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NIAID Strategic Plan for Research on Vaccine Adjuvants—Appendices


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Appendix 1: Planning Process

The assessment and planning process for this strategic plan included the following activities:

  • Review current adjuvant-related research and development activities supported by NIAID
  • Define the current scope of adjuvant discovery and development in the broader research community
  • Identify key stakeholders and partnerships, academic research organizations, U.S. government agencies, not-for-profit organizations, vaccine and pharmaceutical companies
  • Identify areas to be considered:
    • Current understanding of adjuvant discovery and development research, and mechanistic studies of adjuvants
    • Gaps in current knowledge of adjuvant mechanisms of action
    • Opportunities for scientific advancement based on greater understanding of innate immunity
    • Barriers to adjuvant discovery and development
    • Resources and partnerships required for advancement
    • Future areas for research and development activities for adjuvants
  • Identify future areas for initiative development within NIAID to provide support for novel adjuvant approaches

Based on this assessment, immediate and long-term goals were identified for NIAID in three major areas:

  • Basic Immunology and Early Stage Adjuvant Discovery
  • Later Stage Adjuvant Development and Preclinical Testing
  • Clinical Assessment of Adjuvants

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Appendix 2: Examples of Adjuvant Types Approved for Human Use in Preventive Vaccines or Tested in Human Studies

Category

Examples

Target (likely)

Approved

Aluminum salts

Alum

(NALP3)

Multiple vaccines; worldwide

Pathogen components

PamCSK

TLR2

No

PolyI:C

TLR3

No

MPL/TLR-4 agonists

TLR4

EU only

Flagellin

TLR5

No

R848, Gardiquimod

TLR7/8

No

CpG DNA

TLR9

No

Muramyl-dipeptide

NOD2

No

Emulsions

Freund's adjuvant

(APC)

No

MF59

(APC)

Fluad (influenza); EU only

Montanide

(APC)

No

Nanoemulsions

NB-series

(TLR)

No

Liposomes

Virosomes

APC

Inflexal (influenza), Epaxal (HAV); EU only

Microparticles

PLG

APC

No

 

ISCOM

(APC)

No

Cytokines

IL-1, IL-2, IL-12

Cytokine receptor

No

GM-CSF

Cytokine receptor

No

Oligosaccharides

Inulin-derivative

Macrophage/ phagocytosis

No

Combinations

AS0-series

Multiple

Pandemrix (influenza); Fendrix (HBV); EU only
Cervarix (HPV); EU/U.S.

IC31

Multiple (including TLR9)

No

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Appendix 3: Status of NIAID Adjuvant Research Activities

Introduction

NIAID is the major Institute at the National Institutes of Health (NIH) supporting research in the area of vaccine adjuvants, funding 65 to 70 percent of all extramural projects on adjuvants, with another 20 percent funded by the National Cancer Institute and the remainder funded across 11 other Institutes. Within the NIAID intramural program, approximately 10 projects involve adjuvant research. Among approximately 140 extramural projects, 55 are funded as unsolicited investigator-initiated grants, and 85 as solicited cooperative agreement grants or contracts. Across NIAID, a small number of training grants focus on adjuvant discovery and mechanisms of action. Similarly, a small number of NIAID small business innovative research (SBIR) and small business technology transfer research (STTR) grants focus on this area, with topics that include adjuvants for mucosal vaccine delivery, synthetic ligands for innate immune receptors, and development of virus-like particles (VLP) that incorporate adjuvants together with vaccine antigens.

Described below are selected examples of NIAID-supported research on adjuvants to enhance or help create new preventive vaccines against infectious disease. The work is organized according to the various Divisions in NIAID and includes research ranging from the discovery of novel adjuvant compounds to the testing of adjuvanted vaccine candidates in humans.

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NIAID Extramural Research Activities

Division of Allergy, Immunology, and Transplantation (DAIT)

DAIT is the lead extramural NIAID division for the discovery and characterization of vaccine adjuvants, and it supports a portfolio of adjuvant research projects focused on the following research topics:

  • Basic research on innate immune receptors and their ligands to identify new adjuvant targets
  • Discovery of novel adjuvant candidates and platforms using high throughput screening approaches
  • Early development of vaccine adjuvants
  • Immunological basis of adjuvants in current vaccines
  • Mucosal immunology
  • Research resources

Basic research on innate immune receptors and their ligands to identify new adjuvant targets. DAIT supports the basic immunology of individual candidate adjuvants to assess their potential to enhance vaccine efficacy without inducing toxicity. Most of this work is supported by investigator-initiated grants, and several projects are funded under a DAIT-solicited research program, the Cooperative Centers for Translational Research on Human Immunology. Topics include

