The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge–rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector–based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4+ T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Baba, T.W. et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 6, 200–206 (2000).
Mascola, J.R. et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6, 207–210 (2000).
Parren, P.W. et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J. Virol. 75, 8340–8347 (2001).
Deeks, S.G. & Walker, B.D. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27, 406–416 (2007).
VaxGen. VaxGen announces results of its phase 3 HIV vaccine trial in Thailand: vaccine fails to meet endpoints. <http://investor.vaxgen.com/profiles/investor/ResLibraryView.asp?ResLibraryID=5836&GoTopage=16&BzID=923&Category=214> (2003).
Burton, D.R. et al. HIV vaccine design and the neutralizing antibody problem. Nat. Immunol. 5, 233–236 (2004).
Burton, D.R. et al. Public health. A sound rationale needed for phase 3 HIV-1 vaccine trials. Science 303, 316 (2004).
McNeil, J.G., Johnston, M.I., Birx, D.L. & Tramont, E.C. Policy rebuttal. HIV vaccine trial justified. Science 303, 961 (2004).
[Anonymous]. HIV vaccine failure prompts Merck to halt trial. Nature 449, 390 (2007).
Priddy, F. H. et al. Safety and immunogenicity of a replication-incompetent adenovirus type 5 HIV-1 clade B gag/pol/nef vaccine in healthy adults. Clin. Infect. Dis. 46, 1769–1781 (2008).
Allen, T.M. et al. Selective escape from CD8+ T cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. J. Virol. 79, 13239–13249 (2005).
O'Connor, D.H. et al. A dominant role for CD8+ T lymphocyte selection in simian immunodeficiency virus sequence variation. J. Virol. 78, 14012–14022 (2004).
Borrow, P., Lewicki, H., Hahn, B.H., Shaw, G.M. & Oldstone, M.B. Virus-specific CD8+ cytotoxic T lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–6110 (1994).
Koup, R.A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).
Matano, T. et al. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J. Virol. 72, 164–169 (1998).
Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).
Jin, X. et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency viru–infected macaques. J. Exp. Med. 189, 991–998 (1999).
Friedrich, T.C. et al. Subdominant CD8+ T cell responses are involved in durable control of AIDS virus replication. J. Virol. 81, 3465–3476 (2007).
Leynaert, B., Downs, A.M. & de Vincenzi, I. Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. European Study Group on Heterosexual Transmission of HIV. Am. J. Epidemiol. 148, 88–96 (1998).
Pilcher, C.D. et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J. Infect. Dis. 189, 1785–1792 (2004).
Wawer, M.J. et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J. Infect. Dis. 191, 1403–1409 (2005).
Quinn, T.C. et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N. Engl. J. Med. 342, 921–929 (2000).
Gray, R.H. et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1–discordant couples in Rakai, Uganda. Lancet 357, 1149–1153 (2001).
Gray, R.H. et al. Stochastic simulation of the impact of antiretroviral therapy and HIV vaccines on HIV transmission; Rakai, Uganda. AIDS 17, 1941–1951 (2003).
Vogel, T.U. et al. Multispecific vaccine-induced mucosal cytotoxic T lymphocytes reduce acute-phase viral replication but fail in long-term control of simian immunodeficiency virus SIVmac239. J. Virol. 77, 13348–13360 (2003).
Allen, T.M. et al. Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication. J. Virol. 76, 4108–4112 (2002).
Allen, T.M. et al. Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection. J. Virol. 76, 10507–10511 (2002).
Allen, T.M. et al. Induction of AIDS virus–specific CTL activity in fresh, unstimulated peripheral blood lymphocytes from rhesus macaques vaccinated with a DNA prime/modified vaccinia virus Ankara boost regimen. J. Immunol. 164, 4968–4978 (2000).
Thakallapally, R. & Kuiken, C. in HIV Molecular Immunology 2000 (eds. Korber, B. et al.) 73–81 (Los Alamos National Laboratory, Los Alamos, 2000).
Benson, J. et al. Recombinant vaccine–induced protection against the highly pathogenic simian immunodeficiency virus SIV(mac251): dependence on route of challenge exposure. J. Virol. 72, 4170–4182 (1998).
Horton, H. et al. Immunization of rhesus macaques with a DNA prime/modified vaccinia virus Ankara boost regimen induces broad simian immunodeficiency virus (SIV)-specific T cell responses and reduces initial viral replication but does not prevent disease progression following challenge with pathogenic SIVmac239. J. Virol. 76, 7187–7202 (2002).
