The Canarypox Virus Vector ALVAC Induces Distinct Cytokine Responses Compared to the Vaccinia Virus-Based Vectors MVA and NYVAC in Rhesus Monkeys

Teigler, Jeffrey E.; Phogat, Sanjay; Franchini, Genoveffa; Hirsch, Vanessa M.; Michael, Nelson L.; Barouch, Dan H.

doi:10.1128/jvi.02386-13

Cited by 58 publications

(52 citation statements)

References 35 publications

(36 reference statements)

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“…In RV144, an Env IgG3 response was correlated with decreased risk of HIV infection, a response that declined rapidly compared to overall IgG responses (99 (101). It is speculated that ALVAC priming, due to its unique proinflammatory cytokine and chemokine response following vaccination in rhesus monkeys and infection in human peripheral blood mononuclear cells (PBMC), may shift the IgG subclass response to IgG3 in humans after vector priming and envelope protein boosting compared with envelope vaccination alone (102). The contribution of Fc-Fc␥R interaction-mediated functions through mechanisms such as ADCC, antibody-dependent cell-mediated viral inhibition (ADCVI), and ADCP antibodies remains to be explored (103,104).…”

Section: Rv144 Prime-boost Efficacy Trialmentioning

confidence: 99%

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Excler¹,

Ake²,

Robb³

et al. 2014

Clin. Vaccine Immunol.

105

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Animal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nNAb) without neutralizing activity in vitro may play an important role in protection against viral infection in vivo. This was illustrated by the recent human immunodeficiency virus (HIV) RV144 vaccine efficacy trial, which demonstrated that HIV-specific IgG-mediated nNAb directed against the V2 loop of HIV type 1 envelope (Env) were inversely correlated with risk for HIV acquisition, while Env-specific plasma IgA-mediated antibodies were directly correlated with risk. However, tier 1 NAb in the subset of responders with a low level of plasma Env-specific IgA correlated with decreased risk. Nonhuman primate simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) challenge studies suggest that Env-mediated antibodies are essential and sufficient for protection. A comparison of immune responses generated in human efficacy trials reveals subtle differences in the fine specificities of the antibody responses, in particular in HIV-specific IgG subclasses. The underlying mechanisms that may have contributed to protection against HIV acquisition in humans, although not fully understood, are possibly mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other nonneutralizing humoral effector functions, such as antibody-mediated phagocytosis. The presence of such functional nNAb in mucosal tissues and cervico-vaginal and rectal secretions challenges the paradigm that NAb are the predominant immune response conferring protection, although this does not negate the desirability of evoking neutralizing antibodies through vaccination. Instead, NAb and nNAb should be looked upon as complementary or synergistic humoral effector functions. Several HIV vaccine clinical trials to study these antibody responses in various prime-boost modalities in the systemic and mucosal compartments are ongoing. The induction of high-frequency HIV-specific functional nNAb at high titers may represent an attractive hypothesis-testing strategy in future HIV vaccine efficacy trials. The identification of immune markers that correlate with protection against infection or disease after vaccination (or natural infection) remains the "holy grail" for vaccine scientists, as these immune markers have the potential to expedite vaccine development and provide unique insights into the pathogenesis of infection. For most of the vaccines available today, a functional antibody response is the identified correlate of protection (1). In the cases of candidate preventive human immunodeficiency virus (HIV) vaccines and experimental vaccines against the closely related retrovirus simian immunodeficiency virus (SIV), recent studies have suggested an antibody correlate of risk or protection. However, these studies suggested an association with antibodies that did not mediate broad or potent neutralization (2-5).Transmission of HIV type 1 (HIV-1) occurs through homosexual or heterosexual intercourse, through inje...

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Section: Rv144 Prime-boost Efficacy Trialmentioning

confidence: 99%

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Excler¹,

Ake²,

Robb³

et al. 2014

Clin. Vaccine Immunol.

105

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“…Stimulation of innate cytokines by the novel rhesus monkey adenoviruses was assessed by Luminex assays (Milliplex nonhuman primate premix 23-plex), as previously described (33,34). Fresh rhesus monkey peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque density gradient centrifugation.…”

