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Ho Progress Report Abstracts continued

 

Submitted July 30, 2010

Drs. David Ho and Sandhya Vasan at the Aaron Diamond AIDS Research Center (ADARC) have successfully completed the first Phase 1 clinical trial of ADVAX, a DNA-based HIV vaccine candidate delivered with the TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, in healthy volunteers. Strong positive results indicate that in vivo electroporation is safe, tolerable, enhances the cellular immunogenicity of ADVAX, and is dose-sparing.

Drs. Moriya Tsuji and Sandhya Vasan at ADARC have identified a promising new glycolipid-based vaccine adjuvant, 7DW8-5, which significantly enhances the immunogenicity of DNA and adenovirus-based vaccines. Through a fruitful partnership with the U.S. Naval Medical Research Center (NMRC), they are testing the efficacy of this glycolipid-based adjuvant with an Ad5-based vaccine candidate in anticipation of advancing to a Phase 1 clinical trial in humans next year.

Dr. Yaoxing Huang at ADARC has identified novel flagellin variants with increased TLR5 binding affinity.  When co-administrated with the HIV antigen p24, one of these flagellin variants greatly enhances the anti-p24 antibody response, demonstrating potent adjuvant activity and a significant dose-sparing effect in vivo.

Dr. Ralph Steinman at Rockefeller University (RU) has isolated and cloned several monoclonal antibodies that target various dendritic cell (DC) receptors, and are currently evaluating the immune response of different HIV antigens fused to these novel antibodies.  A Phase I study using HIV-1 p24 fused to the most promising of these monoclonal antibodies, targeting DEC-205 on dendritic cells, is underway through the Grand Challenges Program.

 

Submitted January 15, 2010 (Interim Report) 

Drs. Ralph Steinman and Michel Nussenzweig at the Rockefeller University have completed a study comparing a large panel of agonists for pattern recognition receptors and determined that synthetic double stranded RNAs are superior adjuvants for cell mediated immunity (Longhi et al, 2009).  Proof-of-concept studies in humans have begun with adjuvant-only studies, in advance of an impending study of DEC-205 targeted vaccines in humans.

Drs. Moriya Tsuji and Sandhya Vasan at the Aaron Diamond AIDS Research Center (ADARC), continue to advance a promising new glycolipid-based vaccine adjuvant into clinical development.

Drs. Adolfo Garcia-Sastre, Thomas Moran, and Peter Palese have completed initial studies of New Castle Disease Virus (NDV) as a potential vaccine vector with promising preliminary results on the immunogenicity of HIV antigens expressed by NDV.

Drs. David Ho and Sandhya Vasan recently presented results from the first Phase I clinical trial of TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, delivered with ADVAX, a DNA-based HIV vaccine candidate, in healthy volunteers.  Interim analyses indicate that the TriGridTM system is tolerable and acceptable in healthy volunteers, and significantly improves immune responses to the ADVAX vaccine over conventional intramuscular injection

 

Submitted July 31, 2009 

Drs. Ralph Steinman and Dr. Michel Nussenzweig at Rockefeller University (RU) have created mouse monoclonal antibodies to DC receptor targets coupled to test antigens.  The impact of targeting antigens via different DC receptors and different DC subsets on the quality and quantity of the immune response is being investigated in conjunction with various Toll-like receptor (TLR) ligands as vaccine adjuvants. 

Drs. Moriya Tsuji and Sandhya Vasan at the Aaron Diamond AIDS Research Center (ADARC), are advancing a promising new glycolipid-based vaccine adjuvant into clinical development, in anticipation of a Phase 1 clinical trial in humans in the next year.

Dr. Jeffrey Ravetch at RU has identified human Fc sequences which optimize the activation:inhibition ratio.  Dr. Yaoxing Huang at ADARC has shown that varying the Fc sequence has a significant effect on immunogenicity of HIV Gag fused to differing IgG subtypes.  He has also identified novel flagellin variants with increased TLR5 binding affinity, which may increase immunogenicity when fused to HIV proteins.   

