natural treatment for the skin disease smallpox

>> we're moving to the lasttopic of the afternoon. if we can ask dr. harrison toget started in the smallpox vaccine. we have one person signed up forpublic comment this afternoon. so we will go on with that aswell. dr. harrison. >> thank you and good afternoon. i wanted to give you a littleintroduction about the vote that we're about to take.

so there are numerousoccurrences of lab acquired vaccine infections that havebeen reported. the current smallpox vaccineprosides cross infection against all the viruss and smallpoxvaccine has been used to protect health care workers and researchlaboratory work against these viruss. so you've seen some of thesepictures i wanted to remind you what laboratory acquired vaccinelooks like. he was treated with a vig andhad full recovery.

this is a needle stick case as irecall from brazil and the evolution of time. this is another laboratoryacquired infection involving the left eye and the right ear. but one of the working groupmembers that i add a few slides on complications of smallpoxvaccinations so i added this one. this is a fatal case in a childwith immunodeficiency and we also have a case of a woman withcll with regret to vacinia and a

man with eczema. this is a man who had a historyof a-topic dermatitis. he survived with therapy but hewas left with a scar. i should point out that thesecomplications generally do not occur with the screening thatcurrently goes on for contraindications beforeimmunizations. this is a slide from maryreynolds. a discussion was in the papersand in your background information.

talking about vaccination versuslaboratory infection, you get a well formulated virus in thedosage delivered to the place you wanted to go. in terms of laboratory infectionyou have a variety of differ strains out there being used bya variety of differ laboratories. you can get a high concentrationof virus and it may be through an unusual root, deeperinfection and other body sites including the eye.

so acip made recommendations in2003 for a smallpox vaccination of laboratory workers. it was licensed in 2000 andwhich basically put it into retirement so the working groupwas established in march of 2013. it generally had monthlymeetings since that time. it's working through a lot ofthe issues that are before us. i'll go through this veryquickly. you've seen this probably threetimes before.

so we reviewed recommendationsof -- pro2001 and 2003. we reviewed other documentsincluding case reports of exposures and cases we reviewdata on the new vaccine including safety and adverseevents with the current very stringent prescreening program. we also look at datahistorically. now we did briefly touch onmodified vacinia which is not replicating the cells but it isas best i can tell, licensure is not imminent.

so we really weren't making anyrecommendations about this unlicensed vaccine but iangattis pate that this will occur in the future. so we review data and they'reunder investigation in clinical trials to provide the guidancethat we're about to talk about. so the final product of thisdiscussion is going to be a single aciv policy note forpublication. so with that i will stop andhand it over to brett. >> okay.

thank you dr. harrison. thanks for sticking around. today we're going to talk aboutthe use of smallpox vaccine and laboratory and health careworkers at risk of exposure to i'll start with a briefbackground before summarizing the great process and evidencethat the working group reviewed before finishing withpresentation of the proposed revised recommendations. so orthopox viruss are a groupof stranded dna viruss.

there are four known speciesthat infect humans including smallpox, vacinia, monkey poxand cow pox. ortho pox virus infections doprovide cross protection across species and it's this propertythat allows the development as a vaccine for smallpox andultimately resulted in the eradication of smallpox. however they're active subjectof research and in particular they're commonly used inlaboratory research. so there's many historicvaccines and derivatives, some

of which are listed here andeach of the differ strains have varying degrees of safetyprofiles. common viruss are also beingused increasingly in the laboratory for expression offoreign genes, as well as immuno therapies for cancer. >> so smallpox vaccines havebeen recommended since 1980. at which time the vaccine andanimals contaminated or infected with the virus, derived fromstrains or other viruss that infect humans.

it was also recommended that itwill offered to health care workers from clinical studieswhere viruss derived from these strains are used furthermore,laboratory and health care personnel were not recommendedto receive routine vaccinations and the strains referred to arelisted here. in terms of a brief smallpoxvaccine overview, it is currently the only smallpoxvaccine licensed and available in the united states. it was licensed in 2007 andreplaced the previously used

smallpox vaccine which wasreferred to in the previous recommendations. this vaccine is no longeravailable. it's a live virus vaccineproduced in cells under good manufacturing practices. it's derived from new york cityboard of health strain used during the campaign. it's administered via multiplepuncture pictured here. following vaccineadministration, a lesion

develops and the image shows theprogression of vaccination legion and they do containfectious virus that can be transmitted to others as well asother parts of the body. over this vaccination lesion isconsidered a marker of vaccination. historically smallpox vaccinesare associated with a number of adverse events and some aresevere and life threatening so this is the rate of adverseevents that were detected during a study in 1968 which at thetime smallpox was part of the

routine childhood immunization. this table shows the rate ofadverse events from the same 1968 study and you can see therates of adverse events are substantially lower than thosefollowing primary vaccinations. a more recent study during thedepartment of defense and department of health and humanservices, smallpox programs in 2002 to 2005 and those rates areshown here in this table. the first point of note is theabsence which might be attributable to the screeningthat participants underwent.

