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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.


  1. 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.


  1. 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.


  1. 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

  1. 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.

  2. 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.

  3. 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:


  1. 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.

  2. 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

  1. All ruminants vaccinated during the first 6 months of 2008 will need to have a booster dose of vaccine.

  2. 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.

  3. Vaccinate all newborn calves, lambs and kids in zones A, B, C and D.


In the months April, May and June of 2009

  1. Continue to vaccinate all newborn calves, lambs and kids.


In the second half of 2009

  1. Continue to vaccinate all newborn calves (lambs and kids if any born).

  1. 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.













 

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

 

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