Invited review

The effectiveness and limitations of immune memory:

understanding protective immune responses

Manuel Camposa,b,*, Dale L. Godsonc

aDepartment of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, CanadabImmunaxis Inc., P.O. Box 1205, Bragg Creek, Alberta Canada T0L 0K0

cDepartment of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive,

Saskatoon, Saskatchewan Canada S7N 5B4

Received 8 August 2002; received in revised form 31 January 2003; accepted 3 February 2003

Abstract

Immune memory is the foundation of the practise of vaccination. Research on the molecular and cellular events leading to generation and

development of memory T and B lymphocytes explain why there are heightened secondary immune responses after an initial encounter with

antigen. In this review, we discuss how clonal expansion, targeted tissue localisation, more efficient antigen recognition and more proficient

effector functions contribute to the improved effectiveness of memory cells. Despite the enhanced efficacy of memory cells and the recall

immune response, there are numerous experimental and empirical examples in which protection provided by vaccines are short-lived,

particularly against pathogens that replicate and cause pathology at their site of entry. In the absence of active immune effector activities, the

ability of memory cells to respond quickly enough to control this type of infection is limited. The protective efficacy of bovine herpes virus-1

vaccines in experimental and field challenge conditions are used to illustrate the concept that full protection from disease conferred by

vaccination requires the presence of active immune effector mechanisms. Thus, regardless of the many successful technological advances

in vaccine design and better understanding of mechanisms underlining induction of memory responses by vaccination, we should recognise

that vaccine immunoprophylaxis has limitations. Expectations for vaccines should be realistic and linked to the understanding of host

immune responses and knowledge regarding the pathogen and disease pathogenesis.

q 2003 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved.

Keywords: Immune memory; Vaccination; Pathogenesis

1. Introduction

Approximately 2,500 years have passed since the first

recorded observation that individuals previously exposed to

the plague had reduced susceptibility to the disease. Almost

2,300 years later, this and other similar empirical obser-

vations led to the practise of vaccination for the prevention

of smallpox (reviewed by Ahmed and Gray, 1996). Another

100 years elapsed before vaccination was applied to the

control of livestock diseases (chicken cholera and anthrax)

(Dunlop and Williams, 1996). With these successes in

disease prevention, it seemed that all that was required to

produce a successful vaccine was to identify the microbe

responsible for the disease (by following Koch’s postulates)

and develop methods of attenuation or inactivation.

However, efforts to develop effective vaccines for many

diseases of known aetiologies, using old and new technol-

ogies have failed. We know that in many diseases the

immune response that develops during the primary infection

protects the host against disease when there is a second

exposure to the pathogen. The ability of the immune system

to learn from and remember its first encounter with an

antigen, in order to make a better secondary response, is

described as ‘immune memory’, and it is the foundation of

the practise of vaccination. The cells responsible for the

improved protection are antigen-experienced T and B lym-

phocytes that can persist for long periods of time and can

reactivate quickly following re-encounter with the antigen.

Memory cells develop in response to both antigen-specific

and non-specific signals received during the primary

response, and are characterised by their potential to elicit

a heightened secondary immune response to antigens, often

at considerable times after primary immunisation (Ahmed

0020-7519/03/$30.00 q 2003 Australian Society for Parasitology Inc. Published by Elsevier Science Ltd. All rights reserved.

doi:10.1016/S0020-7519(03)00066-3

International Journal for Parasitology 33 (2003) 655–661

www.parasitology-online.com

* Corresponding author. Tel.: þ1-403-949-3119; fax: þ1-403-949-2658.

E-mail address: camposmanuel@msn.com (M. Campos).

and Gray, 1996; Banatvala et al., 2001; Bernasconi et al.,

2002; Zinkernagel, 2002). Thus, the aim of vaccination is

to produce memory cells from naive precursors. We are

beginning to understand many of the mechanisms respon-

sible for the characteristics of memory cells, such as faster

response time, specialised tissue localisation and more

effective antigen recognition and effector functions. Our

knowledge of the cellular and molecular basis of memory

cell development and function, as well as the use of new

molecular biology technologies, new adjuvants and new

delivery systems, enable us to induce immune memory

more appropriately.

Effective prophylaxis for many diseases has not been

achieved despite the advances in vaccine technology.