but it's been since the studywas completed associated with smallpox vaccination under thedepartment of defense vaccine programs. the second point of note was theidentification which had not been previously recognized as acommon adverse event associated with smallpox vaccine. so using this background ourworking group used the grade methodology to identify andassess the outcomes of interest. conduct a literature review.

summarizing the evidence ofoutcomes and evaluate the quality of evidence for theoutcomes. the question was should it berecommended routinely to persons at risk for occupation salexposure. it used a modified analysis tosolicit outcome assessments fro working group members regardingoutcomes of interest. the benefit outcomes identifiedwith disease and cutaneous response and the arms wereserious adverse events. and revolved without it in aninadvertent innocuation.

all were included in the finalevidence profile. systematic literature review wasconducted and identified five control trials that met thecriteria of the policy question and addressed the outcomes ofinterest identified by the working groups. >> the following slides providea brief summary of the critical outcomes evaluated. the response was best assessedin two studies evaluating this outcome previously vaccinatedsubjects that received as a

compare to. this was nonininterior using aresponse butot in the previously evaluated population. they also evaluated the responseand found that it was noninferior in producing aneutralizing antibody response and previously vaccatedsubjects so there was a robust neutralizing response in thesubjects but it was not found to be noninterior to the responsescene in recipients. in terms of serious adverseevents there were no incidents

of deaths. reported in any of the clinicaltrial participants. again possibly secondary to theintense screening that participants underwent. this was reserved though therewas no significant difference between the rate among these twogroups groups. 5.7 cases per 1,000 vacines wasthought to be the best evidence based on the phase threeclinical trial results.

and woman standing cases wereidentified having that. although all cases in theseclinical trials did resolve. so we used the grade metdologyto evaluate the quality of evidence summarized many thistable. there were month concerns forrisk of bias or inconsistency identified in any of the trialshowever indirectness and imprecision were pied as issuesfor several outcomes and evidence types were downgradedaccordingly. i'll talk about these in thefollowing slides.

with respect to indirectness,three outcomes were downgraded for indirectness because theoutcome that was assessed was likely different from that ofprimary interests. so for cutaneous response, thesewere used as surrogates for the out come of primary interest toprevent viral disease. there was no data available forthis primary outcome. the clinical significance thatresolved was really unclear and many of these cases wereactually a disease only due to the intensive cardiac monitoringthat the participants underwent

including the cardiac enzymeevaluations. so for this reason, it wasthought to be more clinically relevant and this was to be theoutcome for primary. the serious adverse events and ioutcomes were downgraded as the trials were not to take eitherof these adverse events and we have ib concluded a number ofthem that have this in the table. so based on our gradeassessments, overall level of evidence was determined to be alevel two which is consistent

with randomized clinical trialwith important limitations. the working group did considerthe risk of exposure and developing the proposedrecommendations and found these risks are difficult to quantify. so the populations at risk arenot known and are difficult to estimate. they give some sense of the sizeof this popular including the number of virus relatedpublications and number of projects and clinical trialslisted on websites as well as

the amount of vaccinesdistributed for use. >> specifically addressing therisk this is also very difficult to estimate in persons workingwith these viruss as infections are not reportable conditions sosurveillance is not robust or well-known. additionally the exposures arecertainly not always reported and particularly when there's noresulting infection it's less likely to be reported and lastlyas dr. harrison also noted, the pathogenicity of the virus maynot be well characterized in

particularly in response to theviruss where it may be enhanced. however cdc does maintain labrelated virus exposures and infections and this slidesummarizes the reports to cdc during the time period of 2004to 2014 and during that time there were 26 exposure incidentsreported. 69% of these involve viruss. more than half of theseexposures did result in infections and among theinfections 86%ened were infections where as two were cowpox infections.

and another 29% actuallyinvolved a strain other than that which the laboratorythought they were working with. 27% of the exposures met therecommendations but one of the 7 that did meet recommendations --who did meet the recommendatns did result in infection. one other infection occurred inan individual vaccinated greater than ten years prior and so wasnot in accord with the recommendations forrevaccination. so in summary the working groupconcluded that it is comparable

to providing protection againstorthopox viruss. the overall evidence type wasfound to be a level 2 and after considering the risk forinfection and adverse events as well as the benefits fromvaccinations, the work group proposes extending the currentacip recommendations for use of smallpox vaccines amonglaboratory and health care workers at risk. the language for the keyrecommendations are contained in the following slides.