Drs. Adolfo Garcia-Sastre and Peter Palese at Mount Sinai School of Medicine are developing Newcastle Disease Virus (NDV) as a potential vaccine vector. Codon-optimized gag has been introduced into the optimal insertion sites in the vector, yielding promising immunogenicity results in mice.

Drs. David Ho and Sandhya Vasan are leading the first Phase I clinical trial of TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, delivered with ADVAX, a DNA-based HIV vaccine candidate, in healthy volunteers at the Rockefeller University Hospital.  All volunteers have completed their vaccinations, with trial completion anticipated in November 2009.

Submitted January 15, 2009 (Interim Report)

The laboratory of Dr. Ralph Steinman at Rockefeller University (RU) has been evaluating the immune response to proteins fused to monoclonal antibodies targeting various dendritic cell (DC) receptors.  The clinical development of DEC-205-Gag, the first DC-targeted vaccine candidate fused to HIV Gag, is proceeding under the Grand Challenges Program.  In the past year, the laboratories of Dr. Steinman and Dr. Michel Nussenzweig have created mouse monoclonal antibodies to other DC receptor targets, coupled to test antigens.  The impact of targeting antigens via different DC receptors and different DC subsets on the quality and quantity of the immune response is being investigated in conjunction with various Toll-like receptor (TLR) ligands as vaccine adjuvants.

Dr. Chi-Huey Wong at Academia Sinica has previously synthesized a library of glycolipid analogues based on known structure-function correlates with alpha galactosyl ceramide.  After extensive characterization and screening for NKT cell activation, cytokine secretion, and adjuvant effect with various vaccines by Dr. Moriya Tsuji at the Aaron Diamond AIDS Research Center (ADARC), the most promising clinical lead is moving forward into clinical development, and GMP manufacturing is underway, in anticipation of a Phase 1 clinical trial in humans in the next year.

The laboratory of Dr. Jeffrey Ravetch at RU has created yeast libraries to express novel human Fc sequences to optimize the activation: inhibition ratio.  Dr. Yaoxing Huang at ADARC is leading the effort to test HIV vaccine candidates fused to differing IgG subtypes to assess differences in immunogenicity and has shown that varying the Fc sequence can have a significant effect on immunogenicity of HIV Gag.

Dr. Huang and colleagues have shown that HIV-1 proteins fused to flagellin, in the absence of any adjuvant, can significantly enhance vaccine immunogenicity, and are now identifying novel flagellin variants with increased TLR5 binding affinity.

Dr. Adolfo Garcia-Sastre and Dr. Peter Palese at Mount Sinai School of Medicine are developing Newcastle Disease Virus (NDV) as a potential vaccine vector. In the past year, codon-optimized gag inserts have been introduced into the optimal insertion sites in the vector, leading to further enhancements in immunogenicity.

Dr. David Franco at ADARC is leading the effort to synthesize a viral-like particle expressing HIV-Gag coupled with CD40L on the surface, in order to both target and mature DCs.  Construction of the murine CD40L VLP has been completed and characterization and immunogenicity evaluations are underway.

Drs. David Ho and Sandhya Vasan are leading a clinical trial to test the effect of in vivo electroporation on enhancing the immune response to ADVAX, a DNA-based candidate HIV vaccine, in healthy HIV-uninfected, low-risk volunteers.  The TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, Inc., has been shown to enhance the humoral and cellular immune response to several DNA-based vaccines in animals.  The first Phase I clinical trial of this device in healthy volunteers is now underway at the Rockefeller University Hospital.  All volunteers have been enrolled and have successfully received two vaccinations.

Submitted August 1, 2008

The laboratory of Dr. Ralph Steinman at Rockefeller University has been evaluating the immune response to proteins fused to monoclonal antibodies targeting various dendritic cell (DC) receptors. In combination with maturation stimuli to ensure DC activation, these DC-targeted immunogens elicit far greater immunogenicity in mice than untargeted proteins, and provide protection in a vaccinia-Gag challenge model developed by Dr. Thomas Moran at Mount Sinai School of Medicine. The DCapproach represents the first time that these pivotal immune sentinel cells have been harnessed directly in vaccine design. The clinical development of DEC-205-Gag, the first DC-targeted vaccine candidate fused to HIV-Gag, is proceeding under the Grand Challenges Program. In the past year, the laboratories of Dr. Steinman and Dr. Michel Nussenzweig have created mouse monoclonal antibodies to other DC receptor targets, coupled to test antigens. The impact of targeting antigens via different DC receptors and different DC subsets on the quality and quantity of the immune response is being investigated in conjunction with various Toll-like receptor (TLR) ligands as vaccine adjuvants.