Experimental and empirical observations have shown that

induction of memory does not ensure protection from a

second infection (Woodland et al., 2002; Zinkernagel,

2002). Often, the reason for these failures may be associated

with the intrinsic pathogenesis of the infection, as well as

the biological limitations of the immune system, rather than

inadequate induction of specific memory responses. Thus it

is essential to discriminate between immune memory as a

quantifiable, biological entity and the complexities of pro-

tection following secondary in vivo challenge. To illustrate

this concept, the differences between the duration of immunity

and duration of protection will be presented using examples

of diseases with distinct pathogenic patterns.

2. Factors influencing the onset of protective immunity

during primary and secondary responses

The time required to generate functional effector cells

from resting precursors is critical in controlling infection

and preventing disease. The speed by which effector cells

are generated from naive T and B cell precursors after the

first encounter with antigen is significantly slower than the

speed with which effector cells are generated from memory

T and B cells upon subsequent exposure to antigen. This

difference is why a second infection can often be controlled

before any serious pathologic changes occur. The heigh-

tened efficiency of memory cells to generate effector cells

has been attributed to increased numbers of antigen-specific

cells, improved recognition and responsiveness and altered

homing and migration patterns of responder cells, as well

as the generation of more functionally effective B and

T cells. This section summarises experimental evidence

that describes the cellular and molecular aspects that are

responsible for the quicker onset of protective immunity

during secondary immune responses.

2.1. Increase in the number of responder cells

To initiate an immune response, antigen must be

specifically recognised by the antigen receptor of the T or

B lymphocyte. The chance of an infecting organism

encountering the appropriate receptor is dependant upon

the frequency of cells in the lymphocyte population bearing

receptors with that specificity. Techniques have been deve-

loped to enumerate antigen-specific lymphocytes, such as

limiting dilution analysis, flow cytometric analysis of major

histocompatibility complex (MHC)–antigen complex (tet-

ramer) binding and ELISPOT assays. One should note that

in vitro analysis of memory cells does not always corre-

spond to in vivo analysis (Panus et al., 2000; Rocha, 2002),

and that a limited number of infectious disease models have

been evaluated. Nevertheless, using these techniques in a

number of models, there is clear evidence that the number of

cells capable of responding to a specific antigen is higher

after the primary immune response. For instance, cytotoxic

T lymphocyte (CTL) precursors specific for an epitope of

lymphocytic choriomeningitis virus occur at a frequency of

about 1 in 105 CD8 T cells, which translates to be about

100–200 cells in a naive mouse (Blattman et al., 2002).

After infection, there is rapid expansion of the antigen-

specific population to about 107 cells. With resolution of the

infection, most effector CTL soon die, but a memory pool of

about 5 £ 105 cells remains. These results are consistent

with other reports that show antigen-specific cells are from

20- to 1,000-fold more prevalent after the primary response

than in the naive mouse (Doherty, 1995). Also, the memory

cell level tends to be about 5–10% of the level of the peak

primary response.

The high prevalence of antigen-specific memory cells

can persist for a long time and a number of mechanisms

have been postulated to explain this persistence. The pre-

sence of small amounts of antigen, which persist after the

infection is resolved, could drive memory cell expansion.

Antigen can be sequestered on the surface of follicular

dendritic cells in germinal centres for months or perhaps

years (Mandel et al., 1981; Tew et al., 1984). Similarly, for

infections that are endemic, periodic exposure would pro-

vide antigen driven rejuvenation of the memory cell popu-

lation. The importance of antigen to maintain memory has

been shown by depriving primed lymphocytes of contact

with antigen by adoptive transfer into naive hosts. Memory

activities of B and T cells have been shown to be short-lived

in the absence of antigen (Gray and Skarvall, 1988; Gray

and Matzinger, 1991; Oehen et al., 1992; Mullbacher,

1994). However, in some cases, memory has been shown

to be maintained by cross-reactive stimulations (Beverley,

1990; Selin et al., 1994) or to be totally independent of

antigen (Ahmed, 1992; Lau et al., 1994), being maintained

even in the absence of T cell receptor stimulation in MHC-

deficient models (Murali-Krishna et al., 1999). Since the

number of total memory cells remains relatively constant,

there are antigen-independent mechanisms postulated to

maintain this homoeostasis. For CD8 cells, interleukin

(IL)-15 appears to be an important cytokine in this

homeostasis (Surh and Sprent, 2002). B cell memory can

be maintained by polyclonal stimuli, such as bystander T cell

help and CpG DNA (Bernasconi et al., 2002). Some of the

M. Campos, D.L. Godson / International Journal for Parasitology 33 (2003) 655–661656

discrepancy in the requirements to maintain memory may

be explained by the discovery that there are different subsets

of memory cells. Memory T cells can be distinguished as

‘central’ and ‘effector’ memory cells by phenotype and

activation requirements (Farber, 2000; Fearon et al., 2001).

