Universal Flu Vaccine Report

8/17/2019 Universal Flu Vaccine Report

1/20

Can a Long Term Universal Flu Vaccine be made?

Steven Wilkinson

Mentor: Dr. lliott !lument"al

#$FW !io %&' ( S)ring *+',


2/20

-bstract

vert ear it is a constant battle to /ind t"e most likel strains o/ t"e in/luen0a virus t"at

1ill circulate during t"e u)coming /lu season to include in t"e /lu vaccine. -lso2 t"ese vaccines

re3uire earl re4administration to kee) u) 1it" t"e ever c"anging strains o/ in/luen0a. During

t"e *+'%4*+', /lu season t"ere 1as a lot o/ )ress about "o1 ine//ective t"e /lu vaccine "as been

based on t"e strains o/ t"e virus included in t"is ear5s vaccines. 6esearc"ers are tring to

develo) a universal vaccine t"at 1ould last /or man ears b identi/ing common com)onents

o/ t"e di//erent in/luen0a virus strains. T"is re)ort 1ill e7)lore t"e met"ods being a))lied and t"e

novel ideas o/ ne1 tec"nologies to /urt"er t"e advancement o/ vaccine tec"nolog in regards to

t"e develo)ment o/ a vaccine /or long term immunit to in/luen0a.


3/20

#ntroduction

T"e /lu vaccine is a 1idel )ublici0ed and )romoted medical )rocedure in our societ. #t

is even )romoted in numerous s"o))ing /orums like 8roger and Walmart and is re3uired /or

em)loment in some medical institutions. #n t"is last ear2 t"e /lu vaccine received a lot o/ )ress

/or its lo1 e//ectiveness 1"ic" 1as stated at around *+ )ercent.

T"e a))earance or diagnosis o/ 9T"e Flu is man time incorrectl attributed to t"e

in/luen0a virus. T)ical ;Flu sm)toms are c"ills2 ac"es2 coug"2 sore t"roat2 runn nose and

most im)ortantl FV6. #t is s)read t"roug" bod /luids and t"e acute sm)toms usuall

resolve over < to , das. Severe cases o/ t"e ;/lu can lead to $=UM>=#-.

o1ever2 t"ere are numerous ot"er res)irator diseases t"at matc" t"ese sm)toms. For

e7am)le2 6es)irator snctial virus @6SVA2 $arain/luen0a viruses2 Meta)neumovirus2

-denoviruses @ColdsA2 !acterial #n/ection and 6"inoviruses all "ave t"e same or similar

sm)toms.

T"ere/ore2 ;T"e Flu can re)resent numerous res)irator diseases 1"et"er viral or

bacterial including $=UM>=#-. #n a re)ort in t"e !ritis" Medical Bournal it 1as noted t"at

;)er"a)s t"e cleverest as)ect o/ t"e in/luen0a marketing strateg surrounds t"e claim t"at ;/lu

and ;in/luen0a are t"e same. ;Fe1 )eo)le reali0e t"at even t"e ideal in/luen0a vaccine2

matc"ed )er/ectl to circulating strains o/ 1ild in/luen0a and ca)able o/ sto))ing all in/luen0a

viruses2 can onl deal 1it" a small )art o/ t"e ;/lu )roblem because most ;/lu a))ears to "ave

not"ing to do 1it" in/luen0a. @Dos"i2 *+'


4/20

in/luen0a is ;/lu2 but onl one in si7 ;/lus mig"t be in/luen0a. So it5s no 1onder so man

)eo)le /eel t"at ;/lu s"ots don5t 1ork t"em: /or most ;/lus2 t"e can5t. 6emember2 ;T"e Flu

Vaccine onl deals 1it" in/luen0a virusesE @Dos"i2 *+'


5/20

Figure '. #n/luen0a Virus and Sur/ace $roteins

"tt):KK111.cdc.govK/luKimages."tm

T"e emagglutinin sur/ace )rotein is 1"at connects to a cell rece)tor allo1ing in/ection.

T"e )icture belo1 @Figure *A s"o1s t"e connection made 1it" t"e sialic acid rece)tor on a

"uman cell allo1ing in/ection.

