Prospects for an AIDS Vaccine

COMMENTARY

Prospects for an AIDS vaccine

Ronald C Desrosiers

Several lines of evidence indicate that development of an effective vaccine for HIV-1 is going to be, at best, extremely difficult. The inability to solve fundamental scientific questions is the root cause for why a successful vaccine is not currently within our grasp. A renewed, organized, focused effort is needed to overcome these scientific obstacles.

“Who are only undefeated because we have that are antigenic escape variants; inherent induces progressive declines in CD4 counts gone on trying.” resistance to antibody-mediated neutraliza- and a progressive disease course in rhesus —T.S. Eliot tion; downregulation of major histocompati- monkeys. What is most disappointing about http://www.nature.com/naturemedicine The Dry Salvages bility class I molecules from the surface of the failure to protect against SIV239 is that infected cells by a viral gene product (Nef); the challenge strain was matched exactly in Twenty years have elapsed since the discovery and destruction of viral-specific CD4+ T sequence to that of the vaccine strain, and of HIV and its association with AIDS. helper cells. For a vaccine to be effective, it challenge occurred at or near the peak of vac- Despite much hope and promise, there is no will need to generate immune responses that cine-induced immune responses. If we can- vaccine to protect vulnerable populations are superior to the natural immune not protect against cloned, homogeneous around the globe. This brief commentary responses to wild-type HIV-1 infection. SIV239 by vaccines exactly matched in attempts to give a realistic assessment of “Superior” does not necessarily mean greater sequence under ideal conditions, there is lit- where efforts stand to develop an effective in magnitude, but different in the sense that tle reason for optimism. vaccine against HIV-1 for worldwide use. it is protective in a way that the natural There is ample evidence to indicate that immune response is not. Superinfection development of an effective vaccine for The failure of controlled HIV-1 infection to HIV-1 is going to be, at best, extremely diffi- Failure to protect monkeys protect against pathogenic superinfection is

© 2004 Nature Publishing Group cult. The most promising vaccine Promising vaccine strategies making their illustrated by a case study published recently approaches currently being forwarded in the way through human clinical trials include by Altfeld et al.9 A man who was seen in the clinic stand little chance of being effective. I recombinant adenovirus and prime-and- clinic shortly after exposure to HIV-1 was present five lines of evidence to support boost protocols that use initial priming with placed on antiretroviral therapy during pri- these contentions. a plasmid DNA vector encoding HIV-1 anti- mary infection. After several rounds of gen(s), followed by boosting with a recombi- strategic therapeutic interruption, the man Natural immune response is not effective nant poxvirus or adenovirus encoding the had low viral loads and quite good immuno- The natural immune response to HIV-1 is same antigen(s). These vaccines express the logic control of HIV-1 in the absence of con- almost never effective. Individuals infected viral gag protein or gag plus additional viral tinued antiretroviral therapy. Nonetheless, with HIV-1 mount apparently strong anti- antigens. Although these vaccine approaches after a high-risk activity, the individual body responses and viral-specific CD8+ cel- have protected against SHIV89.6P challenge became superinfected with a different strain lular responses. Yet, HIV-1 continues to in monkeys3–5, they have failed to protect of the same clade (B) and developed persist- replicate week after week, month after against SIV239 challenge6.The explanation ent moderate to high viral loads. Thus, month, eventually killing the host. It is now for the very different outcomes using immunologic control of the first strain did clear that HIV has evolved a number of spe- SHIV89.6P challenge is not entirely clear. It not protect against superinfection and high cific immune evasion strategies to allow con- should be noted, however, that the pathogen- viral load upon subsequent exposure to a tinuous viral replication (reviewed in refs. esis of SHIV89.6P is not the same as that of different strain of HIV-1. This startling 1,2). Immune evasion strategies used by the lentiviruses, and that virtually every vaccine inability of a controlled HIV-1 infection to virus include: selection for genetic variants approach that has been tried—even immu- protect against superinfection by a naturally nization with peptides7,8—protects against occurring HIV-1 field strain is, of course, SHIV89.6P. In contrast to SHIV89.6P, key only a single example, and it is not known Ronald C. Desrosiers is at the New England Primate biological properties of SIV239 in rhesus how protective (or nonprotective) con- Research Center, Harvard Medical School, monkeys parallel those of HIV-1 in humans: trolled HIV-1 infections may be in general. Southborough, Massachusetts 01772-9102, USA. SIV239 uses CCR5 as a coreceptor for entry However, the situation described by Altfeld e-mail: [email protected] into cells, is difficult to neutralize, and et al. is actually not very different from what

