THE GLOBAL BURDEN of measles disease in-cluded 1.0 million measles deaths an-

nually in the 1990s, and measlesmortality remains at 5–15% in manycountries1,2. Measles eradication is beingpursued through strategic use of liveattenuated measles vaccine, as exempli-fied by the Pan American HealthOrganization programs3. Nevertheless,since live measles vaccine was licensed in1963, protective efficacy has been lowestamong young infants, who are at highestrisk2,4. Therefore, pursuing alternative op-tions for measles immunization is pru-dent. A new measles vaccine strategy isdescribed by Polack et al. in this issue ofNature Medicine5. In this study, the authorsreport that intradermal administration ofa DNA vaccine encoding the measleshemagglutinin (H) or fusion (F) proteinsprotects rhesus macaques from measleschallenge for more than 1 year (ref. 5).

The measles virus is a single-stranded,negative-sense RNA virus of the paramyx-ovirus family that is composed of six pro-teins. The measles H and F envelopeglycoproteins, which mediate fusion afterviral attachment, are targets of host im-mune responses and are well suited for de-velopment as vaccine immunogens,because of their low antigenic variability6.Polack et al. report that administration ofDNA encoding measles H and F inducedproduction of measles-neutralizing anti-bodies and a measles-specific cytotoxic T-cell (CTL) response in macaques5. As seenwith live measles vaccination, neutraliz-ing antibody titers greater than 120 mIUwere correlated with protection, indicat-ing that DNA vaccines elicit a host re-sponse similar to that of a vaccine of

established efficacy. Furthermore, thestudy shows that immunization with plas-mids encoding H or F is sufficient for pro-tection against illness, even thoughsystemic viral spread is not prevented, andthat ‘synergistic’ protection is not seenwith two glycoprotein immunogens5.

Although the live attenuated measlesvaccine now licensed is safe and immuno-genic when administered to children overthe age of 9 months, it is less effective inyoung infants because of the immaturityof their immune systems and interferenceby maternal antibodies. Designing alter-natives to live measles vaccines ischallenging, because the non-infectiousformalin-inactivated measles vaccinesgiven to children in the 1960s led to a se-vere form of disease known as ‘atypical’measles, characterized by an unusual rashand severe pneumonitis2. Measles viruschallenge of macaques vaccinated with

Measles vaccines—A positive step toward eradicating anegative strand

Measles is the leading cause of vaccine-preventable deaths among children worldwide. The development of a measlesDNA vaccine may prevent the complications associated with non-infectious vaccine approaches and eventually

contribute to global measles eradication (pages 776–781).

ANN M. ARVIN

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ings provide further rationale for the de-velopment of therapeutics aimed at se-lectively antagonizing the aberranttranscriptional activity of oncogenictranscription factors.

Potential ‘transcriptional therapies’ in-clude inhibitors of HDAC, which couldbe used to de-repress the target genes ofRA-induced transcription, reactivate RA-induced differentiation and antagonizeAML1–ETO transcriptional repression inAML. Clinical treatment of an RA-resis-tant APL patient with phenylbutyrate, anHDAC inhibitor, induced histone hyper-acetylation in target cells and restoredsensitivity to the anti-leukemic effects of RA (ref. 15). Similar therapeuticapproaches may prove useful in otherneoplastic diseases associated with onco-genic repression of gene transcriptiondue to aberrant recruitment of HDAC.Another potential AML therapy could in-clude the delivery of engineered peptidesthat contain the dimerization domain ofthe various X–RARα proteins or ofAML1–ETO. These compounds could be tested for their ability to interfere with the formation of X–RARα andAML1–ETO homodimers/holigomers,

antagonizing their aberrant transcrip-tional repressive activity. In conclusion,it is becoming apparent that detailedknowledge of the transcriptional mecha-nisms underlying the pathogenesis ofhuman cancer as well as of other diseaseswill offer new opportunities for thera-peutic intervention.

1. Look, A.T. Oncogenic transcription factors in thehuman acute leukemias. Science 278, 1059–1064(1997).

2. Lin, R. J. & Evans, R.M. Acquisition of oncogenic po-tential by RAR chimeras in acute promyelocyticleukemia through formation of homodimers. Mol.Cell 5, 821–830 (2000).

3. Minucci, S., et al. Oligomerization of RAR and AML1transcription factors as a novel mechanism of onco-genic activation. Mol. Cell 5, 811–820 (2000).

4. Melnick, A. & Licht, J.D. Deconstructing a disease:RARα, its fusion partners, and their roles in thepathogenesis of acute promyelocytic leukemia.Blood 93, 3167–3215 (1999).

5. He, L.Z., Merghoub, T. & Pandolfi, P.P. In vivo analy-sis of the molecular pathogenesis of acute promye-locytic leukemia in the mouse and its therapeuticimplications. Oncogene 18, 5278–5292 (1999).

