HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140

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FIG 7

Correlation between T cell and antibody responses. (A) Correlation plot summarizing Spearman's rank-based correlations of CD4⁺ T cell responses with B cell assays for NYVAC-C-KC and NYVAC-C-KC-ΔB19R at week 26, ordered by the overall median correlation for each combination of cytokine and pooled antigen. (B) Correlation plot summarizing Spearman's rank-based correlations of CD8⁺ T cell responses with B cell assays for NYVAC-C-KC and NYVAC-C-KC-ΔB19R at week 26, ordered by the overall median correlation for each combination of cytokine and pooled antigen. CD4⁺ and CD8⁺ T cell responses were assessed for correlation with the gp120.TV1 antigen in BAMAs and ADCC GTL assays and with the MW965.26 isolate in TZM-bl NAb assays. In each case, reported P values were calculated by using a one-sided test with the alternative that the true correlation coefficient is greater than 0.

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DISCUSSION

After the modest efficacy obtained in the RV144 phase III clinical trial, the scientific community has focused on the generation and optimization of HIV/AIDS vaccine candidates to afford protection to a large percentage of vaccinees.

Poxviruses, and in particular the highly attenuated VACV strains MVA and NYVAC, have being widely used as HIV/AIDS vaccine candidates and are included as components of some of the clinical trials planned within the next 5 years on the basis of lessons learned from recent trials (8, 9, 38). However, despite the safety and immunogenicity profiles exhibited by these attenuated VACV strains, more efficient vectors that enhance the magnitude, breadth, polyfunctionality, and durability of the immune responses to exogenously expressed antigens are desirable. Different strategies have been used for poxviruses to achieve this purpose (35). One of them is the deletion of VACV immunomodulatory genes that are still present in the vector genome and whose gene products may be predicted to interfere with the optimal induction of cellular and humoral responses. In this sense, we previously reported enhanced immunogenicity in mice with MVA- and NYVAC-based recombinants by single or multiple deletions of VACV immunomodulatory genes such as B8R and/or B19R (17), A46R (25), C12L (39), C6L and/or K7R (40, 41), A41L and/or B16R (42), N2L (43), and F1L (44). Another strategy is the generation of new vectors with replication competence in human cells in order to increase the timing and levels of expression of the heterologous antigen in the host. To date, some replication-competent recombinant VACV-based vaccines have been used for various infectious diseases, demonstrating that they are able to elicit potent humoral and cell-mediated immune responses and to confer long-lasting protection while maintaining a safety phenotype (23, 45,–47).

In this study, we aimed to define best-in-class protocols of immunization following lessons learned from the RV144 efficacy clinical trial with poxvirus vectors. We have evaluated and compared the immunogenicities in NHPs of two replication-competent NYVAC-C recombinants generated by restoration of replication competence in human cells after the reincorporation of the K1L and C7L host range genes (NYVAC-C-KC) or by a combination of restoration of replication competence and the removal of the immunomodulatory viral molecule B19 (NYVAC-C-KC-ΔB19R) that blocks the type I IFN response. Through extensive analysis of HIV-1-specific immune responses, including measurement of the levels of several immune markers that have been associated with immune efficacy in the RV144 phase III clinical trial (2,–7), we observed that both the NYVAC-C-KC and NYVAC-C-KC-ΔB19R viruses were able to induce a broad spectrum of HIV-1-specific B and T cell responses against the HIV-1 antigens. Thus, the magnitudes of the vaccine-induced T cell immune responses were high in both immunization groups, and the deletion of the immunomodulatory gene B19R on the NYVAC-C-KC recombinant vector improved to some extent the magnitude of the HIV-1-specific CD4⁺ and CD8⁺ T cell immune responses. Moreover, a low level of IgA binding antibodies, a high level of binding IgG antibodies in serum and rectal mucosal samples, ADCC responses, and NAbs against different tier 1 and 2 HIV-1 isolates were elicited by NYVAC-C-KC and NYVAC-C-KC-ΔB19R, with some minor differences between the two groups. Interestingly, at the time of the peak response (week 26), the higher levels of HIV-1-specific CD4⁺ and CD8⁺ T cells elicited by NYVAC-C-KC and NYVAC-C-KC-ΔB19R coincided with similar high levels of antibodies to Env as well as with high HIV neutralization titers of ADCC at the same time, suggesting a correlation between enhanced CD4⁺/CD8⁺ T cell responses and B cell responses and pointing out that CD4⁺ and/or CD8⁺ T cells might influence the B cell response. In fact, a correlation analysis (Fig. 7) showed that the percentages of HIV-1-specific CD4⁺ T cell responses induced by the NYVAC-C-KC-ΔB19R vector have a more favorable trend toward a correlation with antibody responses than with NYVAC-C-KC. However, the correlation between CD8⁺ T cell and B cell responses was less pronounced than that for CD4⁺ T cells.

