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The Immune Space: A Concept and Template for Rationalizing Vaccine Development

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The Immune Space: A Concept and Template for Rationalizing Vaccine Development
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Barouh ! , Pat "ast # , Barne$ %. &raham ' , (erome H. )im * , (ames &. )ublin + , Margaret Mlus-e$  , &iuseppe Pantaleo / , Harriet 0. obinson 1 , 3ina ussell 11 , 4illiam %no5 1 , Margaret 6. (ohnston 11   Affiliations 1 &lobal H67 7aine Enterprise, 3e5 8or-, 38, 9%A 2 Di:ision of A6D%, 3ational 6nstitute of Allerg$ and 6nfetious Diseases, Bethesda, MD, 9%A ! enter for 7irolog$ and 7aine esearh, Beth 6srael Deaoness Medial enter, Boston, MA, 9%A # 6nternational A6D% 7aine 6nitiati:e, 3e5 8or-, 38, 9%A ' 7aine esearh enter, 3ational 6nstitute of Allerg$ and 6nfetious Diseases, Bethesda, MD, 9%A * 9.%. Militar$ H67 esearh Program, 4alter eed Arm$ 6nstitute of esearh, %il:er %pring, MD, 9%A + H67 7aine ;rials 3et5or- and the 7aine and 6nfetious Disease 6nstitute, "red Huthinson aner esearh enter, %eattle, 4A, 9%A  9%A6D, 4ashington, D, 9%A / Di:ision of 6mmunolog$ and Allerg$, 0ausanne 9ni:ersit$ Hospital, 9ni:ersit$ of 0ausanne, 0ausanne, %5itzerland 1 &eo7a< 6n.,   %m$rna, &A, 9%A 11 ;he Bill = Melinda &ates "oundation, %eattle, 4A, 9%A   ;he ontent is solel$ the responsibilit$ of the authors and does not neessaril$ represent the offiial :ie5s of the 9.%. &o:ernment or an$ of the other affiliate organizations. ;he authors dislose no onflit of interest. Running ead > ;he 6mmune %pae !e"#ords > linial 7aine %tudies, H67 pre:ention, H67 :aines, 7aine de:elopment, :aine design Corresponding Author > Amapola Manrique, &lobal H67 7aine Enterprise, 3e5 8or-, 38, 9%A, amanrique?:aineenterprise.org Page 2 of 17Mary Ann Liebert Inc., 140 Huguenot Street, New Rochelle, NY 10801AIDS Research and Human Retroviruses 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960  o  r    P    e  e  r    R   e  v   i    e  w    O   n  l     y    ;    N    o  t    f    o  r    D   i    s  t   r   i    b  u   t   i    o  n   Page $  of 9   A%stract Empirial testing of andidate :aines has led to the suessful de:elopment of a number of lifesa:ing :aines. ;he ad:ent of ne5 tools to manipulate antigens and ne5 methods and :etors for :aine deli:er$ has led to a :eritable e<plosion of potential :aine designs. As a result, seletion of andidate :aines suitable for large@sale effia$ testing has beome more hallenging. ;his is espeiall$ true for diseases suh as dengue, H67, and tuberulosis 5here there is no :alidated animal model or orrelate of immune protetion. Establishing guidelines for the seletion of :aine andidates for ad:aned testing has beome a neessit$. A number of fators ould be onsidered in ma-ing these deisions, inluding, for e<ample, safet$ in animal and human studies, immune profile, protetion in animal studies, prodution proesses 5ith produt qualit$ and stabilit$, a:ailabilit$ of resoures, and estimated ost of goods. ;he immune spae template proposed here pro:ides a standardized approah b$ 5hih the qualit$, le:el, and durabilit$ of immune responses eliited in earl$ human trials b$ a andidate :aine an be desribed. ;he immune response profile 5ill demonstrate if and ho5 the andidate is unique relati:e to other andidates, espeiall$ those that ha:e preeded it into effia$ testing and thus, 5hat ne5 information onerning potential immune orrelates ould be learned from an effia$ trial. A thorough haraterization of immune responses should also pro:ide insight into a de:eloperCs rationale for the :aineCs proposed mehanism of ation. H67 :aine researhers plan to inlude this general approah in up@seleting andidates for the ne<t large effia$ trial. ;his immune spae approah ma$ also be appliable to other :aine de:elopment endea:ors 5here orrelates of :aine@indued immune protetion remain un-no5n. Introduction Ad:anes in moleular modeling and reombinant tehnolog$ ha:e greatl$ e<panded the number of andidate :aines that ould potentiall$ be tested in diseases 5here the absene of a prediti:e animal model or -no5n orrelates of protetion 5ould neessitate empiri effia$ testing. ;his is espeiall$ true for diseases suh as dengue, H67, malaria and tuberulosis 5here there is no :alidated animal model or orrelate of immune protetion. Establishing riteria to that 5ill help selet promising unique :aine andidates, and that not onl$ ha:e to understand earl$ on, their potential   Page 3 of 17Mary Ann Liebert Inc., 140 Huguenot Street, New Rochelle, NY 10801AIDS Research and Human Retroviruses 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960  o  r    P    e  e  r    R   e  v   i    e  w    O   n  l     y    ;    N    o  t    f    o  r    D   i    s  t   r   i    b  u   t   i    o  n   Page &  of 9  for tehnial suess, potential to but 5ill also help guide further future :aine design, is an imperati:e. ne approah, summarized here, is to s$stematiall$ profile the immunologial response indued b$ andidate :aines, thereb$ pro:iding ana potential approah to rationall$ ompare :aine platforms, distinguish those that are most li-el$ to ad:ane the field, and pro:ide insight into potential orrelates of immune protetion. IV vaccine development in $'1( De:elopment of a safe and effeti:e H67 :aine 5ill be entral to an$ global strateg$ to slo5 and one da$ end the H67 epidemi. 8et de:elopment of that :aine faes enormous sientifi hallenges. Although some indi:iduals an ontrol H67 infetion for man$ $ears 5ithout antiretro:iral therap$ 1,2 , H67 suessfull$ e:ades and esapes the natural immune response to infetion in most infeted persons !,# . H67Cs global :ariabilit$, the la- of a :alidated orrelate of proteti:e immunit$ and an animal model that reliabl$ predits :aine effia$ in humans, remain -e$ obstales to :aine de:elopment. 3o:el antigens and :etor deli:er$ s$stems are e<panding the depth, breadth, and durabilit$ of measured immune responses and animal models are being refined 5ith a :ie5 to establishing meaningful orrespondene to obser:ed effia$ data in humans ' . 6n addition, ne5 adu:ants ha:e been heralded as an ad:ane for H67, malaria and ;B :aines, and unique adu:ants ma$ help fill indue unique immune spaes *F responses. 6n the almost three deades sine the epidemi began, si< human effia$ trials that e:aluated four different :aine strategies ha:e been ompleted G;able 1. ;he 71## ;hai trial, 5hih e:aluated a anar$po< prime follo5ed b$ boosts 5ith anar$po< and gp12 en:elope protein in a ommunit$@based trial in ;hailand, 5as the onl$ trial to demonstrate that a :aine andidate an protet against H67 aquisition, although protetion 5as modest G!1.2I effia$ / . A ase@ontrolled e:aluation of speimens from 71## generated speifi h$potheses regarding orrelates of ris- 1 J these h$potheses, 5hih 5ill be e:aluated in future trials, ma$ or ma$ not pro:e to be :alid in other populations G5ith different host genetis, irulating H67 subt$pes, prior antigeni e<posures, en:ironmental fators, andKor transmission routes, or 5hen other :aine designs are e:aluated. "or e<ample, effia$ trials that build diretl$ on 71## are planned for %outh Afria and ;hailand. ;he immune profile of a lade  based :aines similar to that used in the 71## trial 5ill ser:e as the basis for determining if a that :aine should also ad:ane into a liensure trial . 6n addition, Page 4 of 17Mary Ann Liebert Inc., 140 Huguenot Street, New Rochelle, NY 10801AIDS Research and Human Retroviruses 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

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Oct 15, 2019
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