Skip to content
2000
image of The RV144 Trial Set Back HIV-1 Vaccine Development but Might Still Yield Useful Information
file format pdf download PDF

Abstract

This article discusses how the RV144 Phase 3 HIV-1 vaccine trial conducted over 15 years ago impacted the subsequent direction of research intended to create and evaluate vaccines with potentially greater efficacy. Follow-on Phase 2b and Phase 3 trials directly or indirectly inspired by the modest efficacy reported for the RV144 trial have not shown any significant protection against HIV-1 acquisition. No credibly protective new immunogens have emerged from the Correlates of Protection (CoP) or Risk (CoR) analyses conducted after RV144-inspired studies in either humans or various macaque models. Notably, the RV144 trial did not induce neutralizing antibodies (NAbs), only non-NAbs. However, only NAbs have been shown to be protective in macaque models. One possible but underappreciated explanation for the outcome of the RV144 trial could be trained innate immune responses against the non-HIV-1 canarypox virus vector antigens, considering the placebo group only received saline. In this article, the author outlines how monkey model research based directly or indirectly on the RV144 trial could still yield useful information on the possible role of trained immunity in short-term vaccine protection. However, non-human primate research, in general, should now focus on testing new immunogens that have a reasonable chance of inducing NAbs in humans, rather than expending more resources on CoP/CoR studies inspired by the RV144 trial and its follow-ups.

© 2025 The Author(s). Published by Bentham Science Publishers 
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/chr/10.2174/011570162X355671250402083527
2025-04-18
2025-09-05

  • From This Site

    /content/journals/chr/10.2174/011570162X355671250402083527
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/chr/10.2174/011570162X355671250402083527/BMS-CHIVR-2024-HT10-6091-2.html?itemId=/content/journals/chr/10.2174/011570162X355671250402083527&mimeType=html&fmt=ahah

