COMMENTARY

Immunology research: challenges and opportunities in a time of budgetary constraint

Charles J Hackett, Daniel Rotrosen, Hugh Auchincloss & Anthony S Fauci

There have been enormous advances in the field of immunology over the past 3 decades, and those advances have had a positive effect on many subspecialties of medicine. Opportunities for even more notable advances remain. http://www.nature.com/natureimmunology However, present and projected budget constraints for the National Institutes of Health have created formidable challenges. This commentary addresses the opportunities and challenges for the field of immunology during a period of restricted budgets.

any of the world’s major diseases— the 27 NIH institutes and centers fund research $3.7B $4.4B Minfection, cancer, autoimmunity and and training grants on immunology, attesting allergy—critically involve the . to the fundamental importance of immuno- $1.6B Continued progress in understanding basic logy to every main disease area. In the NIH, $944M immune mechanisms is essential for developing the National Institute of Allergy and Infectious $406M $646M

Nature Publishing Group Group Nature Publishing new abilities to treat and prevent diseases that Diseases (NIAID) oversees the largest portion 7 affect millions worldwide. Although federal of research on basic immunology and immune 1999 2003 2005

200 support for biomedical research has increased responses related to infectious and immune- Fiscal year

© considerably over the past decade, funding has mediated diseases. Over the past decade, the Figure 1 Spending on immunology has continued remained flat over the past 3 years, leading to a NIH overall budget has grown considerably, to grow considerably along with the overall budget decrease in ‘purchasing power’ in the face of a increasing from $11.9 billion in fiscal year of the NIAID. As the NIAID budget increased from biomedical research inflation of approximately (FY) 1996 to $28.5 billion in FY 2005. In the $1.6 billion ($1.6B) in FY 1999 to $4.4B in FY 3%. Those budgetary constraints arrive at a same interval, the NIAID budget has grown at 2005, the spending on immunology (red disc; M, time of progress and excitement in the field an even faster pace, making NIAID the second million) also more than doubled. of immunology. This commentary addresses largest NIH institute, with an overall budget certain select opportunities for immunology of $4.4 billion. research, along with the challenges of imple- At present, the NIAID appropriation falls immunology research. Given the importance menting a robust immunology research agenda into three approximately equal categories of the science of immunology to biodefense, in an era of fiscal constraint. aligned with the institute’s main mission areas: HIV-AIDS and other infectious diseases, the human immunodeficiency virus (HIV) and investment by NIAID in immunology research The role of the NIH AIDS; biodefense; and immunology and infec- has the potential to grow considerably. Substantial but by no means the only support tious diseases, a category that includes research for immunology research comes from the on basic immunology, immune-mediated dis- Investigator-initiated research National Institutes of Health (NIH). Most of eases, microbiology, and infectious diseases Advances in fundamental immunology remind not in the HIV-AIDS or biodefense categories. us that the most important breakthroughs Although most immunology research has - in biomedical science generally have been Charles J. Hackett, Daniel Rotrosen, Hugh ditionally been supported by the appropriation achieved through the open-ended enquiry Auchincloss and Anthony S. Fauci are with the for immunology and infectious diseases, the that is the hallmark of investigator-initiated National Institute of Allergy and Infectious Diseases, discipline of immunology has also received research. Basic immunology research also pro- National Institutes of Health, Department of Health support from HIV-AIDS and biodefense vides the critical discoveries and mechanistic and Human Services, Bethesda, Maryland 20892, appropriations (Fig. 1). In FY 2005, the latest insights to underpin targeted programs that USA. year for which final figures are available, the address a growing expectation on the part of e-mail: [email protected] NIAID allocated more than $940 million to the administration, Congress and the general

