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Policy Forum
The Global HIV/AIDS Vaccine Enterprise:Scientific Strategic
PlanCoordinating Committee of the Global HIV/AIDS Vaccine
Enterprise
Introduction
In June 2003, an international groupof scientists proposed the
creation of aGlobal HIV Vaccine Enterprise [1]. Theauthors invited
discussion of this pro-posal, and challenged scientists toidentify
new strategies and mechanismsto accelerate the global effort to
devel-op a safe and effective HIV vaccine. Thispaper describes the
processes that led toagreement on the major roadblocks inHIV
vaccine development, summarizescurrent scientific priorities, and
de-scribes an initial strategic approach toaddress those
priorities. Specific re-search is not prescribed. Rather, theintent
is to stimulate both researchersand funders to explore new,
more
collaborative, cooperative, and trans-parent approaches to
address the majorobstacles in HIV vaccine developmentidentified in
the plan, in addition tocontinuing the productive,
high-qualityprograms already underway.
The motivation behind the proposalfor a Global HIV/AIDS Vaccine
Enter-prise was the recognition that devel-opment of an HIV vaccine
remains oneof the most difficult challenges con-fronting biomedical
research today[2,3]. Fortunately, scientific progresshas created
new opportunities thatcould be harnessed more effectivelythrough
global coordination and col-laboration. These new opportunities
include an expanded HIV vaccinecandidate pipeline, improvements
inanimal models, a growing databasefrom clinical trials, and the
availabilityof new quantitative laboratory toolsthat make
comparisons among vaccinestudies feasible. Confronting
majorroadblocks and harnessing these newopportunities requires an
effort of amagnitude, intensity, and design with-out precedent in
biomedical research,with the Human Genome Project as apotentially
useful model [4]. Morespecifically, the critical scientific
in-sights generated by the creativity ofindividual investigators,
as well as smallgroups and individual networks, couldbe
significantly augmented by a prop-erly organized, managed, and
system-atized international effort targeted onthe design and
clinical evaluation ofnovel HIV immunogens. An interna-tional
collaborative effort that ad-dresses a shared scientific
plan,provides information exchange amonggroups, links clinical
trials with stand-ardized laboratory assays and evalua-tion in
animal models, applies newknowledge to improvements in
vaccinedesign in an iterative manner, andsupports a transparent
process fordecision making in all aspects ofvaccine discovery,
design, development,and clinical testing will prove critical
tosuccess.
The Global HIV/AIDS Vaccine En-terprise represents a novel
paradigm toseek and identify international agree-ment on the
critical roadblocks fordeveloping an HIV vaccine and oncreating a
shared scientific plan thataddresses those roadblocks (see Box
1).The Enterprise proposes to coordinateefforts at a global level,
facilitate use ofcommon tools and technologies, andhelp ensure
access to optimized re-sources. Furthermore, the Enterpriseapproach
is a way of behaving as aglobal community of problem-solvers,more
openly sharing information, en-suring that the shared scientific
plan is
implemented, and basing decisions onevidence rather than
advocacy.
It must be emphasized, however, thatthe major difficulties
encountered inthe development of an HIV vaccine arescientific, not
organizational, and arisedirectly from the complexities of HIVand
AIDS. ‘‘Small science’’ should not
The Policy Forum allows health policy makers around
the world to discuss challenges and opportunities for
improving health care in their societies.
The major difficultiesencountered in the
development of an HIVvaccine are scientific,not
organizational.
Citation: Coordinating Committee of the Global HIV/AIDS Vaccine
Enterprise (2005) The Global HIV/AIDSVaccine Enterprise: Scientic
strategic plan. PLoS Med2(2): e25.
This is an open-access article distributed under theterms of the
Creative Commons Public DomainDeclaration, which stipulates that,
once placed in thepublic domain, this work may be freely
reproduced,distributed, transmitted, modied, built upon,
orotherwise used by anyone for any lawful purpose.
Abbreviations: BMGF, Bill & Melinda Gates Founda-tion; GLP,
Good Laboratory Practices; IP, intellectualproperty; NIH, United
States National Institutes ofHealth; R&D, research and
development; SIV, simianimmunodeficiency virus; UNAIDS, Joint
United Na-tions Programme on HIV/AIDS; WHO, World
HealthOrganization
Members of the Coordinating Committee: M. K. Bhan(Department of
Biotechnology, New Delhi, India), S.Berkley (International AIDS
Vaccine Initiative, NewYork, United States of America), M. DeWilde
(AventisPasteur, Swiftwater, United States of America), J.Esparza*
(Bill & Melinda Gates Foundation, Seattle,United States of
America; Interim Secretariat), A. S.Fauci (National Institutes of
Health, Bethesda, UnitedStates of America), H. Gayle (Bill &
Melinda GatesFoundation, Seattle, United States of America), M.
I.Johnston (National Institutes of Health, Bethesda,United States
of America), P. Kaleebu (Uganda VirusResearch Institute, Entebbe,
Uganda), M. D. Kazatch-kine (Agence Nationale de Recherches sur le
SIDA,Paris, France), R. D. Klausner (Bill & Melinda
GatesFoundation, Seattle, United States of America), E. S.Lander
(Massachusetts Institute of Technology,Cambridge, United States of
America), M. W.Makgoba (University of KwaZulu-Natal, Durban,South
Africa), P. Mocumbi (European and DevelopingCountries Clinical
Trials Partnership, the Hague, theNetherlands), P. Piot (United
Nations Programme onHIV/AIDS, Geneva, Switzerland), O.
Quintana-Trias(European Commission, Brussels, Belgium), W.
Snow(AIDS Vaccines Advocacy Coalition, New York, UnitedStates of
America), M. J. Walport (The WellcomeTrust, London, United
Kingdom), and H. Wigzell(Karolinska Institute, Stockholm,
Sweden).
Competing Interests: The authors have declaredthat no competing
interest exist. Most of the authorshold directive or managerial
positions in agenciesand organizations conducting or supporting
HIVvaccine research and development.
*To whom correspondence should be addressed. E-mail:
[email protected]
DOI: 10.1371/journal.pmed.0020025
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Open access, freely available online
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be replaced with ‘‘big science.’’ Bothapproaches must be
undertaken. Crea-tion of research environments thatsupport the
creativity both of individ-ual investigators and of larger,
collab-orative efforts will accelerate thescientific breakthroughs
needed tosuccessfully develop a safe and effectiveHIV vaccine.
