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NIAID Strategic Plan for Research on Vaccine Adjuvants—Introduction


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Introduction

Vaccines to prevent infectious diseases are the most effective and economical measure to improve human health and have saved millions of lives worldwide. The use of vaccines has led to the elimination of smallpox, the near eradication of polio, and protection against seasonal influenza and a large number of childhood diseases. Yet, there remain many devastating infectious diseases for which no effective preventive vaccines exist, including diseases of great consequence to global health, such as malaria, tuberculosis, and HIV/AIDS, as well as diseases caused by newly emerging infections. Increasingly, efforts to develop efficacious vaccines against these and other infectious diseases involve the use of adjuvants in vaccine formulations. 

The Food and Drug Administration (FDA) defines adjuvants as “agents added to, or used in conjunction with, vaccine antigens to augment or potentiate (and possibly target) the specific immune response to the antigen.” Adjuvants have the potential to make current vaccines more effective and to make vaccines more readily available to larger numbers of people worldwide. Additionally, adjuvants have the potential to help create vaccines against pathogens, for which no vaccines currently exist, and could be especially important for vaccines made from recombinant antigens or DNA, which tend to be poorly immunogenic and do not generally elicit a protective response when used alone. Moreover, given that special populations, such as the elderly, young children, and immunocompromised people, often respond suboptimally to vaccination, the addition of an appropriate adjuvant to a vaccine may enhance the limited immune responses in these groups. Adjuvants can also extend the supply of a vaccine by allowing dose-sparing of the vaccine antigen or reducing the number of immunizations required to generate and maintain protective immune responses. As researchers develop a better understanding of the mechanism of action of different adjuvants, the rational design of adjuvants will result in adjuvanted vaccines that can induce the most effective immune responses against specific pathogens.

NIAID, part of the National Institutes of Health (NIH), has developed a Strategic Plan for Research on Vaccine Adjuvants to guide its adjuvant discovery, development, and translational research program. This strategic plan summarizes the current status of NIAID-sponsored research in the field of adjuvants for preventive vaccines, identifies gaps in knowledge and capabilities, and defines NIAID’s goals for the continued discovery, development, and application of adjuvants for human vaccines that protect against infectious diseases. Both preventive and therapeutic vaccines are of importance to human health. The strategic plan focuses only on adjuvants for use with preventive vaccines that block infection. Therapeutic vaccines, those to be administered only after established infection, and cancer vaccines, may require scientific approaches and clinical development plans that differ from those for preventive vaccines. Appendix 1 outlines the planning process used to develop the draft strategic plan.

The NIAID Strategic Plan for Research on Vaccine Adjuvants is divided into three sections: 1) Basic Immunology and Early Stage Adjuvant Discovery; 2) Later Stage Adjuvant Development and Preclinical Testing; and 3) Clinical Assessment of Adjuvants. This strategic plan is intended to strengthen and guide the NIAID adjuvant research enterprise, accelerate the pathway from adjuvant discovery to U.S. licensure of adjuvanted vaccines, and promote increased adjuvant research and development partnerships among Government, academia, non-profit institutions, and industry. In implementing this strategic plan, NIAID will continue to work closely with its partners in the research community on adjuvant discovery and development within available resources and the context of its overall strategic research mission.

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Scientific Background on Adjuvants

The term adjuvant is derived from the Latin word adjuvare, which means to help. It applies to compounds that target the innate immune system and enhance immune responses to co-administered vaccines. Normally, the first line of defense against microbial infections is the activation of the innate immune system; this leads to the activation of T and B cells of the adaptive immune system to generate antigen-specific responses resulting in pathogen clearance. Adjuvanted vaccines can accelerate the production of protective antibodies and effector T-cell responses and prolong the duration of protection by expanding memory T- and B-cell populations. Most licensed vaccines are thought to mediate protection by antibodies. Adjuvants such as alum (the term used for several insoluble aluminum salts, usually aluminum phosphate or hydroxide), MF59, and monophosphoryl lipid A (MPL) enhance antibody production but are limited in their ability to induce T-cell immunity. By enhancing adaptive immune responses, adjuvants may reduce the number of required immunizations or the amount of antigen needed to elicit a protective immune response; furthermore, they might allow for more durable protection. 