6. Chambon, P. A decade of molecular biology ofretinoic acid receptors. FASEB J. 10, 940–954 (1996).

7. Pandolfi, P.P. et al. Structure and origin of the acutepromyelocytic leukemia myl/RARα cDNA and char-acterization of its retinoid-binding and transactiva-tion properties. Oncogene 6, 1285–1292 (1991).

8. de Thé, H. et al. The PML/RARalpha fusion mRNAgenerated by the t(15;17) translocation in acutepromyelocytic leukemia encodes a functionally al-tered RAR. Cell 66, 675–684 (1991).

9. Kakizuka, A. et al. Chromosomal translocationt(15;17) in human acute promyelocytic leukemiafuses RARα with a novel putative transcription fac-tor, PML. Cell 66, 663–674 (1991).

10. Grignani, F. et al. The acute promyelocytic leukemiaspecific PML/RARα fusion protein inhibits differenti-ation and promotes survival of myeloid precursorcells. Cell 74, 423–431 (1993).

11. He, L.Z. et al. Distinct interactions of PML-RARα andPLZF-RARα with co-repressors determine differentialresponses to RA in APL. Nature Genet. 18, 126–135(1997).

12. Lin, R.J. et al. Role of the histone deacetylase com-plex in acute promyelocytic leukaemia. Nature 391,811–814 (1998).

13. Grignani, F. et al. Fusion proteins of the retinoic acidreceptor-α recruit histone deacetylase in promyelo-cytic leukaemia. Nature 391, 815–818 (1998).

14. Zhong, S., Salomoni, P. & Pandolfi, P.P. The tran-scriptional role of PML and the nuclear body. NatureCell Biol. 2, E85–E90 (2000).

15. Warrell, R.P.Jr., He, L.Z., Richon,V., Calleja, E. &Pandolfi, P.P. Therapeutic targeting of transcriptionin acute promyelocytic leukemia by use of an in-hibitor of histone deacetylase. J. Natl. Cancer Inst.90, 1621–1625 (1998).

Department of Human Genetics and MolecularBiology Program,Memorial Sloan-Kettering Cancer Center,Sloan-Kettering Division, Graduate School ofMedical Sciences,Cornell University,1275 York Avenue,New York, NY 10021, USAEmail: p-pandolfi@ski.mskcc.org

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formalin-inactivated virus also causesatypical disease7. Polack et al. report, how-ever, that macaques inoculated with theDNA vaccines do not develop atypicalmeasles5. Formalin inactivation has beenproposed to destroy antigenic epitopes ofF protein, leading to exclusive productionof antibodies against H and a skewed re-sponse to measles challenge. Polack et al.suggest that there must be an alternate ex-planation, because they found that theformalin-inactivated vaccine induced pro-duction of antibodies against both F andH, and vaccination with DNA encoding Hglycoprotein alone does not predisposemacaques to atypical disease.

The induction of a memory T-cell re-sponse is likely to be an essential differ-ence between vaccination with live orDNA vaccines and formalin-inactivatedmeasles (Fig. 1) (refs. 4,7,8). Childrengiven a formalin-inactivated measles vac-cine developed measles antibodies buttiters decreased rapidly, indicating a lackof a helper T-cell response2. Limited T-cell killing of virus-infected cells and pro-duction of T-cell cytokines that promotesynthesis of immunoglobulin E may con-tribute to atypical measles. Vaccinationwith H and F glycoproteins, combinedwith immune stimulating complexes,also elicited measles-specific T cells, withno adverse consequences after measleschallenge in macaques9. Rules for design-ing single protein or ‘subunit’ vaccinesthat preclude atypical disease still cannotbe provided a priori, but the rhesusmacaque model developed by Polack et

al. will facilitate assessments of safety.Defining correlates of protection is a

universal problem in the development ofnew viral vaccines. It is difficult to dissoci-ate the in vivo contributions of antiviralantibodies and cellular immunity to theprotective immune response. Withmeasles, children with primary agamma-globulinemia were protected frommeasles after re-exposure, indicating thatcellular immunity is sufficient for protec-tion2. The presence of persistent neutraliz-ing antibodies at sufficient titers predictsprotection after live measles or DNA vac-cination5. To further define immunologi-cal mechanisms of protective efficacy, itwill be necessary to analyze the contribu-tions of CD4+ and CD8+ T cells after livemeasles and DNA vaccine administration.Live measles vaccine induced cellular im-munity in the presence of passive anti-bodies8, and DNA vaccines should havethis capacity as well12,13. H or F DNA vac-cines may promote class I-restricted CD8+

responses, whereas measles infection andlive measles vaccine elicit a combinedmemory CD4+ and CD8+ T-cell response.