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public for concrete health-related advances in almost any biological molecule5. Harnessing molecules and antigen presentation mediated the form of ‘deliverables’,or products that can new knowledge about immune system func- by major histocompatibility complex class II be used to diagnose, prevent or treat disease.A tion is leading to ever-increasing capabilities molecules. Based on those principles, a grow- more detailed breakdown of NIAID spending to prevent or treat immune-mediated and ing list of adjuvant candidates now promises shows that growth in immunology research infectious diseases. However, even the consid- to provide improved vaccine immunogenicity occurred in several funding categories, with erable capacity of the immune system can be and reduced nonspecific reactivity while taking the largest continuing to be investigator-ini- overwhelmed by organisms naturally adapted advantage of the ability of the innate immune tiated research, which includes grants such as for virulence and immune evasion. For exam- system to channel adaptive immunity toward the individual R01, the exploratory or develop- ple, poxviruses, which include the smallpox the type of antibody or cellular responses most mental R21, small R03 and 1-year R56 bridge agent Variola major, may devote as many as appropriate for the control of a particular awards. Together these grants account for one half of their to virus-host interac- pathogen15. about 70% of all NIAID immunology research tions6. Understanding of the complexities of Immune tolerance holds the key to control- spending. Historically, solicited and unsolic- the scope of interactions between microbes and ling unwanted immunological attacks on self ited research programs typically have grown the immune system is just beginning. and transplanted tissues.Alloreactive responses in line with the overall budgetary growth of Although innate immunity is the most to transplanted tissues and organs have long the institute, with occasional deviations from ancient form of host defense, it is a key area been recognized as among the most powerful that general trend to address the urgent needs of discovery in contemporary immunology. known in immunology, being at least 100-fold of emerging research areas or the requirements The first ‘cluster of differentiation’ molecule, greater than those elicited by conventional for advanced development of medical coun- CD1, was identified in 1979 (ref. 7); however, antigens; such responses require potent, non- termeasures such as diagnostics, vaccines and more than 15 years passed before its function specific immunosuppression to maintain organ therapeutics. For example, solicited research as as a lipid antigen-presenting molecule in both allografts in clinical practice. In contrast, auto- a fraction of the NIAID immunology research innate and adaptive immunity was estab- immune diseases involve the loss of tolerance portfolio grew from about 20% in FY 1999 to lished8.At present,the field of innate immunity to self antigens. The identification of genes http://www.nature.com/natureimmunology about 30% in FY 2005, due mainly to biode- is moving rapidly and is providing the molec- involved in the establishment and maintenance fense contracts. ular basis for addressing decades-old ques- of central and peripheral tolerance provides a Nonetheless, we remain steadfastly con- tions concerning host defense mechanisms. new level of understanding and, potentially, vinced that it is the ingenuity of individual For example, although the function of type 1 control of deleterious immune responses. For scientists, expressed through investigator-ini- interferon responses to viral infection has been example, induction of central tolerance tiated research, that will drive future discovery appreciated since 1957 (ref. 9), understanding is promoted by thymic expression of periph- in immunology, as in most areas of biomedical of the triggering of interferon synthesis was ill eral antigens related to the function of the science. That principle is broadly supported in defined until studies showed it to be based, for encoding the transcription factor Aire16. In the the scientific community, as demonstrated by many viruses, on cellular recognition of viral peripheral tissues, active antigen-specific sup- editorials and commentaries in the scientific single-stranded or double-stranded RNA. The pression mediated by a variety of T cells has 1

Nature Publishing Group Group Nature Publishing press and by the recommendations of many innate immune system casts a wide net for been repeatedly and reliably observed over 7 focus groups and expert panels convened by viral RNA, including the endosomal recep- decades. The association of the gene encoding

200 the NIAID (http://www.niaid.nih.gov/pub- tors TLR3 (which recognizes double-stranded the transcription factor Foxp3 with immune