Figure 2. Virus attachment to Cell

"tt):KK111.cdc.govK

/luKimages."tm

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6/20

T"e in/luen0a virus belongs to t"e >rt"om7oviruses Famil. #t comes in t"ree /orms: -2

! and C. #n/luen0a C in/ects umans and $igs but is ver rare. #n/luen0a ! in/ects umans and

Seals and ' or * strains are included in t"e #n/luen0a Vaccine eac" ear. #n/luen0a - in/ects

!irds2 $igs2 orses2 Dogs and umans and t"ere are * Strains included in t"e #n/luen0a Vaccine

ac" ear.

T"e #n/luen0a - Viruses are t"e ones 1it" most variation and are identi/ied b t"e

combinations o/ t"eir sur/ace antigens. T"ere are 'I di//erent versions o/ "emagglutinin @A (

' to 'I and '' di//erent versions o/ neuraminidase @=A ( =' to =''. ver Combination o/

5s and =5s can be /ound in nature. o1ever2 since '&HH2 t"e onl in/luen0a - viruses

associated 1it" "uman illness "ave been:


7/20

http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit3/bacpath/antibody/u3fg23.html

T"e second res)onse t"e bod can "ave is a cellular res)onse. T"e in/luen0a gets into t"e

cells and t"e bod uses T Lm)"octes @T el)er Cells and T ctoto7ic cellsA to attack virall

in/ected cells and kill t"em. T"e )icture belo1 s"o1s an e7am)le o/ t"at. @Figure %A T"ere is also

a memor o/ antigen /or /uture )rotection and /ast res)onse.

Figure %. Ctoto7ic T cell res)onse

T"e Current Vaccines

T"ere are currentl t1o /orms o/ t"e #n/luen0a Vaccine. -n inJectable ;inactivated virus

-nd t"e =asal S)ra Live attenuated virus.

T"e inJectable ;inactivated #n/luen0a Vaccines "ave a virus t"at is )artiall destroed b

"eat or c"emicals. T"e -ntigen $roteins @ ( "emagglutinin and = 4 neuraminidaseA are still

t"ere /or immune sstem to react to so t"e bod develo)s antibodies to t"e antigens.

#mmunoglobulin M and antibodies in t"e blood @umoral #mmunitA are created but no ot"er

immune res)onse is elicited.

T"e =asal S)ra live ;attenuated #n/luen0a Vaccines actuall in/ects our bod. ou get

http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit3/bacpath/antibody/u3fg23.htmlhttp://faculty.ccbcmd.edu/courses/bio141/lecguide/unit3/bacpath/antibody/u3fg23.htmlhttp://faculty.ccbcmd.edu/courses/bio141/lecguide/unit3/bacpath/antibody/u3fg23.htmlhttp://faculty.ccbcmd.edu/courses/bio141/lecguide/unit3/bacpath/antibody/u3fg23.html


8/20

in/ected b a ;1eakened virus t"at re)roduces slo1l. our bod "as a Cellular and umoral

res)onse. T"e bod develo)s antibodies to t"e -ntigens including #mmunoglobulin - in mucus

secretions as 1ell as T Lm)"octes attack virall in/ected cells and kill t"em. )ot"eticall

t"e =asal s)ra is a better strateg to combat in/luen0a "o1ever t"e Jur is still out as to an

better e//ectiveness. @Wang2 *++&A

!ut "o1 e//ective are t"e current vaccines? -ccording to t"e CDC2 e//ectiveness

re)resents t"e )ercentage reduction in t"e /re3uenc o/ in/luen0a in/ections among )eo)le

vaccinated com)ared 1it" t"e /re3uenc among t"ose 1"o 1ere not vaccinated2 assuming t"at

t"e vaccine is t"e cause o/ t"is reduction. @CDC2 *+',A. T"e CDC data /or t"e last '+ ears

s"o1s an average e//ectiveness o/ about %+. @See table belo1A

"tt

):KK111.cdc.govK/luK)ro/essionalsKvaccinationKe//ectiveness4studies."tm

T"ere "ave been man ot"ers studies e7amining t"e e//ectiveness o/ t"e in/luen0a

vaccine. For e7am)le2 in $ediatrics2 t"e Coc"rane Collaboration Vaccine $roJect 6evie1ed ,'

