The assessment and planning process for this strategic plan included the following activities:
Based on this assessment, immediate and long-term goals were identified for NIAID in three major areas:
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Multiple vaccines; worldwide
Fluad (influenza); EU only
Inflexal (influenza), Epaxal (HAV); EU only
IL-1, IL-2, IL-12
Pandemrix (influenza); Fendrix (HBV); EU onlyCervarix (HPV); EU/U.S.
Multiple (including TLR9)
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.
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. 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
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
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
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
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
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. 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
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
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.
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
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.
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