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OVERVIEW

The previous sessions introduced methods for setting up simple models of the

transmission dynamics of immunising infections. This session discusses the insights into

the dynamics of infections provided by these models, and subsequently relates model

predictions to data.

OBJECTIVES

By the end of this session you should:

Understand what determines whether the number of new infections will increase or

decrease over time;

Be aware of methods for calculating R0 for an infection from the growth rate of an

epidemic or outbreak;

Understand the factors that lead to cycles in the incidence of immunising infections;

Be able to calculate the inter-epidemic period for an immunising infection;

Know some of the insights into the epidemiology of immunising infections that are

provided by simple models.

This session should take 2-5 hours to complete

This session comprises two parts. Part 1 (1-2 hours) introduces the insights that models

provide into the dynamics of infections; Part 2 (1-3 hours) consists of a practical exercise

using models set up in Berkeley Madonna, during which you will study the cycles in

incidence of immunising infections in detail.

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Section 2: Introduction

page 2 of 78

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The following diagram shows the structure of the models that you worked with during the

last two sessions.

The models that you used are among the simplest models that are used to describe the

long-term transmission dynamics of an immunising infection. We assumed that individuals

mix randomly and that the population size remains unchanged over time. We have also

not stratified the population by age, sex or any other subgroup.

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2.1: Introduction

page 3 of 78 2.1

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despite the simplifications, the models are able to reproduce (at least for a while) cycles in

the number of new infections occurring per unit time that are similar to those seen for

immunising infections (see Figure 2).

The fact that the model's general predictions are reasonably consistent with observed data

suggests that the models, whilst approximations, may be used to help us understand the

behaviour of epidemics.

with measles following the introduction of an infectious person into a

totally susceptible population, assuming that R0 =13, the pre-infectious

period = 8 days, the infectious period = 7 days, the total population size

= 100,000, the average life expectancy = 70 years, the birth rate = the

death rate.

in England and Wales. Data sources: Office for Population and Census

surveys and the Health Protection Agency.

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2.2: Introduction

page 4 of 78 2.1

2.2

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However, the fact that the model predicts that peaks in the epidemics become

progressively less pronounced ("damped") over time, but that we do not see this in the

actual data, suggests that other factors that are not in the model are needed to sustain the

epidemic cycles.

Before discussing the cycles and damping in further detail, we will discuss some of the

other insights into the dynamics of infections provided by this model, specifically:

1. What determines whether or not the number of infectious individuals increases

following the introduction of an infectious person into a totally susceptible

population?

2. How fast might we expect the number of infectious individuals to increase following

the introduction of an infectious person into a totally susceptible population and what

can we infer from it?

3. Why does the incidence of an immunising infection cycle over time?

4. What other factors lead to cycles in the incidence of immunising infections?

5. What inter-epidemic period might we expect to see for immunising infections?

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 5 of 78

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You may remember from previous sessions that if the basic reproduction number (R0)

of a pathogen is greater than 1, the introduction of one infectious person into a susceptible

population should result in an increase in the number of infectious individuals and the

persistence of the infection in the population.

This result can be obtained relatively easily from the differential equations used to describe

the transmission dynamics of immunising infections that you have used previously. We will

illustrate the derivation of this result by considering a "closed" population, i.e. one in which

there are no births into or deaths out of the population. The model has the following

structure:

is the rate at which two specific individuals come into effective contact per unit

time;

f is the rate at which those in the pre-infectious category become infectious;

r is the rate at which infectious individuals recover from being infectious and become

immune;

N is the population size;

D is the duration of infectiousness.

In this diagram shown above S(t)I(t) is the number of new infections occurring per unit

time, fE(t) the number of new infectious individuals occurring per unit time and rI(t) the

number of individuals who recover per unit time.

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 6 of 78 3.1

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When deriving the result, we will use the following equation, which we met in MD01

=

next

R0

ND

This expression can be rearranged to give the following expression for the basic

reproduction number:

R0 = ND

or, equivalently,

R0 =

N

r

Equation 1

Show

We will show that for the number of infectious individuals to increase following the

introduction of an infectious person into a totally susceptible population, ND must be

greater than 1, and that this expression has the literal definition of R0, , i.e. as the average

number of secondary infectious individuals resulting from one infectious person following

his/her introduction into a totally susceptible population.

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 7 of 78 3.1

3.2

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We begin by noting that if the number of infectious individuals increases following the

introduction of an infectious person into a totally susceptible population then the rate of

change in the number of pre-infectious and infectious individuals must be positive, i.e.

dE

dl

> 0 and

>0

dt

dt

As shown in MD02 , the expressions for the rate of change in the number of preinfectious and infectious individuals for the model described on page 5 are:

dE

=S(t)l(t)- fE(t)

dt

Equation 2

dl

=fE(t)-rl(t)

dt

Equation 3

where f is the rate at which pre-infectious individuals become infectious and r is the rate at

which the infectious individuals recover to become immune.

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 8 of 78 3.1

3.2

3.3

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positive, the number of new infections that occur in the population per unit time, S(t)I(t),

has to be greater than the number of pre-infectious individuals who become infectious per

unit time, fE(t), i.e.

S(t)I(t) > fE(t)

In a similar way, for the rate of change in the number of infectious individuals (Equation 3

) to be positive, the number of pre-infectious individuals who become infectious per unit

time,fE(t), has to exceed the number of infectious individuals who recover per unit time,

rI(t), i.e.

fE(t) > rI(t)

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 9 of 78 3.1

3.2

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Combining the logic in the last two expressions , the number of individuals who are

newly infected per unit time must also be larger than the number of individuals who

recover per unit time, i.e.

S(t)I(t) > rI(t)

After dividing both sides of this expression by the number of infectious individuals in the

populations, I(t), we see that for the rate of change in the number of infected individuals to

be positive and therefore for the number of infected individuals to increase, the following

condition must hold:

S(t) > r

Equation 4

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 10 of 78 3.1

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Notice that when the infection is introduced into the population, the number of individuals

who are susceptible, S(t), is the size of the total population, N. Substituting N for S(t) into

the last expression , we see that for the number of infectious individuals to increase

following the introduction of an infectious person into a totally susceptible population, the

following must hold:

N > r

If we divide both sides of this expression by the recovery rate r, we see that the following

condition must hold:

N

>1

r

Equation 5

Substituting for D = 1/r into this expression, we obtain the result that ND >1 for the

number of infectious individuals to increase after the introduction of one infectious person

into a totally susceptible population. You should recognize that the left side of this

expression is the same as that of the basic reproduction number, as presented on page 6

.