The laboratory of Dr. Moriya Tsuji at the Aaron Diamond AIDS Research Center (ADARC) has been working closely with Dr. Chi-Huey Wong and colleagues at Academia Sinica in Taiwan to develop novel glycolipid compounds as vaccine adjuvants. Dr. Wong has synthesized a library of glycolipid analogues based on known structure-function correlates with alpha galactosyl ceramide. After extensive characterization and screening for NKT cell activation, cytokine secretion, and adjuvant effect with various vaccines, the most promising clinical lead is moving forward into clinical development.

The laboratory of Dr. Jeffrey Ravetch at Rockefeller University has created yeast libraries to create novel human Fc sequences to optimize the activation: inhibition ratio. In parallel, Dr. Yaoxing Huang at ADARC is leading the effort to test HIV vaccine candidates fused to differing IgG subtypes to assess differences in immunogenicity.

Bacterial flagellin interacts with TLR5 and primes the immune system to elicit strong adaptive immune responses. Dr. Huang and colleagues have shown that HIV-1 proteins fused to flagellin, in the absence of any adjuvant, can significantly enhance vaccine immunogenicity.

Dr. Adolfo Garcia-Sastre and Dr. Peter Palese at Mount Sinai School of Medicine are developing Newcastle Disease Virus (NDV) as a potential vaccine vector. Unlike the majority of viruses, NDV comes from an avian host and does not inhibit type I-IFN and DC maturation in mammals. There is no pre-existing immunity in humans. Under their guidance, Dr. Elena Carnero has synthesized NDV expressing HIV-Gag at various insertion sites, and has identified the insertion site allowing for maximal antigen expression and immunogenicity in mice, in collaboration with Drs. Antonio Borderia-Giner and Wen-Jinn Li from Dr. Thomas Moran’s group.

Dr. David Franco at ADARC is leading the effort to synthesize a viral-like particle expressing HIV-Gag coupled with CD40L on the surface, in order to both target and mature DCs. Construction of the murine CD40L VLP has been completed and characterization and immunogenicity valuations are underway.

Drs. David Ho and Sandhya Vasan are leading a clinical trial to test the effect of in vivo electroporation on enhancing the immune response to ADVAX, a DNA-based candidate HIV vaccine, in healthy HIVuninfected, low-risk volunteers. The TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, Inc., has been shown to enhance the humoral and cellular immune response to several DNA-based vaccines in animals. The first Phase I clinical trial of this device in healthy volunteers in now underway at the Rockefeller University Hospital.

Submitted January 15, 2008 (Interim Report)

The laboratory of Dr. Ralph Steinman at Rockefeller University has been evaluating the immune response to proteins fused to monoclonal antibodies targeting various dendritic cell (DC) receptors.  In combination with maturation stimuli to ensure DC activation, these DC-targeted immunogens elicit far greater immunogenicity in mice than untargeted proteins, and provide protection in a vaccinia-gag challenge model developed by Dr. Thomas Moran at Mount Sinai School of Medicine.  The DC-approach represents the first time that these pivotal immune sentinel cells have been harnessed directly in vaccine design.  The clinical development of DEC-205-Gag, the first DC-targeted vaccine candidate fused to HIV-Gag, is proceeding under the Grand Challenges Program.  In the past year, the laboratories of Dr. Steinman and Dr. Michel Nussenzweig have created mouse monoclonal antibodies to other DC receptor targets, coupled to test antigens.  The impact of targeting antigens via different DC receptors and different DC subsets on the quality and quantity of the immune response is being investigated in conjunction with various Toll-like receptor (TLR) ligands as vaccine adjuvants. 