Scientific Priorities
Prioritization process. In August2003, the authors of the
Enterpriseproposal invited a group of leadingscientists, public
health experts, andpolicy makers to meet at the AirlieHouse in
Warrenton, Virginia, UnitedStates, to refine the vision for
theEnterprise. The Airlie group agreedthat the Global HIV/AIDS
VaccineEnterprise should be developed as analliance of independent
organizationscommitted to accelerating the devel-opment of a
preventive vaccine forHIV/AIDS through implementation ofa shared
scientific strategic plan, mo-bilization of additional resources,
andgreater collaboration among HIV vac-cine researchers worldwide
[5].
The subsequent initial planningphase of the Enterprise involved
lead-ing government research agencies, pri-vate industry,
non-governmentalorganizations, and funders involved inHIV vaccine
research and development(R&D) activities, including the Bill
&Melinda Gates Foundation (BMGF), theInternational AIDS Vaccine
Initiative(IAVI), the National Agency for Re-search on AIDS of
France (ANRS), theUnited States National Institutes ofHealth (NIH),
the United Nations JointProgramme on HIV/AIDS (UNAIDS),the World
Health Organization (WHO),and the Wellcome Trust. The Enter-prise
is expected to grow with time andinclude additional organizations
andresearch groups willing to contributeto the implementation of
its scientificstrategic plan. A Steering Committeecomposed of
representatives from sev-eral of the founding organizationsprovided
guidance and coordination,with the BMGF serving as
interimSecretariat.
Six Working Groups involving morethan 120 participants from 15
coun-tries, the WHO, and UNAIDS wereformed to develop the
scientific plan ofthe Enterprise. These Working Groupsmet from
January to April 2004, iden-
tified critical unanswered questions,and proposed actions to
address them.In May 2004, the Steering Committeeof the Enterprise
analyzed the recom-mendations from the Working Groupsand identified
the scientific prioritiesfor initial action.
Several common themes emergedfrom the Working Groups. There
wasclear agreement on the key scientificchallenges, as well as
strong consensusthat the HIV vaccine field has pro-gressed to a
point where it should bepossible to answer some of the persis-tent
questions more definitively. Tomeet these challenges, the
WorkingGroups called for enhanced access toreagents and
technologies, adequateresources, and strengthened humancapacity in
several key areas, especiallyin developing countries, where
clinicaltrials need to be conducted. There wasalso agreement that
the present way ofdoing business, which centers primarilyon
individually led research groups ornetworks, needs to be
supplemented byestablishing focused, collaborativestructures and
providing access tocommon standards and technologies,which would
enable comparison of dataand candidate vaccines. This would,
inturn, support a rational process fordecision making to advance
candidatevaccines through the different phasesof evaluation.
Vaccine discovery. One immediategoal is to design HIV candidate
vac-cines that consistently induce potent,broadly reactive,
persistent neutraliz-ing antibodies, as well as memory Tcells that
suppress viral replication andprevent escape of virus from
immunecontrol [6,7]. Additional research is alsoneeded to identify
how mucosal [8] andinnate [9,10] immunity could be har-nessed to
develop effective HIV vac-cines. The ability to develop
effectivevaccines would be greatly enhanced byan understanding of
what specificimmune response or responses corre-late with
vaccine-induced protection[11].
The current state of the art suggests atwo-pronged strategy to
accelerate thedevelopment of a safe and effectiveHIV vaccine. One
component shouldcenter on candidate vaccines already inthe
pipeline, nearly all of which aredesigned primarily to induce T
cellresponses. In some animal models theseT-cell-inducing candidate
vaccinessuppress post-infection viremia and
Box 1. Key Points in theScientific Strategic Plan� More new HIV
infections and AIDSdeaths occurred in 2004 than in any prioryear
(Figures 1–3). A vaccine is critical forthe control of the
pandemic.
� Development of an HIV vaccine is one ofthe world’s most
difficult and importantbiomedical challenges.
� Harnessing new scientific opportunitiesfor HIV vaccine
development will requirean effort of a magnitude, intensity,
anddesign without precedent in biomedicalresearch.
� The Global HIV Vaccine Enterprise is analliance of independent
organizationscommitted to accelerating the develop-ment of a
preventive HIV/AIDS vaccinebased on a shared scientific plan.
� The scientific strategic plan was devel-oped with the
collaboration of over 140scientists and other participants from
17countries and several international organ-izations.
� The plan identifies critical unansweredscientific questions
along the critical pathfor vaccine discovery, from antigen designto
the conduct of clinical trials.
� Novel vaccine candidates need to bedesigned to induce high
levels of broadlyreactive and persistent immune responsesagainst
HIV strains circulating in differentparts of the world.
� Standardization and validation of high-throughput laboratory
assays conductedunder GLP will allow comparison of resultsfrom
different vaccines, which is a linchpinof rational decision making
in vaccinedevelopment.
� The Enterprise will encourage decisionmakers to establish
clear and transparentprocesses to identify and prioritize themost
promising vaccine candidates.
� The Enterprise will seek to engage thebest researchers who are
willing to work ina highly collaborative manner and todedicate the
majority of their efforts tosolve the fundamental roadblocks in
HIVvaccine development.
� To mount an accelerated global searchfor a safe and effective
HIV/AIDS vaccine,annual funding for such research shoulddouble—to
US$1.2 billion per year.
� Several founding partners of the Enter-prise have already
committed, or areplanning to commit, new funding tosupport the
proposed Enterprise activities,and to create a culture of mutual
ac-countability for the effective implementa-tion of the scientific
strategic plan.
� Enterprise activities are guided by aninternational
Coordinating Committee,supported by different technical
expertgroups, including representatives fromfunders and
implementers of HIV vaccineR&D.
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prevent or delay HIV disease, ratherthan prevent infection
[12,13]. In stud-ies of individuals infected with HIV,viral load
correlates with efficiency oftransmission [14], suggesting that
avaccine capable of suppressing viralload might reduce HIV
transmission.