Pal, R. et al. ALVAC–SIV-gag-pol-env–based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency. J. Virol. 76, 292–302 (2002).
Hel, Z. et al. Containment of simian immunodeficiency virus infection in vaccinated macaques: correlation with the magnitude of virus-specific pre- and postchallenge CD4+ and CD8+ T cell responses. J. Immunol. 169, 4778–4787 (2002).
Hel, Z. et al. Equivalent immunogenicity of the highly attenuated poxvirus-based ALVAC-SIV and NYVAC-SIV vaccine candidates in SIVmac251-infected macaques. Virology 304, 125–134 (2002).
Hel, Z. et al. Improved vaccine protection from simian AIDS by the addition of nonstructural simian immunodeficiency virus genes. J. Immunol. 176, 85–96 (2006).
Amara, R.R. et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA-MVA vaccine. Science 292, 69–74 (2001).
Barouch, D.H. et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290, 486–492 (2000).
Rose, N.F. et al. An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants. Cell 106, 539–549 (2001).
Shiver, J.W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti–immunodeficiency virus immunity. Nature 415, 331–335 (2002).
Feinberg, M.B. & Moore, J.P. AIDS vaccine models: challenging challenge viruses. Nat. Med. 8, 207–210 (2002).
Lifson, J.D. & Martin, M.A. One step forwards, one step back. Nature 415, 272–273 (2002).
Casimiro, D.R. et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with DNA and recombinant adenoviral vaccine vectors expressing Gag. J. Virol. 79, 15547–15555 (2005).
McDermott, A.B. et al. Cytotoxic T lymphocyte escape does not always explain the transient control of simian immunodeficiency virus SIVmac239 viremia in adenovirus-boosted and DNA-primed Mamu-A*01–positive rhesus macaques. J. Virol. 79, 15556–15566 (2005).
Mattapallil, J.J. et al. Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge. J. Exp. Med. 203, 1533–1541 (2006).
Letvin, N.L. et al. Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys. Science 312, 1530–1533 (2006).
Wilson, N.A. et al. Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J. Virol. 80, 5875–5885 (2006).
Wyand, M.S., Manson, K.H., Garcia-Moll, M., Montefiori, D. & Desrosiers, R.C. Vaccine protection by a triple deletion mutant of simian immunodeficiency virus. J. Virol. 70, 3724–3733 (1996).
Daniel, M.D., Kirchhoff, F., Czajak, S.C., Sehgal, P.K. & Desrosiers, R.C. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258, 1938–1941 (1992).
Johnson, R.P. et al. Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation. J. Virol. 73, 4952–4961 (1999).
Wyand, M.S. et al. Protection by live, attenuated simian immunodeficiency virus against heterologous challenge. J. Virol. 73, 8356–8363 (1999).
Nilsson, C. et al. Live attenuated simian immunodeficiency virus (SIV)mac in macaques can induce protection against mucosal infection with SIVsm. AIDS 12, 2261–2270 (1998).
Abdel-Motal, U.M. et al. Kinetics of expansion of SIV Gag–specific CD8+ T lymphocytes following challenge of vaccinated macaques. Virology 333, 226–238 (2005).
Yewdell, J.W. Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses. Immunity 25, 533–543 (2006).
Smith, C.L. et al. Immunodominance of poxviral-specific CTL in a human trial of recombinant-modified vaccinia Ankara. J. Immunol. 175, 8431–8437 (2005).
Kastenmuller, W. et al. Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination. J. Exp. Med. 204, 2187–2198 (2007).
Willis, R.A., Kappler, J.W. & Marrack, P.C. CD8 T cell competition for dendritic cells in vivo is an early event in activation. Proc. Natl. Acad. Sci. USA 103, 12063–12068 (2006).
Chen, W., Anton, L.C., Bennink, J.R. & Yewdell, J.W. Dissecting the multifactorial causes of immunodominance in class I–restricted T cell responses to viruses. Immunity 12, 83–93 (2000).
Bennett, M.S., Ng, H.L., Dagarag, M., Ali, A. & Yang, O.O. Epitope-dependent avidity thresholds for cytotoxic T lymphocyte clearance of virus-infected cells. J. Virol. 81, 4973–4980 (2007).
Rollman, E. et al. Killing kinetics of simian immunodeficiency virus–specific CD8+ T cells: implications for HIV vaccine strategies. J. Immunol. 179, 4571–4579 (2007).
Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).
Friedrich, T.C. et al. Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nat. Med. 10, 275–281 (2004).
Leslie, A.J. et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat. Med. 10, 282–289 (2004).