Regardless of whether the longevity of B and T cell

memory requires continuous or intermittent antigen stimu-

lation or depends on other homoeostatic mechanisms, the

above evidence clearly indicates that with more responder

cells the likelihood of contact between appropriate lym-

phocytes and the infecting organism is increased and the

number of generations required and hence, the time to reach

protective effector levels is reduced.

2.2. Improved recognition and responsiveness

In addition to being more prevalent, memory cells

respond more effectively to antigen when they encounter it.

To proliferate and develop effector function, both naive and

memory cells require costimulatory signals in addition to

the stimulation provided by antigen recognition. However,

the nature or amount required of these signals differs

between naive and memory cells. For example, both virgin

and memory B cell responses require T cell help; however,

memory B cells proliferate in response to lower amounts of

antigen, require fewer T helper cells or less lymphokine

(Yefenof et al., 1986; Hilbert et al., 1989).

Compared with naive T cells, memory T cells have a

shorter lag phase from antigen exposure to the initiation of

cell division, an enhanced proliferation rate and more rapid

differentiation to effector function in response to lower

doses of antigen (Rogers et al., 2000; Veiga-Fernandes et al.,

2000). Some of these changes are due to alterations in

intracellular signalling components (Lanzavecchia and

Sallusto, 2000) and consequently require less stringent

costimulatory molecule ligation (Farber, 2000). This results

in less stringent requirements for antigen-presenting cells

(APC) that is, dendritic cells are required to effectively

present antigen to naive T cells (Croft et al., 1992) but

memory cells can respond to other APC such as resting

B cells (Ronchese and Hausmann, 1993).

There are also changes in the structure of the antigen

receptors. Memory B cells are able to respond to antigen

more effectively as a result of somatic mutation of Ig genes

(MacLennan et al., 1990). During development of the B cell

response in germinal centres, cells expressing mutated Ig

genes that code for higher affinity surface Ig compete more

successfully for antigen bound as immune complexes on

follicular dendritic cells (Jacob et al., 1991; Berek, 1992).

Cells that have a higher affinity for antigen are thus selected

and go on to develop as effectors and memory cells (Klaus,

1978; Klaus et al., 1980; Nieuwenhuis and Opstelten, 1984).

Therefore, the memory population tends to have a higher

avidity for antigen than the naive population.

The differences between naive and memory cells

described above lead to memory cells being able to respond

to lower levels of antigen, presented on more types of APC,

with more rapid effector cell expansion and differentiation,

all of which translates to more rapid and effective immunity.

2.3. Altered trafficking and homing

Altered trafficking and tissue homing acquired by T

and B lymphocytes during primary responses can also

contribute to accelerated secondary responses. While naive

cells typically circulate through the blood and lymph nodes,

memory cells preferentially migrate through different

tissues enabling them to survey peripheral tissues where

infections are usually initiated (Picker et al., 1993). Thus

memory cells come in contact with antigen sooner after

infection. For example, T cells draining from the skin of

sheep are all memory cells, whereas T cells exiting the

lymph node via the efferent lymph are mostly of the naive

phenotype (Mackay, 1991).

The differences in homing are due to differential expres-

sion of adhesion molecules and chemokine receptors on

memory vs. naive cells (Mackay, 1991, 1993). In contrast to

naive T cells, mouse memory T cells express low levels of

CD62L and CCR7 (Moser and Loetscher, 2001). CD62L

interacts with peripheral lymph node addressin on high

endothelial venules, which mediates attachment and rolling,

while CCR7 binds the chemokines CCL19 and CCL21 on

the luminal surface of endothelial cells in the lymph node

which causes firm arrest and the initiation of extravasation

(Kaech et al., 2002). Thus, memory cells tend not to exit

circulation in the lymph node, but in peripheral tissues.