The second component should ad-dress critical gaps in scientific
knowl-edge through carefully designed,focused, coordinated, and
well-sup-ported approaches. The fruits of thiswork will be a
clearer understanding ofwhat properties are needed for asuccessful
vaccine and how to designcandidates that incorporate
thoseproperties.
Scientific areas in which a morecollaborative and organized
Enterpriseapproach will be beneficial include thefollowing: vaccine
design based on thecharacteristics of recently transmittedviruses,
evaluation of immune corre-lates of protection in animal models,and
design of novel candidates vaccinesthat induce neutralizing
antibodies andT cell immune responses.
Vaccine design. Strategically, vaccinesthat are designed based
on recentlytransmitted viruses hold the best hopeof inducing
relevant immune responsesagainst currently circulating
strains.Recent data suggest that the subset ofviral strains that
are sexually trans-mitted has unique genetic and anti-genic
properties, including greatersusceptibility to neutralization than
thebulk of circulating virus [15]. Whilesuch observations require
confirma-tion, newly transmitted viruses arenonetheless the crucial
targets of vac-cine-induced immunity. Therefore, vi-rological and
immunologicalcharacterization of acute/early HIVinfection should
inform the design ofvaccines and also guide the design oftrials
capable of determining whetherimmunization impacts virus levels
andthe course of HIV infection.
To address these issues, a represen-tative number of virus
strains derived
from recently infected individuals rep-resenting those
populations who willparticipate in vaccine efficacy
trials,including populations in developingcountries, should be
obtained. Thesevirus isolates should be subjected to acomprehensive
genetic and biologiccharacterization, together with ananalysis of
host immune responses andthe genetic background of those
pop-ulations participating in the clinicaltrials.
This continuous and ongoing effortwill require a
multidisciplinary globalapproach, linking investigators who
areconducting epidemiological and cohortstudies (to allow for
detection of acute/early infections), laboratory scientistsworking
on the virology and immunol-ogy of acute/early infection and on
thegenetic characterization of affectedhuman populations, vaccine
designersand manufacturers, and clinical tria-lists. In addition,
systems for datamanagement and analysis that willfacilitate the
rapid translation of newinformation into improved vaccinedesigns
need to be developed.
Immune correlates. Nonhuman pri-mate models of AIDS offer
opportuni-ties to evaluate potential correlates ofimmune
protection. While a particularimmunization strategy that works
inanimal models may or may not predictprotection in humans,
important in-sights into potential immunologic me-diators of
protection would result fromsuch studies. Several experimental
vac-cines induce varying degrees of pro-tection against
simianimmunodeficiency virus (SIV) or chi-meric simian/human
immunodefi-ciency virus in rhesus macaques. In
particular, studies using models inwhich a very high level of
protectionfrom acquisition of infection wasachieved are needed,
i.e., immunizationwith live attenuated SIV and attenu-ation of SIV
infection by short-termantiretroviral treatment
administeredimmediately after SIV inoculation[16,17].
To facilitate this process, assays formany different immune
responses toSIV and chimeric simian/human im-munodeficiency virus
need to bestandardized, validated, and madeavailable to different
research groups.Likewise, agreements need to bereached on those
monkey challengemodels that most closely resemble HIVtransmission
and infection in humans.Large numbers of animals will beneeded to
achieve statistical signifi-cance for experimental findings
[18],which in turn will require expandedprimate breeding and
housing capa-bility. A multidisciplinary approachthat links
virologists, immunologists,vaccine developers, primatologists,
da-ta and project managers, and otherswill be needed.
Neutralizing antibodies. There is in-creasing agreement that a
successfulvaccine needs to induce both humoraland cell-mediated
immunity. Develop-ment of immunogens capable of in-ducing
antibodies that neutralizeprimary HIV isolates from all
geneticsubtypes and regions of the worldremains the most difficult
challenge inthe field of HIV vaccinology [19,20].Success will
likely require a deeperunderstanding of the structural motifsof the
HIV envelope protein thatinteract with cellular receptors
and/or
DOI: 10.1371/journal.pmed.0020025.g001
Figure 1. Adults and Children Estimated to Be Living With HIV as
of the End of 2004 (Total: 39.4
[35.9–44.3] million)
(Map: UNAIDS/WHO)
Identifying which T cellcandidate vaccine ismost promising
hasbecome an urgent
priority.
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that are recognized by broadly neu-tralizing antibodies [19].
This strategywill require numerous well-character-ized, broadly
neutralizing monoclonalantibodies, the application of peptideand
carbohydrate chemistry, structuralbiology, and genetic engineering
ap-proaches to immunogen design, andthe use of iterative approaches
guidedby the immunogenicity of new designs.
Given the importance of these en-deavors and the uncertainty as
to whatpath will lead to success, multipleintersecting approaches
need to beexplored, including, for example, thedesign, production,
and evaluation of(1) envelope proteins that stably
revealneutralization epitopes that may beonly transiently exposed
during viralentry into target cells, (2) immunogensthat contain
rigid, stable epitopes thatmimic the portion or portions ofenvelope
recognized by broadly neu-tralizing monoclonal antibodies,
(3)modified envelope proteins that betterexpose existing relevant
epitopes, and(4) molecules that resemble a stabilizedversion of the
mature envelope trimeron the virion surface. These are exam-ples of
current approaches being ex-plored, some or all of which may
proveineffective. Additional novel ideas needto be proposed and
explored.
To achieve the above objectives, newtools and technologies such
as thoseable to detect rare, broadly neutralizingmonoclonal
antibodies through large-scale screening of human sera will haveto
be developed. In addition, the verylimited existing capacity to
translatestructural information into stable im-munogen products
needs to be ex-panded.
T cell vaccines. Nearly all currentvaccine candidates in the
clinicalpipeline are T-cell-inducing vaccines,e.g., poxvirus
recombinant vectors,adenoviral vectors, DNA constructswith or
without adjuvants, and lip-opeptides. The ongoing effort to
eval-uate these products and to develop newones is considerable
[21]. Identifyingwhich T cell candidate vaccine orvaccines are most
promising has be-come an urgent priority. However,these evaluations
are being conductedwithin separate preclinical researchgroups and,
to a lesser extent, separateclinical trial networks, with the
resultthat candidate vaccines may not beoptimally compared
preclinically orclinically. This approach may result in
delays in identifying the most promis-ing candidates, and it
risks devotingtime and resources to inferior prod-ucts, although it
is recognized that thespecific immune responses needed fora
successful vaccine remain unknown.