Sacha, J.B. et al. Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J. Immunol. 178, 2746–2754 (2007).
Ali, A. et al. Impacts of epitope expression kinetics and class I downregulation on the antiviral activity of human immunodeficiency virus type 1–specific cytotoxic T lymphocytes. J. Virol. 78, 561–567 (2004).
Palmowski, M.J. et al. Competition between CTL narrows the immune response induced by prime-boost vaccination protocols. J. Immunol. 168, 4391–4398 (2002).
Rodriguez, F., Harkins, S., Slifka, M.K. & Whitton, J.L. Immunodominance in virus-induced CD8+ T cell responses is dramatically modified by DNA immunization and is regulated by γ interferon. J. Virol. 76, 4251–4259 (2002).
Yang, O.O. Will we be able to 'spot' an effective HIV-1 vaccine? Trends Immunol. 24, 67–72 (2003).
Chung, C. et al. Not all cytokine-producing CD8+ T cells suppress simian immunodeficiency virus replication. J. Virol. 81, 1517–1523 (2007).
Loffredo, J.T. et al. Tat28–35SL8-specific CD8+ T lymphocytes are more effective than Gag(=181–189CM9-specific CD8+ T lymphocytes at suppressing simian immunodeficiency virus replication in a functional in vitro assay. J. Virol. 79, 14986–14991 (2005).
Van Baalen, C.A. et al. Kinetics of antiviral activity by human immunodeficiency virus type 1–specific cytotoxic T lymphocytes (CTL) and rapid selection of CTL escape virus in vitro. J. Virol. 72, 6851–6857 (1998).
Yang, O.O. et al. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I–restricted triggering of cytolytic and noncytolytic mechanisms. J. Virol. 71, 3120–3128 (1997).
Tomiyama, H., Fujiwara, M., Oka, S. & Takiguchi, M. Cutting Edge: Epitope-dependent effect of Nef-mediated HLA class I down-regulation on ability of HIV-1–specific CTLs to suppress HIV-1 replication. J. Immunol. 174, 36–40 (2005).
Gaschen, B. et al. Diversity considerations in HIV-1 vaccine selection. Science 296, 2354–2360 (2002).
Valentine, L.E. et al. Recognition of escape variants in ELISPOT does not always predict CD8+ T cell recognition of simian immunodeficiency virus–infected cells expressing the same variant sequences. J. Virol. 82, 575–581 (2008).
Bennett, M.S., Ng, H.L., Ali, A. & Yang, O.O. Cross-clade detection of HIV-1–specific cytotoxic T lymphocytes does not reflect cross-clade antiviral activity. J. Infect. Dis. 197, 390–397 (2008).
Excler J.L., Rida W., Priddy F., Fast P. & Koff, W. A strategy for accelerating the development of preventive AIDS vaccines. AIDS 21, 2259–2263 (2007).
We thank J. Loffredo, A. Espinosa, N. Wilson Schlei, T. Friedrich and L. Valentine for help in preparing this article. We are also grateful to the members of the Watkins Laboratory for advice on its contents and to S. Noble of IAVI for assistance with editing. The preparation of this article and of the research it describes was supported by US National Institutes of Health grants R01 AI049120, R01 AI052056, R24 RR015371 and R24 RR016038 to D.I.W., grants R37 AI36082 and R01 AI45463 to J.P.M., grant U01 AI69420 to E.G.K. and grants R37 AI33292 and R01 AI055332 to D.R.B. We also wish to acknowledge Merck and IAVI for their support of the Watkins Laboratory and Fundação de Amparo à Pesquisa do Estado de São Paulo for support of the Kallas Laboratories.
D.I.W. has enjoyed a long-standing collaboration with scientists at Merck. They have supplied his group with DNA and Ad5 constructs for vaccine studies. E.G.K. is a Federal University of SSãoo Paulo site principal investigator for the STEP trial and has been receiving funds from Merck to run clinical trials; he also provides consultant services for Merck and Bristol-Meyers Squibb.
About this article
Induction of neutralizing antibodies against tier 2 human immunodeficiency virus 1 in rhesus macaques infected with tier 1B simian/human immunodeficiency virus
Archives of Virology (2019)
Propionibacterium acnes Enhances the Immunogenicity of HIVBr18 Human Immunodeficiency Virus-1 Vaccine
Frontiers in Immunology (2018)
DNA prime/MVTT boost regimen with HIV-1 mosaic Gag enhances the potency of antigen-specific immune responses
The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B*08+ Rhesus Macaques
Journal of Virology (2018)