© lications/). Such discussions, including our RNA) and TLR7 and TLR8 (which recognize disorders and the linking of that gene to regula- ongoing dialog with academic and industry single-stranded RNA), as well as the cytosolic tory T cells represent a substantial milestone, scientists, professional societies and advocacy receptors RIG-I, specific for the uncapped 5´- allowing new approaches to determine the groups, emphasize the readiness of the scien- triphosphate of viral RNA, and MDA-5, capa- origin and mode of action of a potentially tific community to pursue the many emerging ble of recognizing the -associated RNA important regulatory T cell population17. An opportunities in immunology, a few examples of picornaviruses4,10–12.Viral evasion of innate emerging understanding of the genetic and of which are discussed below. immune recognition and defense pathways can cellular processes involved in central and peri- now be understood in greater depth, generat- pheral tolerance should enable more robust Select opportunities ing new questions related to viral pathogenesis and antigen-specific approaches to prevent The genetic control of immune responses as well as to host defense mechanisms. Studies organ transplant rejection and provide treat- demonstrates both complexity and flexibility. of virus-host interactions are generating new ment strategies for autoimmunity. Of the 20,000–25,000 genes estimated to com- findings that will enable the development of Protecting mucosal tissues from infection prise the human genome2, more than 4,000 improved strategies for antiviral therapeutics and inflammation is one of the most impor- are broadly associated with immune system and vaccines. tant challenges to immunology research today. function. Although there are many immune- In addition,research on innate immunity has Vaccines against pathogens that enter or tar- related genes, they function with great effi- provided understanding and practical direc- get the mucosa include those for poliomyeli- ciency. For example, frontline recognition of tion for the observation first made more than tis, influenza, rotavirus and genital papilloma pathogens falls mainly to ten Toll-like recep- 70 years ago that most immunogens require virus, demonstrating the enormous benefits tors (TLRs) and several nucleotide-binding adjuvants to induce robust adaptive immune of protecting those complex tissues and using oligomerization domain proteins3,4, whereas responses13,14. With the knowledge that adju- their potential as effective barriers against the just two genetic loci, the immunoglobulin vants target antigen-presenting cells, especially entry of pathogenic microbes into the host. variable-diversity-joining-constant regions dendritic cells, by triggering activation through Among the mucosally spread diseases in urgent and the corresponding T cell genes, TLRs and other pattern-recognition recep- need of protective vaccines are HIV-AIDS and rearrange to provide millions of distinct T cell tors, molecular libraries are being screened a potential pandemic influenza; however,many and specificities, enabling responses to for their ability to upregulate costimulatory scientific hurdles still must be overcome in the

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development of such vaccines. Immunity at gen selection. For example, the tumor necro- (http://www.niddk.nih.gov/fund/diabetes mucosal surfaces must conform to a spectrum sis factor–related cytokines BLyS (also called specialfunds/about.htm) as well as by a variety of demands, from maintaining strict sterility BAFF) and APRIL target three receptors on B of public-private partnerships. Each of those in the lungs and upper genital tract to achiev- cells: BR3, which responds to BLyS to support programs involves cross-disciplinary efforts, ing a dynamic coexistence with over 1014 bac- primary B cell survival and growth; BCMA, with a focus on the underlying basis of dis- teria in the intestines18,19. Because aberrant which promotes memory B cell development in ease and mechanisms of therapeutic efficacy. hyper-reactivity of the mucosal immune sys- response to APRIL; and TACI, which is impor- They provide a framework for ‘bench-to- tem to commensal organisms, foods or even tant in B cell responses to bacterial capsular bedside’ and‘bedside-back-to-bench’ research pathogens can be lethal or very debilitating, polysaccharides24. Additional developmental that is yielding new therapeutic and preven- the innate immune detection of microbes signals may also derive from the stimulation tive approaches and fresh insights into basic is highly adapted to the specific mucosal tis- of innate immune receptors on human B processes. Although the challenges are con- sue. For example, recognition of bacterial cells25. Those findings raise the possibility that siderable, scientific opportunities abound, lipopolysaccharide by TLR4 uses the corecep- coadministration of critical cytokines or their including the potential for breakthroughs that tors CD14 and MD-2 systemically but not in triggers along with vaccine immunogens may could dramatically alter existing treatment mucosal epithelial cells; such a restriction most constitute a new vaccine strategy to expand paradigms. In this framework, it is important likely prevents continuous triggering by min- the capabilities of responding B cells beyond that NIAID resources continue to focus on ute amounts of lipopolysaccharide. Instead, those now appreciated.The prospects for a new underserved populations, such as inner-city data indicate that bacterial adhesion receptors approach to B cell manipulation seem to be children with asthma, and on new approaches may serve as obligate TLR4 coreceptors in the near; however, studies are needed to address that lack industry support or on partnerships mucosa, triggering TLR activation only when whether new approaches might also bring with industry in which the commitment of there is a threat of colonization or invasion by new problems, such as induction of autoim- NIH resources allows academic investigators pathogens20. Restriction of TLR expression to munity. to pose questions unlikely to be addressed by certain cells is an important strategy for pro- Research on HIV-AIDS, emerging infectious industry without NIH involvement. http://www.nature.com/natureimmunology tecting mucosal tissues. ‘Preferential’ expres- diseases, including influenza, and biodefense is sion of TLR5, specific for flagellin present in a public health priority with substantial fund- The way forward most motile bacteria, occurs on lamina propria ing support by the US federal government. Although the generous support and result- cells of the mouse intestine, and those cells do Notably, basic immunology research is central ing achievements of biomedical research in not express TLR4 (ref. 21). An emerging para- to future progress in those areas, including the recent years argue convincingly for continued digm in mucosal immunity is the requirement development of effective therapeutics,diagnos- robust support, the sobering reality is that the for bacterial stimulation to achieve normal tics and vaccines. For example, at present the NIH budget has been essentially flat for the immune system development. For example, ability to induce broadly protective immune past 3 years with little immediate prospect intestinal immune homeostasis depends on responses to HIV or to elicit heterotypic immu- for improvement. Concomitantly, annual TLR signaling; unexpectedly, in a study of nity to the ever-evolving influenza virus is increases in the requested costs of R01 appli-

