Replication-Competent NYVAC-KC Yields Improved Immunogenicity to HIV-1 Antigens in Rhesus Macaques Compared to Nonreplicating NYVAC

Abstract

As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here, we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a nonhuman primate study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140, and Gag/Gag-Pol-Nef-derived virus-like particles (VLPs) from clade C and were used as the prime, with recombinant virus plus envelope protein used as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial. IMPORTANCE Though the RV144 phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 study. With that goal in mind, we have tested in nonhuman primates an attenuated but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 study. The results of this study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate.

Priming with a Potent HIV-1 DNA Vaccine Frames the Quality of Immune Responses prior to a Poxvirus and Protein Boost

“…The same was true for the functional antibody responses. At the end of both studies, however, ADCC and ADCVI titers reached roughly similar levels with no significant differences between the three DNA-poxvirus-protein groups (this study) and the poxvirus-protein-only regimens (29).…”

“…The magnitude of T cell responses at the peak time points as measured by an IFN-␥ enzyme-linked immunosorbent spot (ELISpot) assay was similar in the DNA-poxvirusprotein regimens regardless of whether the parental NYVAC vector or the NYVAC-KC derivative with enhanced replication competence was used. In quantitative terms, the peak responses in the DNA-primed groups were 5-fold and 15-fold higher than responses with the poxvirus-protein-only regimens employing NYVAC-KC and NYVAC, respectively (29). Correspondingly, HIV-specific T cells comprised 0.5% (CD4 ϩ ) and 0.4% (CD8 ϩ ) at week 24 in the poxvirus-protein-only study, as opposed to 1.5% (CD4 ϩ ) and 1.7% (CD8 ϩ ) in the DNA-poxvirus-protein study.…”

“…In contrast, the humoral responses peaked earlier with the poxvirus-protein-only regimen (29), most likely because the first protein immunization took place already at week 12. The same was true for the functional antibody responses.…”

“…In a companion paper (Kibler et al in this issue [29]), a comparison of the immune responses elicited by NYVAC plus TV1 gp120 protein and NYVAC-KC plus TV1 gp120 protein without the DNA prime is described (here referred to as poxvirus-protein-only regimen). Whereas NYVAC-KC was clearly more immunogenic than NYVAC when applied in the poxvirus-protein-only regimen (29), no immunological differences were observed between the groups receiving NYVAC and NYVAC-KC in the context of the DNA-poxvirus-protein regimen (this study).…”

“…In this context, we have previously described that, for HIV-1 antigens, a DNA prime and poxvirus and protein boost regimen (DNA-poxvirus-protein regimen) elicits high-magnitude, broad, and polyfunctional T cell responses, as well as high-titer IgG antibody responses that also exhibit high levels of functional Fc-mediated responses in rhesus macaques (28). The aim of the current study was to assess how a more immunogenic variant of the New York vaccinia virus (NYVAC) strain, termed NYVAC-KC (see the companion paper by Kibler et al in this issue [29] and reference 30) would affect the magnitude and quality of immune responses following DNA priming. In this regard, a side-by-side comparison of three different boost modalities was performed in nonhuman primates.…”