the working group proposes thatroutine vaccition is recommended for laboratoryworkers that directly handle a cultures or b animalscontaminated or infected with it. derived from replicationconfidence or other orthopox viruss that infect humans. the working group proposescategory a for this and evidence type level 2. i'll note that thisrecommendation is essentially

the same as previous 2001recommendation with the exception that it's used inplace of nonhighly attenuated. working group also proposes thatvaccination is not recommended for persons who work only withreplication deficient strains of the virus. for example, ts was alsorecommendation level a and this recommendation is also the samelanguage that was contained in the 2001 recommendation with theexception of the changed language for replicationdeficient as opposed to highly

attenuated strain. working group also proposes thathealth care workers, for example, physicians and nurseswhose contact with replication confident viruss is limitedmaterials. for example dressing and personsadministering the smallpox vaccine would adhere toappropriate infections, prevention measures, be offeredvaccinations. this was suggested as category bgiven the limited data to support this recommendation butalso with the evidence type

level two. the working group proposes thatthe previous contraindication remain in place but alsorecommended that a contraindication for personsless than one year of age be added given that this populationis an increased risk of severe adverse events. the working group also proposesthe removal of the contraindication forrevaccinations of persons who have three or more known majorrisk factors given that it

wasn't seen in participantsundergoing revaccination and was only seen in primaries. the working group was notunanimous in support of the recommendations and one membersuitted the following two slides for your consideration. the majority of lab workerscurrently being vaccinated are receiving a primary vaccinationsince routine smallpox vaccinations was discontinued in1971. so lab workers today maytherefore be at increased risk

of events compared to 1980 whenthis recommendation was first put in place because in 1980many of those workers were likely being revaccinated. it also points out smallpox andmonkey pox cause more severe disease and argue that thesefactors should be considered in the ultimate risk benefitanalysis. this working group member didoffer some alternative language in recommending vaccinations forpersons working with it specifically and suggested alower level be considered for

this population. but i will lastly note thatthere did seem to be general consensus among the workinggroup for a category a recommendation for personsworking to be vaccinated and after the multiple reviews ofthe language and policy note recommendations, i did notreceive individual input from working group members thatsuggested that this should be other than a category acommendation. so that essentially concludes mytalk.

next steps obviously, i havequestions and discussions before a vote so i will just close bythanking again, along with dr. harrison all of the members ofthe working group for the excellent input and discussionsthat went into these recommendations and i'll openthe floor for questions. >> i see a number of hands up. okay. >> thank you. can you tell us a little bitmore about current dod policy

and use of experience. >> sure, in general i would saythe department of defense recommendations are essentiallyin line with acip their contraindications areessentially equivalent to what's contained in the acip. with some of the proposedchanges to contraindications that we have included in ourrevised recommendations those would be the exceptions i thinkto consistenrecommendations. but that would be my generalanswer.

any more recent safety data. >> in terms of safety data wehad it from the department of defense and i don't thinkthere's any new safety signals that were identified in thedepartment of defense smallpox vaccination program so certainlynothing. i think out of the ordinary orunexpected. >> yeah, two questions. the first one when you follow upon this, how many members of the department of defense are nowing vaccinated?

>> well, the department ofdefense is still vaccinating certain individual who is arebeing deployed is my understanding. it's a small number. we are still vaccinating inareas where there's a concern for it. a large number in afternoon. >> so i want to look at theslide and the first bullet. which says it's comparable.

level of evidence and i want togo back and look at slide 16 and 17. and tell me how you get that. i'm looking at slide 16. >> sure. so clearly what we are mostinterested in knowing is howell it protects against orthopoxviral disease. there's not much of it occurringin the world since the so to actually show efficacy ina natural virus infection would

be very difficult to do. so either clearly surrogates forthat outcome which is of primary interest. so response has beendemonstrated as a marker of vaccination success. so historically vaccines werenot studied rigorously. there were no clinical trials toprove their efficacy but their effectiveness was ultimatelydemonstrated by the eradication of disease.

so while we recognize that theseoutcomes are surrogate outcomes, the working group did feel thiswas significant evidence for orthopox viral disease. >> it's different than what yousay in bullet one. you say it's comparable and idon't think your slide 16 and 17 show that's true. in each instance you haveinferiority in buy backs. >> certainly comparable is asubjective assessment and there were differences that wedemonstrated in the data.