Nature Publishing Group Group Nature Publishing intestinal colonization in mice, that require- lacking. Similarly, protective strategies cannot cations are anticipated (the long-term histori- 7 ment for microbial stimulation extended to yet be defined that would thwart many poten- cal average has been about 5% annually), as

200 normal T cell maturation by means of a bac- tial agents of bioterrorism, especially those is continued growth in the number of grant

© terial sugar presented by major histocompat- that could be genetically engineered to lack applications submitted to the NIAID. Adding ibility complex class II (refs. 22,23). Those and immunodominant epitopes or to incorporate to concerns in the scientific community is the other studies present unexpected yet credible immune-evasion molecules. Many immunolo- fact that many US scientists have been fortu- explanations regarding the requirements for the gists have proposed research projects address- nate to have worked most or all of their careers development of a competent mucosal immune ing the challenging questions posed in those relatively unfettered by the fiscal constraints of system. Continued progress on a fundamental priority areas, but even more could be done. previous eras. In the early 1980s, NIH infla- level should enable the rational development We fully anticipate that such projects that are tion-adjusted spending power also decreased, of distinct but conceptually linked capabilities, directed in part toward specific pathogens will but modest growth in the dollars appropriated such as safe and effective mucosal adjuvants advance fundamental knowledge on immune to NIH bolstered morale (http://officeofbud and immunotherapeutics for a wide range of mechanisms that are considerably more get.od.nih.gov/UI/GDP_fromGenBudget. mucosal diseases, including asthma and auto- ‘generic’ and broadly applicable. htm). Today, US researchers are well aware immune diseases of the digestive tract. During the period of doubling of the NIH that national priorities, economic policies Antibodies provide much of the protection budget from FY 1998 to FY 2003, the NIAID and demographic trends seem poised to stress afforded by the vaccines in the present arsenal; expanded its capacity for ‘translational’ and federal discretionary spending programs, however, only recently has an in-depth under- clinical research that included research on including those of the NIH, for an extended standing emerged of the molecular basis of B immune-mediated diseases. For example, the period26,27.An unintended and damaging con- cell development, selection and effector func- Non-Human Primate Tolerance Cooperative sequence of that budget flattening is that new tion that may allow more strategic manipula- Research Study Group and several clinical investigators have fewer opportunities to enter tion of the B cell compartment. Strides made research networks now support preclinical the research arena with independent funding over the past 5–10 years that may allow new studies and clinical trials in asthma, allergic and those who do may lack the resources to strategies for B cell vaccination include an and autoimmune diseases and transplanta- ‘ride out’ times of fiscal stress. understanding of B cell receptor antigen tion. Many of those programs benefit from As enormous scientific opportunities still recognition, receptor editing and growth the support and expertise of multiple NIH remain despite the fiscal constraints,it is impor- factors involved in the chief transitions in B institutes, and are funded in part through tant to map a way forward to optimally use the cell maturation before, during and after anti- special government appropriations of funds resources that are available until the period of

