A global approach to HIV-1 vaccine development

Summary A global human immunodeficiency virus-1 (HIV-1) vaccine will have to elicit immune responses capable of providing protection against a tremendous diversity of HIV-1 variants. In this review, we first describe the current state of the HIV-1 vaccine field, outlining the immune responses that are desired in a global HIV-1 vaccine. In particular, we emphasize the likely importance of Env-specific neutralizing and non-neutralizing antibodies for protection against HIV-1 acquisition and the likely importance of effector Gag-specific T lymphocytes for virologic control. We then highlight four strategies for developing a global HIV-1 vaccine. The first approach is to design specific vaccines for each geographic region that include antigens tailor-made to match local circulating HIV-1 strains. The second approach is to design a vaccine that will elicit Env-specific antibodies capable of broadly neutralizing all HIV-1 subtypes. The third approach is to design a vaccine that will elicit cellular immune responses that are focused on highly conserved HIV-1 sequences. The fourth approach is to design a vaccine to elicit highly diverse HIV-1-specific responses. Finally, we emphasize the importance of conducting clinical efficacy trials as the only way to determine which strategies will provide optimal protection against HIV-1 in humans

GagPol-specific CD4+ T-cells increase the antibody response to Env by intrastructural help

Background: Immunization of rhesus macaques against Gag of SIV resulted in a more rapid appearance of Env antibodies after infection with SIV or SHIV challenge viruses although the vaccines lacked an Env component. We therefore explored whether T helper cells specific for internal HIV proteins could provide intrastructural help for Env-specific B cells and thus increase the Env antibody response. Results: Mice were immunized by adenoviral vector or DNA vaccines against GagPol and then boosted with virus-like particles (VLP) containing GagPol and Env. Env-specific antibody levels after the VLP booster immunizations were significantly higher in GagPol-immunized mice than in mock-vaccinated controls. Adoptive transfer of CD4+ T cells from GagPol-immunized mice also enhanced the Env antibody response to VLP immunization in the recipient mice. Depending on the presence of VLPs, co-cultivation of CD4+ T cells from GagPol-primed mice with BCR transgenic B cells specific for a protein presented on the surface of the VLPs also resulted in the activation of the B and T cells. Conclusions: Our study indicates that GagPol-specific T helper cells may provide intrastructural help for Env antibody responses. This cross-talk between immune responses directed against different components of the retroviral particle may be relevant for the immunopathogenesis of retroviral infections and allow to improve virus like particle vaccine approaches against HIV

Polymer multilayer tattooing for enhanced DNA vaccination

DNA vaccines have many potential benefits but have failed to generate robust immune responses in humans. Recently, methods such as in vivo electroporation have demonstrated improved performance, but an optimal strategy for safe, reproducible, and pain-free DNA vaccination remains elusive. Here we report an approach for rapid implantation of vaccine-loaded polymer films carrying DNA, immune-stimulatory RNA, and biodegradable polycations into the immune-cell-rich epidermis, using microneedles coated with releasable polyelectrolyte multilayers. Films transferred into the skin following brief microneedle application promoted local transfection and controlled the persistence of DNA and adjuvants in the skin from days to weeks, with kinetics determined by the film composition. These ‘multilayer tattoo’ DNA vaccines induced immune responses against a model HIV antigen comparable to electroporation in mice, enhanced memory T-cell generation, and elicited 140-fold higher gene expression in non-human primate skin than intradermal DNA injection, indicating the potential of this strategy for enhancing DNA vaccination.Howard Hughes Medical Institute (Investigator)Ragon Institute of MGH, MIT, and HarvardNational Institutes of Health (U.S.) (NIH AI095109)United States. Dept. of Defense. Institute for Soldier Nanotechnologies (contract W911NF-07-D-0004)United States. Dept. of Defense. Institute for Soldier Nanotechnologies (contract W911NF-07-0004

Design of Lipid Nanocapsule Delivery Vehicles for Multivalent Display of Recombinant Env Trimers in HIV Vaccination

Immunization strategies that elicit antibodies capable of neutralizing diverse virus strains will likely be an important part of a successful vaccine against HIV. However, strategies to promote robust humoral responses against the native intact HIV envelope trimer structure are lacking. We recently developed chemically cross-linked lipid nanocapsules as carriers of molecular adjuvants and encapsulated or surface-displayed antigens, which promoted follicular helper T-cell responses and elicited high-avidity, durable antibody responses to a candidate malaria antigen. To apply this system to the delivery of HIV antigens, Env gp140 trimers with terminal his-tags (gp140T-his) were anchored to the surface of lipid nanocapsules via Ni-NTA-functionalized lipids. Initial experiments revealed that the large (409 kDa), heavily glycosylated trimers were capable of extracting fluid phase lipids from the membranes of nanocapsules. Thus, liquid-ordered and/or gel-phase lipid compositions were required to stably anchor trimers to the particle membranes. Trimer-loaded nanocapsules combined with the clinically relevant adjuvant monophosphoryl lipid A primed high-titer antibody responses in mice at antigen doses ranging from 5 μg to as low as 100 ng, whereas titers dropped more than 50-fold over the same dose range when soluble trimer was mixed with a strong oil-in-water adjuvant comparator. Nanocapsule immunization also broadened the number of distinct epitopes on the HIV trimer recognized by the antibody response. These results suggest that nanocapsules displaying HIV trimers in an oriented, multivalent presentation can promote key aspects of the humoral response against Env immunogens

Power to Detect the Effects of HIV Vaccination in Repeated Low‐Dose Challenge Experiments

Simulation studies were conducted to estimate the statistical power of repeated low-dose challenge experiments in non-human primates to detect a candidate HIV vaccine’s effect. The effect of various design parameters on power was explored. Simulation results indicate repeated low-dose challenge studies with total sample size 50 (25 per arm) typically provide adequate power to detect a 50% reduction in the per-exposure probability of infection due to vaccination. Power generally increases with the maximum number of allowable challenges per animal, the per-exposure risk of infection in controls, and the proportion susceptible to infection

Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization

T cells are an important component of immune responses, and their function is influenced by their expression of inhibitory receptors. Immunization with alternative serotype adenovirus (Ad) vectors induces highly functional T cell responses with lower programmed cell death 1 (PD-1) expression and increased boostability relative to Ad5 vectors. However, a detailed phenotypic characterization of other inhibitory receptors is lacking, and it is unknown whether Ad5-induced CD8 T cells eventually recover function with time. In this report, we measure the expression of various inhibitory receptors and memory markers during early and late time points following vaccination with Ad5 and alternative serotype Ad vectors. CD8 T cells induced by Ad5 exhibited increased expression of the inhibitory receptor Tim-3 and showed decreased central memory differentiation as compared with alternative serotype Ad vectors, even a year following immunization. Moreover, relative to Ad5-primed mice, Ad26-primed mice exhibited substantially improved recall of SIV Gag-specific CD8 T cell responses following heterologous boosting with MVA or Ad35 vectors. We also demonstrate that low doses of Ad5 priming resulted in more boostable immune responses with lower PD-1 expression as compared to high Ad5 doses, suggesting a role for vector dose in influencing immune dysfunction following Ad5 vaccination. These data suggest that Ad5 vectors induce a long-term pattern of immune exhaustion that can be partly overcome by lowering vector dose and modulating inhibitory signals