Uji Klinis Vaccine Tifoid

8/18/2019 Uji Klinis Vaccine Tifoid

1/23

O-ACETYLATED PECTIN

CONJUGATE, A PLANTPOLYSACCHARIDE BASED

TYPHOID VACCINE

Cana Rifza R S


2/23

Latar Belakang

■ Typhoid ever remains an important caumorbidity and mortality in the devecountries Typhoid ever remains seriouincreasingly di!cult to treat

■ Starting in the early "##$%s most Salmenteric subsp serovar Typhi &S Typhi' ro(ekong )elta region *ere multiple drug reto frst line o antibiotics such as chloramphampicillin and treatment re,uired

antibiotics such as cipro-o.acin


3/23

Latar Belakang

■ /i capsular polysaccharide is both an evirulence actor and protective antigen o S Ty

■ /i vaccine licensed in more than #0 countries about 1$2 immunity in individuals 30 years

or at least 4 years■ The immunogenicity o /i *as improv

con5ugation to the carrier protein+ the recomprotein 6 o 7seudomonas aeruginosa &r876'

■ /i capsular polysaccharide con5ugate

demonstrated saety and e!cacy in young chi


4/23

Latar Belakang

■ The e.tremely large molecular *eight made sterile fltration di!cult

■ 9nvestigation has been perormed to structurally similar but immunolo

unrelated plant polysaccharide pectin replacement ra* material or /i polysacch

■ The :;acetylated pectin &:6c7ecantigenically indistinguishable rom /i


5/23

Tu5uan


6/23

(etodologi

■ >ruit pectin *as purifed rom citrus peel and the polysaccharide source to prepare asynthetic typhoid con5ugate vaccine 7ecchemically :;acetylated &:6c7ec' to antig

resemble /i and con5ugated to carrier proteinrecombinant e.oprotein 6 rom 7seudaeruginosa

■ ?0 healthy volunteers+ "@A0 years oldin5ected once *ith :6c7ec;r876 Saety a

antibodies reactive *ith /i and pecti


7/23

Bahan /aksin

■ :6c7ec;r876 con5ugate *as prepared at t9nstitutes o Eealth+ Bethesda+ (aryland

■ The carrier protein r876 *as prepared at D9E oguidelines

■ The ormulation o :6c7ec;r876 used in this stud

polysaccharideHdose in $0 ml o $? ( DaCl+ "$phosphate buIer &pE 1?' and $$"2 thipreservative The ?0 Gg dose is based on our*ith /i;r876 con5ugate 8ach dose o :6c7ec;r87?# Gg o r876

■ The vaccine *as passed saety re,uirements a


8/23

Jlirens 8tik

■ The clinical study *as conducted at the Center+ Dational 9nstitutes o Eealth &D9Eapproved by the 9nternal Revie* Board+ Jennedy Shriver Dational 9nstitute o Child EeaEuman )evelopment &D9CE)'+ D9E

■ /olunteers *ere recruited through the D9E /olunteers :!ce by advertisement

■ 6 consent orm *as read and signed by the vol


9/23

Jriteria /oluntir

■ Eealthy adults "@ to 0 years old *ere recrui

■ 8.cluded *ere thoseF participating in or plaparticipate in another clinical protocol duollo*ing si. months+ *ere vaccinated agains

ever or had typhoid ever *ithin the last *ere regularly taking a prescription drug omedical condition+ had a history o allergy ruit or ruit pectin+ or *ere pregnant or become pregnant during the study period o K


10/23

7rosedur /aksinasi

■ The volunteers *ere in5ected intramuscularly *ith $0 ml o :6c7ec;r876 containing ?polysaccharide /olunteers *ere e.aminedater in5ections or acute hypersensitivity reac

■ The study *as conducted in t*o successive p

volunteers *ere in5ected initially to evaladverse reactions 9 no case o ever &4#$MC' or a local reaction 0 cm o &erythema' or ?0 cm o s*elling &indattributable to the vaccination *ithin @ h o

the remainder o volunteers *ere va


11/23

7rosedur /aksinasi

■ 8ach volunteer took hisHher o*n temperatinspected the in5ection site at K+ ?+ @+ 1? ?K *eeks ater vaccination and measured anyandHor s*elling in ? directions at right anglesother according to instructions provided

■ 9 ever o 34@0 MC or erythema o 3?0indurations o 30 cm developed+ participanre,uired to come to the clinical center e.amined by a doctor *ho *ould continue tothe volunteer or additional @ h


12/23

6nti;/i 9g Serological 6ssay

■ The level o serum anti;/i 9g *as measured busing /i as the coating antigenThe 8L9S6 unit &converted to the *eight unit GgHml based on areerence standard