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fiscal constraint is relieved. An important and ing to find that there were many areas in which increase. Hence, the dichotomy between aspi- difficult challenge will be to preserve as fully research might be carried out more efficiently, rations and resources will probably widen.”28 as possible a robust commitment to the funda- and it is likely that the same holds true today. Although there are no assurances as to when mental, investigator-initiated research that lays Where possible, the NIAID is facilitating more the rebound will occur, we are optimistic about the bedrock of the research enterprise while collaboration among NIH institutes and other the long-term prospects and the certainty that meeting expectations for more applied research, research sponsors,including industry,academic the discipline of immunology will remain including the advanced development of vac- institutions and philanthropic organizations. essential to the research agendas of many NIH cines, therapeutics and diagnostics. In FY 2005, Although a degree of redundancy and repli- institutes and will continue to thrive. the NIAID awarded 2,977 noncompetitive grant cation is beneficial to most scientific inquiry, renewals and 1,164 competing research project unnecessary duplication must be recognized ACKNOWLEDGMENTS We thank M.Johnson of the NIAID Office of grants.However,maintaining our commitment and eliminated. Throughout our clinical trial Financial Management for budgetary numbers; to investigator-initiated research will require networks, the NIAID is striving to improve the T. Hauguel for data analysis and presentation; and the continuation of cost-cutting measures standardization of assays, reagents and end- J. McGowan, G. Folkers and N. Touchette for imposed in recent years and the adoption of points and to establish partnerships that will comments on the manuscript. some unfamiliar measures.Investigators should capitalize on economies of scale. Also, every COMPETING INTERESTS STATEMENT anticipate a continuation of the restriction on effort must be made to streamline those aspects The authors declare that they have no competing yearly inflationary increases on research proj- of clinical research that are especially time con- financial interests. ect grants imposed by the NIH in FY 2006 and suming and costly; for example, more can be 1. Bishop, J.M. & Varmus, H. Science 312, 499 of the longstanding NIAID cap on budgetary done to accelerate protocol development and to (2006). increases for competing awards.Very likely, we evaluate the feasibility and reliability of projec- 2. International Human Genome Sequencing. C. Nature 431, 931–945 (2004). may need to reduce the average dollar amount tions for subject accrual and retention. When 3. Beutler, B. et al. Annu. Rev. Immunol. 24, 353–389 of new awards, as was done in the 1990s when studies fall short of those targets, action must (2006). the NIAID imposed across-the-board single- take place promptly to identify and address 4. Meylan, E. & Tschopp, J. Mol. Cell 22, 561–569 (2006). http://www.nature.com/natureimmunology to double-digit cuts. Despite those and similar impediments. Those principles are already in 5. Janeway, C.A., Jr., Travers, P., Walport, M. & Shlomchik, measures, many of the funding ‘paylines’ (the place,but more can be done to implement them M. Immunobiology: The Immune System in Health funding cutoff based on percentile ranking in practice. Addressing those and other issues and Disease 6th edn. 135–165 (Garland Science Publishing, New York, 2005). from peer review) of NIH institutes, includ- make programmatic and fiscal sense,and doing 6. Clark, R.H., Kenyon, J.C., Bartlett, N.W., Tscharke, D.C. ing those of the NIAID, will decrease under the so will be in keeping with an evolving paradigm & Smith, G.L.J. Gen. Virol. 87, 29–38 (2006). 7. McMichael, A.J. et al. Eur. J. Immunol. 