Studies involving *+2+++ c"ildren. T"e /ound ;=o evidence t"at inJecting c"ildren 4*<

mont"s o/ age 1it" /lu s"ots is an more e//ective t"an a )lacebo @Smit"2 *++A

http://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htmhttp://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htmhttp://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htmhttp://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm


9/20

#n regards to t"e e//ectiveness in -dults and Seniors2 - *+'* stud 1as conducted b

C#D6-$ @Center /or #n/ectious Disease 6esearc" N $olicA at t"e Universit o/ Minnesota

Coc"rane Collaboration Vaccine $roJect. T"e /ound t"at alt"oug" vaccination 1as /ound to

)rovide modest )rotection /rom in/ection in oung "ealt" adults 1"o rarel "ave com)lications

o/ /lu2 t"e aut"ors /ound t"at ;evidence /or )rotection in adults , ears o/ age and older 1"o

re)resent over &+ o/ deat"s /rom /lu is lacking. @>ster"olm2 *+'*A

So 1" can t"e e//ectiveness be so lo1? #t could be t"e World ealt" >rgani0ation

sim)l c"ose a strain o/ t"e in/luen0a virus to )ut in t"e vaccine t"at does matc" t"e currentl

circulating t)e or it could be mutations in t"e virus /rom t"at used in t"e vaccine.

T"e virus mutates t"oug" 1"at5s called antigenic dri/t. Wit" antigenic dri/t2 T"e a

antigenic )ortion o/ t"e Virus @"emagglutininA c"anges ever so slig"tl and t"e antibodies

created /rom t"e vaccine do not matc" anmore. T"is can "a))en /re3uentl. T"e )"oto belo1

@Figure ,A s"o1s e7am)les o/ antigenic sites t"at antibodies could be made /or but t"en mutate.

Figure ,. -ntigenic Sites

"tt):KK111.cdc.govK/luKimages."tm

http://www.cdc.gov/flu/images.htmhttp://www.cdc.gov/flu/images.htm


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-not"er )ossibilit to mention is t"at o/ -ntigenic S"i/t. T"is is t"e /eared )ossibilit

1"ere a novel /orm o/ t"e virus could a))ear and create a )andemic. #t could "a))en b an

intermediate "ost like a )ig getting in/ected b a bird. T"en "e same )ig could get in/ected b a

"uman 1it" a di//erent strain o/ in/luen0a. enetic reassortment could occur in in/ected cells and

a novel in/luen0a virus could a))ear. T"is is 1"at "a))ened 1it" t"e '&'I ;S)anis" Flu and t"e

*++& ;S1ine Flu. T"is rarel "a))ens t"oug".

T"ere is still some e//ectiveness /rom t"e in/luen0a vaccine because o/ 1"at5s called

Cross4$rotection. -ntibodies made in res)onse to vaccination 1it" one /lu virus can sometimes

)rovide )rotection against di//erent but related viruses. T"e antibodies can still attac" to some

viruses and )rovide some )rotection.

Can a Universal Flu Vaccine be Made?

Clearl t"ere is room /or im)rovement in t"e e//ectiveness o/ t"e /lu vaccine but "o1 do

ou create a Universal Flu Vaccine to an ever c"anging Virus? T"e main strateg is to /ind a )art

o/ t"e virus t"at is not ever c"anging or to /ind a di//erent strateg or tec"nolog.

T"e main strateg is t"at o/ /inding a universal e)ito)e. T"e e)ito)e is t"e s)eci/ic )iece

o/ t"e antigen t"at an antibod binds to. Wit" t"e in/luen0a virus2 t"e )rimar )lace t"at an

antibod attac"es is t"e "emagglutinin sur/ace )rotein. !ut are t"ere )laces on t"e

@"emagglutininA t"at are not c"anging? T"e )"oto belo1 @Figure A s"o1s a molecular vie1 o/

T"e 4 "emagglutinin sur/ace )rotein. T"e consists o/ an u))er @"eadA and lo1er @stemA

region. T"e red s"o1s areas o/ "ig" amino acid variabilit 1"ile t"e ello1 on t"e stem s"o1s

areas t"at are "ig"l conserved and a good /or an antibod bonding site long term.