■ Since there is no /i;r876 data available in =S acomparison+ levels o anti;/i 9g *ere comparthe geometric mean &(' o the antibody respthe /i;r876 con5ugate e!cacy trial in /ietna4GgHml &40 8=' *as assumed to be a consestimated protective level against typhoid ever


13/23

6nti;/i 9g Serological 6ssay

■ 9g antibody to pectin in volunteers beoand ater in5ection *as assayed *ith pectcoated 8L9S6 plates

■ To e.amine the specifcity o the observe

antibodies+ K randomly selected poin5ection sera *ere absorbed by /i or pectpolysaccharide


14/23

Statistical 6nalysis

Serum antibody levels *ere e.pressindividually or as ( Comparisons *eperormed *ith the >isherNs e.act unpaior paired t;test *hen appropriate Correlat

coe!cients R *ere calculated by 7earsproduct;moment correlation


15/23

Easil

■ Do vaccine associated serious adverse reaction *as Si. *eeks ater the in5ection o :6c7ec;r876+ K2 ovolunteers elicited 3 old rise o anti;/i 9g 6t ?K *level declined+ but the diIerence bet*een the levels?K *eeks are not statistically signifcant

■ There is a direct correlation bet*een the level o antbeore and ater the in5ection &R? O $#K' There *ascorresponding increase o anti;pectin ater the in5ectindicating the antibody response to :6c7ec;r876 *ato /i The :6c7ec;r876 elicited signifcantly less 9g =S adults than those by /i;r876 in /ietnamese adult


16/23

Easil /aksinasi

T*enty fve volunteers enrolled in the studemales and "" males+ median age ?#$ yrparticipants did not complete a ?K;*eek bdra*n due to moving out o the area T*as no ever+ s*elling or redness at the sin5ection or other vaccine related sereactions T*o volunteers had moderate and mild general muscle ache K h in5ection that subsided in ? h


17/23

6nti;/i 9g response

There is no se. or age dependence in the seranti;/i 9g response beore+ K and ?K *eeks one in5ection o :6c7ec;r876 &male vs emale73$?P correlation *ith age R?Q$4' /olunte

lo* pre;immune levels o anti;/i 9g compare/ietnamese adults in the high endemic regio$@1GgHml vs""#GgHml+ 7Q$$$$"'


18/23

6nti;pectin 9g

■ 6ll volunteers had lo* but detectable levels oimmune anti;pectin 9g The levels remain simor ?K *eeks ater one in5ection o :6c7ec;r876diIerence bet*een pre; and post; in5ection is statistically signifcant &"0? 8=;pectin vs "KK

pectin+ 73$0'■ 6bsorption o K serum samples *ith /i

polysaccharide did not reduce the levels o thpectin antibodies There *as no correlation bethe level o post immune /i antibodies *ith th

pectin antibodies &R?Q$"0'


19/23


20/23

)iskusi

■ 6 novel typhoid con5ugate vaccine based on

polysaccharide pectin sho*ed to be sae andanti;/i 9g in healthy adults

■ There is no corresponding increase o pectin aater the in5ection o :6c7ec;r876+ indicapolysaccharide antibody response is specifc to /

■ 6 direct correlation bet*een the /i antibody pre;and post;in5ection sera *as observed &R? The ( level o anti;/i 9g elicited by :6c7ec;radults *as lo*er than that by /i;r876 in /ieadults The diIerence in the pre;immune levels

the t*o populations might be a actor to the discre anc in the immune res onse


21/23

)iskusi

■ =sing a plant;derived polysaccharide acarbohydrate source or typhoid con5ugate vdoes not re,uire ermentation o the pathog Typhi 7ectin is abundant+ ine.pensive+ easy toand re,uires only a simple chemical modifcaprepare its :;acetyl derivative

■


22/23

)iskusi

■ 9t is kno*n that the :;acetyl groups are compaless stable than the D;acetyl group+ such as in to native /i 9deally a pectin based synthetic /consist o D;acetylated pectin at C;? i teceasible

■ This study did not e.clude volunteers had preantibodies The current study did not investigeIect o booster in5ection and did not include a scomparator group receiving /i polysacharide Based on our past e.perience *ith other conusually there *as no booster response in adults


23/23

Jesimpulan

■ 7ectin :;acetylation oIers another alternatby chemically modiying a plant product anby avoiding genetic manipulation or laboriochemical synthesis

■ The :;acetylated pectin con5ugate+ a plantbased typhoid vaccine+ is sae andimmunogenic in adult volunteers

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Uji Klinis Vaccine Tifoid