Unmet needs in modern vaccinology: Adjuvants to improve the immune response

doi:10.1016/j.vaccine.2010.07.021

Vaccine

Volume 28, Supplement 3, 31 August 2010, Pages C25-C36

https://doi.org/10.1016/j.vaccine.2010.07.021 Get rights and content

Abstract

New vaccine technology has led to vaccines containing highly purified antigens with improved tolerability and safety profiles, but the immune response they induce is suboptimal without the help of adjuvants. In parallel, the development of effective vaccines has been facing more and more important challenges linked to complicated pathogens (e.g. malaria, TB, HIV, etc.) and/or to subjects with conditions that jeopardize the induction or persistence of a protective immune response. A greater understanding of innate and adaptive immunity and their close interaction at the molecular level is yielding insights into the possibility of selectively stimulating immunological pathways to obtain the desired immune response. The better understanding of the mechanism of ‘immunogenicity’ and ‘adjuvanticity’ has prompted the research of new vaccine design based on new technologies, such as naked DNA or live vector vaccines and the new adjuvant approaches. Adjuvants can be used to enhance the magnitude and affect the type of the antigen-specific immune response, and the combination of antigens with more than one adjuvant, the so called adjuvant system approach, has been shown to allow the development of vaccines with the ability to generate effective immune responses adapted to both the pathogen and the target population.

This review focuses on the adjuvants and adjuvant systems currently in use in vaccines, future applications, and the remaining challenges the field is facing.

Introduction

The key objective of vaccination is the induction of an effective pathogen-specific immune response that leads to protection against infection and/or disease caused by that pathogen, and that may ultimately result in its eradication. The concept that the immune response to antigens can be improved by the addition of certain compounds into the vaccine formulation was demonstrated about one hundred years ago, when aluminium salts were introduced in vaccine formulations, and were referred to as “adjuvants”. Since then, aluminium salts have been widely used in vaccines to aid in antigen presentation and delivery, acting as adjuvants in order to generate effective immune responses.

Over decades, research on new vaccine technologies has evolved towards novel vaccines developed on the basis of well characterized and highly purified antigens, such as recombinant proteins and peptides, in order to focus only on the protective targets and therefore avoiding useless or unwanted reactogenicity. New vaccine technology has led to vaccines with improved safety profiles, but the use of these highly refined antigens has often reduced the ability of the antigens of inducing an effective immune response, and has made the use of adjuvants even more necessary.

A greater understanding of innate and adaptive immunity and their close interaction at the molecular level in the response of the host to a pathogen has enabled vaccine researchers to use adjuvants to their full advantage. The use of adjuvants allows for formulation of vaccines that more selectively stimulate immunological pathways to obtain a desired type of antigen-specific immune response (humoral or cell mediated). Adjuvants can also be used to enhance the immune response, allowing for antigen-sparing, which is especially valued when more vaccine doses need to be produced than the available amount of vaccine antigen permits. New vaccine formulation is moving to a more tailored approach of vaccine design in which the careful selection of both the antigens and the adjuvants are extremely important. In the last 15-20 years several vaccines containing new adjuvants have been tested in pre-clinical and clinical studies, and some have been registered for use in humans. The challenges vaccine researchers are facing and the role of adjuvants in current and future vaccine design are reviewed below.

Section snippets

Challenges of modern vaccinology

The development of effective vaccines has been facing more and more important challenges linked to complex pathogens (e.g. malaria, TB, HIV, etc) or to subjects with immune dysfunctions such as the elderly (immunosenescence) and/or the chronically diseased persons or immunocompromised. In these situations classical vaccine formulation approaches have often proven less effective, or have failed completely [1].

Learning and selecting from nature

Modern immunological concepts have helped in understanding that vaccines, consisting of replicating or non-replicating attenuated pathogens or whole inactivated micro-organisms, contain “intrinsic immunodefence triggers”, called Pathogen Associated Molecular Patterns (PAMPs), which are part of the pathogen structure [7]. The innate immune system can identify the so called “danger signals” such as PAMPs, and quickly respond to them [1]. Some inactivated and highly purified vaccines lose part of

Approaches to address vaccine limitations

The better understanding of the mechanism of ‘immunogenicity’ and ‘adjuvanticity’ has fuelled the research of new vaccine design based on new strategies. This research has encompassed investigations on methods to enhance immune responses beyond the classic understanding of antibody production and B-cell memory. Several different approaches have been explored to overcome the limitations of vaccines for challenging and evolving pathogens and for target populations with suboptimal immune responses

Clinical benefit—applications of novel adjuvants and Adjuvant Systems to address unmet immunization needs linked to the pathogen and/or the target population

Combination of antigens and adjuvants has allowed for the development of highly immunogenic new vaccines (Table 2) which provide an increased modulation of innate and adaptive immune responses leading to effective protection against infection. This combination approach is only possible due to a better understanding of the immune system and the specifics of what is necessary to achieve an adequate immune response. Considering all candidate vaccines formulated with novel adjuvants, the most

Safety

Several decades of use have demonstrated the safety profile of aluminium salts. The safety of MF59, and virosomes has been demonstrated through about a decade of use [37], [99], [100], [101], [102].