the argument to down play thedifferences would be that the differences in terms of thecutaneous response we know that it can be effected by peviousvaccinations. so the fact that there'sdifferences in previously vaccinated subjects may berelated to that fact although the numbers are certainlydifferent. so it did not meet inferioritybut there was neutralizing, the antirespond is required toprovide protection and it was very close to meetingnon-inferiority.

so --[ inaudible ] >> i just have to repeat mycomment which is i think you can say you believe it anduy backsisn't an issue anymore. from what you have shown us it'snot common. when you say comparable isuppose that's enough wiggle room so just say equivalent. but it's not equivalent. but when you're using surrogatemarkers. that's what we all recognizethat we don't know exactly what

you mean. >> yes>> i certainly agree with you. people can certainly havedifferences of opinion in terms of language and subjectiveevaluations. >> dr. karron? >> yes. i was wondering about theexposure incidents, the laboratory incidents and tfact that only seven individuals would have met criteria forvaccination.

washat because other 19individuals were worng in laboratories or facilities butnot working directly with the virus? >> perhaps i need to clarifythat the other individuals were not vaccinated at all. i think that is the answer toyour question. >> so excuse me, the other -- soonly one of those actually came down with the disease. so the others were exposed andthey were vaccinated according

to recommendations. >> you met by recommendationsthat they had gotten the recommended vaccine. >> they had been vaccinated. >> all of these people -- ithink the question was were all of these people in a group thatwould have been recommended to get vaccine. were they that kind of lab work? >> dr. weber.

being at the university of northcarolina where we have a large group i've personally taken careof at least two cases from dodment one with progressive --sorry -- one with contact with generalized vacinia and soldiersthat had recent innoculations and were at the hospital fordifferent reasons. can you change the word workerto personnel as i assume graduates will be working onthis as well. they're not necessarily workersso make it more inclusive to include students and traineesand then turning toward health

care personnel, i find it reallydoesn't provide the precision that need. it doesn't describe who makesthe decision. is it the facility? we need to get vaccine from thehealth department or the local health department. is it going to be preexposure? should my hospital have a groupof people that had immunization. is it going to be used takingcare of a person with a

complication of vacinia. is it going to be used postexposure. it doesn't say anything aboutboosters. so the people just immunizeonce? so i encourage you to make itmuch more precise to give guidance as to when it'sindicated. thank you. we can work with you to try tomake this language more precise. it is included but has notchanged from previous

recommendations and didn't makeit a point to discuss that. this is a very specific documenttargeting a very specific occupation. this does not involve personsthat may be vaccinated for other reasons. they make their own decisionsabout smallpox vaccination. and it does not address thepotential first responder population. so we tried to make it asfocused as we could on

specifically the laboratorypersonnel population. >> so what health care are youtalking about? people doing research? or people at a health carefacility providing care to some of these people that developedcomplications? >> we are addressing both ofthose. the laboratory personnel wouldbe recommended to receive smallpox vaccinations. the health care workers as wedescribed them in the language

here which is limited tocontaminated materials and persons administering a smallpoxvaccine would adhere to appropriate infection preventionmeasures could be offered vaccination so this is a littlebit more of a lenient vaccination offered and for thatreason it's a category b recommendation>> my only argument is its not providing enough precision tothe hospitals to know who they should offer them and to whatcircumstances it should actually be offered and who makes thedecision.

whether it's the hospital thatmakes the decision or local county or health statedepartment. >> i'll go to dr. dpeker. decker. >> so the information that'savailable will be pretty robust. the safety data set is notlikely to increase further because of things like thedeployments through the middle east and other factors that willmean we won't be see vaccinations occurring at therate we have in the past.

those vaccinations represent99.9% of all vaccinations. first of all, what's the policyversus you administer this vaccine and therefore theindividual -- does anybody know what anybody -- -->> the question was what does dod do for the providers. >> i'm sorry. >> part of their protection isthey get vaccinated as well. >> they are vaccinated as well. >> right.

that's how i understand it. so part of the problem is -- i'mold enough to have forgotten the vaccine as a child. i'm also old must have to havebeen a vaccinator during the last round of vaccination so allof us that were vaccinating were vaccinated. so i wonder why this is acategory b recommendation instead of category a becausethose individuals are exposed to the vaccine and in my other hatin another institution was on

the bio safety thing. so we've had this question ofwell how do we administer it at an institution where we don'thave somebody that's been vaccinated? you have to address that issueand as was stated previously give more firm recommendationsabout how to use it. >> fair enough. it was simply because it hasn'tbeen studied robustly. we are certainly not aware ofany infections that resulted

from exposures duringvaccination and vaccinators and without a strong data base tosupport that it would be a category b recommendation but iwouldn't be opposed to making that a category arecommendation. >> i think historically in the2002 vaccination program part of the decision to vaccinate thevaccinators if it was assumed that it was also part of theresponse, or in this case, these are individuals who are simplytaking care of patients on study or vaccinating.