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 11 of 78 3.1

3.2

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literal definition of the basic reproduction number

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On average, each infectious person effectively contacts N other individuals per unit time.

When the population is entirely susceptible, each of these contacts will generate a new

infection. Multiplying N by the infectious period D (or 1/r), we obtain the total number of

individuals effectively contacted by the infectious person during their infectious period.

Using this literal definition for R0 in Equation 5 , we conclude that for the introduction of

an infectious person into the population to lead to an increase in the number of infectious

individuals, the basic reproduction number or ND must be greater than 1.

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 12 of 78 3.1

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Using the result on the previous page, we can see that the number of infected individuals

increases ifND >1. Similarly, the force of infection also increases if ND >1, since the

rate at which susceptible individuals are infected is directly proportional to the number of

infectious individuals, i.e.

(t) = I(t)

This is equivalent to Equation 1

in MD01.

We might expect that when the number of infectious individuals increases (or decreases),

the infection incidence rate, (t)S(t)=I(t)S(t), will also increase (or decrease). However,

whilst this relationship approximately holds, it is not quite exact, since an increase in

infected individuals corresponds to a fall in susceptible individuals, and both I(t) and S(t)

appear in the expression for incidence. If we consider outbreaks that only result in

relatively small fluctuations in numbers of susceptible individuals, we can say that,

approximately, incidence increases whenND >1.

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required for the number of infectious individuals to increase

(s>1/R0)

page 13 of 78 3.1

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We can use the logic described on the last few pages to derive the result that the

proportion of a population that needs to be susceptible for the number of infected

individuals to increase at a given time must be greater than 1/R0.

Q1.1 Derive the above result using Equation 4

Hint: Divide both sides of Equation 4 by the total population size (N) and and use the

result that R0 =

.

Answer

Kermack and McKendrick first discussed these results in papers published in 1927 2 ,

although, at the time, they weren't expressed in terms of the basic reproduction number,

which was first defined by Macdonald during the early 1950s3-4 .

For the purposes of this module, you do not need to read these references.They are

mentioned here because of their historical importance.

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infectious individuals increases following the introduction of

an infectious person into a totally susceptible population?

page 14 of 78 3.1

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Note that the expression ND for the basic reproduction number does not account for

deaths that may occur during the pre-infectious or infectious periods. Anderson and May

(1992, Ch 1-4) 5 provide the details for expressions that account for deaths. For most

common immunising infections, the pre-infectious and infectious periods are generally a

few days, whereas the life expectancy (in industrialised populations) is about 70 years. As

such, since the mortality rate is much smaller than the rate at which individuals become

infectious and recover, the effects of these adjustments on the estimate for R0 are

relatively small.

The logic described in this section can be extended to obtain the equations for R0 to

account for mortality or for non-immunising infections (see e.g. the recommended course

text, Panel 8.26 ).

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infectious individuals to increase following the introduction

of an infectious person into a totally susceptible population

and what can we infer from this?

page 15 of 78

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It can be shown that, following the introduction of an infectious person into a totally

susceptible population, the number of infectious individuals will increase at a rate (),

given by the following expression:

R0 - 1

D

Equation 6

Click the "show" button below for an intuitive explanation of this expression.

Show

this result is fairly straightforward although you are not required to know it for this study

module. If you are interested, you can read Appendix A.2.5 of the recommended course

text 6 , Anderson and May (1991) 5 , and Lipsitch, et al (2003) 7 . The expression has

also been extended by Wearing, et al (2005) 8 .

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individuals to increase following the introduction of an

infectious person into a totally susceptible population and

what can we infer from this?

page 16 of 78 4.1

Equation 6

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R0 D+1

Equation 7

Therefore, given empirical estimates of the growth rate of an epidemic or outbreak (), it

should be possible to infer the R0 of a pathogen. Methods for estimating the growth rate

are provided in section 4.2.3.1 of the recommended course text 6 . These estimates of R0

can then be used to infer future trends in infection incidence.

Equation 7 (and its variants) has been used to derive estimates of the basic reproduction

number for HIV during the early stages of the HIV epidemic in Kenya and Uganda9 ,

which ranged between 4 and 11. As shown on the next page, this theory has been applied

for Severe Acute Respiratory Syndrome (SARS ), which was caused by a newly

emergent infectious agent which was first identified in 2003.

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individuals to increase following the introduction of an

infectious person into a totally susceptible population and

what can we infer from this?

page 17 of 78 4.1

4.2

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A variant of Equation 7 was used in studies estimating the basic reproduction number of

Severe Acute Respiratory Syndrome (SARS ), which was caused by a newly emergent

infectious agent that was first identified in 2003. The analyses used estimates of the

average serial interval (calculated as 8.4 days using data from Singapore) and the growth

rate in the cumulative numbers of cases 7 (see Figure 3). In these analyses, R0 for SARS

was estimated to be in the range 2.0 - 3.6.

If you are interested in seeing the derivation of this result, please read section 4.2.3.2.1 of

the recommended course text, which provides a simplified description6 . This low value

for R0 in comparison with that for other infections such as measles or mumps (see MD04

), together with the fact that the peak infectiousness of cases occurs after the onset of

symptoms, suggested that SARS might be controllable.

Figure 3. a) Number and b) cumulative number of probable or reported cases of SARS in Hong Kong in 2003.

Data source: http://www.who.int/csr/sars/country/en/index.html .

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individuals to increase following the introduction of an

infectious person into a totally susceptible population and

what can we infer from this?

page 18 of 78 4.1

4.2

4.3

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the early stages of an outbreak, and

2. The pathogen has only recently been (re)introduced into the population.

Note that if we apply Equation 7 using the growth rate of an epidemic for a pathogen that

has been reintroduced into a population, then we obtain the net reproduction number,

defined as the average number of secondary infectious individuals resulting from an

infectious person in a given population (that may not be entirely susceptible).

Further discussion of the application of Equation 7 and its variants can be found in section

4.2.3 of the recommended course text 6 .

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infection cycle over time?

page 19 of 78

As we saw earlier (Figure 2

typically cycles over time.

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During the first part of the 20th century there were two main theories for the occurrence of

cycles in the numbers of measles cases:

1. The cycles reflected cycles in infectivity of the measles virus, or

2. The cycles resulted from changes in the prevalence of susceptible individuals, as a

result of a constant influx of susceptibles born into the population, and susceptible

individuals becoming immune after becoming infected10 .

