Jeffery Fairman

Colby Pharmaceutical (United States)

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Stella Chang

North Carolina State University

Marla Lay

Juvaris BioTherapeutics (United States)

Shannon R. Matzinger

Colorado Department of Public Health and Environment

Christopher J. Miller

Hospital of the University of Pennsylvania

Bernadette Callejo

Juvaris BioTherapeutics (United States)

Timothy D. Carroll

University of California, Davis

Xiuhua Lu

Linyi People's Hospital

David B. Lewis

Stanford University

Feng Liu

Central China Normal University

Jacqueline M. Katz

The Task Force for Global Health

Cooperative Institutions

National Institute of Allergy and Infectious Diseases

National Institutes of Health

Centers for Disease Control and Prevention

Stanford University

National Center for Immunization and Respiratory Diseases

Cornell University

University of California, Davis

Juvaris BioTherapeutics (United States)

New York State College of Veterinary Medicine

Sutro Biopharma (United States)

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Efficacy of cationic lipid–DNA complexes (CLDC) on hepatitis B virus in transgenic mice

Antiviral Research (2008)

John D. Morrey Neil E. Motter Brandon Taro Marla Lay Jeffery Fairman

Adefovir

10.1016/j.antiviral.2008.01.157

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Citations (15)

A cationic lipid/DNA complexes (JVRS-100) combined with influenza A H5N1 vaccine induce long-term antibody responses and protection against H5N1 virus in BALB/c mice (155.31)

The Journal of Immunology (2011)

Feng Liu Kathy Hancock Jacqueline M. Katz Jeffery Fairman Xiuhua Lu

Abstract Highly pathogenic avian influenza A H5N1 viruses pose a pandemic threat. An adjuvant is needed due to poor immunogenicity of pre-pandemic H5N1 vaccine in humans. JVRS-100 is a novel adjuvant, composed of cationic liposomes and plasmid DNA. Here, we investigated the long-term immunogenicity and protective efficacy of JVRS-100-adjuvanted H5N1 vaccine in mice. One year after immunization with one dose of vaccine with or without JVRS-100 adjuvant, significantly higher levels of hemagglutination-inhibition antibody and IgG antibody could be detected in serum of mice immunized with adjuvanted vaccine compared to that of mice receiving vaccine only. No or limited waning of antibody response was observed up to one year after immunization. IgG2a clearly predominated in serum of mice that received adjuvanted vaccine, suggesting that JVRS-100 preferentially stimulates a Th1 response. Mice were challenged with a high lethal dose of H5N1 virus 14 months after immunization. Co-administration of JVRS-100 with H5N1 vaccine significantly reduced virus titers in the lungs and brains and completely protected mice from severe disease and death. Our results indicate that the addition of JVRS-100 to H5N1 vaccine enhanced long-term antibody responses and protection against H5N1 virus lethal disease in mice. Therefore, JVRS-100 warrants further investigation as a potential adjuvant for use in human vaccination against avian influenza viruses with pandemic potential.

Antibody titer

Inactivated vaccine

Hemagglutination assay

10.4049/jimmunol.186.supp.155.31

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Effective, Broad Spectrum Control of Virulent Bacterial Infections Using Cationic DNA Liposome Complexes Combined with Bacterial Antigens

PLoS Pathogens (2010)

Robin Ireland Norma Olivares-Zavaleta Jonathan M. Warawa Frank C. Gherardini Clayton O. Jarrett

Protection against virulent pathogens that cause acute, fatal disease is often hampered by development of microbial resistance to traditional chemotherapeutics. Further, most successful pathogens possess an array of immune evasion strategies to avoid detection and elimination by the host. Development of novel, immunomodulatory prophylaxes that target the host immune system, rather than the invading microbe, could serve as effective alternatives to traditional chemotherapies. Here we describe the development and mechanism of a novel pan-anti-bacterial prophylaxis. Using cationic liposome non-coding DNA complexes (CLDC) mixed with crude F. tularensis membrane protein fractions (MPF), we demonstrate control of virulent F. tularensis infection in vitro and in vivo. CLDC+MPF inhibited bacterial replication in primary human and murine macrophages in vitro. Control of infection in macrophages was mediated by both reactive nitrogen species (RNS) and reactive oxygen species (ROS) in mouse cells, and ROS in human cells. Importantly, mice treated with CLDC+MPF 3 days prior to challenge survived lethal intranasal infection with virulent F. tularensis. Similarly to in vitro observations, in vivo protection was dependent on the presence of RNS and ROS. Lastly, CLDC+MPF was also effective at controlling infections with Yersinia pestis, Burkholderia pseudomallei and Brucella abortus. Thus, CLDC+MPF represents a novel prophylaxis to protect against multiple, highly virulent pathogens.