How does the B19R gene operate? It has been shown that B19 is a type I IFN binding protein that acts both in solution and when bound to glycosaminoglycans to inhibit the action of a wide range of IFNs from different species, sequestering and suppressing efficiently the function of type I IFNs (48, 49). In cells infected with a NYVAC vector lacking B19, we have shown enhanced IFN-α production, maturation, and expression of IFN-induced pathways, IFN-regulated transcription factors, as well as multiple inflammatory cytokines in human DCs (12). Immunization of mice with NYVAC lacking B19R and expressing Env, Gag, Pol, and Nef clade C (CN54) HIV-1 antigens improved the magnitude and quality of HIV-1-specific CD8⁺ T cell adaptive immune responses and impacted their memory phase, changing the contraction, the memory differentiation, the magnitude, and the functionality profile, while for B cell responses, B19 had no apparent effect on antibody levels (17). The immunomodulatory effects of B19 were more pronounced in mice than in NHPs. Here, in NHPs, we noted the influence of B19 by a trend toward slightly higher levels of T cells and of some cytokines triggered by NYVAC-C-KC-ΔB19R than those elicited by NYVAC-C-KC at some time points after boost immunization. The overall effect of B19 on Env-specific binding IgG antibodies, IgA, NAbs, and ADCC was not different between the NYVAC-C-KC vectors. Thus, it seems that the main effect of B19 is on T cell responses, and the role of B19R in blocking type I IFN could explain the small differences in immunogenicity, in particular in T cell responses, observed in macaques inoculated with NYVAC-C-KC versus NYVAC-C-KC-ΔB19R.

In our previous study in NHPs, we demonstrated that a nonreplicating NYVAC vector expressing the same HIV-1 antigens and the same protocol as those used in this study was superior to the ALVAC vector used in the RV144 phase III clinical trial (13). Comparison of the immunogenicity profiles triggered by the NYVAC-C-KC vectors (this study) with that of the nonreplicating NYVAC vector (13) using the same standardized immune assays revealed an overall higher magnitude of HIV-1-specific T cell and humoral immune responses induced by the NYVAC-C-KC vectors. This is likely due to more antigen expression from the NYVAC-C-KC vectors (Fig. 1), as the virus replicates more efficiently in NHPs than does NYVAC lacking the VACV host range genes K1L and C7L. These results correlated with our previously reported in vitro findings, which demonstrated that NYVAC-KC vectors acquired specific biological characteristics over nonreplicating NYVAC, giving replication competency in human keratinocytes and dermal fibroblasts, the activation of selective host cell signal transduction pathways, and higher-level virus spread in tissues while maintaining a highly attenuated phenotype (19, 26). While antigen exposure was defined recently as a determinant of HIV-1 broadly neutralizing antibody (bnAb) induction (50), the question remains as to how to best induce bnAbs by vaccination approaches. Using the protocols described here, we have been able to trigger a broad spectrum of T and B cell immune responses. A balance of T and B cell immune responses has been correlated with levels of protection by HIV vaccines in NHP models of HIV infection (51). A number of HIV/simian immunodeficiency virus (SIV) vaccine protection studies in NHPs have revealed a role for humoral responses as potential correlates of immunity (52,–54), broadly including the types of immune responses elicited by this vaccine regimen. However, it remains to be defined whether the responses elicited by NYVAC-C-KC vectors confer protection against a simian-human immunodeficiency virus (SHIV) challenge and/or are able to induce bnAbs or other potentially protective immune responses in NHPs in a prophylactic phase I clinical trial.

