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British Medical Bulletin 62:15-28 (2002)
© 2002 The British Council

Immunology of vaccination

P C L Beverley

The Edward Jenner Institute for Vaccine Research, Compton, Berkshire, UK


   Abstract
Top
 Abstract
Introduction
 Initiation of immune responses
 Immunological memory
 Appropriate immune responses
 Conclusions
 Key points for clinical...
 References
 
An ideal vaccine is relatively easy to define, but few real vaccines approach the ideal and no vaccines exist for many organisms, for which a vaccine is the only realistic protective strategy in the foreseeable future. Many difficulties account for the failure to produce these vaccines. All micro-organisms deploy evasion mechanisms that interfere with effective immune responses and, for many organisms, it is not clear which immune responses provide effective protection. However, recent advances in methods for studying immune response to pathogens have provided a better understanding of immune mechanisms, including immunological memory, and led to the realisation that the initiation of immune responses is a key event requiring triggering through ‘danger’ signals. Based on these findings, the development of novel adjuvants, vectors and vaccine formulations allowing stimulation of optimal and prolonged protective immunity should lead to the introduction of vaccines for previously resistant organisms.


   Introduction
Top
 Abstract
 Introduction
Initiation of immune responses
 Immunological memory
 Appropriate immune responses
 Conclusions
 Key points for clinical...
 References
 
It is easy to define the properties of an ideal vaccine. Most of these are obvious (Table 1), but few vaccines approach the ideal. In addition, vaccines do not yet exist for many organisms and it is worth considering why this is so. First it is notable that most successful vaccines are against relatively small organisms. There are excellent vaccines against several viruses and some against bacteria, although several of these do not protect against infection but rather the toxic effects of infection. As yet there are no satisfactory vaccines against parasites. Generally, therefore, successful vaccines are against organisms with smaller genomes although there are of course exceptions to this general rule, for example so far we do not have an effective vaccine against HIV or hepatitis C.


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  		Table 1. Properties of an ideal vaccine

 
Without prior immunisation, most organisms gain a foothold in their host but from very early on in the infectious process must deploy mechanisms to interfere with the host immune response. Even those organisms that rely on rapid multiplication and spread to new hosts must combat innate (non-specific) immune mechanisms. Organisms with a life-style involving co-existence with their host over long periods have also to combat the adaptive (specific) immune response. Thus all micro-organisms have evolved complex defence mechanisms that interfere with every stage of the immune response. Organisms with large genomes have sufficient genetic capacity to carry multiple genes capable of affecting immune response. The sheer magnitude of the enterprise involved in working out all these mechanisms means that there is more complete information available for smaller organisms. A number of viruses have been well studied. Numerous viral gene products that interfere in immune function have been described. These include a large variety of molecules that mimic important regulatory molecules of the immune system, such as interferons, interleukins and chemokines and their receptors. Interference with antigen processing is common and viruses may also prevent apoptosis1,2. Genes dedicated to viral escape may represents at least 10% of viral genomes, indicating the potential magnitude of the task involved in understanding how a complex organism such as a bacterium avoids elimination by the immune system since 10% of a bacterial genome might be 200–400 genes!

Smaller organisms do not have the luxury of devoting tens or hundreds of genes to combating the immune system and must adopt other strategies, one of which is rapid change. Many viruses use this method including influenza, HIV and hepatitis C. Larger organisms also employ this strategy including malaria. Most often, the variation takes place after infection of the host. Of course if the organism has a secondary host, change may take place during infection of this species as is thought to occur in the case of influenza virus3. Pre-existing immunity can prevent the opportunity for multiplication and development of escape variants such as have been well described for HIV4,5. Thus immunisation against an epidemic strain of influenza virus can provide very effective preventive immunity against spread of that strain but not against future variants.

