Gerard Zurawski Ph.D.

Cheng, L., Z. Zhang, G. Li, F. Li, L. Wang, L. Zhang, S. M. Zurawski, G. Zurawski, Y. Levy and L. Su (2017). “Human innate responses and adjuvant activity of tlr ligands in vivo in mice reconstituted with a human immune system.” Vaccine: 2017 Sep [Epub ahead of print].

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TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-alpha production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-alpha than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4+ T cell response, while only R848 and Poly I:C induced CD8+ cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans.

Surenaud, M., C. Lacabaratz, G. Zurawski, Y. Levy and J. D. Lelievre (2017). “Development of an epitope-based hiv-1 vaccine strategy from hiv-1 lipopeptide to dendritic-based vaccines.” Expert Rev Vaccines 16(10): 955-972.

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INTRODUCTION: Development of a safe, effective and globally affordable Human Immunodeficiency Virus strain 1 (HIV-1) vaccine offers the best hope for future control of the HIV-1 pandemic. However, with the exception of the recent RV144 trial, which elicited a modest level of protection against infection, no vaccine candidate has shown efficacy in preventing HIV-1 infection or in controlling virus replication in humans. There is also a great need for a successful immunotherapeutic vaccine since combination antiretroviral therapy (cART) does not eliminate the reservoir of HIV-infected cells. But to date, no vaccine candidate has proven to significantly alter the natural history of an individual with HIV-1 infection. Areas covered: For over 25 years, the ANRS (France Recherche Nord&Sud Sida-HIV hepatites) has been committed to an original program combining basic science and clinical research developing an epitope-based vaccine strategy to induce a multiepitopic cellular response against HIV-1. This review describes the evolution of concepts, based on strategies using HIV-1 lipopeptides towards the use of dendritic cell (DC) manipulation. Expert commentary: Understanding the crucial role of DCs in immune responses allowed moving from the non-specific administration of HIV-1 sequences with lipopeptides to DC-based vaccines. These DC-targeting strategies should improve HIV-1 vaccine efficacy.

Graham, J. P., P. Authie, A. Karolina Palucka and G. Zurawski (2017). “Targeting interferon-alpha to dendritic cells enhances a cd8+ t cell response to a human cd40-targeted cancer vaccine.” Vaccine 35(35 Pt B): 4532-4539.

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Targeting antigens to antigen presenting cells (APC) enhances the potency of recombinant protein CD8+ T cell vaccines. Recent comparisons of recombinant protein-based dendritic cell (DC) targeting vaccines revealed differences in cross-presentation and identified CD40 as a potent human DC receptor target for antigen cross-presentation. Contrary to in vitro-derived monocyte (mo)DC, we found that interferon-alpha (IFNalpha) stimulation of human blood-derived DC was necessary for an antigen-specific IFNgamma CD8+ T cell response to a CD40 targeted cancer vaccine. Importantly, targeting an adjuvant in the form of IFNalpha to DC increased their potency to elicit antigen-specific production of IFNgamma by CD8+ T cells. Thus, we introduce the concept of DC adjuvant targeting to enhance the potency of vaccination.

Graham, J. P., P. Authie, A. Karolina Palucka and G. Zurawski (2017). “Targeting interferon-alpha to dendritic cells enhances a cd8+ t cell response to a human cd40-targeted cancer vaccine.” Vaccine: 2017 Jul [Epub ahead of print].

Full text of this article.

Targeting antigens to antigen presenting cells (APC) enhances the potency of recombinant protein CD8+ T cell vaccines. Recent comparisons of recombinant protein-based dendritic cell (DC) targeting vaccines revealed differences in cross-presentation and identified CD40 as a potent human DC receptor target for antigen cross-presentation. Contrary to in vitro-derived monocyte (mo)DC, we found that interferon-alpha (IFNalpha) stimulation of human blood-derived DC was necessary for an antigen-specific IFNgamma CD8+ T cell response to a CD40 targeted cancer vaccine. Importantly, targeting an adjuvant in the form of IFNalpha to DC increased their potency to elicit antigen-specific production of IFNgamma by CD8+ T cells. Thus, we introduce the concept of DC adjuvant targeting to enhance the potency of vaccination.

Zurawski, G., X. Shen, S. Zurawski, G. D. Tomaras, D. C. Montefiori, M. Roederer, G. Ferrari, C. Lacabaratz, P. Klucar, Z. Wang, K. E. Foulds, S. F. Kao, X. Yu, A. Sato, N. L. Yates, C. LaBranche, S. Stanfield-Oakley, K. Kibler, B. Jacobs, A. Salazar, S. Self, W. Fulp, R. Gottardo, L. Galmin, D. Weiss, A. Cristillo, G. Pantaleo and Y. Levy (2017). “Superiority in rhesus macaques of targeting hiv-1 env gp140 to cd40 versus lox-1 in combination with replication-competent nyvac-kc for induction of env-specific antibody and t cell responses.” J Virol 91(9): e01596-01616.

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We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a P value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+ and CD8+ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1.IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials.