlapping and occupy different biological
niches. In fact the C imicola may be long established and present in Italy at
these sites. So far BTV outbreaks in Italy have stuck with C imicola and have
not infected C obsoletus. The rapid spread of BTV-8 in Northern Europe has
amazed Prof Rudi Meiswinkel who is an entomologist from South Africa with a
lifetime experience of bluetongue now working in the Netherlands (he published
one of the reports in Spring 2007, “The Culicoides snapshot: a novel approach
used to widely and rapidly assess vector densities during the 2006 outbreak of
bluetongue (BT) in the Netherlands”). C obsoletus and C dewulfi between them
cover our European landscape especially where livestock is farmed. C obsoletus
has a strong correlation with forestry and C dewulfi with animal housing and
dung. The older females transmit because they take multiple blood meals (C
impunctatus the fierce midge of the Scottish highlands takes only one blood meal
therefore will not take part in spreading infection even could it could be
infected). They both go indoors with the animals, fly up to 2 km a day in order
to secure a blood meal, and C dewulfi have been caught in daylight taking blood
meals from the back of a cow.
How does BTV-8 overwinter? Vertical
transmission of a female to her egg has recently been claimed in the USA but has
not been found to be the case hitherto. Different viruses and midge vectors make
any work on one not necessarily applicable to another. Young female obsoletus
midges have been recorded all through the winter at a very low rate in the
Netherlands at the monitoring sites in and around animal housing. Older virus
positive females were not found. However the infection emerged again in
ruminants at multiple sites throughout the previous extent of infection early in
the summer. The longevity of infectiousness of a ruminant is rather variable-
not all ruminants infected experimentally are infectious to midges anyway, of
those that are some may be infectious for 60 - 90 days though most are
infectious to midges for up to 21 days. As so many animals are infected those
few at the far end of the bell shaped curve with infectious periods of longer
than 60 days are likely to be significant in number and span the winter. The
attractive theory of the immune cells, the gamma delta cells that are said to
harbour the infection, may not be relevant to overwintering. The theory may be
discredited (unrepeatable), or these cells unlikely to shed sufficient virus to
infect biting midges. They may be a remnant of infection, like the red blood
cells with their long half life in the blood but which though harbouring
sequestered virus lack of infectivity, or if serving any function boost the
immune response.
BTV-8 inactivated vaccine.
It came to light in the Brussels parliament that
the EU have a policy to fund in the main the development of sexy newer molecular
engineered vaccines. The well trodden path of the inactivated vaccine was seen
as old fashioned. Yet this has been used for BTV-2 and BTV-4 in Europe
successfully to prevent disease and to eliminate infection where tried in
islands like the Balearics. The person speaking for the commission was
dismissive of the old technologies. However the problem with molecularly
engineered vaccines has been to get them to be as immunogenic and efficacious as
the older types of vaccines created by the older technologies. These are to hand
quickly with regard for instance to BTV-8 whereas engineering a baculovirus
vaccine presenting VP2 or VP5 of BTV-8 would be years away. The vaccine
manufacturers must bear the cost of development of BTV-8 themselves and get
conditional licensing based upon previous experience with other serotypes and
small safety trials etc. They are prepared to do this indeed Merial is I believe
further along with this than Intervet. The vaccine manufacturers cannot say by
when they would be able to produce even 100 million doses but the intimation is
that this will be difficult to achieve by next July if they do not commence in
earnest before the end of October. It will be a juggling act to use their
present facilities and take years to build a new facility.
South Africa has long experience with inducing
immunity to a number of different serotypes of bluetongue using attenuated live
vaccine combined in 3 doses of vial A B and C to be given as 3 jabs at different
times. BTV-8 is in the mix. However there are disadvantages of using attenuated
BTV-8. It does not exist by itself unless plaque purified from the S African
vial containing it! It is likely to infect the vector and spread- may spread
vertically in ruminants unlike wild virus- and most importantly may not be
sufficiently attenuated anyway. At the moment live attenuated BTV-8 vaccine is
ruled out.
Again, the concept of vaccination against BTV has
been discredited. Though BTV is an RNA virus, having 10 segments of double
stranded RNA, and therefore may drift, recombine and reassort it is in fact
quite stable. In at least 25 years there have not been significant changes in
serotype induction of protective immunity- there is no question of annual
vaccine modifications to counter drift if not shift as in the case of human
influenza vaccines.
Some points of experience of the participants
are:
-
Mortality is the same for both 2006 and
2007.
-
No breed is exempt.
-
So many more deaths in 2007 because so many more
infections.
-
Probably no farm has escaped infection in the
hot zones, or hyperendemic areas where infection was first present in
2006.
-
Not all infected farms have symptomatic cases,
some where all infected but no illness remarked
-
No further diagnosis after the first case on a
farm funded by government.
-
Few herd or flock serologies except where vets
or private persons have made and paid for this survey.
-
No repeat infections and disease confirmed- most
complaints of such have no samples or documentation. Where looked into other
causes, orf in sheep and malignant catarrh in cattle (ovine herpesvirus-2) the
cause.
-
One participant thought the clinical
manifestations had changed somewhat, with laminitis and scouring more
prominent this year in sheep than last year when there was frothing at the
mouth but hardly any laminitis.
-
If survive initially bacterial infection 2 weeks
later can be fatal.
-
Sheep in 6 to 8 weeks have recovered
condition.
-
Abortions and loss of fertility during acute
infection
-
As yet no publication of genetic changes which
might correlate with any changes in for example pathogenicity (await
Pirbright’s results)
-
No evidence of any other serotype of BTV
circulating in Northern Europe than serotype 8
-
In many European countries where bluetongue has
occurred, cattle are in much greater numbers than Britain in relation to
sheep.
Rudi Meiswinkel made the point that when African
Horse Sickness (9 possible serotypes) arrives in Europe or Britain vaccination
will be immediately done whatever the European rules because the infection is
uniformly fatal in horses.
Fields of Fire witness accounts of 2001