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has been observed with live attenuated, nef- deleted SIV. Although live attenuated, nef- deleted SIV has provided very good protection against homologous chal- lenge10,11,live attenuated, nef-deleted SIV239 has not provided strong protection against heterologous challenge with the SIV strain E660 (ref. 12). The degree of sequence variation between SIV239 and SIVE660 is representative of the level of sequence variation among field isolates of HIV-1.

Sequence variability There is enormous sequence heterogeneity among individual isolates of HIV-1. The HIV Sequence Compendium, a large data- base of HIV-1 sequences, reveals that they can be ordered into nine discrete major phy- logenetic groupings, or clades13.There is no evidence to suggest that individual clades represent neutralization serotypes. The vaccines in clinical trials incorporate only one, or in a few cases two, HIV-1 gene sequences. http://www.nature.com/naturemedicine The nature of the sequences that should be Figure 1 Modern-day Sisyphus? An uphill struggle for HIV vaccines (image suggestion: Jeff Lifson. HIV included in HIV-1 vaccines—a regional cell: Science Photo Library). consensus sequence, sequences from a representative local isolate or reconstructed ‘ancestral state’ sequences—has been dis- Where do we go from here? HIV-1? First, we do not know how to elicit cussed in publications and at strategic plan- The HIV vaccine development effort has been antibodies with potent neutralizing activity. ning sessions14,15.The goal of these laregly driven by the philosophy of more prod- Second, we do not know how to deal with the deliberations is to reduce the average ucts in the pipeline and more clinical testing. enormous sequence variability of the virus. sequence distance between vaccine antigen At present, at least 13 different products are at This sequence variability is a serious impedi- and circulating HIV-1 proteins. However, it varying stages of clinical testing in more than ment to the effectiveness of both neutralizing has been suggested that HIV-1 sequences 20 individual human trials. A bold proposal antibody responses and viral-specific CD8+ circulating in a population may largely rep- has been presented for a massive investment in cellular responses elicited by any vaccine. resent cytotoxic T-lymphocyte escape vari- a global enterprise to hasten the development Third, although live attenuated SIV has pro-

© 2004 Nature Publishing Group ants for human leukocyte antigen types that of an AIDS vaccine17.The philosophy of the vided spectacular protection against homolo- predominate in that population16.This proposed enterprise, driven by a perceived gous challenge by SIV239 and other such would not bode well for the ability of cyto- problem with translation into clinical applica- strains10–12,we do not understand the crucial toxic T lymphocyte–based vaccines to pro- tion, seems to embody prevailing attitudes components of the protective immune vide protection. In any event, we do not yet toward what is needed: more products in the response. The experiments of Lifson et al.18 know how to construct vaccines in a way pipeline and more clinical testing. The vision and recent results from my own laboratory that can deal with the enormous sequence of this philosophy calls for expansion of the indicate that high levels of antiviral immune heterogeneity of HIV-1. capacity to conduct clinical trials, assurance of responses measured in the peripheral blood by manufacturing capacity and harmonization of standard assays are not necessary to achieve Failure of VaxGen trial regulatory approaches. If we can get more strong vaccine protection against homologous The results of the first phase 3 HIV-1 vac- products into clinical testing, so the thinking challenge, even against strains such as SIV239. cine trials—the VaxGen gp120 trials—were goes, we will eventually find our way to success. What is responsible for this remarkable pro- released in 2003. In these trials, volunteers While it is true that empirical trial-and-error tection and by what other methods can we were immunized with a recombinant HIV-1 approaches have been sufficient for the devel- induce this type of immunity? Finally, we do gp120 protein (one of the subunits of the opment of other successful vaccines, it is highly not know whether immunologic memory will virus envelope) in an attempt to generate unlikely, based on what we know today, that ever be sufficient to protect against HIV-1. If it virus-neutralizing antibodies that would this is going to be enough to make an effective will not be sufficient, we need to learn how to protect against subsequent exposure to vaccine against HIV-1. The major difficulties elicit protective immune responses in a way HIV-1. Vaccine and placebo recipients were blocking development of an effective vaccine that will persist. followed for 30 months. The vaccine did not against HIV-1 are fundamental scientific ques- If what I believe is true—that major discov- provide any protection against infection and tions, not issues of manufacturing, numbers of eries are needed to make a vaccine feasible— did not lower viral loads. Given what we trial sites, international site preparation or vali- then the scientific obstacles need to become now know regarding the resistance of HIV-1 dated testing procedures. the major targets of our intermediate goals. I to antibody neutralization, it is no surprise What are the principal scientific obstacles to believe that a renewed, organized and focused that the VaxGen gp120 vaccine failed. development of an effective vaccine against effort is required to deal with these funda-