  • Structural studies of innate immune receptors
  • Direct targeting of human dendritic cells using antigen conjugated to antibodies that bind dendritic cell surface proteins
  • Defective interfering Sendai virus genome particles as novel adjuvants
  • Sulfoglucosylceramide to induce NKT-cell responses and promote activation of dendritic cells for antigen presentation
  • Non-propagating Venezuelan equine encephalitis virus replicon particles, which target to draining lymph nodes and induce mucosal immunity
  • Complement receptor agonists, such as C3d, to enhance antibody responses to vaccine antigens

Discovery of novel adjuvant candidates and platforms using high throughput screening approaches. In 2003 and 2004, as part of its biodefense research program, DAIT solicited projects under a new Innate Immune Receptor and Adjuvant Discovery Program, and funded five contracts to discover novel adjuvants based on interactions with TLRs. These projects used high throughput methods to screen small molecule and natural product libraries to identify novel compounds with adjuvant activity. Each contract resulted in the identification of one or more lead compounds for further development. In 2009, this program was renewed to support the discovery of additional lead compounds, expanding the scope to innate immune receptor targets in addition to TLR, through six new contracts. Topics include:

  • Small molecule screens of chemical libraries to identify agonists for RIG-I receptors, NOD-like receptors, and TLRs
  • Nanoemulsion formulations that activate innate immune responses without signs of inflammation

Early development of vaccine adjuvants. In 2008 and 2009, DAIT funded four contracts for the further development of novel adjuvant candidates, beyond the discovery stage, under its new Adjuvant Development Program. This program supports the optimization of lead adjuvant candidates, formulation studies, and preclinical pharmacology, toxicity, and efficacy studies. Topics include:

  • CpG oligodeoxynucleotides as TLR9 agonists
  • Glucopyranosyl lipid A and R848 as TLR agonists
  • Delta-inulin, a natural plant polysaccharide, to activate signal transduction pathways
  • Aminoalkyl glucosaminide phosphate as a TLR4 agonist
  • Synthetic, chemically defined versions of naturally occurring adjuvant compounds
  • Structural variants and “minimal congeners” of known adjuvants that retain immunostimulatory properties of the parent molecule, but have minimal reactogenicity
  • Small molecule analogs of known adjuvants with improved pharmacological properties

Immunological basis of adjuvants in current vaccines. DAIT-funded work in this area includes mechanistic studies of known adjuvants in order to link their in vivo properties to specific immunological parameters, such as identification of their cellular and molecular targets, the signaling pathways induced, and the quality of the adaptive T- and B-cell immune responses that are enhanced, including antibody isotypes, cytotoxic T cell activities, and involvement of chemotactic factors and dendritic cells, macrophages, mast cells, NK cells, NKT cells, and γδT cells. Research also includes the characterization of intrinsic adjuvant activity present in live-attenuated, inactivated virion, and carbohydrate vaccines. While much of this work is supported by investigator-initiated grants, efforts in this area will receive enhanced support through the recently awarded Human Immunology Project Consortium program that will include studies of human immune responses to current vaccines. Topics include:

  • Mechanisms of action of alum and oil-in-water emulsion adjuvants
  • Properties of biopolymers acting as both emulsifiers and immunomodulators
  • Molecular basis of adjuvant activation of innate immune responses
  • Pathways associated with adjuvant pyrogenicity and reactogenicity
  • Molecular signatures of adjuvants in human vaccinees

Mucosal immunology. In 2011, DAIT will expand its targeted research program by establishing the Immune Defense at the Mucosa Cooperative Study Group, which will support additional research in this area. Future NIAID activities will build on this research foundation.

Research resources. DAIT supports a cooperative agreement grants program on Reagent Development for Toll-like and Other Innate Immune Receptors, focused on generating new reagents for the analysis and modification of innate immune responses. Four groups are funded to discover, characterize, and distribute reagents that are broadly useful to the scientific community for research on vaccine adjuvants. Topics include:

  • High throughput screens of peptide mimetic chemical libraries to identify novel TLR4 agonists and antagonists
  • High throughput screens of small molecule libraries to identify novel agonists and antagonists of TLR3, TLR7, and RIG-I
  • Production of antibodies and soluble receptors reactive with innate immune cell scavenger receptors
  • Identification and characterization of novel members of NOD-like receptor families and the generation of antibodies reactive with each new protein

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Division of Microbiology and Infectious Diseases (DMID)

DMID is the lead extramural NIAID division for the development of vaccines against non-HIV infectious agents, including preclinical and clinical testing of adjuvants to define new preventive adjuvant:vaccine formulations. DMID supports a portfolio of adjuvant research projects focused on improving current vaccines and creating vaccines for infectious agents that have been intractable to prior vaccine development efforts. This work is supported by investigator-initiated grants as well as cooperative agreement grants under the Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Program and a series of Partnership programs funding collaborative research between academic and commercial institutions.

