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  • Review Article
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The contribution of immunology to the rational design of novel antibacterial vaccines

Nature Reviews Microbiology volume 5, pages 491–504 (2007)Cite this article

Key Points

  • Infections with bacterial pathogens remain a major health problem, causing more than 5 million deaths annually. The major culprits are pneumococci and meningococci in both the developing and developed world; agents of nosocomial infections, many of them being multidrug-resistant, mostly in the industrialized world; tuberculosis, which afflicts >85% of the population in developing countries and <15% in industrialized countries; and bacterial pathogens, which cause food-borne diseases that frequently have diarrhoeal sequelae (not covered in this article).

  • Vaccines are amongst the most successful measures of modern medicine — they save several million lives annually and have remarkable cost efficiency. Bacterial pathogens that are controlled successfully by vaccines include Clostridium tetani, Corynebacterium diphtheriae and Haemophilus influenzae b. Conjugate vaccines against meningococci and pneumococci are also available but need further improvements.

  • Vaccines achieve different outcomes. Most vaccines prevent disease outbreak rather than infection itself. Yet, in many cases, vaccinated individuals ultimately eradicate the pathogen. In more complex diseases, however, vaccinated individuals can only control infection if the bacterial load remains under the threshold for active disease. In such individuals, becoming immunocompromised can allow disease outbreak despite previous vaccination.

  • Rational vaccine design can benefit from recent insights into the immunology of host defences against infectious agents. This includes our better understanding of: how the innate immune response senses infectious agents; how it instructs the acquired immune response to develop the most appropriate defence mechanisms; the pathways through which antigens are presented to T cells; the cytokines and co-stimulatory cell-surface molecules which fine-tune T- and B-cell responses; the cytokines produced by T cells that help other immune cells to perform effector functions; and the mechanisms underlying memory for B cells and T cells. Although successful vaccines mostly rely on antibody production, the next generation of vaccines will need to exploit T cells to achieve the required efficacy.

  • Novel vaccination strategies can be roughly separated into three groups. First, vaccines based on antibody-mediated protection could lead to improved vaccines against pneumococci and meningococci as well as against nosocomial infections. Second, vaccines based on T-cell immunity will be needed against intracellular pathogens, notably Mycobacterium tuberculosis and Chlamydia trachomatis. Third, novel vaccines that prevent infection will be needed for diseases in which existing vaccines prevent disease outbreak by reducing the bacterial load under the threshold of active disease.

Abstract

In most cases, a successful vaccine must induce an immune response that is better than the response invoked by natural infection. Vaccines are still unavailable for several bacterial infections and vaccines to prevent such infections will be best developed on the basis of our increasing insights into the immune response. Knowledge of the signals that determine the best possible acquired immune response against a given pathogen — comprising a profound T- and B-cell memory response as well as long-lived plasma cells — will provide the scientific framework for the rational design of novel antibacterial vaccines.

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Figure 1: The fathers of immunology and vaccinology.
Figure 2: Pattern-recognition receptors: TLRs and NODs.
Figure 3: Antigen presentation to different T-cell subsets: direct presentation and cross-priming.
Figure 4: Different subpopulations of CD4+ T cells.
Figure 5: Memory generation in cells of the immune system.

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Acknowledgements

I am grateful to S. Sibaei and M.L. Grossman for excellent support, D. Schad for graphical work and S. Reece for critically reading the manuscript. I also thank A. von Gabain for sharing unpublished work. Studies on vaccine development have been carried out with support from the following: The European Union Framework Program 6 Projects, Design and Testing of Vaccine Candidates Against Tuberculosis (TBVAC) and Mucosal Vaccines for Poverty-related Diseases (MUVAPRED); the Bundesministerium für Bildung und Forschung KompetenzNetzwerk PathoGenoMikPlus, KompetenzNetzwerk-RNA Technologie, and National Genome Research Network 2 (Germany); DFG Priority Programme Novel Vaccination Strategies (Germany); Bill & Melinda Gates Foundation Grand Challenges in Global Health (US). Studies on the history of vaccinology have been generously supported by Fonds der Chemischen Industrie (Germany).