In addition to this quantitative effect, vaccine adjuvants may also provide qualitative benefits in immune responses, such as broader cross protection to related, heterologous strains of pathogens. By exploiting these effects on the strength and diversity of adaptive immune responses, adjuvants may prove to be critical for the design of vaccines of increased immunogenicity and efficacy in special populations. For example, an MF59-adjuvanted influenza vaccine demonstrated enhanced immunogenicity in children and the elderly and greater clinical efficacy in elderly nursing-home residents. Recent limitations in the vaccine supply for pandemic influenza strains also highlight the potential for dose-sparing that can be achieved by adjuvanted vaccines intended for large populations. 

Despite the benefits that adjuvants confer, the molecular mechanisms underlying their activity are only partially understood. Adjuvants are believed to activate the innate immune system, at least in part, by targeting professional antigen presenting cells, such as dendritic cells, leading to the upregulation of cytokines, costimulatory molecules, and MHC molecules resulting in the migration and recruitment of effector cells and the activation of antigen-specific T cells. Novel insights for rational development of new adjuvants arose in the 1990s from the discovery and characterization of Toll-like receptors (TLRs). TLRs are proteins that belong to a growing number of pattern recognition receptor (PRR) families, and they are expressed on the cell surface or within the cytosol of innate immune cells. Cell surface and intracellular TLRs and other PRRs recognize pathogen associated molecular patterns (PAMPs), which are products of bacteria, viruses, protozoa, and fungi. Upon recognition of PAMPs, the TLRs initiate a signaling cascade leading to release of cytokines and chemokines, maturation of antigen presenting cells and immune activation. Other recently characterized PRRs recognize microbial derivatives in the cytosol and include the nucleotide-binding oligomerization domain-like receptor (NLR) family of proteins recently identified as components of the inflammasome; the RNA-detecting retinoic acid inducible gene-based-I-like helicase receptor family (RIG-I, MDA5); and at least two DNA-sensors, the DNA-dependent activator of interferon-regulatory factors (DAI) and the molecule “absent in melanoma 2” (AIM2). Other types of non-TLR PRRs include Dectin-1, a natural killer (NK) cell receptor-like C-type lectin involved in innate immune responses to fungal pathogens; complement components; and scavenger receptors expressed by macrophages and dendritic cells, which play an important role in uptake and clearance of microbes and their products.

Vaccines made from inactivated or live-attenuated pathogens generally contain naturally occurring molecules such as PAMPs that act as adjuvants. In contrast, vaccines made from recombinant proteins or purified subunits of a pathogen are often poorly immunogenic because they lack the endogenous innate immunostimulatory components of the pathogen and, therefore, may necessitate the addition of an adjuvant to elicit an effective immune response. Some polysaccharide conjugate vaccines, such as Prevnar-7 and -13, are formulated with alum as an adjuvant; although others are effective in the absence of any known adjuvant; it is not yet known whether the latter vaccines engage innate immune pathways.

Previously, vaccines and adjuvants were developed empirically, but an emerging understanding of innate immune receptors and signaling pathways is now providing opportunities for the rational design of novel adjuvants. More recently, knowledge of many components of the innate immune system has led to a new understanding of the mechanism of action of alum, the most widely used adjuvant in human vaccines. Alum was the first vaccine adjuvant to be widely used in the United States beginning in the 1920s. It was thought initially to function primarily by its ability to adsorb vaccine antigens, enabling the antigen-alum complex to function as a depot that allows the gradual release of antigen over time. More current work, published in 2008 by several groups, demonstrated that activation of the NALP3 inflammasome also plays a role in alum adjuvanticity; however, it is still unclear if alum acts directly on the inflammasome or indirectly through other innate immune mediators.

A “one size fits all” adjuvant will not be ideal for all vaccines because qualitatively distinct responses may be needed in certain settings. Adjuvanted vaccines that use alum result in a predominant Th2 response and antibody production. In contrast, Th1 responses or cytotoxic CD8+ T-cell responses may be required to generate protective immunity to certain pathogens. Thus, there are numerous efforts to develop different adjuvants that can direct immune responses to activate different T-cell subsets, to target particular antigen presenting cell subsets, or to target mucosal responses.