Experimental studies in mice populations carried out in the 1930s found no evidence for

changes in the infectivity11 , and the second argument has since become accepted.

Before discussing how changes in the prevalence of susceptible individuals lead to

epidemic cycles for immunising infections, we will first review the relationship between the

net reproduction number (Rn), the trend in incidence and the proportion of individuals in the

population who are susceptible.

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cycle over time?

page 20 of 78 5.1

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The net reproduction number (Rn ) is defined as the average number of secondary

infectious individuals resulting from each infectious person in a given population (in which

some individuals may be immune). Rn is related to R0 as follows:

Rn = R0 s

Equation 8

where s is the proportion of the population that is susceptible. For example, if each

infectious person generates 4 secondary infectious individuals in a totally susceptible

population, then in a population in which only 25% of individuals are susceptible, the

infectious person will generate only 1 (= 4 0.25) secondary infectious individuals.

When the number of infected individuals is increasing, Rn > 1; when the number of infected

individuals is decreasing, Rn < 1; and when the number of infected individuals is stable, Rn

= 1. As discussed on page 12, we can approximately say that when the incidence is

increasing, Rn > 1; when the incidence is decreasing, Rn < 1; and when the incidence is

stable, Rn = 1.

Given Equation 8 and the relationship between the trend in incidence and the net

reproduction number, we can now infer what proportion of the population is likely to be

susceptible when the incidence is increasing, decreasing, or at a peak.

For example, when the incidence is increasing, Rn > 1 and therefore, using the fact that Rn

= R0 s, we can say that:

R0 s > 1

Rearranging this expression, we see that whilst the incidence is increasing:

s >1/R0

Equation 9

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cycle over time?

page 21 of 78 5.1

5.2

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Q1.2 Given Equation 8 and the relationship between Rn and the trend in incidence,

what can we say about the proportion of the population which is susceptible when the

incidence is

a) Decreasing?

Answer

b) Stable?

Answer

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cycle over time?

page 22 of 78 5.1

5.2

5.3

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Before continuing, we first reflect on our use of the word incidence

In the above discussion, we have related the "incidence" to the net reproduction number

and the proportion susceptible. As you may recall from your previous epidemiological

training, the incidence is defined as the number of new events (such as new infections or

infectious individuals or other outcome of interest) in the population at risk (usually

susceptibles) per unit time.

However, most of the figures presented in the rest of this session will plot the number of

new infectious individuals in the population or per 100,000 population rather than the

incidence. We have done this for two main reasons:

1. People are generally more used to working with statistics such as the number of new

infectious individuals per person or per 100,000 population than they are with the

incidence, since these statistics are similar to those presented for many infections in

surveillance reports or in epidemiological papers.

2. Our goal is to explore the relationship between the incidence, the net reproduction

number and the proportion of the population that is susceptible. For acute

infections, this relationship is identical to that between the last two statistics and the

number of new infectious individuals in the population or per 100,000 population.

For example, if the incidence of infectious individuals increases, then the number of

new infectious individuals per 100,000 population per unit time will also increase.

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Note that for acute infections, trends in the number of new infectious individuals per unit

time will also generally be similar to those in the number of new infections per unit time.

For example, any increases in the number of new infectious individuals will start only a few

days (approximately equal to the average pre-infectious period) after the number of new

infections per unit time starts to increase.

Therefore for acute infections, the relationship between the number of new infections per

100,000 population, the net reproduction number and the proportion of the population that

is susceptiblewill be identical to that between the latter statistics and the number of new

infectious individuals per 100,000 population.

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population that is susceptible and trends in the number of

new infectious individuals per unit time

page 24 of 78 5.1

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Figure 4

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infectious person with measles into a completely susceptible population, assuming that the

basic reproduction number is 13.

Q1.3 What proportion of the population might be expected to be susceptible whilst the

number of new infectious individuals per day is

a) Increasing?

Answer

b) Decreasing?

Answer

c) At a peak?

Answer

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population that is susceptible and trends in the number of

new infectious individuals per unit time

page 25 of 78 5.1

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Figure 4. Predictions of the number of new infectious individuals per day (red line, right hand axis) and the

number of susceptible and immune individuals following the introduction of an infectious person with measles into

a totally susceptible population, assuming that R0 = 13, the pre-infectious period = 8 days, the infectious period =

7 days and the total population size = 100,000.

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susceptible, Rn and trends in incidence

page 26 of 78 5.1

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The previous exercise highlights the fact that the proportion of the population which is

susceptible has to be above a certain threshold value (1/R0) for the incidence (or the

number of new infections or infectious individuals) to increase, and it has to be below the

same threshold for the incidence (or the number of new infections or infectious individuals)

to decrease. When the proportion of individuals who are susceptible equals this threshold

value, the incidence is stable.

Table 1 and Figure 5 summarise the relationship between trends in incidence and the size

of the net reproduction number and the proportion of the population that is susceptible.

Incidence (or

number of

new

infections or

infectious

individuals)

Rn

Proportion susceptible

Increasing

>1

>1/R0

Decreasing

<1

<1/R0

Peaking

=1

=1/R0

Figure 5.Relationship between Rn , the proportion susceptible and number of new infectious individuals per day.

See the caption to Figure 4 for details of the assumptions in the model.

We will now apply the above results to explain why the incidence of immunising infections

cycles over time.

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cycle over time?

page 27 of 78 5.1

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During the course of an epidemic following the introduction of an infectious person into a

totally susceptible population, we see that the following events occur in succession:

1. The number of new infectious individuals increases as there are sufficient numbers

of susceptible individuals for each infectious person to lead to >1 secondary

infectious people.

2. The proportion of individuals that are susceptible in the population decreases.

3. Once this proportion is sufficiently low (<1/R0) each infectious person leads to <1

infectious person, and the number of new infectious individuals starts to decrease.

Without the entry of new susceptibles into the population (e.g. as a result of births or

immigration), the proportion of the population that is susceptible would remain consistently

below the threshold level (i.e. <1/R0) and transmission would eventually cease.

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cycle over time?

page 28 of 78 5.1

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The entry of new susceptibles as a result of new births into the population, however,

means that the following occurs:

Stage 1. The proportion of susceptible individuals(s) will eventually start to increase once a

sufficient number of births have been added (see Figure 6).

Figure 6. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible

and the number of new infectious individuals. Stages 4 and 5 are identical to the stages discussed on pages 2426 and are greyed out. We will discuss these stages again once we have discussed stage 3.