The ability of micro-organisms to deploy escape mechanisms even early in immune responses suggests that, for organisms so far insusceptible to vaccines, we need to decide what the vaccine is intended to do. Do we wish to prevent infection completely, or simply suppress replication of the organisms to an extent compatible with a normal life-span? Is prevention of transmission to other and perhaps more susceptible individuals (for example infants) the objective, or is the aim not the prevention of infection but pathology? Recent understanding of the complex interactions of micro-organisms with their hosts suggests that if we are to make progress in containing many infectious diseases caused by complex organisms, we should better define our objective and tailor our vaccine strategies accordingly. Better understanding of the crucial events in immune responses will help in doing this and may lead to development of new vaccines capable of combating infections in very different ways. This review describes some of the most important stages of an immune response and raises some of the issues that need to be resolved if progress toward a new generation of vaccines is to be made.


   Initiation of immune responses
Top
 Abstract
 Introduction
 Initiation of immune responses
Immunological memory
 Appropriate immune responses
 Conclusions
 Key points for clinical...
 References
 
Danger signals

A key stage of any immune response is the phase of initiation. Antigens must be recognised as foreign for an immune response to occur. Micro-organisms are usually recognised because they carry ‘danger’ signals that signal the immune system through conserved pattern recognition receptors6. Tissue damage also leads to the expression of self molecules that can also activate cells of the innate immune system7. The receptors for external and internal ‘danger’ signals are diverse. They include low affinity IgM, serum mannan binding protein, pentraxins and cellular receptors such as complement receptors, mannose and other lectin-like receptors for carbohydrates, the phosphatidylserine receptor, heat shock proteins8–10 and the recently described family of IL-1R-Toll-like molecules11,12. The latter may function as homodimers, but they frequently form heterodimers with other Toll-like receptors or may work in concert with other cell surface or soluble molecules such as CD14. They recognise molecules that are often abundant, contain repeating subunits and are not produced by vertebrates. These include bacterial polysaccharides and lipopolysaccharides, complex fungal polysaccharides, flagellin and bacterial DNA or viral RNA (Table 2).


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  		Table 2. Pattern recognition receptors

 
Initial recognition of micro-organisms as foreign is likely to take place in non-lymphoid tissues and the most important cells in this process are tissue resident macrophages and dendritic cells (DCs). Activation of dendritic cells is crucial as these cells have been shown to be uniquely capable of initiating a primary immune response13. DCs are also actively pinocytic and take up soluble antigens as well as those bound by their surface receptors14. Uptake of antigen and ligation of one or more DC receptors, initiates three key processes: antigen processing, migration to lymph nodes, and maturation of the DCs.

Antigen processing

Antigens entering cells by endocytosis are broken down in lysosomal vesicles and peptides from them encounter major histocompatiblity class II antigens (MHC II) in a specialised intracellular loading compartment where the peptides are loaded onto MHC II molecules for transport to the cell surface (exogenous antigen processing)15. Antigens synthesised in the cell, as is the case for viruses and other intracellular pathogens, are broken down to peptides by the proteasomes and the resulting peptides are transported into the rough endoplasmic reticulum for loading onto MHC class I molecules (endogenous antigen processing). Loaded MHC molecules are then transported to the cell surface (Fig. 1)16.



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  		Fig. 1 The figure shows the two modes of antigen processing. In the exogenous modes, antigens are captured from the extracellular space, degraded to peptides in endosomes and the peptides displayed on MHC II molecules. Endogenous processing of intracellular antigens is carried out by the proteasomes and the resulting peptides are loaded on to MHC class I molecules in the endoplasmic reticulum.

 
Tissue resident DCs are active antigen processing cells. Following activation by ‘danger’ signals, surface expression of MHC increases greatly and subsequently antigen processing decreases17.

Migration and maturation

At the same time, the cells migrate from the tissues to the draining lymph nodes, a process controlled by chemokines and their receptors18,19. Thus in the tissues, DCs express CCR1, CCR5 and CCR6 – the receptors for chemokines produced by tissue cells. Down-regulation of these receptors and up-regulation of CXCR4 and CCR7 are induced by ‘danger’ signals and signals from inflammatory cytokines such as tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-1 (IL-1). This allows the DCs to receive chemotactic signals from the lymph node chemokines, secondary lymphoid tissue chemokine (SLC) and EBV-induced-receptor ligand chemokine (ELC; Fig. 2). During migration and entry of DCs into the T-cell areas of nodes, the DCs show considerable changes in phenotype (maturation) in addition to the up-regulation of MHC already described. The most important is the up-regulation of surface molecules that are important for interaction of DCs with T-cells. CD40, CD80 and CD86 (B7.1 and B7.2) deliver crucial co-stimulatory signals for T-cell activation, while several members of the TNF–TNFR (tumour necrosis factor receptor) family of molecules are up-regulated. These include CD40, Ox40 and 4-1BB and they appear to play important roles in differentiation of different types of effector T-cells (see below)20–22. In concert with this, the DCs up-regulate production of many different cytokines that affect T-cell differentiation and function23.



