ReviewUnmet needs in modern vaccinology: Adjuvants to improve the immune response
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.
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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.
References (107)
Principles of vaccine design—lessons from nature
Vaccine
(2010)- et al.
TLR signaling
Semin Immunol
(2007) - et al.
Key concepts in immunology
Vaccine
(2010) - et al.
New horizons in adjuvants for vaccine development
Trends Immunol
(2009) - et al.
Mechanism of action of licensed vaccine adjuvants
Vaccine
(2009) - et al.
Immunological adjuvants: desirable properties and side-effects
Mol Immunol
(1991) (How) do aluminium adjuvants work?
Immunol Lett
(2006)Aluminium adjuvants—in retrospect and prospect
Vaccine
(2004)Mechanisms of stimulation of the immune response by aluminium adjuvants
Vaccine
(2002)- et al.
Role of aluminium-containing adjuvants in antigen internalization by dendritic cells in vitro
Vaccine
(2005)
Mechanism of action of clinically approved adjuvants
Curr Opin Immunol
The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine
Vaccine
MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18-60 years of age) with chronic diseases who are at risk of post-influenza complications
Vaccine
Vaccine adjuvants revisited
Vaccine
Immunogenicity and protectivity of a new liposomal hepatitis A vaccine
Vaccine
Immunogenicity and safety of a novel IL-2-supplemented liposomal influenza vaccine (INFLUSOME-VAC) in nursing-home residents
Vaccine
Interchangeability and tolerability of a virosomal and an aluminium-adsorbed hepatitis A vaccine
Vaccine
Immunogenicity and adverse effects of inactivated virosome versus alum-adsorbed hepatitis A vaccine: a randomized controlled trial
Vaccine
Eleven years of Inflexal V-a virosomal adjuvanted influenza vaccine
Vaccine
Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly
Vaccine
The virosomal influenza vaccine Invivac: immunogenicity and tolerability compared to an adjuvanted influenza vaccine (Fluad in elderly subjects)
Vaccine
Topical delivery of imiquimod to a mouse model as a novel adjuvant for human immunodeficiency virus (HIV) DNA
Vaccine
Reduction of recurrent HSV disease using imiquimod alone or combined with a glycoprotein vaccine
Vaccine
Induction of cross-reactive cytotoxic T-lymphocyte responses specific for HIV-1 gp120 using saponin adjuvant (QS-21) supplemented subunit vaccine formulations
Vaccine
Saponin-adjuvanted particulate vaccines for clinical use
Methods
ISCOMATRIX adjuvant for antigen delivery
Adv Drug Deliv Rev
ISCOMs and ISCOMATRIX
Vaccine
Single dose intranasal immunization with ISCOMATRIX vaccines to elicit antibody-mediated clearance of influenza virus requires delivery to the lower respiratory tract
Vaccine
Evaluation of ISCOMATRIX and ISCOM vaccines for immunisation against Helicobacter pylori
Vaccine
Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS,S/AS02A
Vaccine
Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial
Lancet
Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial
Lancet
Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial
Lancet
Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial
Lancet
Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial
Lancet
Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults
Vaccine
Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial
Vaccine
The aging of the immune system
Adv Immunol
Immunosenescence: role and measurement in influenza vaccine response among the elderly
Vaccine
Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly
Vaccine
B virus infection in hemodialysis patients
Semin Nephrol
C and renal failure
Infect Dis Clin North Am
Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04
Vaccine
A prophylactic hepatitis B vaccine with a novel adjuvant system
Vaccine
Development of an adjuvant to enhance the immune response to influenza vaccine in the elderly
Biologicals
Current status and progress of prepandemic and pandemic influenza vaccine development
Expert Rev Vaccines
Challenges for vaccination in the elderly
Immun Ageing
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