Yersinia pestis

10.1371/journal.ppat.1000921

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A cationic lipid/DNA adjuvant (JVRS-100) dramatically improves the immunogenicity and protection after immunization of elderly rhesus monkeys with a licensed inactivated seasonal influenza vaccine (Fluzone®). (52.21)

The Journal of Immunology (2010)

Tmothy Carroll Shannon R. Matzinger Marla Lay Stella Chang Jeffery Fairman

Abstract To determine if an adjuvant can improve the efficacy of an inactivated seasonal influenza vaccine in immunosenescent primates, elderly rhesus monkeys were vaccinated with Fluzone. In a subset of the animals, Fluzone was mixed with a cationic lipid/DNA adjuvant (JVRS-100). After influenza A/Memphis/7/2001 (H1N1) challenge, the 9 monkeys vaccinated with Fluzone alone had no detectable reduction in viral shedding in tracheobronchial secretions relative to the 9 non-immunized control animals. However, the 9 animals immunized with JVRS-100 and Fluzone had a 4-fold lower peak level of virus in tracheobronchial secretions compared to unimmunized control animals (p<0.05) and Fluzone-only immunized monkeys (p<0.01). The cumulative level of viral replication as determined by an area under curve analysis were 7-8 fold lower (p<0.05) in animals immunized with JVRS-100 and Fluzone compared to both Fluzone-only and non-immunized monkeys. Moreover, monkeys immunized with JVRS-100 and Fluzone had no evidence of fever or weight loss whereas both signs of illness were evident in the non-immunized and Fluzone-only animals in the first week after challenge. Thus, addition of JVRS-100 to Fluzone generates protective immunity that blunts virus replication and eliminates the clinical signs seen in the elderly monkeys that are not protected by Fluzone alone.

Viral Shedding

Inactivated vaccine

10.4049/jimmunol.184.supp.52.21

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Rapid immunity to vaccination with woodchuck hepatitis virus surface antigen using cationic liposome–DNA complexes as adjuvant

Journal of Medical Virology (2009)

Paul J. Côté Scott D. Butler Andrea L. George Jeffery Fairman John L. Gerin

Complexes of cationic liposomes and non-coding DNA (CLDC) have shown promise as vaccine adjuvant. Using the woodchuck animal model of hepatitis B virus (HBV) infection, the immunogenic effects of CLDC were evaluated following vaccination with three doses of woodchuck hepatitis virus surface antigen (WHsAg) adjuvanted with either CLDC or conventional alum and administered intramuscularly (im) or subcutaneously (sc). IM vaccination with WHsAg and CLDC elicited antibodies earlier, in more woodchucks, and with higher titers than WHsAg and alum. After two vaccine doses, antibody titers were higher following im than sc administration. Woodchucks administered two vaccine doses sc received the third vaccine dose im, and antibody responses reached titers comparable to those elicited by im administration. Following the second vaccine dose, im vaccination with WHsAg and CLDC induced T cell responses to WHsAg and selected WHs peptides and expression of the leukocyte surface marker CD8 and of the Th1 cytokines interferon-gamma and tumor necrosis factor alpha in woodchucks. T cell responses and CD8/cytokine expression were diminished in woodchucks from the other groups suggesting that this vaccine regimen induced a skew toward Th1 immune responses. The present study in woodchucks demonstrates that CLDC-adjuvanted WHsAg vaccine administered im resulted in a more rapid induction of humoral and cellular immune responses compared to conventional, alum-adjuvanted WHsAg vaccine. While less rapid, the immune responses following sc administration can prime the im immune responses. This adjuvant activity of CLDC over alum may be beneficial for therapeutic vaccination in chronic HBV infection.