The identification and optimizationof promising candidates will
require (1)defining clear, transparent processesfor decision
making, (2) establishingagreement on vaccine characteristicsupon
which decisions should be based,(3) developing and using
validatedassays to assess those parameters, toallow for preclinical
and clinical com-parison among candidates, and (4)
establishing closer coordination anddata-sharing among product
develop-ers, which will accelerate the availabil-ity of critical
information needed toidentify and further develop the mostpromising
candidates.
Research is also needed to developimproved novel T-cell-inducing
candi-date vaccines, especially those thatavoid or otherwise
circumvent anti-vector immune responses [22], andthose that induce
persisting high levelsof immunity, especially mucosal im-munity. In
addition, a thorough, sys-tematic exploration of adjuvants
thatmarkedly enhance the quantity, quality,and durability of immune
responses toHIV vaccines is needed.
Laboratory standardization. Com-parison of results from
preclinical andclinical studies is the linchpin ofrational decision
making regardingfurther development of vaccine candi-dates.
Therefore, the initiation of ap-proaches that will permit
validcomparisons is crucial.
Progress to standardize and validatea limited number of T cell
assays hasbeen made within the laboratories ofvaccine developers
and within somepartnering research networks. Thisapproach now needs
to be morebroadly applied and extended to theanalysis of
neutralizing antibody re-
sponses. A robust infrastructure thatdevelops, expands, and
ensures broadaccess to quality assay technologies willallow valid
comparison of data acrosstrials and networks worldwide.
In order to achieve this goal, thefollowing are required: (1) a
decision-making process to select a set of robustassays,
standardized and validatedacross laboratories, for measuring
vac-cine-induced immune responses inhumans and animals; (2) wide
avail-ability of common reagents (such aspeptides, control sera,
and virus pan-els); (3) capacity for developing novelassays and
reagents of potential valueand for their translation to
preclinicaland clinical settings; (4) ‘‘core’’ labora-tories that
run selected assays and serveas a reference laboratory for
satellitelaboratories (clinical and preclinicalwork would take
place in separatefacilities, and clinical studies wouldrequire Good
Laboratory Practices[GLP] conditions); (5) satellite labora-tories
located at or very near clinicaltrial sites to carry out a range
ofactivities such as processing blood,storing and shipping
specimens, andconducting basic immunological eval-uation, and to
participate in otherEnterprise-organized activities such
asacute/early infection studies; (6) anongoing global quality
assurance func-tion encompassing all participatingcore and
satellite laboratories andcovering both routine safety as well
asimmunologic and virologic assess-ments; and (7) transfer of
researchassays and, when and where feasible,validated endpoint
assays to satellitelabs, including the necessary
trainingactivities.
In addition, new assay developmenthas failed to keep pace with
currentunderstanding of the biology of theimmune system and recent
advances intechnology. A more active program ofapplied research and
assay develop-ment is needed to explore new con-cepts that would
advance technicalabilities and provide a better under-standing of
the immune responsesgenerated by HIV vaccines.
Cellular immunity. Two assays arecurrently used for the primary
evalua-tion and enumeration of antigen-spe-cific T cells:
Interferon-c ELISPOT andmultiparameter flow cytometry. TheELISPOT
assay was initially developedto measure CD8þ T cell
responses.Several observations in both mice and
Development of an HIVvaccine remains one of
the most difficultchallenges confrontingbiomedical research
today.
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humans have indicated that protectiveimmune responses will
likely requirestimulation of both CD4þ and CD8þ Tcell effector and
memory functions; itis unlikely that induction of
Interferon-c-secreting T cells alone correlates withprotective
immunity [11]. Therefore,additional laboratory assays
measuringmultiple HIV-specific cell types as wellas functional
capabilities will beneeded to thoroughly evaluate vaccine-induced
immune responses. These as-says should also permit rapid
assess-ment of the magnitude and breadth ofimmune responses, and
enumerate thespecific epitopes that are recognized.
Humoral immunity. Different labora-tories use different assays
to measureantibodies that neutralize HIV andrelated viruses, SIV
and chimeric sim-ian/human immunodeficiency virus.These assays vary
technically, but themost widely accepted assays measurereduction in
virus infectivity in cellsthat express the receptors necessary
forvirus entry. Assays that offer the great-est value are those
that are validated,amenable to high throughput, low incost, readily
transferable, and that canbe performed according to
GLPguidelines.
The ability to measure the magni-tude and breadth of
neutralizationagainst diverse HIV strains is essentialto evaluating
responses generated bycandidate HIV vaccines. Only withmultiple
strains of virus can neutrali-zation breadth be ascertained in
ameaningful way. Standard panels ofHIV strains are in early stages
ofdevelopment. Expansion or extensionof current standardization and
valida-tion activities, production and provi-sion of necessary
reagents, and access
to quality assurance programs areneeded to ensure worldwide
compara-bility of assay results [23]. The strains ofvirus
incorporated into a worldwidepanel need to be carefully selected
toreflect the current epidemic andshould include early isolates
fromindividuals at potential vaccine trialsites [24]. Molecular
epidemiologicalstudies and elucidation of the role of
genetic factors and immune responsesof the host in the
transmission of HIVat the population level will also helpguide
vaccine design and evaluation[25,26]. Another specific priority is
anassessment of the neutralizing antibodyresponse generated in the
recentlycompleted Phase III trials of HIVenvelope glycoprotein 120
candidatevaccines using a global virus panel. Theresults would
establish a baseline levelof neutralization potency and breadththat
is non-protective, which would beextremely valuable in reaching
in-formed decisions about advancing fu-ture antibody-based
candidatevaccines.
A major obstacle to designing asuitable global virus panel is
the pauc-ity of information on neutralizationserotypes. There is
general agreementthat if a reasonably small number ofneutralization
serotypes exist, their
identification would guide the creationof an optimal panel of
isolates forneutralizing antibody assays and thedesign of
polyvalent immunogens.Although there is some controversy asto
whether HIV-1 neutralization sero-types exist, the magnitude of
benefitthat would result if serotypes wereidentified warrants
establishment of aneutralization serotype discovery pro-gram that
employs the latest technolo-gies.
Product development and manufac-turing. Manufacture of vaccine
candi-dates for large clinical trials and tomeet eventual worldwide
demand re-quires the development of processesfor producing
consistent, active vac-cine batches on a large scale. Develop-ment
of these bioprocesses must beintegrated with analytical work
(e.g.,toxicity and stability testing), incorpo-rate validated
assays, and be applicableto the manufacture of sufficient vac-cine
to meet global needs after licen-sure. These processes are
typicallyindividually developed as a candidatevaccine advances from
early clinicaltesting to late-stage evaluation andlicensure.
Worldwide expertise andcapacity for this bioprocess develop-ment
work is already limiting and existsalmost exclusively in the
private sector.As more HIV candidate vaccines enterthe pipeline,
current capacity will berapidly exhausted.
The initial priority is to identify orestablish one or more
dedicated HIVvaccine bioprocess and analytical de-velopment groups
that bring togetherthe skill set and capacity to manufac-ture
different promising candidates forclinical trials. The bioprocess
develop-ment groups would also help trainpeople and transfer
manufacturingskills in whole or in part to manufac-turing sites
around the world. Thistraining program would address theacute
shortage of bioprocess experts.
At a later stage, building, acquiring,or contracting facilities
to carry outbioprocess and analytical work and toproduce several
different types ofcandidate vaccines should be consid-ered. Such
facilities would further assistin transferring manufacturing
tech-nology to other production facilities,preferably in one or
more developingcountries. Decisions about which can-didates a
facility undertakes would bemade through a well-defined,
compre-hensive evaluation process. The facili-
DOI: 10.1371/journal.pmed.0020025.g002
Figure 2. Estimated Number of Adults and Children Newly Infected
with HIV during 2004 (Total: 4.9
[4.3–6.4] million)
(Map: UNAIDS/WHO)
As more HIV candidatevaccines enter thepipeline, currentcapacity
will be
exhausted.
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ties could eventually be expanded toprovide production capacity
to launcha vaccine for public health use, shouldno manufacturer be
available to pro-duce the vaccine quickly upon licen-sure.
Clinical trials capacity. As a growingnumber of HIV candidate
vaccinesbegin to move through the clinicaltrials pipeline, the gap
between existingglobal capacity and future require-ments for
conducting large efficacytrials has grown in magnitude andurgency,
especially in developingcountries. This gap in developingcountries
must be addressed through(1) increasing the quantity and qualityof
research staff, (2) establishing sus-tainable research facilities
to supporttrials, and (3) expanding access to large,well-defined
populations of uninfectedpeople at high risk of HIV infection.
The recommended solutions take along-term view and are aimed
atbuilding site capacity rather than pre-paring for specific
trials. Sites shouldnot be confined to conducting HIVvaccine trials
but should be positioned
to contribute to other research ofpublic health importance to
the com-munity and the country, including, forexample, other areas
of HIV research(e.g., microbicides and treatment) and/or other
diseases. Additional field trialsites must be developed to be able
toconduct planned and anticipated effi-cacy trials. Sites should be
selected in astrategic, data-driven manner, andshould demonstrate
the ability to re-cruit and retain large numbers of HIV-negative
volunteers from populationswith substantial HIV incidence.
Newefficacy trial sites should be developedin regions with emerging
epidemicsrather than only in areas with already-established
disease. ‘‘Early-warningsystems’’ must be available to
identifythese newly emerging sub-epidemics.Defining optimal methods
for collec-tion of HIV incidence data frompopulations at potential
efficacy trial
sites is essential. Whenever possible,efficacy trial sites
should be linked to(1) academic medical centers to en-hance
research capacity and help trainclinical researchers, (2)
accredited localand regional laboratory facilities toprovide
infection endpoint and safetyassessments, and (3) centers that
canprovide appropriate care and treat-ment to trial
participants.
The acute shortage of qualified per-sonnel is a major bottleneck
to theconduct of clinical trials in developingcountries with severe
or rapidlyemerging HIV epidemics. Developmentof intellectual
capacity at these sitesshould emphasize (1) expanding re-search
training opportunities for per-sonnel in the broad range of
topicsrequired to conduct high-quality clin-ical research, (2)
establishing and ad-equately supporting long-term careerpaths for
such individuals, and (3)fostering political and social
environ-ments locally and nationally that sup-port the conduct of
clinical research.Building HIV scientific and operationalexpertise
at clinical trial sites should belinked to other HIV/AIDS
researchactivities (e.g., identifying and charac-terizing
incident/early HIV infections,collecting newly transmitted
strains,and measuring incidence in high-riskpopulations).
Site development must includestrategies to develop or enhance
exist-ing capacity to deliver health care,including HIV prevention,
care, andtreatment, to the local communityparticipating in clinical
trials. Provi-sion of, or referral to, basic clinicalservices such
as voluntary counselingand testing and diagnosis and treat-ment of
sexually transmitted infectionswill be essential.
In addition, site development shouldinclude building skills that
are ancillarybut critical to the actual conduct ofclinical trials,
such as educating com-munities, building community part-nerships,
managing site finances, andpiloting applications through
regula-tory decision-making processes.
Regulatory considerations. The En-terprise must address a number
ofproblems that currently impact thereview of HIV vaccine trial
protocolsand that could delay future decisionsregarding product
licensure in devel-oping countries. Most regulatory chal-lenges
arise from the fact thatregulatory approvals are granted at
thenational level, but many developingcountries lack the expertise,
well-de-fined processes, clear delineation ofauthority, and/or
other system compo-nents needed to make regulatory deci-sions
expeditiously. As a result, newproducts are often licensed in
theseregions based on prior approval in theUS or Europe and/or
endorsement bythe WHO. Under these circumstances,data specific to
developing countrypopulations (e.g., disease burden orchildhood
vaccination schedules) oftendo not enter into the decision
making.The absence of defined pathways toapprove products targeting
a country’sneeds when a product is not alsosubmitted to regulators
in the US orEurope remains another obstacle. TheEnterprise process
has identified theseaction-item priorities: (1) harmonizeand
exchange information needed byregulatory bodies within the
differinglegal frameworks of different countries,(2) facilitate
regulatory decision mak-ing, possibly using regional approachesfor
conducting reviews and makingrecommendations, (3) build
regulatory
DOI: 10.1371/journal.pmed.0020025.g003
Figure 3. Estimated Adult and Child Deaths from AIDS during 2004
(Total: 3.1 [2.8–3.5] million)
(Map: UNAIDS/WHO)
The acute shortage ofqualified personnel is amajor bottleneck to
theconduct of clinical trialsin developing countries.