These projects include the following types of research:

  • Basic research to discover effective combinations of pathogen antigens with known adjuvants
  • Targeted development of new adjuvant:vaccine candidates
  • Clinical testing of new adjuvant:vaccine candidates
  • Research resources

Basic research to discover effective combinations of pathogen antigens with known adjuvants. DMID funds a comprehensive array of basic science projects on vaccines for a variety of bacteria, viruses, parasites, and fungi to identify and characterize the most effective combination of known adjuvants with pathogen antigens for the prevention or treatment of infection or to allow antigen dose sparing. Topics include:

  • Optimization of TLR4 ligands as adjuvants for Yersinia pestis vaccine development
  • Use of CpG, monophosphoryl lipid A, Glucopyranosyl Lipid A (GLA), and other TLR agonists in various vehicles or combinations (e.g., oil-in-water emulsion, aqueous formulation, liposome, and alum) as adjuvants for Leishmania vaccine development
  • Heat shock proteins as adjuvants for protective cytotoxic T cells against influenza
  • Development of novel schistosome vaccines employing the Sm-p80 schistosome antigen-based DNA construct with Th1 cytokines or using the recombinant protein-based immunogen in combination with alum, TLR4, 7, 8, or 9 agonists
  • Mycobacterium tuberculosis epitopes incorporated into virus vectors together with one or more known adjuvants
  • Incorporation of the QS21 adjuvant into alum-adjuvanted anthrax vaccines
  • Replication-restricted vesicular stomatitis virus as a vector to generate immunity to Francisella tularensis in combination with IL-12 or GM-CSF
  • Alum, CpG, and GLA adjuvants used for novel vaccines against Entamoeba histolytica

Targeted development of new adjuvant:vaccine candidates. DMID also supports the discovery of novel adjuvants for use in the development of pathogen-specific vaccines. Topics include:

  • Mucosal adjuvants based on the edema toxin of Bacillus anthracis
  • Co-adjuvant activity of NAD (nicotinamide adenine dinucleotide), which targets the cellular receptor CD38, to promote leukocyte migration to sites of influenza infection
  • A powder vaccine formulation for nasal immunization against West Nile Virus using small molecule mast cell activating compounds as adjuvants, either alone or in combination with TLR agonists
  • Novel cationic lipid DNA complexes to enhance immune responses against influenza, Burkholderia mallei, and Burkholderia pseudomallei
  • Novel lipid A compounds based on low toxicity lipopolysaccharides isolated from anaerobic gram negative bacteria as adjuvants in experimental vaccines against Yersinia pestis and Francisella tularensis
  • Self-assembling polypeptide nanoparticles, and a VLP carrier system composed of the woodchuck hepadnavirus core protein, as adjuvants for malaria vaccines that genetically display B and T cell epitopes of Plasmodium falciparum
  • A human hepatitis B core antigen-based VLP for chemical conjugation with Plasmodium vivax proteins
  • Novel, inulin-based microparticles that stimulate adaptive immune responses to influenza and other vaccines, with dose sparing effects

Clinical testing of new adjuvant:vaccine candidates. DMID supports clinical trials of new adjuvant:vaccine combinations through its clinical networks such as the Vaccine Treatment and Evaluation Units.

Research resources. In 2003, as part of its biodefense program, DMID established the Biodefense and Emerging Infections (BEI) Research Resources Repository, which provides a broad spectrum of research resources such as pathogens, plasmids, proteins and peptides; cell lines; and antibodies reactive with a variety of immune molecules, including receptors and ligands of the innate immune system that are useful in adjuvant studies. DMID also supports development of animal models and provides access to these models for researchers to evaluate novel vaccine candidates.

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Division of Acquired Immune Deficiency Syndrome (DAIDS)

DAIDS research includes a portfolio of grants that study adjuvants in the context of HIV-1 vaccine development. The discovery of novel adjuvant candidates is supported partly through the DAIDS Center for HIV/AIDS Vaccine Immunology Program, which is exploring the use of certain polymers and chemoattractant cytokines as enhancing components for HIV-1 vaccines.

Other adjuvant work is supported by unsolicited investigator-initiated and solicited cooperative agreement grants, with a focus on using known adjuvants to help generate protective anti-HIV-1 or -SIV immunity. Topics include:

  • Mechanisms of QS21 activity to design improved analogs with fewer safety issues
  • Preclinical studies of novel HIV-1 structures and epitopes as immunogens combined with known adjuvants
  • Plasmid forms of mucosally expressed chemokines such as CTACK, MEC, and TECK as adjuvants with HIV-1 DNA vaccines
  • HIV-1 VLP administered together with C3d or CpG
  • GM-CSF adjuvant activity with DNA prime/MVA boost strategies for HIV-1 vaccine development
  • IL-12 and IL-15 as adjuvants for HIV-1 vaccine development
  • siRNA as an adjuvant approach to inhibit negative regulators of immune activation for HIV-1 vaccine development

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NIAID Intramural Research Activities

Division of Intramural Research (DIR)

DIR researchers are studying the basic biology of infectious diseases and mechanisms of immunity to pathogens, and are also conducting translational work for new vaccine development.