Besides alum-containing vaccines, no other adjuvanted vaccines received approval by FDA until 2009, when the human papilloma virus vaccine Cervarix containing AS04 was approved. AS04 contains both alum and MPL, which is a component of lipopolysaccharide (LPS) and is the first TLR ligand approved as a vaccine adjuvant in humans worldwide. AS04 was also approved in Europe as a component of Fendrix, a hepatitis B virus vaccine. From the mid-1990s to the present, other adjuvants have gained regulatory approval in Europe, including MF59 and liposomes for inclusion in influenza vaccines (Fluad and Inflexal, respectively). Also in Europe, AS03, a squalene-based adjuvant, was used in the 2009 H1N1 pandemic influenza vaccine Pandemrix. Thus, a number of new adjuvanted vaccines have recently been licensed and others are being evaluated in clinical trials (see Appendix 2).

Based on their dominant mechanisms of action, the few approved and many experimental adjuvants have frequently been divided into two classes: immunopotentiators or antigen delivery systems; however, there appears to be some functional overlap between the classes. A number of newly discovered adjuvants target TLRs or NLRs, such as MPL (TLR4) and muramyl dipeptide (NOD2), CpG oligonucleotides (TLR9), flagellin (TLR5), and single or double stranded RNAs (TLR3, 7, or 8). The hepatitis B vaccine, human papilloma virus vaccine, and malaria RTS,S candidate vaccine are all particle formulations. Particulate adjuvants such as liposomes, virosomes, ISCOMs (immune stimulatory complexes), nanoemulsions, or virus like particles are used to encapsulate and enhance delivery of antigen, and some may have additional immunostimulatory properties. In addition, cytokines and chemokines can be broadly included as adjuvants when incorporated into DNA vaccines. Other classes of adjuvants include emulsions (MF59 or Montanide ISA-51), saponins (QS21), bacterial toxins (cholera toxin), polysaccharides (Advax, a crystalline particle derived from inulin), and cell based adjuvants (e.g., antigen-pulsed dendritic cells). Understanding how effective vaccines work has led to testing combinations of adjuvants, as in AS04, to target multiple receptors or pathways mimicking natural infection. Many other natural and synthetic compounds have been shown to have adjuvant activity and currently are being studied.  

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Governmental Sponsorship of Research on Adjuvant Discovery and Development

In addition to the pharmaceutical and biotechnology industries, a number of non-governmental organizations and governmental agencies fund research on adjuvant discovery and development. Among the U.S. federal agencies, major support is provided by the Department of Defense (Defense Advanced Research Projects Agency, Walter Reed Army Institute of Research, and the Defense Threat Reduction Agency) and the U.S. Department of Health and Human Services (NIAID, the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Centers for Disease Control and Prevention, FDA, and the Biomedical Advanced Research and Development Authority). After the events of September 11, 2001, and the anthrax mailings just a little later that year, considerable resources and efforts have been directed at the development of countermeasures related to biological agents that pose the greatest threat to civilian populations, including naturally emerging pathogens such as the SARS, West Nile, dengue, and pandemic influenza viruses (see NIAID category A, B, and C priority pathogens). Several NIAID planning documents provided an early impetus for development of NIAID’s current adjuvant research programs but did not define a set of research goals and recommendations focused specifically on adjuvants. 

Federal agencies, including NIAID, also collaborate on adjuvant discovery and development with global partners, including the World Health Organization (WHO) and the European Medicines Agency (EMA). A number of workshops and meetings were convened and guidelines published to assess regulatory issues regarding the use of adjuvants in humans. Examples of these activities include:

  • December 2002 meeting of the FDA Center for Biologics Evaluation and Research and the Society of Toxicology focused on the nonclinical safety evaluation of vaccines
  • WHO guidelines published in 2003, including the nonclinical evaluation of vaccines, with a section on adjuvants
  • 2005 EMA publication of guidelines on adjuvants in vaccines for human use
  • December 2008 joint workshop, sponsored by the FDA and NIAID, on adjuvants and adjuvanted preventive and therapeutic vaccines for infectious diseases

In addition, the European Adjuvant Advisory Committee (EAAC), composed mostly of biotechnology and pharmaceutical companies, was established in 2003 to promote consensus on issues related to adjuvant development and use, as well as to encourage further adjuvant research in Europe.