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capacity, (4) perform risk/benefit eval-uations in the context
of differingepidemic dynamics and country needsand resources, (5)
identify and removepotential scientific impediments torapid
regulatory decision making, and(6) address ethical issues that
interfacewith regulatory decision making, suchas ensuring informed
consent anddefining the degree to which trialparticipants should
receive a standardof care that is higher than others intheir
community.
Intellectual property issues. Giventhe Enterprise focus on
stronger col-laboration, data sharing, and use ofcommon materials
and reagents, anintellectual property (IP) frameworkthat
facilitates this ‘‘enabling environ-ment’’ is crucial for success.
While IPissues may arise throughout the vaccinedevelopment process,
at present thetop priority is to stimulate early stageresearch and
vaccine design by in-creasing scientific freedom to operateand
sharing of data and biologicalmaterials.
Specific areas for further consider-ation include: (1)
minimizing restric-tions on freedom of operation, perhapsby early
stage covenants not to litigateand followed by later stage
agreementsbased on true valuations of IP; (2)sharing of information
(including clin-ical trial data), materials, expertise,trade
secrets, and platform technolo-
gies in a protected and secure mannerwhile also remaining in
compliancewith national laws devised to preventmonopolies and
insider trading; (3)recognizing the contribution of differ-ent
countries to HIV vaccine develop-ment through approaches that
assureaffordable access to successful vaccines;and (4) maximizing
access to essentialtechnologies and inventions.
Scientific Plan
Scientific activities. On October 21,2004, a group of
participants from 16countries, the European Commission,UNAIDS, and
the WHO met to finalizethe scientific plan and to discuss how
toformulate specific actions.
Participants noted that the structureof an activity should
depend on severalfactors, including, for example, thedegree to
which the activity can bepredefined, the degree to which
thecreativity of academic researchersneeds to be harnessed, and the
mech-anisms available to the funding organ-ization.
A number of options were discussed,with consensus as to those
that wouldfit various scientific priorities.
First, networks of focused consortiaand real or virtual centers
are wellsuited to systematically address manyof the major
scientific roadblocksidentified in this plan. These consortiaor
centers would link to each other to
ensure a comprehensive, systematicapproach, sharing information
so thateach can be as productive as possible,and also to share
reagents and proce-dures so that data among groups can becompared
and, where possible, mergedfor analysis (Figure 4). The
specificscientific areas that could be supportedby consortia or
centers include (1)addressing fundamental scientificproblems, such
as the definition ofcorrelates of immune protection inselected
animal models and the char-acterization of acute/early infection
inpotential vaccine trial sites; (2) design-ing and evaluating
novel vaccines, suchas immunogens that neutralize primaryisolates,
and improved T cell vaccinesthat avoid immunological escape and/or
that induce persisting mucosal orpersisting systemic responses; and
(3)providing for a systematic evaluation ofpotential adjuvants. The
success ofconsortia or virtual centers will dependon engaging the
best researchers, get-ting them to work collaboratively anddedicate
the majority of their effort toHIV vaccine research, resolving
IPissues, obtaining support for research-ers from their
institutions, and keepingthe group focused on specific,
well-defined questions. More than one con-sortium may be needed for
systematiccoverage of vaccine design research(e.g.,
monoclonal-antibody-identified
DOI: 10.1371/journal.pmed.0020025.g004
Figure 4. A Possible Model to Address Key Scientific Questions
through an Appropriate Organizational Infrastructure
(Courtesy of John Mascola; illustration: Giovanni Maki)
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epitopes, native envelope, and modi-fied envelope).
Second, a global system of centrallaboratories linked to
satellite labora-tories that work together (using GLP)would provide
a range of standardizedfunctions, help ensure the quality
ofclinical research, and enable compar-ison of data from different
trials(Figure 5). Together this system could(1) conduct preclinical
or clinical as-says, particularly critical endpoint as-says that
require standardization and/or validation; (2) develop, optimize,
andvalidate new assays and platforms; (3)transfer assays from
central labs tosatellite labs; (4) develop and imple-ment a global
quality control/qualityassurance program and proficiencytesting for
assays performed at centraland satellite laboratories; (5)
imple-ment vaccine-related research that re-quires validated assays
and closecooperation and collaboration amonglabs globally, such as
a Virus Neutral-ization Serotype Discovery Program,and the
characterization of recentlytransmitted HIV isolates; and (6)
con-tribute to the development of techno-logical infrastructure in
developingcountries.
Third, a number of contract labora-tories capable of developing,
acquiring,storing, and distributing common re-agents will prove
critical to the successof collaborative research and develop-ment
projects, and to ensuring reagentquality. These reagents could
include(1) peptides, antisera/antibodies, andviral isolates for
immune assays, in-cluding a standard panel of virusstrains and sera
representative of theglobal genetic and immunologic varia-bility of
HIV, and (2) additional broadlyneutralizing monoclonal
antibodies,especially from non-clade B viruses, tofacilitate
elucidation of the motif ormotifs they recognize. These
contractlaboratories would be expected to workvery closely with and
enable the workof Enterprise consortia, centers, im-mune assessment
laboratories, andclinical sites.
Fourth, a network of Clinical Re-search Training Centers in
developingcountries could work collaboratively toensure development
of quality trialsites. These centers would (1) conductor facilitate
training of trial site per-sonnel in activities that are generic
tothe conduct of clinical trials, as well asthose specific for HIV
vaccine trials, for
example, an HIV vaccine fellowshipprogram for developing country
scien-tists; (2) coordinate and work togetherwith other Enterprise
consortia orcenters, such as those established tocharacterize
acute/early infection indeveloping country settings or to pre-pare
a standard panel of HIV strainsrepresentative of currently
circulatingviruses; and (3) share standard operat-ing procedures,
vaccine developmentplans, and strategies for engaging andensuring
community and political sup-port.