Other changes in adhesion molecules allow preferential

trafficking of memory cells, such that lymphocytes initially

activated in the gut preferentially migrate back to the gut,

whereas cells draining from the skin or from lymph nodes

preferentially migrate back to the skin or lymph nodes

(Cahill et al., 1977; Butcher et al., 1980; Chin and Hay,

1980). A good example of tissue-selective homing by B cells

is the strong association of IgA plasma cells with mucosal

tissues (Yednock and Rosen, 1989). Thus memory cells are

concentrated at the initial site of antigen encounter, the

likely site for subsequent infections.

2.4. Improved effector functions

The quality of the immune response derived from

memory cells may be more effective than that of the

primary response by naive cells. Memory cells are capable

of producing a broader range of cytokines than naive cells.

Naive CD4þ cells have been shown to produce high levels

of IL-2, but little or no amounts of other cytokines (Powers

et al., 1988). Only memory T cells were capable of

transcribing mRNAs for IL-3, IL-4, IL-5, IL-6, interferon

(IFN)-g and granulocyte/macrophage colony-stimulating

factor (GM-CSF) (Ehlers and Smith, 1991). As naive T cells

differentiate into memory cells, their gene expression profile

is reprogrammed by changes in chromatin structure and the

M. Campos, D.L. Godson / International Journal for Parasitology 33 (2003) 655–661 657

profile of active transcription factors (Agarwal and Rao,

1998). For instance, genes that encode IFN-g and cytotoxic

molecules, such as perforin and granzyme B are not

expressed in naive CD8þ T cells, but are constitutively

expressed in memory CD8þ T cells (Grayson et al., 2001).

Although the production of these proteins are still dependant

upon antigen recognition, the existing mRNA transcripts

enable memory CD8þ T cells to produce more of these

proteins more rapidly than naive cells (Kaech et al., 2002).

The relevance of specialised effector function is more

clearly illustrated in antibody responses where it is well-

established that the biological function of antibody

molecules is dependant on the constant region of H chain.

Naive B cells express surface IgM and IgD (Coffman and

Cohn, 1977). During the primary response, isotype switch-

ing occurs in which other Ig class CH genes replace CHm

genes. Thus, memory resides within an IgG þ population

(or IgA or IgE in the case of responses of these classes) and

cells carrying IgM or IgD contribute little to the memory

pool (Schittek and Rajewsky, 1990; McHeyzer-Williams

et al., 1991). This change dramatically influences secondary

B cell responses. For example, the a chain in IgA directs the

molecule to various mucosal secretions, while the 1 chain of

IgE promotes interactions with mast cells and basophiles.

These changes focus the immune response to the tissues

most appropriate to combat the infection.

In summary, the signals delivered during the primary

response serve to educate lymphocytes, producing an

expanded memory population of cells with altered pheno-

type and function, so that subsequent responses are

qualitatively and quantitatively more effective than the

primary response (Gray, 1994).

3. Limitations of immune memory

As discussed above, memory cells endow the immune

system with the long-term ability to respond more quickly

and effectively to subsequent infections. Over the past two

centuries, vaccination has increasingly been used as an

effective alternative to infection to produce memory cells.

However, if vaccination induces immune memory and

immune memory is long-lasting, why is it that some

vaccines fail to induce long-lasting protection from disease?

To address this question, one can first evaluate the ability

of the vaccine to produce adequate immune memory, both

in terms of the quantity and quality of the memory response.

For instance, because the number of memory T cells is

determined primarily by the extent of clonal expansion

(burst size), it is essential that a vaccine should elicit as large

an effector T cell population as possible (Kaech and Ahmed,

2001; Kaech et al., 2002). Antigen dose is an important

factor in this regard, as is antigen persistence, structure and

tissue distribution (Banatvala et al., 2001). In addition,

delivery of appropriate cytokine signals may be used to

increase the size of the memory cell pool (Cheng and

Greenberg, 2002).

As important as the magnitude of the memory response

is, the effectiveness of the immune response induced by

vaccination is also critical. It is important to define the most

important correlates of protection in each disease and design

vaccines that are appropriate for inducing these responses.

For example, vaccines that induce primarily systemic IgG

are less protective against rotavirus infection than vaccines

that induce mucosal IgA (Yuan et al., 1998). As we better

understand the mechanisms of memory development and

persistence, it will be possible to design vaccines to selec-

tively stimulate different types of memory cells. The quality

of the memory response may be enhanced, for instance, by

influencing the production of effector vs. central memory

T cells (Esser et al., 2003).