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  		Fig. 2 The figure illustrates key events in the initiation of an immune response. Introduction of antigen and an accompanying danger signal, leads to release of cytokines and chemokines and influx of inflammatory cells. Dendritic cells take up antigen and migrate to draining nodes where they interact with T- and B-cells to generate specific immune responses. Effector cells leave the node and some of these home to the inflammatory site.

 
Two aspects of this complex series of processes are particularly crucial from the point of view of vaccines. The first is the need for ‘danger’ signals to initiate responses. While whole micro-organisms, even if killed, may well deliver appropriate signals, subunit vaccines may be poorly immunogenic so that adjuvants are needed. In humans, the most commonly used is alum. Alum has been shown to favour Th2 responses in mice, inducing strong antibody responses24. This observation leads to the second crucial point, that the nature of the ‘danger’ signal has an important bearing on the type of immune response generated25. Clearly for vaccines where a Th1 type of response is required, alum may not be an appropriate adjuvant and, further more, the danger signals carried by the vaccine itself or a live vector must also be taken into account. So far, few alternative adjuvants are available for routine use in humans26,27. However, better understanding of the mechanisms of action of adjuvants and the signals that control differentiation of DCs and, therefore, T-cells will eventually allow design of vaccine-adjuvant preparations tailored to induce appropriate protective responses for particular infections28.


   Immunological memory
Top
 Abstract
 Introduction
 Initiation of immune responses
 Immunological memory
Appropriate immune responses
 Conclusions
 Key points for clinical...
 References
 
What is immunological memory?

Irrespective of the type of immune response required for protection, for almost all vaccines long-lasting protection (memory) is a desirable objective. However, while it is easy to state this, it is less certain how it should be achieved, although a great deal has been learnt about immunological memory over the last two decades. During a primary immune response, lymphocytes proliferate and change their phenotype. Memory populations of cells are, therefore, both quantitatively and qualitatively different from those that have not yet encountered antigen29. Thus memory consists of expanded clones of lymphocytes with altered function. Among thymus-derived (T) lymphocytes, this is reflected in rapid production of effector cytokines such as IFN-{gamma} or interleukins. Primed cells express higher levels of several adhesion molecules, such as ICAM-1 and integrins, as well as homing molecules such as CD44, CD62L and the cutaneous lymphocyte antigen (CLA)30–33. Among B-cells, the hallmark of immunological memory is the production of isotype switched, somatically mutated, high affinity immunoglobulin34. It is also clear that memory is a dynamic state. In both man and experimental animals, phenotypically defined memory cells have been shown to divide more rapidly than naive cells35,36. This appears to be an inherent property of memory cells since division continues in the absence of antigen37,38.

Constraints on the duration of memory

In vitro at least, human T lymphocyte clones can only undergo a finite number of cell divisions and, as they approach senescence, no longer express the co-stimulatory molecule CD28, can no longer up-regulate telomerase on activation, and show progressive shortening of telomeres39. These mechanisms may limit the duration of memory in the absence of re-exposure to antigen, which would recruit new clones. In addition to these constraints on survival of individual clones, there is also the constraint of space in the memory pool. Although during an acute infection lymphocyte numbers may increase greatly40, in the longer term numbers of cells with naive and memory phenotypes change only slowly. Thus every time a new antigen is encountered and a new set of clones undergoes expansion and enters the memory pool, other cells must die to provide space. What factors favour one cell or clone over another in this competition for survival are not known. However, experimental evidence suggests that memory persists longer if the initial clonal expansion is large41.