Cellular immunity

10.1002/jmv.21566

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JVRS-100 adjuvanted universal influenza A vaccine based on a multiple antigenic peptide of M2e protects from lethal challenge (132.6)

The Journal of Immunology (2009)

Bernadette Callejo Stella Chang Marla Lay Lily Liang Jeffery Fairman

Abstract Background: The conventional vaccine strategy for control of influenza A is vulnerable to antigenic drift and the emergence of unmatched epidemic strains that cause primary vaccine failure. A vaccine strategy that targets an influenza antigen, which is less susceptible to antigenic variation, would be a major improvement. Methods: Balb/c mice were vaccinated three times with the M2e peptide in the context of a multiple antigenic peptide (MAP) complex and combination with the cationic lipid DNA complex adjuvant (JVRS-100). Antibody titers were monitored over the time course of vaccination and the mice received a lethal challenge with H1N1 (PR/8/34) or H3N2 (HKx31) two weeks after the final vaccination. Results: Vaccination of mice with JVRS-100-MAP4-M2e compared to MAP4-M2e resulted in increased survival following lethal challenge with 6x LD50 PR/8/34 H1N1 (100% vs. 30%, P=0.002) or 10x LD50 HKx31 H3N2 (80% vs. 20%). Recipients of 200µl serum from MAP-4-M2e/JVRS-100 vaccinated mice and challenged with H1N1 (6x LD50 PR/8/34) resulted in survival of 60% (P=0.014) compared with control mice which received 200µl naive serum (0% survival). Furthermore, recipients of 300µl serum from MAP-4-M2e/JVRS-100 vaccinated mice and challenged with H1N1 (2x LD50 PR/8/34) resulted in survival of 100% (P=0.0026) compared with control mice which received 200µl naive serum (0% survival). Conclusion: These studies demonstrate that a simple, synthetic M2e vaccine in a MAP configuration with a strong adjuvant may result in a viable vaccine candidate for universal flu vaccination and the protective immunity is primarily due to an antibody response.

Lethal dose

10.4049/jimmunol.182.supp.132.6

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A Lipid/DNA Adjuvant–Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge

The Journal of Infectious Diseases (2018)

Timothy D. Carroll Sinthujan Jegaskanda Shannon R. Matzinger Linda Fritts Michael B. McChesney

Influenza A virus (IAV) vaccines offer little protection from mismatched viruses with antigenically distant hemagglutinin (HA) glycoproteins. We sought to determine if a cationic lipid/DNA complex (CLDC) adjuvant could induce heterosubtypic protection if added to a whole inactivated IAV vaccine (WIV).Adult rhesus macaques (RMs) were vaccinated and at 2 weeks boosted with either an H1N1-WIV or an H3N2-WIV, with and without CLDC adjuvant. Four weeks postboost, animals were challenged with an H1N1 IAV matched to the H1N1-WIV vaccine.After challenge, viral RNA (vRNA) levels in the trachea of control RMs and RMs vaccinated with the unadjuvanted H1 or H3 WIV vaccines were similar. However, vRNA levels in the trachea of both the H1-WIV/CLDC- and the H3-WIV/CLDC-vaccinated RMs (P < 0.01 and P < 0.05, respectively) were significantly lower than in unvaccinated control RMs. Heterosubtypic protection in H3-WIV/CLDC RMs was associated with significantly higher levels of nucleoprotein (NP) and matrix-1-specific immunoglobulin G antibodies (P < 0.05) and NP-specific nonneutralizing antibody-dependent natural killer cell activation (P < 0.01) compared with unprotected H3-WIV RMs.Addition of the CLDC adjuvant to a simple WIV elicited immunity to conserved virus structural proteins in RMs that correlate with protection from uncontrolled virus replication after heterosubtypic influenza virus challenge.

