Multiple Immunizations with Attenuated Poxvirus HIV Type 2 Recombinants and Subunit Boosts Required for Protection of Rhesus Macaques

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141

The recombinant canarypox vector, ALVAC-HIV, together with human immunodeficiency virus (HIV) gp120 envelope glycoprotein, has protected 31.2% of Thai individuals from HIV acquisition in the RV144 HIV vaccine trial. This outcome was unexpected, given the limited ability of the vaccine components to induce CD8 ؉ T-cell responses or broadly neutralizing antibodies. We vaccinated macaques with an immunization regimen intended to mimic the RV144 trial and exposed them intrarectally to a dose of the simian immunodeficiency virus SIV mac251 that transmits few virus variants, similar to HIV transmission to humans. Vaccination induced anti-envelope antibodies in all vaccinees and CD4؉ and CD8 ؉ T-cell responses. Three of the 11 macaques vaccinated with ALVAC-SIV/gp120 were protected from SIV mac251 acquisition, but the result was not significant. The remaining vaccinees were infected and progressed to disease. The magnitudes of vaccine-induced SIV mac251 -specific T-cell responses and binding antibodies were not significantly different between protected and infected animals. However, sera from protected animals had higher avidity antibodies to gp120, recognized the variable envelope regions V1/V2, and reduced SIV mac251 infectivity in cells that express high levels of ␣ 4 ␤ 7 integrins, suggesting a functional role of antibodies to V2. The current results emphasize the utility of determining the titer of repeated mucosal challenge in the preclinical evaluation of HIV vaccines.

mentioning

confidence: 99%

Antibodies with High Avidity to the gp120 Envelope Protein in Protection from Simian Immunodeficiency Virus SIV _mac251 Acquisition in an Immunization Regimen That Mimics the RV-144 Thai Trial

Pegu

Vaccari

Gordon

et al. 2013

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129

141

“…In animal models, MVA as a vaccine vector has been found to induce very immunogenic responses to its inserts when administered by systemic and mucosal routes as well as providing protection against various infectious agents, including immunodeficiency viruses (for reviews, see references 18, 30, and 92). The NYVAC vector is derived from the vaccinia virus strain Copenhagen (94), is able to express multiple antigens from a wide range of species (93), and has been evaluated in several preclinical and clinical trials (7,29,45,66,87). The complements of genes that have been altered, modified, or lost are very different between these two vectors, as has recently been revealed by gene profiling (36).…”

mentioning

confidence: 99%

Differential CD4⁺versus CD8⁺T-Cell Responses Elicited by Different Poxvirus-Based Human Immunodeficiency Virus Type 1 Vaccine Candidates Provide Comparable Efficacies in Primates

Mooij

Balla-Jhagjhoorsingh

Koopman

et al. 2008

Poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. Recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (HIV) vaccine candidates, New York vaccinia virus (NYVAC) and modified vaccinia virus Ankara (MVA). To understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, we undertook a head-to-head vaccine immunogenicity and efficacy study in the pathogenic HIV type 1 (HIV-1) model of AIDS in Indian rhesus macaques. Differences in the immune responses in outbred animals were not distinguished by enzymelinked immunospot assays, but differences were distinguished by multiparameter fluorescence-activated cell sorter analysis, revealing a difference between the number of animals with both CD4 ؉ and CD8 ؉ T-cell responses to vaccine inserts (MVA) and those that elicit a dominant CD4 ؉ T-cell response (NYVAC). Remarkably, vector-induced differences in CD4 ؉ /CD8 ؉ T-cell immune responses persisted for more than a year after challenge and even accompanied antigenic modulation throughout the control of chronic infection. Importantly, strong preexposure HIV-1/simian immunodeficiency virus-specific CD4 ؉ T-cell responses did not prove deleterious with respect to accelerated disease progression. In contrast, in this setting, animals with strong vaccine-induced polyfunctional CD4 ؉ T-cell responses showed efficacies similar to those with stronger CD8 ؉ T-cell responses.

“…NYVAC-derived vectors are able to express antigens from a wide range of species (50). A number of examples have been reported, using NYVAC as a recombinant vaccine delivery system against pathogens and tumors (5,10,31,46). Clinical trials using NYVAC-based vectors show a good safety profile, with induction of high levels of immunity against heterologous antigens (24, 34).…”

mentioning

confidence: 99%

Host Response to the Attenuated Poxvirus Vector NYVAC: Upregulation of Apoptotic Genes and NF-κB-Responsive Genes in Infected HeLa Cells

Guerra¹,

López-Fernández²,

Pascual-Montano

et al. 2006

Attenuated strains of vaccinia virus (VV) were developed in response to the need for safer vaccines (37). NYVAC is a derivative of the VV Copenhagen strain in which 18 open reading frames were specifically deleted from the parental viral genome; genes involved in host range, virulence, and pathogenesis were thus lost (49). NYVAC-derived vectors are able to express antigens from a wide range of species (50). A number of examples have been reported, using NYVAC as a recombinant vaccine delivery system against pathogens and tumors (5,10,31,46). Clinical trials using NYVAC-based vectors show a good safety profile, with induction of high levels of immunity against heterologous antigens (24, 34).Since phase I/II clinical trials using this vector are currently under way, particularly for human immunodeficiency virus type 1 (HIV-1) (www.eurovacc.org), it is essential to obtain a comprehensive understanding of the effect of NYVAC infection on human host gene expression (34). DNA microarray technology allows monitoring of the expression of several thousand individual genes (22) and has been used to identify the differential expression of cellular genes in response to infection by several animal viruses, including VV strains WR (Western Reserve) and MVA (modified vaccinia Ankara) (15,16,29,55).Host genes that govern vital cell processes such as replication, transcription, and translation are downregulated during the course of WR infection. The expression of genes involved in apoptosis or the proteasome-ubiquitin degradation pathway is also repressed; few genes are upregulated after WR infection (15). A larger number of genes than that seen with WR is upregulated during strain MVA infection; most encode immune modulator proteins, some of which may be involved in host resistance and immune modulation during MVA infection (16). Wiskott-Aldrich syndrome protein (WASP) family members are upregulated after MVA or WR infection (15,16). This family includes the gene that codes for the N-WASP protein, implicated in the actin-mediated motility of VV as a mechanism for intercellular viral spreading (8,11). Additional studies show that WASP is required for VV pathogenesis (17). The results of microarray analysis have implicated cell signaling events and cell proteins as important regulators of VV infection.For this study, we used cDNA microarray technology to analyze host gene expression changes in HeLa cell cultures following NYVAC infection. This is the first large-scale analysis of the transcriptional response of HeLa cells to NYVAC infection. It provides a better understanding of the mechanisms of vaccine protection against VV infection and will aid in the development of NYVAC recombinant-based vaccines against pathogens and tumors. MATERIALS AND METHODSCells, viruses, and infection conditions. HeLa cells (ATCC) were cultured in Dulbecco's medium supplemented with 10% newborn bovine serum and antibiotics. The VV WR strain was cultured in monkey BSC-40 cells, purified by sucrose gradient banding, and titrated on BSC-40 cells by a p...