However, memory B and T cells do not combat infection;

effector cells (cytotoxic and helper T cells) and antibody

(produced by B cells) do (Ahmed and Gray, 1996). Thus a

pertinent question regarding the protective efficacy of

vaccination is whether memory cells induced by vaccination

differentiate into effector populations soon enough to halt

infection before disease develops. In other words, while the

presence of memory cells ensures a timely response, it does

not guarantee protection, since the speed of this response

may not be sufficient to halt infection and control disease

(Zinkernagel, 2002). Thus, the ability of vaccination to

induce long-lasting protective immunity may in some

instances be dictated by the race between the time it takes

memory cells to proliferate and differentiate into effector

cells and the speed with which the pathogen invades,

replicates and damages host tissues.

With these ideas in mind, the effectiveness of vaccines

in preventing disease is to some extent dependant on the

pathogenesis of the disease. Certain pathogens cause

damage (disease) at the initial site of infection and

replication, whereas others replicate relatively innocuously

at the entry site causing disease only after systemic spread

and replication at secondary sites. A well-known example of

a pathogen that replicates at entry sites in the absence of

pathology and causes disease only when it reaches its

secondary site of replication is smallpox virus. The success

of vaccination in controlling smallpox is in part due to the

long incubation time (usually 12–14 days) required for this

virus to reach the secondary site of replication, the skin,

after which clinical disease occurs (Fenner, 1985). This

allows memory cells the time to generate effector

mechanisms capable of halting the spread of infection and

preventing disease. In contrast, for other pathogens such as

viruses that cause pathology at mucosal sites, the initial site

of replication and the site of pathology are the same, so

disease ensues rapidly after viral replication begins. In these

instances, the time required for memory cells to differentiate

into effector populations and infiltrate the infection site may

be too long to prevent disease, although the severity is

reduced in some cases (Flynn et al., 1998).

M. Campos, D.L. Godson / International Journal for Parasitology 33 (2003) 655–661658

Results from bovine herpes virus type 1 (BHV-1) vacci-

nation studies clearly illustrate that immune mechanisms

can induce solid protection from disease caused by

pathogens which produce pathology at the entry site, but

that this level of protection is difficult to maintain for

prolonged periods of time. BHV-1 is a common respiratory

pathogen of cattle; this rapidly invading virus causes

clinical disease 2–3 days after infection. The immune

responses responsible for protection against BHV-1 include

both T and B cell (virus neutralising antibody) responses

(Babiuk et al., 1996). The appearance of antibodies in serum

of infected animals correlates with recovery from disease

and it is presumed that they contribute significantly to

protection after vaccination. Antibodies and effector cells in

nasal secretions have also been associated with protection

(Gerber et al., 1978). Similar to other acute viral infections,

the effector phase of the T cell response induced by BHV-1

is short-lived, being detectable only from 4 days to 3 weeks

in a secondary response (Campos and Rossi, 1986).

Both conventionally killed virus and subunit antigen

vaccines have been effective at controlling disease, as

measured by the absence of fever and clinical signs and the

reduction of virus shed, when experimental challenge is

performed 2–4 weeks after immunisation (van Drunen

Littel-van den Hurk et al., 1993). Under these experimental

conditions, challenge is performed at the time when

neutralising antibody titres are high in serum and nasal

secretions and cell mediated effector mechanisms also are

active.

In field trials, testing the ability of BHV-1 vaccination to

protect animals from disease under natural challenge

conditions, in which virus exposure presumably occurred

at different times after booster immunisation, the protective

effect of vaccination declined over time (Bosch et al., 1998).

Studies measuring antibody responses after vaccination

indicate that neutralising antibody titres peak approximately

2 weeks after the second vaccination and decline steadily

thereafter to reach very low levels 16 weeks after booster

vaccination. The number of animals with detectable

antibody levels also declines steadily until only half of the

animals have detectable antibody 16 weeks after vacci-

nation (Fulton et al., 1995). However, all of these animals

respond dramatically to a third immunisation, indicating

that memory cells are present.

The studies described above illustrate how the protective

ability of vaccination depends on the time of challenge. The

high degree of protection observed when challenge was

performed shortly after vaccination (14 days after boost)

may be attributed to the presence of existing antibody and

active effector T cells that limit infection prior to the

development of pathology. In contrast, when exposed to the

virus under field conditions, at times when active effector

mechanisms were low, memory cells were not capable of

generating effector populations quickly enough to control

viral replication and prevent disease.