Fifth, a network of individuals andcompanies with manufacturing
experi-ence, particularly process development
expertise, could link to consortia, cen-ters, and others
involved in vaccinedevelopment to provide developmentand
manufacturing expertise to facili-tate the advancement of improved
HIVvaccine candidates.
The above structures are proposed toaddress the initial
Enterprise scientificpriorities. Additional consultativegroups,
reference and centralized fa-cilities, and other mechanisms may
beneeded to facilitate collaborative workand strengthen the global
capacity forthe conduct of HIV vaccine researchand development as
the field pro-gresses.
Different implementing and funding
DOI: 10.1371/journal.pmed.0020025.g005
Figure 5. A Possible Model for a Comprehensive Global Laboratory
Network for the Standardized
Assessment of Humoral Immune Responses
(Courtesy of David Montefiori; illustration: Giovanni Maki)
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agencies will need to work in closecollaboration to ensure
harmoniousimplementation of the scientific plan.Initial actions
should focus on the areasof vaccine discovery and standardiza-tion
of laboratory assays, which areconsidered critical for the success
ofthe Enterprise and the eventual devel-opment of a safe and
effective HIVvaccine. Activities to address recom-mendations in the
areas of productdevelopment and manufacturing, clin-ical trials
capacity, regulatory consid-erations, and IP issues shouldbe
launched after these initialcomponents of the plan areunder
way.
Regardless of timing, eachscientific endeavor needs tooutline
specific strategies toensure information exchangeand capacity
building amongthe collaborating partnersand institutions. The
fundingmechanisms employed (i.e.,contracts, grants,
interagencyagreements, etc.) will dependon the task to be
accom-plished and the needs andcapabilities of each
fundingorganization. In the spirit ofcoordination,
collaboration,and transparency promotedby the Enterprise, two
ormore partners may jointlysupport one or more activ-ities, taking
care to avoidduplication in the use of theirrespective resources.
When aresearch area is jointlyfunded, all communicationregarding
goals, researchplans, progress, obstacles, etc.,should be openly
and trans-parently shared among allstakeholders—funders, proj-ect
managers, and researchers.
Guiding principles. As an alliance ofindependent entities, the
Global HIV/AIDS Vaccine Enterprise will be chal-lenged to carry out
three essentialfunctions. One is to continue regularscientific
assessments. The scientificpriorities outlined in this paper
willneed to be monitored, re-evaluated,and updated. An evolving
scientificplan must reflect lessons learned, newopportunities, and
the influence of newscientific findings and new technolo-gies.
Revised versions of the scientificplan must be made fully and
publiclyavailable. The second essential function
is to establish global processes. Tooptimize progress across a
large andcomplex set of activities at the globallevel, standards,
performance criteria,and processes for data sharing,
com-munication, and convening must beestablished. The Enterprise
will con-vene fora to address policy issues suchIP, clinical
trials, site development, andregulatory hurdles. And the third
es-sential function is shared accountabil-ity. The partners in this
alliance will
need to create a culture of mutualaccountability for the
effective imple-mentation of the scientific strategicplan. Since
the Enterprise is not asingle organization, a shared ‘‘way ofdoing
business’’ is one of its mostimportant defining traits.
Articulatingan explicit set of ‘‘working principles’’is therefore
crucial to the identity andsmooth functioning of the
Enterprise.
For the Enterprise as a whole thefollowing conditions apply: (1)
thecentral task is to develop and imple-ment an ambitious
scientific plan withthe necessary scale, balance and se-
quence of activities, and structure tocarry it out; (2) the plan
must focus oncritical roadblocks that would benefitsubstantially
from global collaborationwhile fostering continued R&D
byindividuals, small groups, and individ-ual networks; (3) the
incentives holdingthe alliance together will include col-laborative
arrangements and structuresthat give people the resources,
neces-sary critical mass, centralized facilities,common reagents,
assays and technol-ogies, and data they need to effectively
remove critical roadblocks; (4) allactivities will reflect the
commit-ment to create an environmentthat maximizes the ability
ofparticipants to share data andbiological materials, e.g.,
throughthe use of common standards formeasurements and appropriate
IParrangements; and (5) the Enter-prise also commits to working
forrapid global access to a successfulvaccine.
For participating investigatorsand organizations, key
principlesinclude (1) the willingness anddesire to work in an open,
col-laborative fashion, sharing dataand reagents in a collegial
fashion,with the appropriate balance be-tween productive
competitionand effective collaboration, and(2) the willingness and
ability todevote the majority of their timeto tackling these
problems withina focused environment, com-pletely committing to
solve theproblems at hand.
Organizational structure of theEnterprise. The implementationof
the scientific plan of the Enter-prise will be overseen and
sup-ported by the organizationalstructure described in Figure
6.
The Coordinating Committee willfacilitate all aspects of the
Enterprise’sactivities. This committee consists ofrepresentatives
of the Enterprisefounders as well as additional scientificleaders
selected from inside and out-side the field of HIV vaccine
researchand development. The committee willdevelop procedures for
term rotationand inclusion of new members, toensure appropriate
representation ofall relevant partners, and will engageexternal
stakeholders for advice, ex-pertise, and assistance,
appointingtechnical expert groups as needed. ASecretariat will
provide logistical and
DOI: 10.1371/journal.pmed.0020025.g006
Figure 6. Proposed Organizational Structure of the Global
HIV/
AIDS Vaccine Enterprise (Illustration: Giovanni Maki)
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administrative support to the Coordi-nating Committee and
Enterprisepartners. The BMGF will serve asInterim Secretariat until
a permanentSecretariat is established.
The Funders Forum will be an openforum of sovereign,
independentfunding organizations, starting with anucleus of those
who already embracethe principles of the Enterprise andwho are
actively supporting or intendto support and fund HIV
vaccineresearch and development. Members ofthe Funders Forum will
be high-leveldecision makers within the ranks offunding
organizations and govern-ments, as close as possible to the
sourceof resources. Since the Enterprise is nota discrete
organization with a pool ofmoney, funders will support specific
areas using their own mechanisms,according to their own
practices andpolicies, and following Enterpriseprinciples. The
scientific plan willprovide guidance that may help fun-ders better
align existing resources but,more importantly, will facilitate
theefficient and focused application ofnew resources as they become
available.Multiple funders who wish to support asingle
Enterprise-defined project couldform collaborative agreements,
memo-randa of understanding, or other formsof written agreement
among them-selves to outline their respective rolesand
responsibilities; address IP, pro-gram management, oversight, and
oth-er issues; and establish mechanisms forcommunication and
conflict resolu-tion. The funders with greatest flexi-bility could
provide incentives forsharing reagents and data, and
linkingprojects together, e.g., by supportingthe additional work
that nationally orregionally funded laboratories wouldneed to
undertake in order to partic-ipate in a global network, or
bysupporting a program to develop andshare reagents.
