the global hiv/aids vaccine enterprise: scientific strategic...

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

PLoS Medicine | http://www.plosmedicine.org February 2005 | Volume 2 | Issue 2 | e250001

Open access, freely available online

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.


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.


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.


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-


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.


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


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.


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


Figure 4. A Possible Model to Address Key Scientific Questions through an Appropriate Organizational Infrastructure

(Courtesy of John Mascola; illustration: Giovanni Maki)


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


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)


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


Figure 6. Proposed Organizational Structure of the Global HIV/

AIDS Vaccine Enterprise (Illustration: Giovanni Maki)


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.


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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