A study published in the January 2 issue of Science Translational Medicine reports that a dendritic cell (DC)-based therapeutic HIV vaccine was able to significantly lower viral load after an antiretroviral therapy (ART) interruption, albeit only transiently. The publication drew considerable press coverage, most of it reasonably accurate although some headline writers got carried away (while potentially representing a step forward for therapeutic HIV vaccine research, the results are not a “huge breakthrough” as one headline stated).
A number of prior trials have offered hints that therapeutic vaccination can mildly improve immune control of HIV replication, but they have tended to be small and uncontrolled (lacking a placebo comparator). A randomized, placebo-controlled trial of the Merck Ad5-based HIV vaccine conducted by the ACTG did find a trend toward lower viral load during a treatment interruption, but the result did not quite reach statistical significance. The major strengths of this new study, led by Felipe García from the University of Barcelona, are that it was randomized and placebo-controlled, and that the viral-load difference between vaccine- and placebo recipients was statistically significant at the 24-week timepoint after ART interruption (−0.80 vs. −0.19 logs, P = 0.01). However, after 48 weeks of follow-up, the difference was no longer significant (P = 0.66).
The researchers also report the following number of participants who displayed viral-load decreases of greater than 1 log (a reduction of 90 percent or more compared to baseline) in the vaccine versus placebo groups at different timepoints during follow-up:
- Week 12: 12/22 (55%) versus 1/11 (9%)
- Week 24: 7/20 (35%) versus 0/10 (0%)
- Week 48: 3/17 (18%) versus 1/6 (17%)
These differences were statistically significant in favor of the vaccine group at weeks 12 and 24, but not at week 48. There were no significant differences in CD4 T-cell counts between the two groups at any time over the 48-week period. Analyses of HIV-specific T-cell responses (using an ELISPOT assay measuring interferon-gamma production in response to HIV Gag, Nef, and Env gp41 peptides) revealed a statistical trend toward an inverse association with viral load in the vaccine group (P = 0.08), while in the placebo group there was a significant positive association with viral load. This result suggests that HIV-specific T-cell responses in vaccine recipients were at least partly effective, whereas in placebo recipients the detected HIV-specific T cells were flailing away ineffectively.
The researchers manufactured the vaccine by harvesting monocyte-derived DCs from study participants and exposing them to heat-inactivated HIV isolated from the same individuals. The placebo consisted of DCs unexposed to HIV. A relatively high dose of ~10 million DCs was administered three times, at two-week intervals (either before or immediately after ART interruption). In discussing the results, the researchers point out that several DC-based vaccines have previously shown hints of promise, with the use of HIV or HIV antigens from individual study participants (autologous HIV) appearing to be important for achieving significant viral-load effects. They acknowledge that the degree of virological control achieved in their study is far from the optimal goal of achieving a functional cure, which is defined as a long-lasting reduction in viral load to undetectable levels after ART interruption. Despite this caveat, they conclude: “This is a proof of concept justifying further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to ART for life.”
The publication of this study occurs at a time of renewed interest in therapeutic HIV vaccines in the context of cure research, prompted by a study suggesting that HIV-specific immunity needs to be enhanced in order to help eradicate HIV reservoirs. Furthermore, there is some evidence that a proportion—perhaps even the majority—of the latent HIV reservoir resides in HIV-specific CD4 T cells, leading to the hypothesis that therapeutic HIV vaccines could also help activate these CD4 T cells and thus awaken the virus they contain, making it visible to the immune system. Studies are now being planned that will further investigate these issues.
Sci Transl Med 2 January 2013: Vol. 5, Issue 166, p. 166ra2 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004682
Felipe García1,*,†, Nuria Climent1,*, Alberto C. Guardo1, Cristina Gil1, Agathe León1, Brigitte Autran2, Jeffrey D. Lifson3, Javier Martínez-Picado4,5, Judit Dalmau4, Bonaventura Clotet4, Josep M. Gatell1, Montserrat Plana1,*, Teresa Gallart1,*, For the DCV2/MANON07-ORVACS Study Group
1Hospital Clinic-IDIBAPS, HIVACAT, University of Barcelona, 08036 Barcelona, Spain. 2INSERM UMR-S-945, Université Paris-VI Pierre-et-Marie-Curie, Hôpital Pitié-Salpêtrière, 75013 Paris, France. 3AIDS and Cancer Virus Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. 4AIDS Research Institute IrsiCaixa, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. 5Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.
*These authors contributed equally to this work.
Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1–infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1–specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to “cART for life.” We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. Patients on cART with CD4+ >450 cells/mm3 were randomized to receive three immunizations with MD-DCs or with nonpulsed MD-DCs. Vaccination was feasible, safe, and well tolerated and shifted the virus/host balance. At weeks 12 and 24 after cART interruption, a decrease of plasma viral load setpoint ≥1 log was observed in 12 of 22 (55%) versus 1 of 11 (9%) and in 7 of 20 (35%) versus 0 of 10 (0%) patients in the DC–HIV-1 and DC-control groups, respectively. This significant decrease in plasma viral load observed in immunized recipients was associated with a consistent increase in HIV-1–specific T cell responses. These data suggest that HIV-1–specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1–infected patients treated in early stages. This proof of concept supports further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to cART for life.