The Laboratory of Malaria Immunology and Vaccinology, formerly the Malaria Vaccine Development Branch, incorporates adjuvant studies into its general vaccine development path. The primary goal is to enhance immunogenicity of malaria vaccine candidates. Over the years, the laboratory evaluated vaccine candidates formulated with various adjuvants including alum, Montanide, MF59, ISCOMs, QS21, liposomes, and multiple TLR agonists in preclinical animal studies. The laboratory also demonstrated that the immunogenicity and response longevity of malaria antigens may be enhanced by conjugation to carrier proteins such as the outer membrane protein complex of Neisseria meningitidis and a non-toxic ExoProtein A (EPA) of Pseudomonas aeruginosa. These carrier proteins served as adjuvants. The laboratory is also forming new partnerships to evaluate novel adjuvants.

The adjuvanticity of CpG 7909 for a candidate vaccine against clinical malaria is being tested in U.S. and Malian adult volunteers. Alum and GLA were shown to further enhance the immunogenicity of a Pfs25-EPA conjugate, a malaria transmission-blocking vaccine candidate. A Phase I trial is being planned to evaluate safety and immunogenicity of the Pfs25-EPA conjugate formulated with Alhydrogel or with GLA.

The Laboratory of Infectious Diseases has used adjuvants for respiratory virus vaccines in preclinical studies. Addition of the adjuvants AS01(B) or AS03 to an inactivated SARS-CoV vaccine resulted in enhanced antibody titers and prolonged protection in rodents. Addition of a stabilized chemical analog of double-stranded RNA (PIKA) as an adjuvant to an inactivated influenza H5N1 influenza virus vaccine resulted in antigen sparing and both quantitative and qualitative improvements of the immune responses in mice.

The Laboratory of Immunology is engaged in studies examining the distribution of adjuvants and adjuvanted vaccine antigens, their effects on the behavior of immune cells in vivo, and the functional consequences of these effects using advanced imaging tools and other platforms. The Program in Systems Immunology and Infectious Disease Modeling is using high throughput RNAi screening to better understand signaling through PRRs such as TLRs and to develop computational models of PRR signaling pathways that can be used to help predict the effects of single and combination adjuvant agents. Through its involvement in the trans-NIH Center for Human Immunology, DIR is conducting studies aimed at developing an extensive database of the state of the normal immune system to serve as a basis for comparison of measurements made in volunteers and during clinical trials of adjuvants and adjuvanted vaccines. Currently, studies of influenza vaccines are underway and future plans include studies on the role of adjuvants in the efficacy of hepatitis B vaccines, as well as immune signatures of such adjuvants as MF59.

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Vaccine Research Center (VRC)

The primary focus of the VRC is to develop, produce, and test vaccines against HIV-1 and a variety of other human pathogens. In the context of HIV-1 vaccine development, the VRC is conducting pre-clinical studies on the incorporation of known adjuvants into vectored vaccine candidates using adenovirus, lymphocytic choriomeningitis virus, and Bacillus Calmette-Guerin (BCG) vectors for antigen delivery. In addition, candidate vaccines based on soluble HIV-1 env trimers with heterologous trimerization motifs are being tested in macaques with or without co-administration of the GSK adjuvant, AS01B, a mixture of monophosphoryl lipid A and QS21.

Protein-based adjuvants and vaccines are being tested in combination with other vaccine modalities, such as viral vectors, DNA, and BCG, using prime-boost strategies. In particular, prime-boost regimens are under study as highly promising methods to induce optimal T cell- and antibody-mediated immunity for a variety of human pathogens.

Specifically, novel prime-boost approaches are being tested to create a “universal” influenza vaccine that could provide broad protection against diverse influenza virus strains. Recent results indicate that a variety of H1N1 strains isolated over the past 70 years could be neutralized after immunization of mice or ferrets with a plasmid HA-DNA prime/inactivated seasonal influenza vaccine boost, or a plasmid HA-DNA prime/HA-adenovirus 5 (replication-defective) boost regimen. Interestingly, many of the antibodies generated were reactive with the conserved stem region of the HA molecule. In addition to neutralization of diverse H1 viruses, some cross-neutralization was also achieved for H3 and H5 viruses. These results suggest that new generation influenza vaccines that provide extensive heterosubtypic immunity might be feasible.

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Last Updated June 24, 2011

Last Reviewed June 23, 2011