To make adjuvants more accessible to the broader research community for testing in experimental vaccines, WHO coordinates the Global Adjuvant Development Initiative (GADI). GADI was created to support the evaluation and comparison of different adjuvants through a network of laboratories called AdjuNet, which facilitates access to a variety of adjuvants for new vaccine development. In 2009, the European Network of Vaccine Research and Development (TRANSVAC) was established. Through TRANSVAC, 13 European institutions in 5 countries share resources for vaccine development. In collaboration with this network, the Platform for Harmonization of Vaccine Adjuvant Testing (PHARVAT) will choose assays to test adjuvants for future use in vaccines. It is clear that adjuvant discovery and development is a global enterprise that will benefit from greater harmonization and wider access to certain reagents and research resources including animal models.

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Evolution of NIAID Adjuvant Research Programs

Within NIH, NIAID is the lead institute for comprehensive research on infectious diseases. NIAID’s research mission includes understanding the biology of infectious agents and the pathogenesis of infectious diseases, the response of the host to infection or vaccination, and the basic immunological principles of protection against infection. Key to this effort is support for development of diagnostics, therapeutics, and vaccines to prevent infectious diseases. Basic, translational, and clinical research on adjuvant discovery and development play a critical role in this endeavor.

Through multiple programs, NIAID supports the development of new candidate vaccine adjuvants that stimulate the innate immune response to initiate a protective vaccine response against infection. Previous research agendas on Category A-C Priority Pathogens and the 2002 Summary of the Expert Panel on Immunity and Biodefense pointed to the need for novel adjuvants and identified this as a gap in our knowledge. Such adjuvants would have the potential to improve current vaccines, to serve as essential components of novel vaccines against diseases for which effective vaccines are currently lacking, and to extend vaccine supplies to larger numbers of people worldwide. The 2007 update of the NIAID Strategic Plan for Biodefense Research focused on new approaches that have implications broader than one reagent for one pathogen. The goal was to establish a more flexible and broad spectrum approach, including the development of “universal” vaccines. Development and utilization of a range of new adjuvant platforms may be one means to achieve this.

The NIAID Strategic Plan for Biodefense Research recommends the evaluation of inducers of innate immunity for use as first-line therapies and as adjuvants for augmenting vaccine efficacy against pathogens that might be used in a bioterrorist attack. In an effort to promote the discovery of additional immune stimulating molecules, the NIAID Division of Allergy, Immunology, and Transplantation (DAIT) established the Innate Immune Receptors and Adjuvant Discovery Program in 2003. This program was renewed in 2009, to continue support for identification and optimization of lead candidates for adjuvant discovery. 

In 2008, to move beyond the discovery phase and begin development of lead adjuvant candidates, DAIT initiated a new Adjuvant Development Program to advance novel vaccine adjuvants towards licensure for human use. This initiative supports the advancement of candidate vaccine adjuvants through immunological characterization studies, lead compound optimization, and/or Investigational New Drug (IND)-enabling studies. Also in 2008, research on innate immune receptors was further supported by the establishment of a DAIT program for Reagent Development for Toll-like and Other Innate Immune Receptors. This program, funded through a cooperative agreement, supports the development of new reagents and research tools to study the expression and function of TLRs and other innate immune receptors in humans and animal model systems. These programs that are specifically focused on adjuvants are complemented by many additional projects within broader NIAID research programs and as individual investigator-initiated grants (for a more detailed summary, see Appendix 3). Despite the increase in adjuvant research in recent years, many gaps still exist in our basic understanding of, and practical experience with, adjuvants for preventive vaccines. The following sections address these gaps and outline NIAID goals to advance progress in adjuvanted vaccine development.

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Last Updated June 24, 2011

Last Reviewed June 23, 2011