malaria vaccine expectations and realities.pptx

malaria vaccine expectations and realities.pptx

1. Malaria vaccines expectations and r ealities By Amira T aman, PhD, CP H Q

2. Agenda A. T ama n 2 Why mal a ria? Ma l aria v a c c ine candid a tes S t a g es of v a c c ine devel o pment Ma l aria v a c c ines

3. Why Malaria ? A. T ama n 3

4. A. T ama n 4

5. In 2 15, the global technical st r ategy (GTS) of W HO ca l led for eli m ination of m alaria in 20 countr i es by 2025, and 35 by 2035, and r educt i on of at l east 90% of clinical inc i dence and m or t ali t y in the re m ainde r . A. T ama n 5

6. • R es i s t ance t o a n tima l arial a g e n ts Inc r ease • R es i s t ance o f the mosqu i t o v ec t o r t o i nsect i ci des Inc r ease A. T ama n 6

7. V accine develop m ent is tricky - Complex life cycle - Antige n ic variation - Alleli c diversity P . fal c ipa r um P . viv a x A. T ama n 7

8. 8 Malar i a vacc i ne development A. T ama n

9. 9 A. T ama n

10. 10 A. T ama n

11. A. T ama n 11

12. A. T ama n 12

13. V accines Unique pharmac e uti c al product s . Mechanism of a c tion (i n d u cing a lo n g - lasti n g i mm u n e res p o n se) De v elopment of a new vac c ine is the r esult of se v e r al sta g e s : The init i al r esea r ch phase ( 1 – 5 years). P r ecl i nical and clini c al phases ( 15 to 2 year s ) bef o re lic e n s u r e. 13 Quali t y control test i ng (safet y A. T , a m p an otenc y , purit y , steri l ity).

14. Key stages for vaccine develop m ent 14 A. T ama n

15. Animal studies The choice of the r ele v ant animal: Immu n e res p on s e to vac c ine sim i lar to t he ex p ect e d in huma n s Susc e ptible to infection by the wil d -type o r g a nism Ro d e n ts a n d ra b bits are oft e n us e d , mo n k e ys are t he most a p pr o pri a te Ap p ly the 3Rs c o n c e p t of “ Repla c e, Reduce, Refin e ” Imm u ne res p o n ses are fre q u e ntly speci es -specifi c . Ad m inistration of a f u ll h u man d o se is re c om m e n ded 15 A. T ama n

16. A. T ama n 16 The schedule of vaccine administrations (animals) Sho u ld mi m ic the cl i nical p r ot o col . Regulatory agencies recom m end using the R + 1 rule Inter v als bet w een doses m a y be r educed in p r ecl i nical studies t o 2–3 weeks com p ared to longer intervals in cl i nical s tudies. This interval may be defined based on t he kinetics of the i m mune res p o n se o b ser v ed in anima l s.

17. A. T ama n 17

18. A. T ama n 18 Clinic a l p h a s es of v ac c ine de vel o pment Pha s e 1 tria l s Pr o vi d e a p r eli m inary e valuation of safety a nd i m m u n o g enicit y . Con d ucted in a s m all n u m ber of a d ult healthy v olu n t e e rs ( 20 to 80 subjec ts ). Usuall y , o n ly two or three d o ses are tested. The b est d o se is th e lo west do s e g i ves app r o priate i mm u n e res p o n se with a n a c c e p t able safety pr ofi l e. Usuall y , p h ase 1 stu dies are bl i n d ed, plac e b o -cont r ol l ed May last up to 1 yea r . If th e ta r get po pulatio n for the va c cine is in f ants or yo u ng child r e n , the first ad m inis t ratio n of vac c in e c a n did ate in h u m ans is a lways d o ne in adu l ts

19. A. T ama n 19 Clinical phases of vac c ine develop m ent Pha s e 2 s t u dies In v o lve several h u n d red participants (u sually 1 0 to 3 ) . Often ran d o m ized a nd w e ll co ntr o lle d . P r o vid e furt h er in f o r m ation on safety and i m m u n o g enicity and d ata on th e d o ses and sc h edu l e th at will b e u s ed in p h ase 3