11/20

Figure . ig"l Conserved Sites on Stem

http://www.nature.com/nm/ournal/!1"/n12/#g$tab/nm121%&13'($F1.html

T"e /irst strateg a))lied to t"e universal e)ito)e ")ot"esis 1as t"e use o/

Monoclonal -ntibodies. W"en it comes to antibodies2 one ! Lm)"octe can make one

S)eci/ic -ntibod /or a s)eci/ic antigen but /inding t"e rig"t universal one /or in/luen0a could be

di//icult.

>ne monoclonal antibod 1as discovered named C6*'. #t 1as a "uman monoclonal

-ntibod t"at 1as isolated /rom a Collection o/ ! Cells taken /rom a "ealt" individual 1"o 1as

recentl vaccinated 1it" t"e seasonal /lu vaccine. T"e C6*' antibod 1as /ound to neutrali0e

multi)le in/luen0a subt)es including '=' and ,='. @kiert2 *++&A

T"e C6*' antibod 1as t"en tested on Ferrets against "ig"l )at"ogenic avian ,='.

#t 1as tested )ro)"lacticall like a vaccine and t"era)euticall like a medicine /or t"e in/ected.

@Friesen2 *+'+A. $ro)"lacticall it 1as "ig"l e//ective at t"e rig"t dose. See Figure H belo1.

http://www.nature.com/nm/journal/v16/n12/fig_tab/nm1210-1389_F1.htmlhttp://www.nature.com/nm/journal/v16/n12/fig_tab/nm1210-1389_F1.html


12/20

Figure H. C6*' ( $ro)"lactic 6esults

@Friesen2 *+'+A

T"era)euticall it 1as also ver e//ective 1it" a "ig" dosage. See Figure I belo1.

Figure I. C6*' ( T"era)eutic 6esults

@Friesen2 *+'+A


13/20

T"e Friesen stud s"o1ed "ig" e//ectiveness 1"en com)ared to t"e deat" rates o/ t"e

control in bot" )ro)"lactic and t"era)eutic a))lications.

-/ter t"e good results o/ t"e C6*' researc"2 more researc" 1as done to /ind ot"er

antibodies. #n one stud2 '+%2+++ ! Cells @$lasma CellsA 1ere taken /rom I individuals 1"o

1ere recentl vaccinated or in/ected 1it" ,='2 '' or H=H. From one donor t"e isolated %

)lasma cells t"at )roduced an identical antibod t"at t"e called F#. #t 1as called F' because i/

1as /ound to attac" to e)ito)es on all #n/luen0a - /rom ' to '. @Corti2 *+''A

T"e F' antibod 1as t"en tested on Mice against an LD,+ '='. #t 1as tested like t"e

C6*' bot" )ro)"lacticall like a vaccine and t"era)euticall like a medicine /or t"e in/ected.

@Corti2 *+''A $ro)"lacticall it 1as "ig"l e//ective at t"e rig"t dose. See Figure & belo1.

Figure &. F' ( $ro)"lactic 6esults

@Corti2 *+''A

T"era)euticall it 1as also ver e//ective 1it" a )ro)er dose but onl /or a limited time.

See Figure '+ belo1.


14/20

Figure '+. F' ( T"era)eutic 6esults

@Corti2 *+''A

T"e F' stud again s"o1ed "ig" e//ectiveness 1"en com)ared to t"e deat" rates o/ t"e

control in bot" )ro)"lactic and t"era)eutic a))lications.

W"en it comes to Monoclonal -ntibodies2 t"e advantages are t"at t"e are isolated /rom

umans2 t"e a))ear to attac" to more universal e)ito)es on t"e stem o/ emagglutinin and t"e

1ere ver e//ective 1"en tested $ro)"lacticall and T"era)euticall. T"e could be ver

"el)/ul /or Seniors and t"e immune com)romised. o1ever t"e )roblem 1it" Monoclonal

-ntibodies is t"at t"ere is no long term immunit. T"e -ntibodies are gone in to & mont"s.