References

  1. Rerks-Ngarm S. Pitisuttithum P. Nitayaphan S. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 2009 361 23 2209 2220 10.1056/NEJMoa0908492 19843557
    [Google Scholar]
  2. Rerks-Ngarm S. Paris R.M. Chunsutthiwat S. Extended evaluation of the virologic, immunologic, and clinical course of volunteers who acquired HIV-1 infection in a phase III vaccine trial of ALVAC-HIV and AIDSVAX B/E. J. Infect. Dis. 2013 207 8 1195 1205 10.1093/infdis/jis478 22837492
    [Google Scholar]
  3. Gilbert P.B. Berger J.O. Stablein D. Statistical interpretation of the RV144 HIV vaccine efficacy trial in Thailand: A case study for statistical issues in efficacy trials. J. Infect. Dis. 2011 203 7 969 975 10.1093/infdis/jiq152 21402548
    [Google Scholar]
  4. Rolland M. Gilbert P. Evaluating immune correlates in HIV type 1 vaccine efficacy trials: What RV144 may provide. AIDS Res. Hum. Retroviruses 2012 28 4 400 404 10.1089/aid.2011.0240 21902593
    [Google Scholar]
  5. Desrosiers R.C. Protection against HIV acquisition in the RV144. Trial. J. Virol. 2017 91 18 e00905 e00917 10.1128/JVI.00905‑17 28701398
    [Google Scholar]
  6. Desrosiers R.C. The failure of AIDS vaccine efficacy trials: Where to go from here. J. Virol. 2023 97 3 e00211 e00223 10.1128/jvi.00211‑23 36916947
    [Google Scholar]
  7. Klasse P.J. Moore J.P. Reappraising the value of HIV-1 vaccine correlates of protection analyses. J. Virol. 2022 96 8 e00034 e22 10.1128/jvi.00034‑22 35384694
    [Google Scholar]
  8. Burton D.R. Desrosiers R.C. Doms R.W. HIV vaccine design and the neutralizing antibody problem. Nat. Immunol. 2004 5 3 233 236 10.1038/ni0304‑233 14985706
    [Google Scholar]
  9. Moore J.P. Disappointing, but not surprising results from the first HIV-1 vaccine efficacy trial. Clinical Care Options for HIV. Available from: http://clinicaloptions.com/hiv 2014
    [Google Scholar]
  10. Belshe R. Franchini G. Girard M.P. Support for the RV144 HIV vaccine trial: Response. Science 2004 305 5681 177 180 10.1126/science.305.5681.177b
    [Google Scholar]
  11. Ringe R.P. Sanders R.W. Yasmeen A. Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. Proc. Natl. Acad. Sci. USA 2013 110 45 18256 18261 10.1073/pnas.1314351110 24145402
    [Google Scholar]
  12. Sanders R.W. Moore J.P. Native‐like Env trimers as a platform for HIV‐1 vaccine design. Immunol. Rev. 2017 275 1 161 182 10.1111/imr.12481 28133806
    [Google Scholar]
  13. Gray G.E. Bekker L.G. Laher F. Vaccine efficacy of ALVAC-HIV and bivalent subtype C gp120-MF59 in adults. N. Engl. J. Med. 2021 384 12 1089 1100 10.1056/NEJMoa2031499 33761206
    [Google Scholar]
  14. Barouch D.H. Tomaka F.L. Wegmann F. Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet 2018 392 10143 232 243 10.1016/S0140‑6736(18)31364‑3 30047376
    [Google Scholar]
  15. Gray G.E. Mngadi K. Lavreys L. Mosaic HIV-1 vaccine regimen in southern African women (Imbokodo/HVTN 705/HPX2008): A randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Infect. Dis. 2024 24 11 1201 1212 10.1016/S1473‑3099(24)00358‑X 39038477
    [Google Scholar]
  16. Reed B. HIV vaccine trial in Africa halted after disappointing initial results. 2023 Available from: https://www.theguardian.com/global-development/2023/dec/07/prepvacc-hiv-trial-africa-halted-after-disappointing-initial-results-for-combination-vaccine (Accessed on: 7 Dec 2023).
    [Google Scholar]
  17. Hammer S.M. Sobieszczyk M.E. Janes H. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N. Engl. J. Med. 2013 369 22 2083 2092 10.1056/NEJMoa1310566 24099601
    [Google Scholar]
  18. Plotkin S.A. Correlates of protection induced by vaccination. Clin. Vaccine Immunol. 2010 17 7 1055 1065 10.1128/CVI.00131‑10 20463105
    [Google Scholar]
  19. Klasse P.J. Moore J.P. Good CoP, bad CoP? Interrogating the immune responses to primate lentiviral vaccines. Retrovirology 2012 9 1 80 10.1186/1742‑4690‑9‑80 23025660
    [Google Scholar]
  20. Khoury D.S. Cromer D. Reynaldi A. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 2021 27 7 1205 1211 10.1038/s41591‑021‑01377‑8 34002089
    [Google Scholar]
  21. Pegu A. Borate B. Huang Y. a meta-analysis of passive immunization studies shows that serum-neutralizing antibody titer associates with protection against SHIV challenge. Cell Host Microbe 2019 26 3 336 346.e3 10.1016/j.chom.2019.08.014 31513771
    [Google Scholar]