In some cases, funders may wish tosupport an implementing
organizationthat will take responsibility for manag-ing the project
and reporting back tothe funder and other stakeholders. Inother
cases, funders may have thecapability and capacity to play a
sub-
stantial role in facilitating the project.In still other cases,
funders may havethe capability to assume a leadershiprole in
overseeing the conduct of theactivity, particularly in cases where
theactivity is well defined in advance.
In addition, an Annual StakeholdersForum will be organized to
bringtogether the broader community ofscientists, policy makers,
public healthofficials, and community representa-tives involved in
the search for an HIV/AIDS vaccine. This meeting will serveas a
forum to (1) update the broadercommunity on Enterprise activities
andprogress, and (2) provide the com-munity with a mechanism for
feedbackand dialog.
Funding issues. Global expenditureson HIV vaccine research and
develop-ment in 2002 were tentatively esti-mated to be on the order
of US$624–670 million, the large majority (67.3%)provided by the
public sector, followedby the philanthropic sector (17.4%)and
industry (15.3%). An analysis ofhow those funds have been
investedrevealed that the large majority (43.1%)is being used in
preclinical researchactivities, followed by clinical trials(28.2%),
basic research (20.7%), cohortdevelopment and clinical trial
infra-structure (6.5%), and vaccine educa-tion, advocacy, and
policy development(1.4%) [27].
The largest funder of HIV vaccineresearch and development
activitieshas been the NIH, with almost US$350million in 2002. The
NIH budget forHIV vaccine research has grown fromless than US$50
million in 1996, to anestimated US$514.6 million for
2005,corresponding to 17.6% of the NIHtotal HIV-related research
budget for2005.
The Enterprise Coordinating Com-mittee will analyze the
additional fi-nancial requirements to fullyimplement the scientific
plan of theEnterprise, and the Enterprise Secre-tariat will explore
options to leveragethese funds from the public and privatesector.
Initial estimates by Enterprisepartners suggest that US$1.2 billion
peryear, or double the current expendi-tures on HIV vaccine
research anddevelopment, will be needed. Althoughthis amount may
appear unrealistic atpresent, it would represent only afraction of
the total global expendi-tures in response to the AIDS pan-demic
and a very reasonable
investment in view of the enormoussocial, political, and
economic conse-quences of the pandemic. However, it isessential
that the proposed increase infunding for HIV vaccine R&D be
addi-tional to existing AIDS expenditures,and not at the expense of
currentprevention, treatment, and care efforts.
The founding partners of the Enter-prise, including the NIH, the
BMGF,and the Wellcome Trust have alreadycommitted, or are
considering com-mitting, resources towards new initia-tives that
will begin to enact portions ofthe Enterprise scientific plan over
thenext six to nine months. Each funderwill utilize their own
funding processesand will align the design, scope, andscale of
programs to those laid out inthis plan. For example, the NIH
Na-tional Institute of Allergy and Infec-tious Diseases will
establish the Centerfor HIV Vaccine Immunology, whichwill target
several scientific prioritiesidentified here.
Political support. As a sign of globalrecognition of the
importance of bet-ter, more strategic coordination in thesearch for
an HIV vaccine, the ‘‘Groupof Eight’’ leading industrialized
nationsin June 2004 endorsed the goals of theEnterprise and agreed
to review pro-gress in implementation at its 2005summit meeting in
the United King-dom [28]. Likewise, on October 19,2004, Ministers
of Health from sevenEuropean countries (France, Germany,Italy, the
Netherlands, Spain, Sweden,and the United Kingdom) adopted
astatement of intent to coordinate ef-forts to accelerate research
for an HIVvaccine within the context of the globaleffort.
Next Steps
With almost 5 million new HIVinfections and 3 million AIDS
deathsoccurring every year worldwide, thedevelopment of a safe,
effective, andaccessible HIV vaccine represents oneof the most
urgent global public healthneeds. This global emergency led to
theproposal to harness the power ofscience to find a definitive
solution toone of the most catastrophic healthproblems of our time.
The Global HIV/AIDS Vaccine Enterprise has evolvedover the past 18
months from a conceptproposed in a scientific journal by acadre of
researchers to a global con-sensus concerning the major
scientificroadblocks facing HIV vaccine devel-
The road to success willbe a bumpy one.
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opment, a strategic approach to ad-dress those roadblocks, and
guidingprinciples for the plan’s implementa-tion in a manner and
degree commen-surate with the challenges at hand.Several
organizations have already em-braced the Enterprise concept and
aremoving to tackle portions of the sci-entific plan. Still, much
more remainsto be done. The road to success will bea bumpy one
requiring the energy,commitment, and action of a widenumber of
government and non-gov-ernmental organizations globally.
Rec-ognizing the enormity of theroadblocks as well as the
potentialbenefits of a safe and effective HIVvaccine, it is
essential that many moreorganizations and agencies
contributeadditional expertise and resources andwork together as a
global community ina cooperative, collaborative, andtransparent
manner to fully implementthe Enterprise scientific plan. &
Acknowledgments
The scientific strategic plan of the GlobalHIV/AIDS Vaccine
Enterprise was developedthough a complex process of
consultationthat involved more than 140 participantsfrom 17
countries, the European Commis-sion, the WHO, and UNAIDS. Special
thanksare given to the Co-Chairs of the differentWorking Groups of
the Enterprise thatprovided invaluable insights and
recom-mendations for the development of thisdocument (L. Corey, G.
Douglas, E. Emini, N.Ketter, A. McMichael, G. Monroy, D.
Mon-tefiori, G. Nabel, G. Pantaleo, H. Rees, G.Sadoff, and J.
Wasserheit). Thanks are alsogiven to C. Hankins and J. Whitworth
fortheir valuable comments and suggestions.
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