>> the volume of vaccine beingadministered by this specific vaccination is likely to be muchlower given that a whole lot of laboratory worker who is areadministering vaccine. so their risk of being exposedmay be lower than in other larger smallpox vaccinationprograms. >> dr. bennett. >> just one quick question. as the new recommendations arenot to close someone that has three or more known cardiac riskfactors can you talk more about

the relationship between theknown risk factors and miocarditis. my understand is it can happento anybody. >> that's correct. this is one of the moredifficult cull issues that the working group dealt with soyou're correct that with myopericarditis there's no knownrisk factors to preticket who may have this adverse event butthe rational that was used to support this recommendation isthe fact that if somebody did

undergo this adverse event andthey would more likely have a more severe outcome based oneither known heart disease or known cardiac risk factors andthat's why ultimately this recommendation is proposed. >> i just wanted to answer thequestion. i'm the only one old enough toremember this the protection is antibody. it lasts as a matter of fact aslong as 70 years and remains protective, at least partiallyprotective during that time.

the level of anti-body that isprotective has been estimated to be 1 to 32. so the geometric mean is wellabove that. however it might be more usefulto give a percentage of those that had 1 to 32 or greater. also i take it there are none onthe cellular response which is important in closing off thereplication but since they apparently did that, that illplies that they did develop a cellular response.

so i think it may not have thesame level of antibody response but as long as the levelpersists it should be just as effective. >> i was just wondering if youcould comment at all on the issue of whether vaccinia, infact, the outcomes when we look at vaccinia infections arepotentially less severe and whether you're able to repeatany these analyses based on that data and maybe someonemight be able to comment on whether that's really a concernor not.

>> well, certainly there hasbeen studies in the past looking at the historical smallpoxvaccine and it's observed that cutaneous response is previousvaccinations and so this could be looked at. i don't believe it has. but that's something we can lookinto. that would be one example ofdirect demonstration of protecting against orthopoxvirus infection. >> and dr. moore.

>> yes, thanks. my question was actually apractical one, how do these civiln laboratory personnelreceive the vaccines because they can't call my office andget them and so i have had a graduate student contact me fromanother state because they were beginning projects where theywere working with the virus and they couldn't figure out how toobtain the vaccine. and also are there any safeguards in place to ensure that laboratory personnel that have acategory a recommendation have

adequate access to the vaccine. that it doesn't a function ontheir behalf. >> thank you for thosesuggestions. we did include in the policynotes updated information on how to request the vaccine. you're correct that cdc is theonly source of smallpox vaccine. but it is made freely available. and explicit instructions on howto request the smallpox vaccine. so there shouldn't be anybarriers to receiving smallpox

what i have heard in the past isone of the main barriers is finding somebody willing toadminister the vaccine with the thought that they needed to bevacinated. part of it is to help it. >> so at this point, it seemslike there are a number of unresolved questioning outthere. in terms of identification. who should get this. you know, having a laboratory inyour community indicate that one

of your hospitals should havepersonnel aboard and so on. the question i have for thecommittee is whether or not we want to push on with thistonight? do we want to -- i don't thinkthere is appropriate time for the work group to meet, modify,and so on by and this is something that we would feelcomfortable sending back like we did with the yellow fever voteand just have a little bit more to bring it back for themeeting. and in particular he can addressthese issues and there's the

option to present tomorrow arevised recommendation that addresses these issues? i don't know what your thoughtis about? >> happy to discuss with dr. weber how we can clarify some ofthe language and identify where there might be deficiencies. >> i think there's some minorpoints but things that i think we would like to have a littlebit and dr. harrison did make the point that we would like tohave things layed out clearly

before we make a vote and rightnow there's been a lot of talk. so i would propose that we comeback to this first thing in the morning. i think after the agency updatesif that would be acceptable. is that -- okay. that being the case i'm going togo ahead and it is robert benjamin still here? discussion? if that's the case -- oneannouncement, the hotel shuttle

is available for anyone thatwants to ride on over. i'm not sure if it's raining outthere or not. but other than that i think westand adjourned for the day and thank you everybody for yourattention and getting through this.

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