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cycle over time?

page 29 of 78

5.1 5.2

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Stage 2. At some point, the proportion of susceptible individuals(s) is sufficiently large (i.e.

>1/R0) for each infectious person to generate >1 infectious people. Once this occurs the

number of new infectious individuals starts to increase, as shown in Figure 7.

Figure 7. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible

and the number of new infectious individuals

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cycle over time?

page 30 of 78

5.10 5.11

5.4

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Stage 3. At some point, the number of susceptibles who are being removed by infectious

individuals exceeds the number being added to the population through new births. Once

this occurs, the increase in the proportion of susceptible individuals slows and then

reverses (Figure 8).

Figure 8. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible

and the number of new infectious individuals

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cycle over time?

page 31 of 78

5.10 5.11 5.12

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Stage 4. Once the proportion of the population that is susceptible has decreased to reach

1/R0, the number of new infectious individuals peaks (so we have now returned to Stage 4

in Figures 6-8).

Stage 5. The continuing reduction in the susceptible population means that eventually, the

proportion of the population that is susceptible becomes sufficiently low (<1/R0) that each

infectious person generates <1 secondary infectious people. Consequently, the number of

new infectious individuals starts to decrease, illustrated in Figure 9.

Figure 9. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible

and the number of new infectious individuals

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Section 6: Exercise

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Q1.4 Figure 10 shows how the number of new infectious individuals per unit time changes

as the proportion of the population that is susceptible changes. Copy this figure onto a

piece of paper.Add plots of the following as they change with the number of new infectious

individuals per unit time and the proportion susceptible:

a) The net reproduction number

b) The proportion of the population that is immune

Figure 10. The relationship between the cycles in incidence or the number of new infectious individuals per unit

time, the proportion susceptible and the net reproduction number.

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You should have plotted something similar to the plot in Figure 11:

Figure 11. The relationship between the cycles in the numbers of new infectious

individuals, the proportion susceptible and the net reproduction number

a) Note that the net reproduction number follows the same pattern as the proportion of the

population that is susceptible, i.e. the two statistics peak, decrease or reach a trough

simultaneously. This follows from the fact that the net reproduction number is directly

proportional to the proportion susceptible, through the relationship:

Rn = R0 s

Also, at a peak or trough in the number of new infectious individuals, Rn is equal to 1;

whilst the number of new infectious individuals is increasing Rn is greater than 1 and

whilst the number of new infectious individuals is decreasing Rn is less than 1.

b) The plot of the proportion of the population that is immune is just the mirror image of the

plot of the proportion susceptible. This follows from the fact that the proportion immune

is approximately equal to 1-proportion susceptible.This approximation follows from the

(reasonable) assumption that, for an immunising infection, the number of infectious or

pre-infectious individuals is typically small in a population, in comparison with the

Therefore, at a peak or trough in the number of new infectious individuals, the

proportion immune equals the herd immunity threshold (1-1/R0); whilst the number of

new infectious individuals is increasing, the proportion immune is less than the herd

immunity threshold (i.e. it is <1-1/R0); whilst the number of new infectious individuals is

decreasing, the proportion immune exceeds the herd immunity threshold (i.e. it is >11/R0).

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Hamer used a similar argument to that presented on the previous pages to explain the

cycles in measles deaths seen during the early part of the 20th century. His argument,

employing the "mass action" principle, was based implicitly on the following difference

equations:

Ct+1 = kC tS t

Equation 10

S t+1 = B + S t - Ct+1

Equation 11

where:

Ct and S t are the number of cases and susceptibles, respectively, at time t;

k is the proportion of the total possible contacts that actually lead to new cases 1 ,

B is the number of births in each time step.

The time step used in this original model was the serial interval for the infection.

The difference between this model and the other models that we have used so far is that

the generations of cases in this model do not overlap. In other words, all cases have onset

and infect each other at time steps of 1 serial interval.

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Hamer argued that when the number of susceptible individuals was at a peak or a trough

(i.e. reached a maximum or a minimum), the number of new measles cases occurring in

the population equalled the number of births into the population.

Q1.5 Look at the equations for Hamer's model

this result.

Hint: Use the result that when the number of susceptible individuals is at a peak or a

trough at time t, the number of susceptible individuals at time t+1 equals that at time t (i.e.

S t+1 =St).

Answer

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Figure 12 shows the number of susceptibles and cases predicted by Hamer's model over

time.

In contrast with the models used so far in this module, this model predicts that the cycles in

the numbers of cases should never damp out .

Further theoretical elaborations by Soper (1929) 12 found that when the simple mass

action model was adapted to assume that the infectious period was not fixed and followed

a variable distribution, the cycles damped out. Therefore, the simple mass action model

did not include sufficient assumptions to fully explain the cycles in incidence for immunising

infections.

Figure 12. Number of cases and susceptibles over time predicted using Hamer's mass action model, assuming

that C0 = 50, S 0 = 1200, B = 50 and k = 0.001 per serial interval. See the Excel file massact.xls

this model.

for details of

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incidence of immunising infections?

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As we saw in Figure 1 , the model that we worked with during the last few sessions

predicted that the cycles in the number of new infectious individuals damp out, which is

inconsistent with the data observed in many populations. For example, as shown in Figure

2 , measles epidemics occurred regularly every two years in England and Wales before

the introduction of vaccination. This discrepancy between model predictions and the

observed data has led to suggestions that other factors must have a role in sustaining

these cycles. These factors are discussed in detail in Anderson and May (1991) 1 ; we

discuss the main factors on the next few pages.

You will also find it helpful to read section 4.3.2 of the recommended course text 6 .

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of immunising infections?

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Seasonality in transmission

Seasonal transmission is the most obvious factor that is likely to lead to cycles in the

incidence of immunising infections. There have been many modelling and observational

studies investigating the effect of seasonality on incidence. Analyses by Fine and Clarkson

(1982) 1 have found evidence for seasonal transmission of measles in England and

Wales, occurring as a result of intense mixing between children during term-time, and less

intense mixing during the school holidays (Figure 13).

These analyses used a model-based approach, calculating the transmission parameter k,

in Hamer's simple mass action model (i.e. the proportion of the total possible contacts that

actually lead to new cases), using the ratio between the number of cases observed in the

UK each week over the time period 1950-77, and the estimates of the number of

susceptible individuals.

As shown in Figure 13B , the transmission parameter was lowest during the school

holidays.