20. A. T ama n 20 Clinical p h ases of vaccine development Phase 3 studies La r g e -sc a le to pro v ide a defin i te ass e ssment of e f fica c y a n d saf e t y . Usually invo l ve thousands of subjects or tens of thousands when they are d e signed to ev a lua t e ra r e adverse even t s (e.g., 7 0,0 00 subjects for rotavirus vaccine phase 3 trial to ass e ss the risk of intussusc e ptio n )

21. A. T ama n 21 Clinical phases of vac c ine develop m ent Phase 4, pos t- market i ng Stud i es are desi g ned to provide addi t ional asse s smen t s of rare adverse events and assess e f fec t iveness of the new vaccine in “ r eal l i f e ” and dura t ion of vacc i ne - in d uced i m mun i ty . During the pos t- ma r ket i ng phase, the r e is cont i nued surve i l l ance of the product and of the manufa c tu r e r ’ s product i on act i vities

22. 22 A. T ama n

23. falciparum vac c ines A. T ama n 23

24. P r e- eryth r ocytic vaccines (PEV) S po r o z o i tes an d liv er s t a g es In d uce anti b o d ies to c lear sp oro zoites T c e ll res p o n ses th at atta c k in fect e d hepat o cytes Ant i - in f e c ti o n v accine (AIV) “completely cle a r p r e - eryt h ro cytic parasites bef o re rele a se in to b l o o d s trea m ” R TS, S a nd CS P - based v a c cines 24 A. T ama n

25. 25 A. T ama n

26. R TS,S/AS 1 R: P . fa l c i pa r um CSP f r ag m ent co n t a ining central re p eat (A A 207 to 395 ) , 18 c o p ies, NF5 4 P . fal ci p ar u m stra in , species spec i fic, rec o gn i z ed b y the n eutra liz i n g a n ti b o d ies, c o n tri bu tes to spor o z o ite d e v el o p ment in m o sq u ito T : C t er m inal re g ions co n t a ining T cell epitopes S: f u sed to he p a t i t is B su r face antigen S: ex p ressed in y e ast that carry he p a t i t is B “S” ex p ression casse t te , Saccharo m yces ce r evisi a e yeast AS0 1 : adju v a n t 1 8 c o pi es o f th e ce n t r al r epe a t and th e C - t ermi nal dom a in o f P fCS P fu s ed t A o . T h a e m p a a n titis B v i r us s u r f ace a n ti g en ( HBsAg ) with e xt r a HBsA g in a 1: 4 2 r a 6 ti o. N C

27. 27 A. T ama n

28. A. T ama n 28 R TS,S/AS 1 “ Spor o zoite Sub u nit V accin e ” Mo s quirix va c cine for prev e ntion of P . falcipa r um mal a ria Immune resp o ns e s ag a inst the major circum s porozoite protein. Mo s quiri x , the world ’ s first licen s ed mal a ria va c cine Phase 3 trial in 7 African countries in which 8922 young children and 6537 infants “ 48 and 38 months” The vaccine e f ficacy against uncom p l i cated malaria in child r en “ 2 8 % ” without boo s te r , “ 3 6 %” w ith bo o ste r . The vaccine received the a p proval of the European Medical Age n cy i n 201 5 .

29. Phase 3 A. T ama n 29

30. A. T ama n 30 P r oblems W aning p r otect i on is a challenge for inc l us i on of R TS , S/AS01 in EPI. V acc i nat i on in the f i rst 2 y e ars of lif e , chi l dren have le s s i m mun i ty against ma l ar i a than unvaccina t ed, be at an increased r i sk af t er vaccine protec t ion has w orn o f f resul t ing in a r ebound or age - sh i ft of infec t ion s . Low e r leve l s of protec t ion in chi l dren l i ving in hig h - exposu r e areas than those i n low - expos u re area s . Prot e ct i on is par t ia l , wanes over ti m e , and may be age dependent (protection wa s lower in infants 6 –12 we eks of age than in y o u ng children 5 –17 m o nths old). Confir m ed r i sk of febri l e convul s ions with i n 7 days of vaccina t ion in the 5– 17 m o nth age categ o r y , all r eso l ved witho u t lo n g - term seque l ae

31. A. T ama n 31 Reco m mendations An i de a l v a c c i ne for a c h i l dhood v a ccin a t i on program p r ovi d es nea r -c o mp l ete and lifelong p r ot e cti o n. T o h a ve an imp a ct on t ra n smission in a p o p ul a tion, It w o uld be critic a l to v a c c inate all a g e g r oups of the enti r e populati o n for mal a ria elimination within a time wi n d o w of less th a n 20 d a y s . ( Based on mathemat i cal model, a ssume the l e ng t h of infe c tion and thus infe c tious per i od of 200 da y s ). Ass u ming a c o st of USD $ 5/d o se, a f o u r -dose re g imen will c o st $2 0/c h ild.