  22. Pauthner M.G. Nkolola J.P. Havenar-Daughton C. Vaccine-induced protection from homologous tier 2 SHIV challenge in nonhuman primates depends on serum-neutralizing antibody titers. Immunity 2019 50 1 241 252.e6 10.1016/j.immuni.2018.11.011 30552025
    [Google Scholar]
  23. Moldt B. Rakasz E.G. Schultz N. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. USA 2012 109 46 18921 18925 10.1073/pnas.1214785109 23100539
    [Google Scholar]
  24. Dugast A.S. Chan Y. Hoffner M. Lack of protection following passive transfer of polyclonal highly functional low-dose non-neutralizing antibodies. PLoS One 2014 9 5 e97229 10.1371/journal.pone.0097229 24820481
    [Google Scholar]
  25. Hangartner L. Beauparlant D. Rakasz E. Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates. Sci. Transl. Med. 2021 13 585 eabe3349 10.1126/scitranslmed.abe3349 33731434
    [Google Scholar]
  26. Burton D.R. Hessell A.J. Keele B.F. Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc. Natl. Acad. Sci. USA 2011 108 27 11181 11186 10.1073/pnas.1103012108 21690411
    [Google Scholar]
  27. Parsons M.S. Lee W.S. Kristensen A.B. Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques. J. Clin. Invest. 2018 129 1 182 191 10.1172/JCI122466 30475230
    [Google Scholar]
  28. Haynes B.F. Gilbert P.B. McElrath M.J. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 2012 366 14 1275 1286 10.1056/NEJMoa1113425 22475592
    [Google Scholar]
  29. Gray GE Huang Y Grunenberg N Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa. Sci Transl Med 2019 11 510 eaax1880 10.1126/scitranslmed.aax1880 31534016
    [Google Scholar]
  30. Zolla-Pazner S. deCamp A. Gilbert P.B. Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PLoS One 2014 9 2 e87572 10.1371/journal.pone.0087572 24504509
    [Google Scholar]
  31. Gottardo R. Bailer R.T. Korber B.T. Plasma IgG to linear epitopes in the V2 and V3 regions of HIV-1 gp120 correlate with a reduced risk of infection in the RV144 vaccine efficacy trial. PLoS One 2013 8 9 e75665 10.1371/journal.pone.0075665 24086607
    [Google Scholar]
  32. Perez L.G. Martinez D.R. deCamp A.C. V1V2-specific complement activating serum IgG as a correlate of reduced HIV-1 infection risk in RV144. PLoS One 2017 12 7 e0180720 10.1371/journal.pone.0180720 28678869
    [Google Scholar]
  33. Kim J.H. Excler J.L. Michael N.L. Lessons from the RV144 Thai phase III HIV-1 vaccine trial and the search for correlates of protection. Annu. Rev. Med. 2015 66 1 423 437 10.1146/annurev‑med‑052912‑123749 25341006
    [Google Scholar]
  34. Duerr R. Gorny M.K. V2-specific antibodies in HIV-1 vaccine research and natural infection: Controllers or surrogate markers. Vaccines (Basel) 2019 7 3 82 10.3390/vaccines7030082 31390725
    [Google Scholar]
  35. Zolla-Pazner S. Cardozo T. Structure–function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nat. Rev. Immunol. 2010 10 7 527 535 10.1038/nri2801 20577269
    [Google Scholar]
  36. Cardozo T. Wang S. Jiang X. Kong X.P. Hioe C. Krachmarov C. Vaccine focusing to cross-subtype HIV-1 gp120 variable loop epitopes. Vaccine 2014 32 39 4916 4924 10.1016/j.vaccine.2014.07.026 25045827
    [Google Scholar]
  37. Zolla-Pazner S. deCamp A.C. Cardozo T. Analysis of V2 antibody responses induced in vaccinees in the ALVAC/AIDSVAX HIV-1 vaccine efficacy trial. PLoS One 2013 8 1 e53629 10.1371/journal.pone.0053629 23349725
    [Google Scholar]
  38. Aiyegbo M.S. Shmelkov E. Dominguez L. peptide targeted by human antibodies associated with HIV vaccine-associated protection assumes a dynamic α-helical structure. PLoS One 2017 12 1 e0170530 10.1371/journal.pone.0170530 28107435
    [Google Scholar]
  39. Kenny A. van Duijn J. Dintwe O. Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: A two-phase case-control study. EBioMedicine 2024 108 105320 10.1016/j.ebiom.2024.105320 39236556
    [Google Scholar]
  40. Vanshylla K. Tolboom J. Stephenson K.E. Mosaic HIV-1 vaccine and SHIV challenge strain V2 loop sequence identity and protection in primates. NPJ Vaccines 2024 9 1 179 10.1038/s41541‑024‑00974‑1 39349488
    [Google Scholar]
  41. Grunst M.W. Gil H.M. Grandea A.G. III Potent antibody-dependent cellular cytotoxicity of a V2-specific antibody is not sufficient for protection of macaques against SIV challenge. PLoS Pathog. 2024 20 1 e1011819 10.1371/journal.ppat.1011819 38252675
    [Google Scholar]