The immunological profiles induced by the NYVAC-C-KC vectors, including the induction of CD4⁺ and CD8⁺ T cell immune responses; the high levels of anti-Env binding antibodies to both gp140 and V1/V2 sites; and enhanced ADCC responses and neutralizing capacity, together with low levels of IgA antibodies, are all potential correlates of protection, suggesting that these viral vectors could be considered improved HIV/AIDS vaccine candidates.

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MATERIALS AND METHODS

Replication-competent recombinant vectors NYVAC-C-KC and NYVAC-C-KC-ΔB19R expressing clade C HIV-1 antigens.

The VACV K1L and C7L genes were inserted into poxvirus recombinant vectors NYVAC-gp140 and NYVAC-Gag-Pol-Nef, as previously described (24), to generate the replication-competent recombinants NYVAC-KC-gp140 and NYVAC-KC-Gag-Pol-Nef, respectively, according to the same methodology as the one described previously (19). Thus, the replication-competent NYVAC-C-KC vector consists of two NYVAC-KC viruses that express different clade C HIV-1 antigens under the control of the same synthetic early/late poxvirus promoter (55), one (NYVAC-KC-gp140) expressing Env gp140 from strain 96ZM651 and the other (NYVAC-KC-Gag-Pol-Nef) expressing Gag from strain 96ZM651 and Pol and Nef from strain CN54. A description of the HIV-1 gp140 and Gag-Pol-Nef sequences included in the NYVAC-KC recombinant vectors was previously reported (10, 24). Next, the VACV B19R gene (B18R in the WR strain) was deleted from the replication-competent recombinant vectors NYVAC-KC-gp140 and NYVAC-KC-Gag-Pol-Nef to generate the replication-competent recombinant NYVAC-KC-gp140-ΔB19R and NYVAC-KC-Gag-Pol-Nef-ΔB19R vectors, respectively, according to the same methodology as the one described previously (19). Once generated, the resulting replication-competent NYVAC-KC-gp140, NYVAC-KC-Gag-Pol-Nef, NYVAC-KC-gp140-ΔB19R, and NYVAC-KC-Gag-Pol-Nef-ΔB19R recombinant viruses were expanded in large cultures of primary chicken embryo fibroblast (CEF) cells followed by virus purification through two 36% (wt/vol) sucrose cushions. Titers were determined by plaque immunostaining in BSC-40 cells. The expression of HIV-1 antigens by Western blotting and analysis of plaque size were done as previously described (24). Infection of human macrophages (THP-1 cells) and RNA analysis of IFN-β, MIP-1α, IL-8, and IL-1β by quantitative real-time PCR were done as previously described (40, 41). For simplicity of terminology, we refer to the combined mixed inoculation of NYVAC-KC-gp140 plus NYVAC-KC-Gag-Pol-Nef as NYVAC-C-KC and that of NYVAC-KC-gp140-ΔB19R plus NYVAC-KC-Gag-Pol-Nef-ΔB19R as NYVAC-C-KC-ΔB19R.

HIV-1 proteins.

For the immunizations performed in this study, we used a bivalent HIV-1 gp120 protein containing a mixture of TV1 gp120 and 1086 gp120, both from clade C. These proteins were expressed from stably transfected Chinese hamster ovary (CHO) cell lines, purified, and characterized as previously described (56).

Nonhuman primates.