The more recent novel adjuvants as well as the combination Adjuvant Systems also have been shown to have acceptable reactogenicity and good safety profiles in clinical trials across a variety of applications and in post-licensure experience for some of them. Note that increased reactogenicity,

Adjuvants approaches beyond preventive vaccines

The better knowledge of how adjuvants can be selected and tailored to achieve the desired immune response has opened a new field of interest and research beyond vaccines against infectious diseases. It is becoming increasingly clear that there are chronic disorders such as allergies and cancers that could benefit from an immunotherapy able to modulate a specific immune response. Today the application of the immunotherapy is most advanced in the field of cancer. The cancer immunotherapy approach

Conclusions

In order to target specific populations and diseases, induction of well-characterized CMI responses in addition to enhancement of antibody production are required from adjuvanted vaccines. It is becoming increasingly clear that it is as important to select an adjuvant for a vaccine as it is to develop the antigen. Both components are of vital importance in order to induce an immune response that will protect against future infection. Building on our advanced knowledge of naturally induced

Trademark statements

Arepanrix, Boostrix, Cervarix, Daronrix, Engerix B, FENDrix, Fluarix, Havrix, Infanrix, Infanrix hexa, Pandemrix, Pediarix and Prepanrix are trademarks of the GlaxoSmithKline group of companies. Gardasil, Recombivax and Vaqta are trademarks of Merck & Co. Avaxin, Daptacel, Humenza, Pediacel, Pentacel, Repevax are trademarks of Sanofi Pasteur. Cimavax EGF is a trademark of Bioven. Fluad, Focetria and Quinivaxin/Vaxem-Hib are trademarks of Novartis. Epaxal and Inflexal are trademarks of Crucell.

Disclosure statement

Geert Leroux-Roels was principal investigator of clinical vaccine evaluations for the following manufacturers: Baxter, GSK Biologicals, Novartis, SanofiPasteur. The Ghent University and University Hospital received sponsoring for the conduct of these studies. Performed consulting services for the following manufacturers: GSK Biologicals, Novartis.

Role of the funding source

GSK Biologicals funded all costs associated with the development and the publishing of the present manuscript.

Acknowledgements

Nathalie Garçon, Marcelle van Mechelen, Alberta Di Pasquale (GSK Biologicals) for scientific advice, Muriel Moser (Université Libre de Bruxelles, Belgium), Oberdan Leo (Université Libre de Bruxelles, Belgium), and Fred Zepp (University of Mainz, Germany) for scientific input, Anna Dow for assistance in preparing the manuscript, Slavka Baronikova and Luise Kalbe (GSK Biologicals) for editorial assistance and coordination of manuscript development.

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ReviewUnmet needs in modern vaccinology: Adjuvants to improve the immune response

Abstract

Introduction

Section snippets

Challenges of modern vaccinology

Learning and selecting from nature

Approaches to address vaccine limitations

Clinical benefit—applications of novel adjuvants and Adjuvant Systems to address unmet immunization needs linked to the pathogen and/or the target population

Safety

Adjuvants approaches beyond preventive vaccines

Conclusions

Trademark statements

Disclosure statement

Role of the funding source

Acknowledgements

Vaccine

Semin Immunol

Vaccine

Trends Immunol

Vaccine

Mol Immunol

Immunol Lett

Vaccine

Vaccine

Vaccine

Curr Opin Immunol

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Methods

Adv Drug Deliv Rev

Vaccine

Vaccine

Vaccine

Vaccine

Lancet

Lancet

Lancet

Lancet

Lancet

Vaccine

Vaccine

Adv Immunol

Vaccine

Vaccine

Semin Nephrol

Infect Dis Clin North Am

Vaccine

Vaccine

Biologicals

Current status and progress of prepandemic and pandemic influenza vaccine development

Expert Rev Vaccines

Challenges for vaccination in the elderly

Immun Ageing

Review
Unmet needs in modern vaccinology: Adjuvants to improve the immune response