Influenza virus represents another well-studied example

of an agent that causes pathology at the entry site for which

memory cells may not be able to generate effector cell

functions fast enough to prevent pathology. Infection of

mice with influenza virus induces CTL and T helper cells

to cross-serotype antigens. These T cells are capable of

providing full protection for 2 months when animals are

challenged with serologically unrelated viruses that share

these T cell epitopes (Liang et al., 1994). However, the level

of protection waned substantially over the next 6 months,

indicating that protective responses induced by the primary

infection were relatively short-lived. These results also

suggest that at later times, the memory cells presumably

induced during primary infection were not capable of

differentiating into protective effector cells prior to the

development of disease. Similar observations have been

made during investigation of successive influenza epi-

demics in human beings (Frank et al., 1983; Sonoguchi et al.,

1985).

Immune protection to some parasite infections also

indicates that memory cells may not be able to differentiate

into protective effector mechanisms fast enough to control

disease and that the persistence of effector mechanisms may

be required for disease resistance. In cattle, Theileria parva

infection and drug treatment protocols confer solid protec-

tion against homologous challenge (Maritim et al., 1989).

However, this method of inducing protection results in the

development of a chronic, subclinical carrier state, which

can be postulated to represent a continuous antigen chal-

lenge (low-grade parasitaemia) that maintains adequate

levels of effector mechanisms to prevent the development of

exacerbated pathology.

Malaria is another example of the inability of established

memory cells to confer protection from disease. Naturally

acquired resistance to malaria in humans develops slowly

over a prolonged period of time through intermittent epi-

sodes of infection that induce non-sterilising immunity

capable of preventing severe morbidity or mortality. Never-

theless, adults living in malaria endemic areas who move to

disease-free regions and then return to endemic areas are

highly susceptible to re-infection suggesting that mainten-

ance of protective immunity to human Plasmodia spp. is

relatively short-lived in the absence of intermittent or

continuous parasite exposure which maintains an adequate

level of effector mechanisms (Day and Marsh, 1991;

Taylor-Robinson, 1998).

It can be speculated that the protective immunity in the

above examples is due to persistence of effector mechan-

isms and not memory cells per se. That is, an ongoing active

immune response, stimulated by persistent antigen exposure

is capable of preventing disease, whereas memory cells

induced during first encounter with the agent are not able to

respond fast enough to provide protection upon subsequent

exposure to the pathogen. Antigen persistence also has been

used to explain the epidemiological evidence of long-lived

immunity to measles virus (Katayama et al., 1995). Expo-

sure to cross-reactive antigens and polyclonal stimulation of

M. Campos, D.L. Godson / International Journal for Parasitology 33 (2003) 655–661 659

memory B cells are alternative mechanisms for maintaining

a large memory cell pool and sustaining protective antibody

levels for prolonged periods of time (Bernasconi et al.,

2002).

Thus, distinctive features of infection and pathogenesis,

rather than vaccine design, may explain why vaccination

against certain pathogens induces long-lasting protection

whereas vaccination against others does not. Unfortunately,

these simple facts are often overlooked when designing new

vaccines and establishing vaccination regimens. While

vaccines have been successful in combating a number of

diseases, there is unlikely to be a simple recipe for vaccine

formulation for those that remain. Vaccines designed in the

future will need to take into account the pathogenesis of the

disease and the biological constraints of the immune system.

With these factors in mind, various vaccine technologies

can be utilised to induce and maintain protective immunity.

In some cases, vaccines can be developed to maximise the

induction of memory or perhaps drive the production of one

type of memory over another. However, for many infec-

tions, memory is not sufficient and vaccines will need to

stimulate a persistent immune response to maintain the level

of effectors at a protective level. Whether this can be

achieved by depot or pulsatile release antigen formulations

or booster immunisation schedules tailored for pathogen

and host remains to be seen.

In summary, a person or animal can be considered to be

immune if they can make a recall immune response, i.e. the

duration of immunity ¼ the duration of the existence of

memory cells. The duration of protection is a more com-

plicated equation, which not only takes into account the

duration of immunity, but also requires additional factors

related to the kinetics of both infection (pathogen invasive-

ness and replication) and the generation of active immune

effectors. Solving this equation is the challenge for effective

immunoprophylaxis for diseases in which duration of

protection after vaccination is short-lived.

Acknowledgements

Our grateful thanks are due to Colleen Tabbernor for her

assistance in preparing this manuscript.

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