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  1. Department of Immunology, Max Planck Institute for Infection Biology, Charitéplatz 1, Berlin, D-10117, Germany

    Stefan H.E. Kaufmann

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Stefan Kaufmann is a member of the Scientific Advisory Board of Intercell AG, Austria, and VPM (Vakzine Projekt Management) GmbH, Germany.

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DATABASES

Entrez Genome Project

Staphylococcus aureus

Streptococcus pneumoniae

Neisseria meningitidis

Mycobacterium tuberculosis

Chlamydia trachomatis

Helicobacter pylori

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Glossary

Passive vaccination

The provision of protective immunity by the transfer of immunoglobulins or T cells.

Plasma cell

A non-dividing, terminally differentiated, immunoglobulin-secreting cell of the B-cell lineage.

Regulatory T cell

(TReg cell). A population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor α-chain) and the transcription factor forkhead box P3 (Foxp3), and that have suppressive regulatory activity towards effector T cells and other immune cells.

Pattern-recognition receptor

(PRR). A host receptor (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane-bound (such as TLRs) or soluble cytoplasmic receptors (such as NLRs).

Dendritic cell

(DC). 'Professional' antigen-presenting cells that are found in the T-cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

CD4+ T cell

A subpopulation of T cells that express the CD4 receptor. These cells aid in immune responses and are therefore referred to as T helper cells.

CD8+ T cell

A subpopulation of T cells that express the CD8 receptor. CD8+ cells recognize antigens that are presented on the surface of host cells by MHC class I molecules, leading to their destruction, and are therefore also known as cytotoxic T lymphocytes (CTLs).

γδ T cell

A minor population of T cells that express the γδ T-cell receptor, and that are more abundant in epithelial-rich tissues such as skin and gut and reproductive tracts. Like NKT cells, γδ T cells can be cytolytic and produce high levels of cytokines and chemokines.

Perforin

A calcium-sensitive membrane-lytic protein that is found in cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells.

Granzyme

A family of serine proteinases that are found primarily in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells. These proteinases enter target cells through perforin pores, then cleave and activate intracellular caspases and induce apoptosis of target cells.

Phagosome

The functional definition of the organelle in which bacteria are internalized. Phagosomal and endosomal pathways undergo interconnected maturation and merge before fusion with lysosomes. Some bacterial pathogens inhibit the acidification of the phagosome and its fusion with lysosomes.

T helper 1 cell

(TH1 cell). A type of activated TH cell that promotes responses associated with the production of a particular set of cytokines, including interleukin (IL)-2 and interferon (IFN)-γ, the main function of which is to stimulate phagocytosis-mediated defences against intracellular pathogens.

T helper 2 cell

(TH2 cell). A type of activated TH cell that participates in phagocytosis-independent responses and downregulates pro-inflammatory responses that are induced by TH1 cells. TH2 cells secrete interleukin (IL)-4 and IL-5.

Central memory T cell

A memory T cell that lacks immediate effector function but can mediate rapid recall responses and has the capacity to circulate from the blood to the secondary lymphoid organs. Rapidly develops the phenotype and function of effector cells after restimulation with antigen.

Effector memory T cell

A memory T cell that homes to inflamed tissues. Can exert immediate effector functions without the need for further differentiation.

High endothelial venule

(HEV). A specialized venule with a cuboidal endothelial lining that occurs in peripheral lymph nodes and Peyer's patches. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.

Heterologous prime–boost strategies

When a single application of a vaccine is insufficient, repeated vaccinations are carried out using different vaccine preparations, allowing the sequential stimulation of a better immune response.

Germinal centre

A highly specialized and dynamic microenvironment in the follicles of secondary lymphoid tissues (spleen, Peyer's patches and lymph nodes) that gives rise to secondary B-cell follicles during an immune response. The main site of B-cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibody.

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Kaufmann, S. The contribution of immunology to the rational design of novel antibacterial vaccines. Nat Rev Microbiol 5, 491–504 (2007). https://doi.org/10.1038/nrmicro1688

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