Figure 13. Analysis of average biennial measles patterns, based on data from the UK (1950-55).Shaded blocks indicate school summer

and Christmas holiday periods 1 .

a) Average number of cases notified per week;

b) Calculated weekly transmission parameters;

c) Estimated numbers of susceptible individuals.

Reproduced from Fine PEM and Clarkson JA (1982) Measles in England and Wales I - an analysis of factors underlying seasonal

patterns. Int J Epidemiol 11(1):5-14 1 ,. By permission of Oxford University Press.

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of immunising infections?

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cycles for pertussis than for measles, as the epidemics for pertussis occur at different

times each year (see Figure 14). This has led to suggestions that other factors (for

example, relating to climate) may be important in sustaining the cycles.

Figure 14. Seasonal patterns in measles and pertussis notifications (left and right-hand figures respectively),

based on weekly case reports in England and Wales, 1941-1991. Based on Figure 11 in Anderson et al (1984)13

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of immunising infections?

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Work by Schenzle (1984) 14 has shown that if the populations in models are set up so that

transmission is confined to individuals within specific annual birth cohorts (corresponding

to classes within school years), then the models predict regular cycles in incidence. Other

assumptions about age-dependent mixing did not lead to predictions of regular cycles in

incidence.

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of immunising infections?

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Stochastic effects

The models discussed so far have been deterministic and do not take account of the fact

that individuals come in integer (not fractional!) quantities. The work of Bartlett (1956) 15

and Anderson and May (1986) 16 have shown that models that are amended to deal with

discrete (integer) numbers of individuals and that allow for stochastic variation in

transmission predict regular cycles in incidence (so long as the population size is

sufficiently large), as shown in Figure 15. See chapter 6 of the recommended course text 6

for further discussion of stochastic models.

Figure 15. Comparison between the observed notification rates of measles in the UK and Greenland and those

predicted using a stochastic model (Anderson and May, 1986)16 .

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see for immunising infections?

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infections. For example, epidemics of measles used to occur every two years in England

and Wales before the introduction of vaccination, whereas those for smallpox used to

occur roughly every 5 years (see Figure 4.16 in the recommended text 6 , and Figure 2

).

It can be shown (see Anderson and May (1991) 5 for a detailed proof) that the interepidemic period (T) (defined as the time-interval between successive peaks of an

epidemic) for immunising infections, predicted by the simple models used in the last two

sessions, is given by the following expression:

T 2A(D+D')

Equation 12

where A is the average age at infection, D' and D are the average pre-infectious and

infectious periods, respectively.

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immunising infections?

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We can adapt equation 12 to express T in terms of R0. For example, in the absence of

vaccination or control programs, the average age at infection A, the average life

expectancy L and the basic reproduction number are related through the following

expression for some types of populations:

R0 1 + L/A

We will discuss the derivation of this expression in MD04.

This equation can be re-arranged to give the expression A L/(R0- 1). If we substitute this

expression for A into Equation 12, the equation for the inter-epidemic period in the

absence of control becomes:

T 2

L(D+D')

R0 - 1

Equation 13

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immunising infections?

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are generally consistent with the observed inter-epidemic period.

Table 2. Estimates of the observed and predicted inter-epidemic periods for different infections in various

locations (extracted from Anderson and May (1991)5 ).

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Equation 12

into a population may lead to increases in the inter-epidemic period. For example,

vaccination reduces the prevalence of infectious individuals in the population, which will

reduce the force of infection and thus lead to an increase in average age at infection.

According to Equation 12, the inter-epidemic period will therefore increase.

Equations 12

transmission of pathogens. Considering measles for example, the inter-epidemic period

after the introduction of vaccination has been shorter than that predicted5 . This

discrepancy between predictions and the observed data has been attributed to the fact

that the model makes the simplifying assumption that individuals mix randomly. As we

shall see in MD06 , there is much evidence to show that contact between individuals is

age-dependent.

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This session has mainly focused on simple immunising infections (such as measles,

mumps and rubella), for which the pre-infectious and infectious periods are measured in

days, and are therefore short relative to the lifetime of individuals. The pattern seen for

these infections does not necessarily hold for non-immunising infections. Similarly, the

logic is not easily extendible to diseases such as tuberculosis, for which the interval

between infection and disease may be long (e.g. decades), as conditions (such as the

number of individuals contacted by each infectious person) have probably changed over

time.

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We suggest that you now read Chapter 4 of the recommended course text 6 , where the

issues covered in this session are explained in further depth.

Some of the issues presented in this session are discussed in further detail in the following

articles:

control by vaccination. Science, 215:1053-1060 . Re-used with permission from

AAAS.

analysis of factors underlying seasonal patterns. Int J Epidemiol 11(1):5-14

persistency of type. Lancet, 11:733-9 .

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The rest of this session (the practical component) is likely to take 1 - 3 hours

may wish to take a short break before starting it.

next

. You

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OVERVIEW

We will now start parts 2 and 3 of this session, which consist of a practical using models

set up in Berkeley Madonna.

Part 2 of this session revises the relationship between the basic and net reproduction

numbers (R0 and Rn), the herd immunity threshold and the trends in the number of new

infectious individuals. Part 3 (which is optional) explores how the size of the basic

reproduction number affects the inter-epidemic period.

OBJECTIVES

By the end of the practical part of this session you should understand the relationship

between:

The basic and net reproduction numbers and the herd immunity threshold;

The peaks in the number of new infectious individuals for an immunising infection

and the prevalence of susceptible and immune individuals in the population;

The basic reproduction number and the inter-epidemic period.

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basic and net reproduction numbers and trends in the

numbers of new infectious individuals

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The relationship between the net reproduction number and trends in the

number of new infectious individuals

We will first focus on how the net reproduction number, Rn changes during the epidemic

cycles for a simple immunising infection. As discussed on page 20 ,

Rn= R0 * proportion susceptible

1. Start up Berkeley Madonna and open the file 'measles2 equations.mmd ' , or

'measles2 flowchart.mmd ' depending on whether you prefer to work with the

equation or flowchart editor versions of the models. Unless otherwise stated, the

instructions for this practical are identical for both files.

The structure of the model is as follows:

You should recognise that this model is identical to the model you created in the last

session, except that it has 2 new variables (prop_sus and prop_imm). You can see

these variables by viewing the equations window (for those using the equation

editor) or by clicking on the globals button in the flowchart window (for those using

the flowchart editor). prop_sus and prop_imm are defined as the proportion of the

population that is susceptible and immune respectively and we are using the

approximation that prop_imm 1- prop_sus. Please see page 33 for the basis of

this assumption.

Note that the R0 is currently equal to 13.