Nucleoprotein

Viral Shedding

10.1093/infdis/jiy238

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Citations (13)

Inverse relationship between innate and acquired immune responsiveness in mice initially dosed with cationic lipid DNA complexes (JVRS‐100)

The FASEB Journal (2008)

Marla Lay Bernadette Callejo Thierry Giffon David Y. Lewis Stella Chang

Hyporesponsiveness to excessive innate immune stimulation (i.e., lipopolysaccharide, lipoteichoic acid, and CpG oligonucleotides) has been studied extensively in vitro and documented in clinical treatment of sepsis patients with low inflammatory cytokine production, reduced leukocyte expression of HLA‐DR, and decreased antigen presentation. Closely spaced intravenous (IV) administration of JVRS‐100 has been shown to induce a short (7–10 day) refractory period for innate immune activation, with 50% of responsiveness restored after three days and 100% by 10–14 days. This refractory period was observed in interferon‐gamma and IFN‐gamma receptor knockout mice as well as mice pre‐dosed with IFN‐gamma or depleted of NK cells or plasmacytoid dendritic cells. In contrast to reduced capacity for antigen presentation (sepsis patients), IV administration of JVRS‐100, one day prior to vaccination with HKx31 heat‐inactivated influenza virus adjuvanted with JVRS‐100 significantly enhanced the influenza‐specific humoral immune response. Enhancement of the adaptive response to vaccination was greatest at the timepoints showing the maximum refractory period, suggesting an inverse relationship between cytokine production and immune activation. These findings may have implications for development of future vaccines, in which single or limited vaccination strategies are critical.

10.1096/fasebj.22.1_supplement.1068.27

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Adjuvanting influenza vaccines for enhanced immunity to seasonal or pandemic influenza virus. (75.9)

The Journal of Immunology (2012)

Jeffery Fairman Tim Carroll Feng Liu Kathy Hancock Jacqueline M. Katz

Abstract The efficacy of FDA approved influenza vaccines depends on eliciting neutralizing antibodies that provide protection against antigenically well-matched viruses. To determine if the JVRS-100 adjuvant could enhance vaccine-induced protection against matched and non-matched influenza virus challenge, mice or non-human primates (NHP) were immunized with vaccine +/- the JVRS-100 adjuvant. All animals that received JVRS-100 adjuvanted vaccine had significantly lower levels of virus replication following viral challenge. In matched and cross-clade challenge experiments JVRS-100 adjuvanted H5N1 vaccine elicited enhanced humoral responses, T-cell responses, and protection in mice. In heterosubtypic challenge experiments, mice and nhp immunized with adjuvanted H1N1 vaccine demonstrated enhanced antibody responses, T-cell responses, and protection against H3N2 challenge compared with groups that received nonadjuvanted vaccine. These data demonstrate that JVRS-100 enhances antibody and T-cell responses, resulting in matched, cross-clade, and heterosubtypic immunity for influenza vaccination.

Vaccine efficacy

Pandemic

Antibody response

10.4049/jimmunol.188.supp.75.9

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Immunotherapy of Acute Leukemia with Cationic Lipid DNA Complexes (JVRS‐100)

The FASEB Journal (2008)

Stella Chang Zachary Herse David F. Claxton Thierry Giffon David Y. Lewis

Acute leukemias have long been recognized as suitable targets for immunotherapy. Administration of cationic liposome‐DNA complexes (JVRS‐100) elicits cytokines of the TH1 subset, especially IL‐12, IFN‐gamma and IFN‐alpha. These cytokines are particularly important in mediating host defense against cancer. In multiple experiments using the 32Dp210‐GFP model, intravenous dosing of JVRS‐100 prevented or significantly delayed death from leukemia when delivered between 7 and 15 days following leukemic challenge. Specifically, control animals died at ∼19 days of leukemia whereas 80% of similarly leukemia challenged but JVRS‐100 treated animals (1 ug) were alive >40 days with weekly treatment beginning at day 15 (4 days prior to expected mortality). Animals dying of leukemia had splenomegaly and leukemic infiltration of spleen and liver. The GFP expression allowed quantification of leukemia in peripheral blood (PB). At day 12 following challenge PB leukocytes were ∼30% GFP positive with either no treatment, or 0.1 ug JVRS‐100, <0.1% with 1.0 ug or 5.0 ug JVRS‐100 treatment at days 2 and 9. Furthermore there is a similar cell activation profile and cytokine response in vitro following exposure of human PBMCs to JVRS‐100 as is observed following in vivo administration of JVRS‐100 to mice, making this immunostimulation technology a promising candidate for product development and eventual clinical evaluation.

10.1096/fasebj.22.1_supplement.1077.17

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Citations (2)