DNA vaccines should afford new oppor-tunities to increase protection against in-fectious pathogens with minimal immuneside effects, particularly in the immatureimmune systems of infants10–13. Passivelyacquired maternal antibodies should notaffect DNA vaccine uptake and proteinsynthesis by host cells or antigen presenta-tion12,13. As more is learned about the rela-tive deficiencies of the infant developingimmune system, it will be possible to mod-

ify DNA vaccines to include additionalcomponents, such as compensatory cy-tokines or co-stimulatory molecules thatenhance antigen presentation11.

The macaque model of measles vac-cine efficacy will also be a valuable toolfor further analysis of measles vaccines,as it will be useful in the development ofstrategies to prevent deleterious immuneresponses and achieve sustained measlesprotection through immunomodulatory,prime–boost or other strategies11.Although they hold much promise, DNAvaccines will rival the available live at-tenuated vaccines only when inocula-tion procedures are simplified andtheoretical advantages for enhancing im-munogenicity in early infancy are trans-lated into practice.

1. Murray, C.J.L. & Lopez, A.D. Mortality by cause foreight regions of the world: global burden of diseasestudy. Lancet 349, 1269–1276 (1997).

2. Redd, S.C., Markowitz, L.E. & Katz, S.L. in Vaccines 3rd

edn. (eds. Plotkin, S.A. & Ornstein, W.A.) 22–266(W.B. Saunders, Philadelphia,1999).

3. deQuadros, C.A. et al. Measles elimination in theAmericas: Evolving strategies. J. Am. Med. Assoc. 275,224–229. (1996).

4. Gans, H.A. et al. Deficiency of the humoral immuneresponse to measles vaccine in infants immunized atage 6 months. J. Am. Med. Assoc. 280, 527–532(1998).

5. Polack, F. P. et al. Successful DNA immunizationagainst measles: Neutralizing antibody against eitherthe hemagglutinin or fusion glycoprotein protectsrhesus macaques without evidence of atypicalmeasles. Nature Med. 6, 776–781 (2000).

6. Tamin, A. et al. Antigenic analysis of current wild typeand vaccine strains of measles virus. J. Infect. Dis. 170,795–801 (1994).

7. Polack, F.P. et al. Production of atypical measles inrhesus macaques: evidence for disease mediated byimmune complex formation and eosinophils in thepresence of fusion-inhibiting antibody. Nature Med.5, 629–634 (1999).

8. Gans, H.A. et al. IL-12, IFN-γ and T cell proliferation tomeasles in immunized infants. J. Immunol. 162,5569–5575 (1999).

9. van Binnendijk, R.S., Poelen, M.C., van Amerongen,G., deVries, P. & Osterhaus, AD. Protective immunityin macaques vaccinated with live attenuated, recom-binant, and subunit measles vaccines in the presenceof passively acquired antibodies. J. Infect. Dis. 175,524–532(1997).

10. Liu, M.A., Fu, T-M., Donnelly, J.J., Caulfield, M.J. &Ulmer, J.B. DNA vaccines: mechanisms for generationof immune responses. Adv. Exp. Med. Biol.452,187–191 (1998).

11. Rodriquez, F & Whitton, J.L. Enhancing DNA immu-nization. Virology 268, 233–238 (2000).

12. Seigrist, C-A. et al. Influence of maternal antibodieson vaccine responses: inhibition of antibody but not Tcell responses allows successful early prime booststrategies in mice. Eur. J. Immunol. 28, 4138–4148(1998).

13. Wang, Y., Xiang, Z., Pasquini, S. & Ertl, H.C. Immuneresponse to neonatal genetic immunization. Virology228, 278–284 (1997).

Pediatric Infectious DiseasesStanford University School of Medicine300 Pasteur Drive, Room G312Stanford, California 94305-5208, USAEmail: AArvin@Stanford.edu

Fig. 1. Vaccine-induced measles immunity. Live measles vaccine induces neutralizing antibodiesagainst fusion (F) and hemagglutinin (H) proteins, cytokine production and measles-specific CD4and CD8 T cells. Measles DNA vaccines expressing F or H proteins elicit production of neutralizingantibodies against F and H and measles-specific CD8+ T cells. Whether measles DNA vaccines elicitmemory CD4 T cells remains to be determined. Formalin-inactivated vaccines also induce produc-tion of antibodies against F and H proteins, but neutralizing antibody production decreases rapidly(*). Formalin-inactivated vaccines do not stimulate measles-specific T-cell immunity. Additionally,formalin-inactivated vaccines result in ‘atypical measles’ disease after challenge with wild-typemeasles virus. Aberrant T-cell activation may result in production of cytokines that favor synthesis ofimmunoglobulin E during atypical measles. In contrast, measles F and H DNA vaccines have thesafety profile of live measles vaccine in rhesus macaques challenged with measles virus.

Measlesvaccine

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