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and net reproduction numbers and trends in the numbers of

new infectious individuals

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2. If you are using the equation editor, set up Rn in the equations window using the

appropriate expression. If you are using the flowchart editor, set up a new variable

called Rn in the globals window for the net reproduction number using the

appropriate expression.

3. Open the parameters window and run the model, which has been set to run for

73,000 days.

Click here to check your expression.

Click here to see the figure that you should have obtained.

PLEASE AVOID CLICKING ON THE BUTTON ON THE

TOP RIGHT

HAND CORNER OF THE FIGURES WINDOW during this session, as this

will result in the contents of the figures window being deleted.

Unfortunately, the figures are then irrecoverable and will need to be set

up again, unless you use one of the solution files that are available in

this session.

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and net reproduction numbers and trends in the numbers of

new infectious individuals

page 52 of 78 14.1

14.2

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We first focus on the relationship between Rn and the daily number of infectious individuals

over time.

4. Set up a new figure (called page 2) by clicking on the "New Page" button

toolbar of the figures page. We will now add a plot of Rn to this figure.

on the

The simplest way to add another variable, such as Rn to the graph is to select the

appropriate button for that variable at the bottom of the window. Berkeley Madonna

automatically includes buttons for the first few variables in the model, but has not

included a button for Rn. We therefore need to add a button for Rn manually.

5. Follow the instructions provided here

At present, it is difficult to see how Rn changes with the number of new infectious

individuals per day. We will therefore change the scales on the x- and y-axes before

trying to interpret the figure.

6. Change the scale on the y-axis for Rn to range from 0 to 1.5. Click here

instructions if you don't recall how to do this.

for

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and net reproduction numbers and trends in the numbers of

new infectious individuals

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14.2

14.3

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7. We are interested in how the net reproduction number changes during an epidemic

cycle (e.g. over a 10 year period). Therefore, in a similar way, change the x-axis to

go from time t = 14600 days (i.e. year 40) to time t = 18250 days (i.e. year 50).

The axis settings window should now look as follows:

Once you have entered the appropriate options into the axis settings window, click on OK

to continue.

Click here to see the output you should have by this stage.

If your output does not resemble this figure, you can check your settings against those in

the files measles2 - equations_solna.mmd or measles2 - flowchart_solna.mmd .

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and net reproduction numbers and trends in the numbers of

new infectious individuals

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14.2

14.3

14.4

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Q2.1 How does the net reproduction number change over time? What is the value of the

net reproduction number when the number of new infectious individuals per day peaks?

What is the value when the number of new infectious individuals per day reaches a

trough?

Answer

Q2.2 What is the trend in the number of new infectious individuals per day when

a) Rn <1?

b) Rn >1?

c) Rn =1?

Are these trends reasonable?

Answer

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proportion susceptible and trends in the numbers of new

infectious individuals

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We will now explore how the number of new infectious individuals per day changes with

the proportion of the population that is susceptible.

8. Copy the figure on Page 2 to Page 3 by clicking on the "New Page" button . Add

prop_sus to the new plot (on the left hand y-axis) by clicking on the prop_sus button

at the bottom of the figure window. Remove Rn from the plot by clicking on the Rn

button at the bottom of the window.

9. Change the scale of the left hand y-axis to range from 0 to 0.15, in the same way

that you did before.

Click here if you need to remind yourself of how you can change the scales on axes in

Berkeley Madonna.

Click here to see the output you should have by this stage.

If your output does not resemble this figure, you can check your settings against those in

the files measles2 - equations_solnb.mmd or measles2 - flowchart_solnb.mmd .

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proportion susceptible and trends in the numbers of new

infectious individuals

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Q2.3 What proportion of the population is susceptible to infection when the number of new

infectious individuals per day is at a peak or trough? Is this what you would expect and

why?

Answer

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herd immunity threshold and trends in the number of new

infectious individuals

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For transmission of an infection to cease, the proportion of the population which is immune

must be kept higher than the herd immunity threshold (H), which is given by the following

expression:

H = 1 - 1/R0

Q2.4 What is the herd immunity threshold in the population in the model?

Answer

1. Copy the figure on Page 3 to a new page (called Page 4). Add prop_imm to the plot

on the left hand y-axis and remove prop_sus from the plot. Change the scale of the

left-hand y-axis to range from 0.8 to 1.0 to see the prop_imm.

Click here to see the output you should have by this stage.

If your output does not resemble this figure, you can check your settings against those in

the files measles2 - equations_solnc.mmd or measles2 - flowchart_solnc.mmd .

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immunity threshold and trends in the number of new

infectious individuals

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Q2.5 What is the value of the proportion immune when the number of new infectious

individuals per day peaks or reaches a trough? What do you notice about the value of

prop_imm when the number of new infectious individuals per day is declining or when it is

increasing? How does this relate to your estimated value for the herd immunity threshold?

Answer

Q2.6 What is the long-term equilibrium value for the proportion of the population which is

susceptible or immune? How do these values relate to the herd immunity threshold

calculated in Q2.4 ?

Answer

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herd immunity threshold and the impact of vaccination

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We will now adapt the model to explore how vaccinating a fixed proportion of the

population at a level of coverage close to the herd immunity threshold affects transmission.

Before continuing, deselect prop_imm and prop_sus from the plot on Page 1 of the Figure

window.

1. Set up a new parameter (in the Equation window if you're using the equation editor

or in the Globals window if you're using the flowchart editor) called prop_vacc,

reflecting the vaccination coverage in the population. Set this equal to 0.75.

We will assume that vaccination is introduced some time (e.g. 50 years) after

the infection has started circulating in the population.

2. Add the following text to your model on the line immediately after the definition for

prop_vacc:

eff_cov = if (time>18250) then prop_vacc else 0

This indicates that the parameter eff_cov (which we will take to reflect the

proportion of newborns which are effectively vaccinated) takes the value of

prop_vacc 18250 days (i.e. 50 years) after the start of the simulations;

otherwise the value is zero.

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immunity threshold and the impact of vaccination

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The following is the general structure of the model that we are currently working with:

3. On a separate piece of paper, draw arrow(s) to show how you would change the

model diagram to show newborns being vaccinated.

Answer

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immunity threshold and the impact of vaccination

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17.2

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Q2.7 Set up the equation for the following in terms of the total population, birth rate, and

effective coverage:

a)The number of newborns entering the population per day who are

susceptible (denoted by the arrow "Susceptible births").

b)The number of newborns entering the population per day who are immune

(denoted by the arrow "Immunised births").