Section: Isolation and Vectorization Of Novel Old World Monkey Adenovmentioning

confidence: 99%

Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

Abbink

Maxfield

Ng’ang’a

et al. 2015

J Virol

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Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. IMPORTANCEAlthough there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. R ecombinant adenoviruses (Ads) are currently being explored as candidate vaccine vectors for multiple pathogens (1-6), as a result of their safety profile, manufacturability, and ability to induce broad and strong immune responses (7-16). Multiple human and chimpanzee adenovirus vectors have been developed to date (8,9,(11)(12)(13). The majority of these adenovirus vectors are from species B, C, D, and E. Adenovirus vectors from avian, bovine, and other species have also been constructed, but their different genomic structures may necessitate the development of a novel manufacturing platform for clinical development (17, 18). Old World monkey adenoviruses have been hypothesized to be distinct from both human and chimpanzee adenoviruses and may offer unique advantages, such as the ability to more efficiently bypass preexisting immunity to human adenoviruses (12,(19)(20)(21)(22)(23)(24), while maintaining the genomic structure and growth properties of human adenoviruses.We isolated simian adenoviruses from fecal samples from rhesus monkeys (Macaca mulatta) that were positive for adenoviruses by metagenomics sequencing (25). We performed whole-genome sequencing of these novel adenoviruses and determined their phylogeny in comparison with that of other human and simian adenoviruses. The basic genetic structure of these novel rhesus monkey adenoviruses proved similar to that of human adenoviruses (7,16,26). We vectorized three rhesus monkey adenoviruses and then assessed humans in sub-Saharan Africa for seroprevalence of these adenoviruses and ...

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“…Distinct poxvirus vectors induce substantial differences in chemokine and cytokine profiles (21), which influence the adaptive immune responses. Whereas DCs and neutrophils transport VACV antigens to lymphoid organs and directly induce antigen-specific T cell responses (22,23), NK cells can generate the environment necessary to induce recruitment of activated T cells (20) or cross talk with DCs for the generation of antigen-specific T cell immunity (24).…”

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confidence: 99%

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Pilato

Mejías-Pérez

Sorzano

et al. 2017

J Virol

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Poxviruses use a complex strategy to escape immune control, by expressing immunomodulatory proteins that could limit their use as vaccine vectors. To test the role of poxvirus NF-B pathway inhibitors A52, B15, and K7 in immunity, we deleted their genes in an NYVAC (New York vaccinia virus) strain that expresses HIV-1 clade C antigens. After infection of mice, ablation of the A52R, B15R, and K7R genes increased dendritic cell, natural killer cell, and neutrophil migration as well as chemokine/cytokine expression. Revertant viruses with these genes confirmed their role in inhibiting the innate immune system. To different extents, enhanced innate immune responses correlated with increased HIV Pol-and Gag-specific polyfunctional CD8 T cell and HIV Env-specific IgG responses induced by single-, double-, and triple-deletion mutants. These poxvirus proteins thus influence innate and adaptive cell-mediated and humoral immunity, and their ablation offers alternatives for design of vaccine vectors that regulate immune responses distinctly.IMPORTANCE Poxvirus vectors are used in clinical trials as candidate vaccines for several pathogens, yet how these vectors influence the immune system is unknown. We developed distinct poxvirus vectors that express heterologous antigens but lack different inhibitors of the central host-cell signaling pathway. Using mice, we studied the capacity of these viruses to induce innate and adaptive immune responses and showed that these vectors can distinctly regulate the magnitude and quality of these responses. These findings provide important insights into the mechanism of poxvirus-induced immune response and alternative strategies for vaccine vector design.KEYWORDS NF-B, NYVAC, T cell immunity, adaptive immunity, human immunodeficiency virus, immunomodulation, innate immunity, poxvirus, vaccines, vaccinia virus S everal vaccine strategies have been developed to improve immune responses to heterologous antigens expressed by attenuated poxvirus vectors (1). Given the limited effectiveness of the ALVAC poxvirus vector in the RV144 phase III HIV/AIDS clinical trial (2), the need remains to improve poxvirus vector capacity as an immunogen, to increase protection levels, and to understand how innate and adaptive immune responses can be regulated.The attenuated poxvirus strain NYVAC (New York vaccinia virus) has been used as a vaccine vector in HIV clinical trials (3,4). Studies in nonhuman primates showed that NYVAC expressing Env and/or the Gag-Pol-Nef (GPN) clade C HIV antigens elicited a balanced CD4/CD8 T cell response (5) or robust T cell immunity (6). In clinical trials in healthy volunteers and in chronically HIV-infected patients, NYVAC showed clear immunogenic potential to induce expansion of preexisting T cell responses as well as the appearance of newly detected polyfunctional CD8 T cell responses (7).

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The Canarypox Virus Vector ALVAC Induces Distinct Cytokine Responses Compared to the Vaccinia Virus-Based Vectors MVA and NYVAC in Rhesus Monkeys

Cited by 58 publications

References 35 publications

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

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