9, 205–210 proposed NIH budget in FY 2007, and success for stewardship of NIH-sponsored research. In (1979). rates (the proportion of grant applications that this context, the NIH director has established 8. Beckman, E.M.et al. Nature 372, 691–694 (1994). receive funding) throughout the NIH will drop the Office of Portfolio Analysis and Strategic 9. Isaacs, A. & Lindenmann, J.Proc. R. Soc. Lond. B 147, 258–267 (1957). from about 22% in FY 2005 to about 18–19% Initiatives to provide‘trans-NIH’programmatic 10. Gitlin, L.et al. Proc. Natl. Acad. Sci. USA 103, 8459– in FY 2006 and perhaps lower in FY 2007 to and budgetary authorities. That office will be 8464 (2006). 11. Hornung, V.et al. Science 314, 935–936 (2006). Nature Publishing Group Group Nature Publishing FY 2009. charged with the responsibility of developing 12. Pichlmair, A.et al. Science 314, 997–1001 (2006). 7 Beyond those steps, additional measures and promoting cross-cutting strategic initiatives 13. Janeway, C.A., Jr.Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989). 200 may be needed. In FY 2006 (and in NIAID and of evaluating their achievements and the 14. Lindblad, E.B.Vaccine 22, 3658–3668 (2004). © planning for FY 2007 through FY 2008), fund- rationale for their continued support.Given the 15.Pulendran, B. & Ahmed, R. Cell 124, 849–863 ing for solicited research programs has been importance of immunology to nearly all bio- (2006). reduced to sustain the NIAID ‘payline’ for medical disciplines and the range of immune- 16.Anderson, M.S. et al. Immunity 23, 227–239 (2005). investigator-initiated research. Some planned mediated diseases under the purview of many 17. Fontenot, J.D. & Rudensky, A.Y. Nat. Immunol. 6, initiatives have been eliminated or postponed; NIH institutes, we foresee many opportunities 331–337 (2005). 18. Gill, S.R.et al. Science 312, 1355–1359 (2006). others will proceed, but at lower funding levels. for the NIAID and the immunology research 19. Lefrancois, L. & Puddington, L. Annu. Rev. Immunol. The NIAID and most other NIH institutes plan community to have critical involvement in 24, 681–704 (2006). to fund first R01 grants of individual applicants those activities. 20.Fischer, H., Yamamoto, M., Akira, S., Beutler, B. & Svanborg, C.Eur. J. Immunol. 36, 267–277 (2006). at a more lenient‘payline’to provide new inves- History has shown that support for bio- 21.Uematsu, S. et al. Nat. Immunol. 7, 868–874 tigators a competitive edge as they enter the medical research on the part of the US federal (2006). 22. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, grant arena. Having taken those steps, our government has repeatedly rebounded from F., Edberg, S. & Medzhitov, R. Cell 118, 229–241 challenge will be to achieve our objectives in periodic times of fiscal constraint. Facing (2004). clinical research and critical product develop- similarly sobering prospects for budgetary 23. Mazmanian, S.K., Liu, C.H., Tzianabos, A.O. & Kasper, D.L.Cell 122, 107–118 (2005). ment, endeavors that rely heavily on solicited constraints on the NIH 10 years ago, one of us 24.Treml, L.S., Crowley, J.E. & Cancro, M.P. Semin. research programs. (A.S.F.) wrote that“…resources for biomedical Immunol. 18, 297–304 (2006). A decade ago, the NIH was facing the pros- research in general are unlikely to increase sub- 25. Ruprecht, C.R. & Lanzavecchia, A. Eur. J. Immunol. 36, 810–816 (2006). pect of an equally sobering budget. To ensure stantially in the foreseeable future, and in some 26.Begley, S. Wall Street Journal A11 (1 September the best use of the available resources, the areas will be constrained. Yet the opportuni- 2006). 27. Bernasek, A. The New York Times Section 3, p.3 (3 NIAID undertook a top-to-bottom review of ties for advances in knowledge and the prac- September 2006). its entire research portfolio. It was enlighten- tical application of these advances will surely 28. Fauci, A.S.Lancet 348, 1002–1003 (1996).

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