The laboratory of Dr. Moriya Tsuji at the Aaron Diamond AIDS Research Center (ADARC) has been working closely with Dr. Chi-Huey Wong and colleagues at Academia Sinica in Taiwan to develop novel glycolipid compounds as vaccine adjuvants.  Dr. Wong has synthesized a library of glycolipid analogues based on known structure-function correlates with alpha galactosyl ceramide.  After extensive characterization and screening for NKT cell activation, cytokine secretion, and adjuvant effect with various vaccines, the most promising clinical lead is moving forward into clinical development.

The laboratory of Dr. Jeffrey Ravetch at Rockefeller University has created yeast libraries to create novel human Fc sequences to optimize the activation: inhibition ratio.  In parallel, Dr. Yaoxing Huang at ADARC is leading the effort to test HIV vaccine candidates fused to differing IgG subtypes to assess differences in immunogenicity. 

Bacterial flagellin interacts with TLR5 and primes the immune system to elicit strong adaptive immune responses.  Dr. Huang and colleagues have shown that HIV-1 proteins fused to flagellin, in the absence of any adjuvant, can significantly enhance vaccine immunogenicity.   

Dr. Adolfo Garcia-Sastre and Dr. Peter Palese at Mount Sinai School of Medicine are developing Newcastle Disease Virus (NDV) as a potential vaccine vector. Unlike the majority of viruses, NDV comes from an avian host and does not inhibit type I-IFN and DC maturation in mammals.  There is no pre-existing immunity in humans.  Under their guidance, Dr. Elena Carnero has synthesized NDV expressing HIV-gag at various insertion sites, and has identified the insertion site allowing for maximal antigen expression and immunogenicity in mice, in collaboration with Drs. Antonio Borderia-Giner and  Wen-Jinn Li from Dr. Thomas Moran’s group.

Dr. David Franco is leading the effort to synthesize a viral-like particle expressing HIV-gag coupled with CD40L on the surface, in order to both target and mature DCs.  Construction of the murine VLP has been completed and characterization and immunogenicity evaluations are underway. 

Drs. David Ho and Sandhya Vasan are leading a clinical trial to test the effect of in vivo electroporation on enhancing the immune response to ADVAX, a DNA-based candidate HIV vaccine, in healthy HIV-uninfected, low-risk volunteers.  The TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, Inc., has been shown to enhance the humoral and cellular immune response to several DNA-based vaccines in animals.  The first Phase I clinical trial of this device in healthy volunteers in now underway at the Rockefeller University Hospital.

Submitted August 1, 2007

Drs. Ralph Steinman and Michel Nussenzweig at Rockefeller University (RU) are evaluating the immune response to proteins fused to monoclonal antibodies targeting various dendritic cell (DC) receptors. These DC-targeted immunogens elicit greater immunogenicity in mice than untargeted proteins, and provide protection in a vaccinia-gag challenge model developed by Dr. Thomas Moran atMount Sinai School of Medicine (MSSM). Dr. Moriya Tsuji at the Aaron Diamond AIDS Research Center (ADARC) and Dr. Chi-Huey Wong at Academia Sinica are developing novel glycolipid compounds as vaccine adjuvants. Based on in vitro and in vivo screening, a lead compound is now entering clinical development. Dr. Jeffrey Ravetch at RU is screening novel Fc sequences to maximize activation. Dr. Yaoxing Huang at ADARC is leading the effort to test HIV vaccine candidates fused to differing IgG subtypes to assess differences in immunogenicity. Blockade of inhibitory FcRs is being studied by Dr. Jerry Zaharatos ADARC as a potential vaccine adjuvant. Dr. Adolfo Garcia-Sastre and Dr. Peter Palese at MSSM are developing Newcastle Disease Virus (NDV) as a potential vaccine vector. Unlike the majority of viruses, NDV comes from an avian host and does not inhibit type I-IFN and DC maturation in mammals. There is no pre-existing immunity in humans. Under their guidance, Dr. Elena Carnero has synthesized NDV expressing HIV-gag at various insertion sites, and is comparing the relative immunogenicity in mice for further development. Dr. David Franco has synthesized a viral-like particle expressing HIV-gag coupled with CD40L on the surface, to target and mature DCs.

 
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