32. Th e W orld H e alth O r g ani za tion and its partne r s wi l l t e s t the public h e alth e f f e c t o f immun i z a ti o n in parts of Mal a wi, G hana, and K e n y a A. T ama n 32

33. A. T ama n 33

34. 34 A. T ama n

35. 35 Fi r st malaria vaccine r oll e d out in Africa—despite lim i ted efficacy and n agging safety concerns A. T ama n

36. A. T ama n 36

37. Whole spo r ozoite vac c ines PfSPZ from saliv a ry gla n ds of as e ptic mos q uito e s infe c ted by cultur e d lab o ratory par a sites followed by p u rification, vialin g , a n d cr y o p res e rvation in liquid nitro g en ( San a ri a , 2010 ). PfSPZ a r e att e n u at e d by di f fer e nt a p pr o a c h e s to pr e p a re a v a c c ine c a n d idate pr o d u ct A. T ama n 37

38. A. T ama n 38 Live PE V a c cine App r o a ches Ir r adiation of the sp o ro z oite, c a usi n g liver sta g e to arrest its d e v e lopment at the t i me of n u cle a r divisi o n ( Pf S P Z ). C o -delivery of no r mally infe c tive sp o roz o ite with an ant i - mal a rial dr u g ( Pf S P Z -Cv ac ). Genetic mod i fication of the par a site, so it will arre s t at a d e fin e d p o int (PfS P Z -GA 1 ).

39. A. T ama n 39 Radiation Attenuated Spo r ozoites (RAS) In fe c ted m os q ui t oes are irradiated with a d o se st r o n g enou g h to ensu r e no s p o r ozo i te will pro g r ess to bl o od s t a g e devel o p m ent Dose m ay ki l l sp o r o z oi t es or r ender the n o n -in v as i ve After f i ve ad m inis t ratio n, e f fica c y 52 % in in tense ende m ic areas After 3 ad m inis t ratio n, tested in adu l t and in fant, st i ll aw a iti n g for p u bl i c a tio n.

40. A. T ama n 40 Para s ites Attenuated by Chemother a py Chemopr o phyla x is with spo r ozoites (CPS) Chlor o q u ine (CQ ) - kil l s as e x u al blo o d stages. A n t i biotics that inhibit the repl i cat i on of t he apicoplast in the l i ver stage, namel y , azi t h r om y cin and cl i n d amycin p r otect i on was found to be s t ro n ger and more du r able than t hat induced by CQ - CPS

41. A. T ama n 41 Genetically Attenuated Para s ites (GAP) Del e t i on of ge n es nece s s a ry at di f fe r ent phases of l i ver s t a ge develo p m ental pr o gres s ion ( s p o rozoite s ). G A P has we l l- char a c t er i z e d ge n e t ic chan g es (RA S , DNA da m age) T i m ing of para s i t e arr e st c a n be co n trol l ed I m m u n i z a t ion with gre a t e r nu m ber of par a s i t e s or those pro g r e ss furth e r into infe c t i on c a n pr o vi d e superior i mm u n i t y . Not r e q u i r e co - ad m ini s t r a t ion with drug Safe and n o t i nfec t ive, fl e xi b le with ad d ing m ore e n g inee r ing chan g es

42. Blo o d- sta ge v a ccines (BSV) A. T ama n 42

43. Bloo d - stage vaccines (BSV) T a r get blo o d mer o zoites (dise a s e -ca u sing stag e ) Passive tra n sfer of IgG cl e ar p a rasite m ia Ch a llen g es (sh o rt time wh e n me r o z oites p a ss betw e en eryt h rocytes, antig e nic pol y morphism, la r ge nu m ber of par a sites n e e d ed to be ta r g e ted ) . A. T ama n 43