Animals used in this study (designated AUP513) were outbred adult male Indian rhesus macaques (Macaca mulatta), which were housed, fed, given environmental enrichment, and handled at the animal facility of Advanced BioScience Laboratories (ABL), Inc. (Rockville, MD). The study protocol and animal care are in accordance with the standards of the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC International). The study was approved by the ABL, Inc., Institutional Animal Care and Use Committee in accordance with international guidelines. All procedures were carried out under anesthesia (ketamine administered at 10 mg/kg of body weight) by trained personnel under the supervision of veterinary staff, and all efforts were made to ameliorate animal welfare and to minimize animal suffering. During the study, macaques were observed for general behavior, clinical symptoms, and local reactions at the injection sites twice daily the week after immunizations. When animals were sedated for immunizations or sample collections, body weight and temperature were measured. The age of the animals ranged between 2.5 and 2.8 years, with a mean of 2.6 years, and the weight range was between 3.1 and 5.7 kg, with a mean of 3.8 kg. At selected time points, a physical examination was performed by a veterinarian, and clinical chemistry and hematology parameters were measured. All rhesus macaques were negative for tuberculosis, simian retrovirus (SRV), simian T cell leukemia virus 1 (STLV-1), herpesvirus B, SIV, measles virus, and poxvirus immunogens prior to the study and also had negative fecal cultures for salmonella, shigella, campylobacter, and yersinia. Furthermore, animals were immunologically naive for the vaccine components. A total of 16 animals were divided into two groups of 8 animals each.

Vaccines and immunization schedule.

Two immunization groups of eight rhesus macaques were included in the study protocol (termed AUP513), which was also reported previously (13). Group 1 received two immunizations with NYVAC-C-KC (containing a 1:1 mixture of NYVAC-KC-gp140 and NYVAC-KC-Gag-Pol-Nef) at weeks 0 and 4 and was boosted with two immunizations of NYVAC-C-KC plus bivalent HIV-1 gp120 proteins from clade C (containing a 1:1 mixture of TV1 gp120 and 1086 gp120) at weeks 12 and 24. Group 2 received two immunizations with NYVAC-C-KC-ΔB19R (containing a 1:1 mixture of NYVAC-KC-gp140-ΔB19R and NYVAC-KC-Gag-Pol-Nef-ΔB19R) at weeks 0 and 4 and was boosted with two immunizations of NYVAC-C-KC-ΔB19R plus bivalent HIV-1 gp120 proteins from clade C (TV1 gp120 and 1086 gp120) at weeks 12 and 24. All immunizations with the replication-competent NYVAC-C-KC vectors and proteins were given i.m. in the deltoid muscle of the upper right arm for the replication-competent NYVAC-C-KC vectors and in the opposite site, the upper left arm, for the gp120 proteins. A dose of 1 × 10⁸ PFU of each replication-competent NYVAC-C-KC vector (NYVAC-KC-gp140 plus NYVAC-KC-Gag-Pol-Nef in the case of NYVAC-C-KC and NYVAC-KC-gp140-ΔB19R plus NYVAC-KC-Gag-Pol-Nef-ΔB19R for NYVAC-C-KC-ΔB19R; 2 × 10⁸ PFU of total virus in 1.0 ml of Tris-buffered saline) and 50 μg each of the TV1 and 1086 clade C HIV-1 gp120 proteins (with adjuvant MF59; 100 μg of total protein in 1.0 ml) were used for each immunization. At weeks 0, 6, 14, 26, and 36 (at the beginning of the study; 2 weeks after the second, third, and fourth immunizations; and at the end of the study, respectively), PBMCs and serum samples were obtained from each immunized animal, and HIV-1-specific T cell and humoral immune responses were analyzed. Blood samples were processed according to current procedures (57).

Peptides.

Overlapping peptides (15-mers with 11 amino acids overlapping) spanning the Env, Gag, Pol, and Nef HIV-1 clade C regions were matched to the inserts expressed by NYVAC-C-KC and NYVAC-C-KC-ΔB19R. Peptides used in the IFN-y ELISpot and ICS assays for T cell stimulation were grouped into nine different peptide pools (Env-1, Env-2, Env-3, Pol-1, Pol-2, Gag-1, Gag/Pol, Gag-2/Pol, and Nef), with about 60 peptides per pool.

IFN-γ ELISpot assay.