T"ere is not currentl a 1a to get t"e bod to co) and re)licate t"e antibodies. T"e science o/

retro4 vaccinolog is dedicated to t"at but cannot do it at t"is )oint.

T"e ne7t strateg a))lied to t"e universal e)ito)e ")ot"esis 1as t"e use o/ sel/4

assembling =ano)article Vaccines. Ferritin2 an iron storage )rotein t"at sel/4assembles into

nano)articles 1as used. W"en e7)osed to #n/luen0a Viruses2 t"e 1ould sel/4assemble to assume


15/20

t"eir s"a)e 1it" outside subunits a))arentl identical to emagglutinin )rotein. o1ever2 t"eir

inside 1as "ollo1 so t"ere 1as no virus inside. So 1as it an identical co)? T"e =ano)articles

1ere tested 1it" t"e a/orementioned C6*' antibodies and t"e C6*' antibodies bound to t"e

snt"etic virus. =e7t a trivalent Vaccine 1as made /rom < virus strains t"at 1ere cloned b t"e

=ano)articles. T"e vaccine 1as tested against a standard trivalent vaccine in /errets. T"e 6esults

S"o1ed t"at t"e =ano4Vaccine )roduced muc" "ig"er titres2 less viral s"edding on da ' o/

#n/ection and less 1eig"t loss in in/ected /errets. @8anekio2 *+'


16/20

against let"al ,=' in/ection. @-ls"ari/i2*++&A

T"e vaccine 1as /ound to inducing a strong cross4reactive ctoto7ic T cell res)onse

similar to an actual in/ection. Figure '' belo1 s"o1s t"at t"e vaccine 1as com)arable to an

actual in/ection in regards to )roducing as ctoto7ic T cell res)onse.

Figure ''. Ctoto7ic T cell res)onse Vaccine vs #n/ection vs Control

@-ls"ari/i2*++&A

T"e /ound t"at t"e intranasal administration 1as t"e onl e//ective means o/ a))lication.

See Figure '*.


17/20

Figure '*. #ntranasal -dministration 6e3uired

@-ls"ari/i2*++&A

Finall t"e '=' vaccine 1as tested intranasall /or e//ectiveness against let"al ,='

in/ection. #t 1as '++ )ercent e//ective against t"e in/ection 1"ile t"e entire control grou) died.

See Figure '


18/20

amma4#rradiated #n/luen0a Viruses and subse3uent vaccine a))ear to be a ver

//ective strateg against in/luen0a and a goal /or a universal vaccine. More researc" needs to be

done in regards to it e//ectiveness.

Conclusion

T"ere is an obvious need /or a universal /lu vaccine. T"ere a))ears to be a /e1 good

o)tions /or bot" treatment o/ in/luen0a @monoclonal -ntibodiesA and /or a vaccine @amma4

#rradiated VaccineA2 "o1ever t"e old tec"nologies still )revail because some c"anges 1ould need

to be made in t"e industr to make t"e ne1 tec"nologies available and o/ course more researc"

needs to be done to )rove t"eir sa/et and e//ectiveness. Un/ortunatel2 1e are still a long 1a

/rom a Universal Flu Vaccine. -s t"e c"ie/ scientist at t"e FD- Besse oodman "as said2

G=ature is ver trick and as t"is is a ver cra/t virus2 so #d be ver "esitant to )redict... # t"ink

t"e earliest 1ed begin to see somet"ing 1it" clinical bene/it mig"t be , to '+ ears.; @6oos2

*+'


19/20

6e/erences

-ls"ari/i M2 Furua 2 !o1den T2 et al.@*++&A #ntranasal Flu Vaccine $rotective against

Seasonal and ,=' -vian #n/luen0a #n/ections. PLoS ONE . *++&O%@%A:e,


20/20

Lung.org2 @*+'+A. Trends in $neumonia and #n/luen0a Morbidit and Mortalit. A!erican Lung

Association. "tt):KK111.lung.orgK/inding4curesKour4researc"Ktrend4re)ortsK)i4trend4

re)ort.)d/ 4 6etrieved Marc" '

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