Use the terms provided in the drop down menus to complete the expressions that you

might use in your model for these terms. Terms may be used more than once or not at all.

Susceptible births =

Immunised births =

Answer

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

Choose...

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17.2

17.3

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Q2.8 Identify the correct differential equations from the list below that incorporate i)

immunised newborns and ii) susceptible newborns entering the population.

a)d/dt(Susceptible) = beta*Susceptible*Infectious - total_popn*b_rate*(1eff_cov) - Susceptible*m_rate

b)d/dt(Susceptible) = beta*Susceptible*Infectious - total_popn*b_rate*(1eff_cov) + Susceptible*m_rate

c)d/dt(Susceptible) = -beta*Susceptible*Infectious + total_popn*b_rate*(1eff_cov) - Susceptible*m_rate

d)d/dt(Susceptible) = -beta*Susceptible*Infectious + total_popn*b_rate*(1eff_cov) + Susceptible*m_rate

e)d/dt(Immune) = Infectious*rec_rate - Immune*m_rate +

total_popn*b_rate*eff_cov

f) d/dt(Immune) = Infectious*rec_rate + Immune*m_rate +

total_popn*b_rate*eff_cov

g)d/dt(Immune) = - Infectious*rec_rate + Immune*m_rate +

total_popn*b_rate*eff_cov

h)d/dt(Immune) = - Infectious*rec_rate - Immune*m_rate +

total_popn*b_rate*eff_cov

Answer

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immunity threshold and the impact of vaccination

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17.2

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4. Change the model (either in the equations or flowchart editor, depending on which

approach you're working with) so that:

a)A proportion eff_cov of newborn individuals are effectively vaccinated (i.e.

enter the immune compartment) after they are born.

b)The remaining proportion (1 - eff_cov) of newborns enter the susceptible

compartment.

Click the show button below to check your model if you are using the flowchart editor.

Show

Click here to check your model if you are using the equation editor.

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immunity threshold and the impact of vaccination

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17.2

17.3

17.4

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5. Run the model. Your output on Page 1 of the Figures window should resemble the

following at this stage - you should notice that the epidemic cycles change after

vaccination of 75% of newborns is introduced on day 18250.

If your model is failing to run or your figure looks different from this figure, clickmeasles equations_solnd.mmd or measles - flowchart_solnd.mmd to access the file that

you should have developed by this stage.

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immunity threshold and the impact of vaccination

page 65 of 78 17.1

17.2

17.3

17.4

17.5

17.6

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6. Run the model for values of prop_vacc that are either above or below the herd

immunity threshold, either by setting up and using the sliders or by changing the

value in the parameter window. If you are using the sliders, set the maximum to

equal 1.0 and the increment for prop_vacc to equal 0.01.

Click here

Q2.9 Look at Page 1 of the Figures window. What happens to the number of new

infectious individuals per day if the proportion of the population which is effectively

vaccinated is above the herd immunity threshold? What happens to the number of new

infectious individuals per day if the value is below the herd immunity threshold?

Answer

If you have time, try Part 3 of this session, in which we explore how R0 and other factors

(e.g. the vaccination coverage and the birth rate in the population) affect the epidemic

cycles. Please save your Berkeley Madonna files before continuing.

Figure 16. Model predictions of the effect of different levels of effective vaccination coverage among newborns,

introduced in year 50, on the long-term number of new infectious individuals per day.

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1. Reset the proportion of the population which is vaccinated to be zero. Re-run the

model and look at Page 1 of the figures window.

Q3.1 What is the inter-epidemic period 50-100 years following the introduction of one

infectious person into this population? Note that we are focusing on the time period 50 100 years after the introduction of one infectious person since at this time, the cycles

should have stabilized and epidemics should be occurring at approximately regular

intervals.

Hint: How many cycles in the number of new infectious individuals per day occur in each

10 year period?

You may wish to change the x-axis to use annual, rather than daily time units.

Click here

Answer

to remind yourself of how you can change what is plotted on the x-axis.

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Anderson and May (1992) 5 , provide the following formula for estimating the interepidemic period for immunising infections:

T 2

L(D+D')

R0 - 1

Equation 14

where D' is the average duration of the pre-infectious period, D is the average duration of

infectiousness, L is the life expectancy and is the constant (3.14...).

Q3.2 Are your results from Q3.1 consistent with this formula? Note that the life

expectancy currently equals 70 years.

Answer

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18.2

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2. Run the model for values of R0 of 5 and 18. R0 of measles was estimated to be 5-6

in Kansas (US 1918-9), 13-14 in Cirencester (UK 1947-50) and 18 in England and

Wales (1950-68).

Q3.3 How does the inter-epidemic period resulting from an R0 of 18 compare against that

resulting from an R0 of 5? Why might this occur?

Note that, as mentioned in MD02 , you can see the effect of changing a given parameter

value on model predictions by clicking on the overlay button

and then running the

model.

Answer

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18.2

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Q3.4 How should the introduction of vaccination affect the inter-epidemic period? Check

your answer by changing the value of prop_vacc and re-running the model.

Answer

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18.2

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Q3.5 How should the birth rate in the population influence the inter-epidemic period? Test

your hypothesis by changing the birth rate assuming that the population size remains

constant over time.

Answer

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Q3.6 Would you expect the inter-epidemic period for measles to be longer or shorter than

that for:

a)Chickenpox?

b)Mumps?

c)Rubella?

Hint: R0 for measles is typically higher than that for rubella and mumps; the average preinfectious and infectious periods for these infections are shorter than those for measles.

Answer

3. Change the parameters in the model to be those for influenza (pre-infectious and

infectious period = 2 days, R0 = 2). Reset the birth rate to be that in the original

model (i.e. corresponding to a life expectancy of 70 years) and, making sure that no

one is vaccinated in the population, run the model.

Q3.7 Why might you be cautious about using the predictions of the inter-epidemic period

for influenza from this model?

Answer

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To consolidate your understanding, we suggest that you try the exercises associated with

the model files for chapter 4 in the recommended course text 6 .

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1. For immunising infections, for the numbers of infectious individuals to increase once

an infectious person enters a totally susceptible population, the basic reproduction

number, R0, which is given by the expression ND, must be bigger than 1.

Here N is the total population size, D is the duration of infectiousness and is the

rate at which two specific individuals come into effective contact per unit time.

2. During the early stages of an epidemic of a new infection, R0 can be estimated from

the epidemic growth rate () using the expression: R0 1+D, and variants of this

expression.