The overall strength of the HIV-1-specific T cell immune responses induced was analyzed by an IFN-γ ELISpot analysis using freshly isolated PBMCs obtained from each immunized rhesus macaque, as previously described (10). Briefly, PBMCs were stimulated in triplicate with HIV-1 Env, Gag, Pol, and Nef peptide pools at 1 μg/ml or with phytohemagglutinin (PHA) (2.5 μg/ml) as a positive control, while the addition of medium only served as a negative control, according to protocols described previously (10). SFUs were counted as a measure of the magnitude of HIV-1-specific T cell responses.

ICS assay.

The HIV-1-specific CD4⁺ and CD8⁺ T cell immune responses induced were analyzed by polychromatic ICS using PBMCs obtained from each immunized rhesus macaque, as previously described (13, 57). In short, cryopreserved PBMCs were thawed and rested overnight in R10 medium (RPMI 1640 [BioWhittaker, Walkersville, MD], 10% fetal bovine serum [FBS], 2 mM l-glutamine, 100 U/ml penicillin G, 100 μg/ml streptomycin) with 50 U/ml Benzonase (Novagen, Madison, WI) in a 37°C incubator with 5% CO₂. The next day, 1 × 10⁶ to 3 × 10⁶ cells were stimulated in 96-well plates with the corresponding HIV-1 Env, Gag, Pol, and Nef peptide pools (2 μg/ml) in the presence of brefeldin A (10 μg/ml; BD Biosciences, San Jose, CA) for 6 h. Negative controls received an equal concentration of dimethyl sulfoxide (DMSO) instead of peptides. For staining, cells were fixed, permeabilized, and stained with different antibodies. The following fluorescence-labeled antibodies were used: CD3-Cy7-allophycocyanin (APC) (clone SP34.2; BD Biosciences), CD4-BV421 (clone OKT4; BioLegend), CD8-BV570 (clone RPA-T8; BioLegend), IFN-γ–APC (clone B27; BD Biosciences), IL-2–phycoerythrin (PE) (clone MQ1-17H12; BD Biosciences), and TNF-α–fluorescein isothiocyanate (FITC) (clone Mab11; BD Biosciences). An Aqua Live/Dead kit (Invitrogen, Carlsbad, CA) was used to exclude dead cells. All antibodies were previously titrated to determine the optimal concentration. Samples were acquired on an LSR II flow cytometer and analyzed by using FlowJo version 9.8 (TreeStar, Inc., Ashland, OR).

HIV-1-specific binding antibody assay.

HIV-1-specific binding IgG and IgA antibodies to HIV-1 gp120/gp140 proteins and MuLV gp70-scaffolded V1/V2 were measured in serum and rectal weck elutions from each immunized rhesus macaque by using a BAMA, as previously described (6, 7, 58). HIV-1 antigens used to analyze the levels of IgG or IgA binding antibodies included (i) consensus gp140 proteins of clade A (A1.con.env03 140 CF), clade B (B.con.env03 140 CF), clade C (C.con.env03 140 CF), and group M (Con S gp140 CF); (ii) primary Env variants, including 1086 gp120 (clade C), TV1 gp120 (clade C), JRFL gp140 (clade B), and MSA4076 gp140 (clade A1; also known as OOMSA); and (iii) MuLV gp70-scaffolded V1/V2 (from clade B; gp70_B.CaseA2 V1/V2). Different plasma serial dilutions were made, and the primary readout was the mean fluorescence intensity (MFI). For IgA, results are expressed as the MFI minus the background MFI at a dilution of 1/80. For IgG, MFI data were transformed to values defining the area under the curve (AUC), which resemble the integral of the curve for the MFI plotted against serial dilutions. Moreover, the specific activity of rectal mucosal IgG binding antibodies was calculated by dividing the antibody titer by the total IgG concentration. Values 3-fold above the values for the baseline visit were considered positive, and the cutoff was established by using negative serum samples. All assays were performed under good clinical laboratory practice (GCLP)-compliant conditions.

Antibody-dependent cellular cytotoxicity assay.