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mental scientific obstacles. These problems Where do we go from here? The concept lacking in attempts to elicit adaptive are not likely to be overcome by repeated clin- of dedicated AIDS vaccine research centers immune responses that will be protective ical testing of weak products that stand little roughly outlined in the proposal of against HIV-1. chance of being effective. While continued Klausner et al.17 would be an efficient means

testing of feeble long-shots in the clinic is of achieving targeted goals. But the princi- 1. Desrosiers, R.C. Nat. Med. 5, 723–725 (1999). inevitable (and even useful), we need to do a pal focus of such research centers should be 2. Johnson, W.E. & Desrosiers, R.C. Annu. Rev. Med. much better job of bringing promising prod- solving the fundamental scientific obstacles. 53, 499–518 (2002). 3. Amara, R.R. et al. Science 292, 69–74 (2001). ucts to the clinic. Much has been made of the Let there be no mistake: a successful course 4. Barouch, D.H. et al. Nature 415, 335–339 (2002). concept that the clinical testing process needs will require enormous will, dedication in 5. Shiver, J.W. et al. Nature 415, 331–335 (2002). 6. Horton, H. et al. J. Virol. 76, 7187–7202 (2002). to be iterative. In the absence of answers to the face of doubt, lots of money, scientific 7. Chen, X. et al. Nat. Med. 7, 1225–1231 (2001). the major scientific questions, the iterative leadership and a structure that will allow 8. Letvin, N.L. et al. J. Virol. 75, 4165–4175 (2001). process will necessarily continue to rely on concerted, organized, systematic, creative 9. Altfeld, M. et al. Nature 420, 434–439 (2002). 10. Daniel, M.D., Kirchhoff, F., Czajak, S.C., Sehgal, P.K. blind guesses. Although it is true that correla- solutions to the scientific problems. And & Desrosiers, R.C. Science 258, 1938–1941 tive analyses from human vaccine trials may even then there are no guarantees of a suc- (1992). help answer some of the fundamental ques- cessful outcome. Given this pessimistic out- 11. Johnson, R.P. et al. J. Virol. 73, 4952–4961 (1999). 12. Wyand, M.S. et al. J. Virol. 73, 8356–8363 (1999). tions, the major fundamental discoveries—if look (Fig. 1), every opportunity should be 13. Kuiken, C. et al. HIV sequence compendium (Los indeed they ever occur—are much more taken to think laterally. For example, pro- Alamos National Laboratory, Los Alamos, 2002). 14. Gaschen, B. et al. Science 296, 2354–2360 (2002). likely to come from the laboratory bench, phylactic use of antiviral therapies, which 15. Nickle, D. et al. Science 299,1515–1517 (2003). from mice and from monkeys. The huge cost has been a very successful approach in mon- 16. Moore, C.B. et al. Science 296, 1439–1443 (2002). of these human trials must be weighed against key trials19,needs to be aggressively pursued 17. Klausner, R.D. et al. Science 300, 2036–2039 (2003). their likelihood for failure and what is likely in high-risk humans. Prophylactic use of 18. Lifson, J.D. et al. J. Virol. 74, 2584–2593 (2000). to be learned from them. antivirals has a certain feasibility that is 19. Tsai, C.C. et al. Science 270, 1197–1199 (1995). http://www.nature.com/naturemedicine © 2004 Nature Publishing Group

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