3. These equations have been used to estimate R0 for HIV during the 1980s, for SARS

when it first emerged and for pandemic influenza.

4. For an immunising infection, the proportion of the population susceptible for the

number of infectious individuals to increase (or equivalently, for an epidemic to

occur) must be bigger than 1/R0. This result can be obtained by using the facts that:

For the number of infectious individuals to increase, the net reproduction

number, Rn (defined as the average number of secondary infectious

individuals resulting from an infectious person in a given population) must be

bigger than 1.

Rn is related to R0 and the proportion of the population that is susceptible (s)

through the equation Rn = R0 s.

If Rn>1, then R0 s must be bigger than 1 for the number of infectious

individuals to increase. Rearranging the expression R0 s >1 leads to the result

that s>1/R0 for the number of infectious individuals to increase.

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5. In general, for the incidence or the number of new infectious individuals to decrease

for an immunising infection, the proportion of the population that is susceptible has to

be below1/R0.

6. The following table summarises the relationship between trends in incidence or the

number of new infections per unit time, Rn, the proportion susceptible and the

proportion immune:

Incidence

(or number

of new

infections

or

infectious

individuals)

Rn

Proportion Proportion

susceptible

immune

Increasing

>1

>1/R0

<1-1/R0

Decreasing

<1

<1/R0

>1-1/R0

Peaking

=1

= 1/R0

= 1-1/R0

together with the removal of susceptible individuals after they become infected (and

subsequently immune) following contact with infectious individuals lead to changes

in the proportion of the population that is susceptible over time. These changes, in

turn, lead to the epidemic cycles for immunising infections.

8. Further factors, such as changes in the amount of contact between individuals during

the course of a year (e.g. due to intense mixing between children during school

terms and little mixing during school holidays) are required for the cycles to persist.

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approximation:

T 2A(D+D')

where A is the average age at infection, D' and D are the durations of the preinfectious and infectious periods respectively, L is the average life expectancy.

10. The following approximation can be used to calculate the inter-epidemic period in the

absence of vaccination:

T 2

L(D+D')

R0 - 1

11. This approximation is obtained by using the fact that, in the absence of vaccination

R0, A and L are related through R01+L/A (see EP301 and discussed further in

MD04 ), or after rearranging, AL/(R0 -1), where L is defined as the average life

expectancy. After substituting the latter expression for A into the approximation

described in point 9 above, we obtain the equation:

T 2

L(D+D')

R0 - 1

12. These approximations have usually led to estimates of the inter-epidemic period

which are reasonably consistent with those observed for many infections.

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decreases. This follows from the fact that, if R0 is low, the proportion of the

population that needs to be susceptible for an epidemic to occur (1/R0) is greater

than that required when R0 is high. This means that it takes longer for the size of the

susceptible population to grow, through the accumulation of susceptible births, to the

required threshold for the epidemic to occur when R0 is low than when R0 is high.

14. Likewise, the introduction of vaccination (e.g. of very young children) leads to an

increase in the inter-epidemic period. This follows from the fact that it takes longer

for the size of the susceptible population to grow, through the accumulation of

susceptible births, to the threshold required for an epidemic to occur than when no

individuals have been vaccinated.

15. The results described in this session largely relate to acute immunising infections

and assume that individuals mix randomly. The results will not necessarily hold for

non-immunising infections and for infections which have long incubation periods for

which conditions (such as the amount of contact between individuals) has probably

changed over time, at least in many Western populations.

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Changing what is plotted on the x--axis

How to use Sliders

1. Double click in the middle of the graph. This opens a new window called "Choose

Variables".

2. Double click on the variable that you would like to plot from the variables list on the

left hand side of this window, so that the variable appears in the list under the "Y

Axes" section on the right hand side. This section lists the variables for which

buttons will be set up at the bottom of the figures window.

3. Click on "OK" to continue and re-run the model. Your selected variable should now

Note: Unless you re-run the model, the variable will not appear in the plot!

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References

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1. Fine, P.E. and J.A. Clarkson, Measles in England and Wales--I: An analysis of

factors underlying seasonal patterns. Int J Epidemiol, 1982. 11(1): p. 5-14.

2. Kermack, W.O. and A.G. McKendrick, Contributions to the mathematical theory of

epidemics--I. 1927. Bull Math Biol, 1991. 53(1-2): p. 33-55.

3. Macdonald G. The analysis of equilibrium in malaria. Trop Dis Bull 1952; 49:

81329.

4. Macdonald G. The epidemiology and control of malaria. London: Oxford University

Press, 1956.

5. Anderson, R.M. and R.M. May, Infectious diseases of humans: dynamics and

control. 1991, Oxford: Oxford University Press.

6. Vynnycky, E. and R.G. White, An Introduction to Infectious Disease Modelling. 2010,

Oxford: Oxford University Press.

7. Lipsitch, M., et al., Transmission dynamics and control of severe acute respiratory

syndrome. Science, 2003. 300(5627): p. 1966-70.

8. Wearing, H.J., P. Rohani, and M.J. Keeling, Appropriate models for the management

of infectious diseases. PLoS Med, 2005. 2(7): p. e174.

9. Anderson, R.M., May, R.M. and A.R. McLean, Possible demographic consequences

of AIDS in developing countries. Nature, 1988. 332(6161): p. 228-34.

10. Hamer, W.H., Epidemic disease in England - the evidence of variability and of

persistency of type. Lancet, 1906(i): p. 733-9.

11. Fine, P.E., John Brownlee and the Measurement of Infectiousness: An Historical

Study in Epidemic Theory. Journal of the Royal Statistical Society, 1979. 142(3): p.

16.

12. Soper, M.A., The interpretation of periodicity in disease prevalence. J.R. Stat. Soc.

Ser. A, 1929. 92: p. 34-61.

13. Anderson RM, Grenfell BT, May RM. Oscillatory fluctuations in the incidence of

infectious disease and the impact of vaccination: time series analysis. J Hyg (Lond).

1984 Dec;93(3):587-608.

14. Schenzle, D., An age-structured model of pre- and post-vaccination measles

transmission. IMA J Math Appl Med Biol, 1984. 1(2): p. 169-91.

15. Bartlett, M., On theoretical models for competitive and predatory biological systems.

Biometrika, 1957. 44: p. 27-42.

16. Anderson, R.M. and R.M. May, The invasion, persistence and spread of infectious

diseases within animal and plant communities. Philos Trans R Soc Lond B Biol Sci,

1986. 314(1167): p. 533-70.

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