The ADCC activity against recombinant gp120 proteins from isolate 1086 or TV1 (clade C) in serum from each immunized rhesus macaque was analyzed according to the ADCC GranToxiLux (GTL) procedure, as previously described (59, 60). The results of the GTL assay were considered positive if the percentage of granzyme B activity after background subtraction was ≥8% for the infected target cells (61). The log₁₀ titer of the ADCC antibodies present in plasma was calculated by interpolating the log reciprocal of the last plasma dilution that yielded positive granzyme B activity (≥8%). The GTL ADCC assay was performed under GCLP-compliant guidelines.

Neutralizing antibodies against HIV-1.

NAbs against HIV-1 in serum from each immunized rhesus macaque were analyzed by using the TZM-bl cell assay and the more sensitive A3R5 cell assay, as previously described (62,–65). For the TZM-bl assay, the following isolates carrying Envs were used: BaL.26 (tier 1B, clade B), Ce1086 (tier 2, clade C), Ce1176 (tier 2, clade C), Ce2010 (tier 2, clade C), Du151.2 (tier 2, clade C), MN.3 (tier 1A, clade B), MW965.26 (tier 1A, clade C), SF162.LS (tier 1A, clade B), TH023.6 (tier 1, clade AE), TV1.21 (tier 2, clade C), and MuLV (as a negative control). For the A3R5 cell assay, we used viral infectious molecular clones (IMCs), which encoded luciferase on the genome (expressed in the cells only upon infection) and carried the ectodomains of env genes of the following isolates: Ce1086 (tier 2, clade C), Ce1176 (tier 2, clade C), Ce2010 (tier 2, clade C), Du151.2 (tier 2, clade C), and TV1.21 (tier 2, clade C). For both assays, the neutralization titers are represented as the log₁₀ serum dilution at which relative luminescence units (RLU) were reduced by 50% (50% infective dose [ID₅₀]) compared to values for virus control wells after subtraction of background RLU in cell control wells. Both assays were done under GCLP-compliant conditions.

Statistical procedures.

The Wilcoxon rank sum test was used to compare differences between groups. P values of <0.05 were considered significant. All values used for analyzing the proportionate representation of responses were background subtracted. Box plots were used to summarize the distribution of various immune responses, where the midline of the box indicates the median, the ends of the box denote the 25th and 75th percentiles, and whiskers extended to the extreme data points that are no more than 1.5 times the interquartile range (IQR) or, if no values meet this criterion, to the data extremes. Spearman's rank-based correlations were used to compare the association of CD4⁺ and CD8⁺ T cell responses with antibody responses from BAMAs, GTL ADCC assays, and NAb assays at week 26 between the NYVAC-C-KC and NYVAC-C-KC-ΔB19R vectors. Specifically, the DMSO-adjusted percent positivity for each cytokine and pooled antigen combination from the CD4⁺ and CD8⁺ T cell responses was assessed for correlation with (i) the AUC against the gp120.TV1 antigen for the IgG subclass in the BAMA assay, (ii) the titer against the gp120.TV1 antigen in the ADCC GTL assay, and (iii) the titer against the MW965.26 isolate in the TZM-bl NAb assay. The significance of the correlations was derived by using a one-sided P value with the alternative that a true correlation is greater than 0.

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ACKNOWLEDGMENTS

This investigation was supported by the PTVDC/CAVD Program with support from the Bill and Melinda Gates Foundation (BMGF). Humoral immune monitoring data were supported by BMGF CAVIMC grant 1032144 and the NIH/NIAID Duke Center for AIDS Research (CFAR; 5P30 AI064518). Novartis Vaccines received support for this work under contract number HHSN266200500007C from the DAIDS, NIAID, NIH.

We thank Marcella Sarzotti-Kelsoe for quality assurance oversight; William T. Williams, Robert Howington, R. Glenn Overman, Cristina Sánchez, and Victoria Jiménez for technical assistance; Sheetal Sawant for BAMA data management; and Hua-Xin Liao and Bart Haynes for envelope and V1/V2 protein reagents.

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