  42. Snow B.J. Keles N.K. Grunst M.W. Janaka S.K. Behrens R.T. Evans D.T. Potent broadly neutralizing antibodies mediate efficient antibody-dependent phagocytosis of HIV-infected cells. PLoS Pathog. 2024 20 10 e1012665 10.1371/journal.ppat.1012665 39466835
    [Google Scholar]
  43. Alpert M.D. Heyer L.N. Williams D.E.J. A novel assay for antibody-dependent cell-mediated cytotoxicity against HIV-1- or SIV-infected cells reveals incomplete overlap with antibodies measured by neutralization and binding assays. J. Virol. 2012 86 22 12039 12052 10.1128/JVI.01650‑12 22933282
    [Google Scholar]
  44. von Bredow B. Andrabi R. Grunst M. Differences in the binding affinity of an HIV-1 V2 apex-specific antibody for the SIVsmm/mac envelope glycoprotein uncouple antibody-dependent cellular cytotoxicity form neutralization. MBio 2019 10 4 e01255 e19 10.1128/mBio.01255‑19 31266872
    [Google Scholar]
  45. Sui Y. Lewis G.K. Wang Y. Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response. J. Clin. Invest. 2019 129 3 1314 1328 10.1172/JCI122110 30776026
    [Google Scholar]
  46. Lercher A. Cheong J.G. Bale M.J. Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease. Immunity 2024 57 11 2530 2546.e13 10.1016/j.immuni.2024.08.018 39353439
    [Google Scholar]
  47. Baydemir I. Dulfer E.A. Netea M.G. Domínguez-Andrés J. Trained immunity-inducing vaccines: Harnessing innate memory for vaccine design and delivery. Clin. Immunol. 2024 261 109930 10.1016/j.clim.2024.109930 38342415
    [Google Scholar]
  48. Brueggeman J.M. Zhao J. Schank M. Yao Z.Q. Moorman J.P. trained immunity: An overview and the impact on COVID-19. Front. Immunol. 2022 13 837524 10.3389/fimmu.2022.837524 35251030
    [Google Scholar]
  49. Escobar L.E. Molina-Cruz A. Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). Proc. Natl. Acad. Sci. USA 2020 117 30 17720 17726 10.1073/pnas.2008410117 32647056
    [Google Scholar]
  50. Noble C.C.A. Messina N.L. Pittet L.F. Curtis N. Interpreting the results of trials of BCG vaccination for protection against COVID-19. J. Infect. Dis. 2023 228 10 1467 1478 10.1093/infdis/jiad316 37558650
    [Google Scholar]
  51. Faustman D.L. Lee A. Hostetter E.R. Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes. Cell Rep. Med. 2022 3 9 100728 10.1016/j.xcrm.2022.100728 36027906
    [Google Scholar]
  52. Hilligan K.L. Namasivayam S. Clancy C.S. Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge. J. Exp. Med. 2022 219 2 e20211862 10.1084/jem.20211862 34889942
    [Google Scholar]
  53. Kato Y. Kumanogoh A. The immune memory of innate immune systems. Int. Immunol. 2024 67 7908808 10.1093/intimm/dxae067
    [Google Scholar]
  54. Angulo M. Angulo C. Trained immunity-based vaccines: A vision from the one health initiative. Vaccine 2025 43 Pt 2 126505 10.1016/j.vaccine.2024.126505 39520776
    [Google Scholar]
  55. Sviridov D. Miller Y.I. Bukrinsky M.I. Trained immunity and HIV infection. Front. Immunol. 2022 13 903884 10.3389/fimmu.2022.903884 35874772
    [Google Scholar]
  56. Xu L. Tudor D. Bomsel M. The protective HIV-1 Envelope gp41 antigen P1 acts as a mucosal adjuvant stimulating the innate immunity. Front. Immunol. 2021 11 599278 10.3389/fimmu.2020.599278 33613520
    [Google Scholar]
  57. Stamatatos L. Pancera M. McGuire A.T. Germline‐targeting immunogens. Immunol. Rev. 2017 275 1 203 216 10.1111/imr.12483 28133796
    [Google Scholar]
  58. Kwong P.D. Mascola J.R. HIV-1 vaccines based on antibody identification, B cell ontogeny, and epitope structure. Immunity 2018 48 5 855 871 10.1016/j.immuni.2018.04.029 29768174
    [Google Scholar]
  59. Burton D.R. Antiviral neutralizing antibodies: From in vitro to in vivo activity. Nat. Rev. Immunol. 2023 23 11 720 734 10.1038/s41577‑023‑00858‑w 37069260
    [Google Scholar]
  60. Haynes B.F. Wiehe K. Alam S.M. Weissman D. Saunders K.O. Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development. Curr. Opin. HIV AIDS 2023 18 6 300 308 10.1097/COH.0000000000000820 37751363
    [Google Scholar]
  61. Sanders R.W. Moore J.P. Progress on priming HIV-1 immunity. Science 2024 384 6697 738 739 10.1126/science.adp3459 38753801
    [Google Scholar]
/content/journals/chr/10.2174/011570162X355671250402083527
Loading

  • Article Type:     Research Article
Keywords: RV144 trial ; Vaccine trial ; antibodies ; immunogens ; Phase 2b ; HIV-1

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test