Alternatively, persistence of antigen may favour clonal survival as occurs in chronic infections such as EBV or CMV40. It is now clear that there is considerable heterogeneity among antigen-specific T-cell populations detected by binding to MHC-peptide tetramers42,43 and it is thought that some memory cells may revert to a more slowly dividing state44. This suggests two alternative strategies for ensuring persistence of memory. Either vaccines should be designed to ensure maximal clonal expansion by providing an optimal dose of antigen and appropriate adjuvant, or vectors should be chosen to ensure long persistence of antigen.


   Appropriate immune responses
Top
 Abstract
 Introduction
 Initiation of immune responses
 Immunological memory
 Appropriate immune responses
Conclusions
 Key points for clinical...
 References
 
Heterogeneity of immune responses

One of the major discoveries of the modern era of immunology is that not all immune responses are the same. In truth, this is not a new discovery since it has been long been known that there are many types of immune response and these may be both beneficial, for example the development of neutralising antibody to viruses, or pathological, for example the production of IgE antibody leading to anaphylaxis. What is new is the greatly increased, though not complete, understanding of how different types of response are generated.

Immune responses are influenced by many factors, but key cells that control the functions of other immune cells are the T helper cells (Th cells). These cells, which express the CD4 surface antigen and recognise antigenic peptides displayed by MHC II molecules, influence the function of important effector cells such as CD8 cytotoxic cells, antibody producing B lymphocytes and macrophages, both by cell–cell contact and production of soluble cytokines. Two major types of Th cells (and analogous CD8 subsets) have been described. Th1 effectors produce IL-2, IFN-{gamma}, and lymphotoxin and mediate ‘cellular’ immunity45–47. The dominant cytokine is IFN-{gamma}, immune CD4 and CD8 cells are both readily demonstrable, and antibody is not a prominent feature of the response.

In contrast, in Th2 cell responses, the dominant cytokines produced are IL-4, IL-5, IL-10, and IL–13. CD8 cytotoxic cells are not prominent and high titres of antibody may be produced, with a bias toward IgG as well as IgA and IgE. In general, Th1 cell responses are adapted to deal with intracellular parasites through direct and indirect mechanisms – cell killing or production of cytokines (particularly IFN-{gamma}) that activate cellular protective mechanisms. Th2 cell responses are particularly effective at coping with extracellular parasites through antibody-dependent mechanisms. It should be emphasised that, although some response are almost exclusively Th1 or Th2 and very biased responses are associated with some disease states48, in most immune responses both Th1 and Th2 components can be detected. Furthermore, many cytokines including TNF-{alpha}, IL-3, IL-6 and GM-CSF are produced by both Th1 and Th2 cells46.

Control of T-cell responses

It is important to understand what controls the development of a Th1 or Th2 biased response. In experimental animals, the genetic background of the host has been shown to be important. Thus Balb/c mice mount a Th2 response to the parasite Leishmania major, while other strains of mice make a Th1 response. The former strain is susceptible to infection while others are resistant, demonstrating the important of making the ‘right’ type of response49. This model illustrates another important aspect of the Th1/Th2 balance – that manipulation of the balance of cytokines can have profound effects. Treatment of susceptible Balb/c mice with antibody to the Th2 cytokine IL-4 or administration of the Th1-inducing cytokine IL-12, makes them resistant50,51. Apart from the genetic background of the host, it has been shown that the route, dose and form of the antigen and whether an adjuvant is given can have profound effects on the type of immune response generated52.

More recent experiments show that treatment of DCs with products of micro-organisms such as lipopolysaccharide (LPS) or the filarial worm antigen ES62, can bias their ability to stimulate Th1 and Th2 responses to a protein antigen25. Thus it appears that micro-organisms signal DCs, probably through binding to Toll-like, lectin-like and other surface receptors, to differentiate along different pathways, that have been termed DC-1 and DC-253. These DC subtypes show different patterns of cytokine production, which in turn influence Th cell generation. IL-12 produced by DCs has been shown to be a key cytokine for induction of Th1 cells while IL-4 and IL-10 are important for generation of Th2 cells54–56.