44.  M S P1 and AMA1 - GMZ2 (e f fica c y: 14%)  Lit t le e v ide n ce of pr o tection a g ain s t c o ntr o lled h u man inf e ction (CHMI) or n a tur a lly o c c u rring inf e ctio n . A. T ama n 44

45. A. T ama n 45 Bloo d - stage vaccines (PfR H 5) P . falcipar u m reticulo c yt e -b i ndi n g pr o tein ho m olog 5 ( P fRH5) Binds the ess e ntial r ed cell r e c eptor basigin a n d sh o ws limited p o lym o r phis m , a n d e n tered clinical tri a ls PfRH5 is the f i rst high l y c o nser v ed me r o z oite antig e n sh o wn to ind u ce br o a d ly n e utr a lizing a n tibo d y in p r e c li n ical stud i es. Natural i n fecti o ns ind u ce mo d est or no antib o dy ag a inst PfRH5

46. Bloo d - stage vaccines(AMA 1 - RO N 2) AMA 1 binds to t he rhoptry neck protein RO N 2 at the me r ozoi t e ery t hrocy t e int e rfa c e to ini t ia t e invasion When compl e xed w ith RO N 2 peptid e, A M A1 gener a te more potent anti-invasion antibo d ies. A M A 1 displays extensive seq u ence variation , the need t assess the numb e r of al l el e s or chi m er i c sequen c es that will be required for A M A1 -RO N 2 to confer broad l y e f fe c tive imm unit y . o A. T ama n 46

47. p r o t ection against P . f alcipar u m challenge A. T ama n 47 Bloo d - stage vaccines ( PfGARP ) A no n - PfE M P 1- infec t ed er y thr o cyte su r face protein cal l ed PfG A RP has just been described as t he ta r get of protect i ve antibo d ies A n t i b o dies to Pf G ARP ind u ced p r o g rammed cell dea t h of intraeythrocytic trop h ozoites in vi t r o In mo n key studies, Pf G ARP vaccines co n fer r ed par t ial

48. g a me t es in t he pr e s e nce of co m ple m ent A. T ama n 48 T rans m ission - Blocking V accines (TBV) T B V incorp o ra t e surf a ce antigens of m o squito/s e x u a l - s t a g es (ga m e t es and zy g otes) in order to i n d uce ant i b o dies that ki l l p a r a s i t es in t he m osq u i t o blo o d m e a l and inte r rupt p a rasi t e transmi s s i on th r o u gh the ve c tor Gamet e s : Pfs230 and Pfs48/45 of P . f a l c i parum Z y g ote surface p r otein : P f s 25 and Pfs2 8 . Pfs25 has been the focus of c l ini c al t r ials Pfs2 3 antibo d i e s ra i s e d in ani m a l s sh o w lytic activity a g ainst P . f alciparum

49. • T wo DBP c a n d idat e s ha v e co m plet e d P A h . T a a m s a e n 1 tr i als. 49 Plasmodium vivax vaccines P . v i vax is incr e a s in g ly re c o g nized as a p u blic heal t h thre a t c ausing s e vere m o rbidity a n d m o rtal i t y . P v CSP vacc i ne fail e d to ind u ce s t e r i l e p r otec t ion against cha l l e n g e with P . v i v ax spor o zoit e s. P v s25 expre s s e d in S. c e r e v i s iae c a used sys t em i c r eac t o g eni c i t y . P v s23 D 1 - E P A is curr e ntly being m an u fa c tured in anti c ipat i on of tr i als that m ay l a u n ch in 2 2 1 . P . v i vax BSV tr i a l s focused on D u ffy - Bindi n g P r otein ( P v DB P ) w h i c h bi n ds the D u f fy A n t i gen Rec e pt o r for C h e m o k ines (DA R C) on erythrocytes and is required for m erozoite invas i o n .

50. 50 A. T ama n

51. R TS,S/AS01E safe and e f ficac i ous for reducing c l ini c al ma l aria in African children. Upon co m ple t ion of ongoing i m ple m enta t ion progra m s i n 202 2 in t hree African coun t ries the resul t s will be reviewed by WHO. BSV ta r get mero z oi t e inv a sion protei n s have disappointing r esults in clin i cal trials. TBV have advanced to Phase 2 cl i nical tria l s A. T ama n 51

52. Amira T aman, PhD, C P H Q e. mail : ami r ataman@man s .edu.eg A. T ama n 52