The observations discussed above indicate why particular adjuvants may induce Th-biased responses. Although the exact mechanisms of action of alum are not well understood, it induces strong Th2 responses in mice and humoral responses in man, presumably by inducing DCs to produce Th2-inducing cytokines24,26. In contrast, the experimental adjuvant, Freund's complete adjuvant, which contains BCG in mineral oil generates a strongly Th1-biased response. Since the mechanism underlying Th bias is a cytokine milieu, it is perhaps not surprising that strong cytokine inducers can bias not only on-going immune responses but appear to be able to bias other subsequent responses. Thus BCG vaccination (a Th1 response) has been shown to protect against subsequent development of allergy (a Th2 response)57. This has led to attempts to use the strong Th1 inducer, Mycobacterium vaccae, as an immunomodulating agent for treatment of a number of diseases58. Similarly, it has led to the suggestion that early exposure to micro-organisms capable of biasing the immune response may have a life-long effect on subsequent immune responses (the hygiene hypothesis)59.


   Conclusions
Top
 Abstract
 Introduction
 Initiation of immune responses
 Immunological memory
 Appropriate immune responses
 Conclusions
Key points for clinical...
 References
 
A key issue in vaccine development today is what type of immune response is needed to best protect against the ‘difficult’ organisms for which there are currently no effective vaccines. Most of the present generation of successful vaccines depend principally on generating high titres of antibody and many are given with the Th2-biasing adjuvant alum. However, natural protection against many organisms, particularly intracellular parasites, is mainly Th1 in nature. Furthermore, for organisms that vary rapidly (e.g. HIV, malaria) even if neutralising antibody could be induced, escape variants would rapidly make this ineffective, as is the case with influenza virus. For these difficult organisms, it remains unclear whether a strong cellular response, induced by a vaccine, could either prevent infection becoming established or suppress it to a subclinical level compatible with normal life, although it is clear that the cellular immune response does contribute to protection against HIV60,61.

Nevertheless, in the absence of concrete evidence that cellular immunity can be protective, many new vaccines are being designed to induce strong Th1 and CD8 cytotoxic T lymphocyte (CTL) responses. To induce CTLs, presentation of antigen via MHC I is required and, as yet, the most effective way of doing this is through the use of live vectors that infect cells and thereby introduce antigens into the cytosol (Fig. 1), although particulate antigens and some adjuvants can also induce CTLs. DNA has the advantage that, like live vectors, it can generate antigens inside cells, and the additional advantage that the DNA may also code for genes such as cytokines that have adjuvant effects and can bias responses in a desired direction62–64.

Although these approaches are promising and are explored in other chapters of this issue, there is an additional problem for vaccines that induce cellular immunity. Clearly, for cells to have a protective effect and prevent establishment of detectable infection, they must be able to enter tissues that are the site of entry for micro-organisms, particularly the respiratory, gastrointestinal and genito-urinary tracts. It is clear that among CD4 and CD8 memory cells, not all cells can do this. Among CD4 cells, central and effector memory has been defined. Central memory cells express the chemokine receptor CCR7 which enables them to re-circulate through lymphoid tissues, while effector memory cells express CCR3 and CCR5 and can enter non-lymphoid tissues65. CD8 memory cells have similarly been further divided into subsets with differing expression of chemokine receptors and other surface molecules32,33,66. While as yet it is not clear how to influence the proportions of these re-circulating or tissue homing memory cells, it has been shown experimentally that recent activation by antigen provides memory that is optimally protective against tissue infection67. This may indicate that means of ensuring persistence of antigen over long periods of time will be essential if protective cellular immunity is to be maintained and be useful. Novel adjuvants and vectors will be needed to achieve this.


   Key points for clinical practice
Top
 Abstract
 Introduction
 Initiation of immune responses
 Immunological memory
 Appropriate immune responses
 Conclusions
 Key points for clinical...
References
 

  1. Protective mechanisms are poorly understood for many organisms
  2. It remains unclear whether vaccines aimed at stimulating cell-mediated immunity will induce protective immunity
  3. New and safe adjuvants and vectors are needed for human use


   Footnotes
 
Correspondence to: Prof. P C L Beverley, Scientific Head, The Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK


   References
Top
 Abstract
 Introduction
 Initiation of immune responses
 Immunological memory
 Appropriate immune responses
 Conclusions
 Key points for clinical...
 References
 

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