Malaria - NCEASsjryan/PPP/lectures/zoonotic_malaria.pdf · Malaria Epidemiology Global Burden of Malaria 300-500 million worldwide cases of acute malaria annually (see UN Millenium

Malaria

James Holland JonesDepartment of Anthropology

Stanford University

19 May 2008

Malaria Epidemiology

Global Burden of Malaria

300-500 million worldwide cases of acute malaria annually(see UN Millenium Project Report on Malaria1.1-2.7 million deaths annually, mostly to children < 5Sub-Saharan Africa carries 90% of the world’s malariaburden20% of childhood deaths in Africa attributable to malariaMalaria slows economic growth in Africa by 1.3% (Gallup &Sachs 2001)Malaria hyperendemicity has cascading economic effects(Sachs & Malaney 2002)

James Holland Jones Malaria


The Malaria Vector

!430 Anophelesspecies!70 malaria vectors40 of major medicalimportance

3200 species of mosquitoworldwide, belonging to 42generaOnly one genus, Anopheles,transmits human malariaAnopheles can transmit somearboviruses and filariasis, butthese are more commonlytransmitted by culicinemosquitoesAnopheles belongs to thesubfamily Anophelinae, familyCulicidae, order Diptera


Engorged Anopheles Mosquito

Primate Malarias• P. faciparum sister to P.

reichenowi, a malaria of chimpanzees

• This split corresponds with the human-chimp split

• P. vivax sister to P. cynomolgi, a malaria of SE Asian monkeys

P. reichenowi

P. cynomolgi

P. vivax

P. falciparum

Escalante & Ayala 1994

P. vivax Arose in SE Asia

• Despite earlier suggestions that P. vivax has African origin, evidence suggests otherwise

• P. vivax is sister group to P. cynomolgi

• Phylogeny indicates the P. vivax originated from a Plasmodium species related to species currently infecting SE Asian macaques

• P. vivax diverged 45-81Kya Cornejo & Escalante 2006; Escalante et al. 2005

Green=AsiaRed = MelanesiaIndia-Middle-East=YellowAmericas=BlueSize proportional to frequency

Haplotype Network for P. vivax

• Highest haplotype diversity in Asia• Most frequent haplotypes in Asia

Notes on the Evolution of Malaria


• The P. falciparum-P. reichenowi split suggests that falciparum malaria has been with humans for at least 5 million years



• The remoteness of the bird Plasmodium species to the human Plasmodia provides further evidence that malaria is not a new infection of humans (Escalenate & Ayala 1994)




• The various Plasmodium species that infect human appear to be phylogenetically independent




• The various Plasmodium species that infect human appear to be phylogenetically independent

• ∴ Malaria has spilled-over from a primate host multiple times

The Origin of P. falciparum


• Volkman et al. 2001 suggest modern P. falciparum arose approximately 6,000 years ago (Volkman et al. 2001)



• P. falciparum shows very low levels of genetic polymorphism




• This is paradoxical given how difficult malaria is to treat chemically and how rapidly it evolves resistance





• They find nearly all genetic diversity in P. falciparum occurs in genes related to drug resistance or immune escape





• They find nearly all genetic diversity in P. falciparum occurs in genes related to drug resistance or immune escape

• Otherwise, there is essentially no genetic diversity (e.g., there are virtually no synonymous substitutions)

Is P. falciparum Recent or Ancient?


• A number of studies have suggested that modern P. falciparum is more ancient



• Mu et al. (2002) suggest, instead that P. falciparum arose 100-180 Kya, corresponding to the origin of modern humans




• Similar results come from Hughes & Verra (2001)




• Similar results come from Hughes & Verra (2001)• A way to reconcile these results is that while P.

falciparum rapidly expanded 6,000 years ago in Africa, other regional populations are more like 50-100 years old




• Similar results come from Hughes & Verra (2001)• A way to reconcile these results is that while P.

falciparum rapidly expanded 6,000 years ago in Africa, other regional populations are more like 50-100 years old

• This is precisely what Joy et al. (2003) find evidence for

Generation 0

Generation 3Generation 2Generation 1

Index Case

Conditions for an Epidemic

Malaria Control:

Malaria Control:• Residual Spraying

Malaria Control:• Residual Spraying• Draining “Swamps”

Malaria Control:• Residual Spraying• Draining “Swamps”• Insecticide-Treated Bed Nets

Malaria Control:• Residual Spraying• Draining “Swamps”• Insecticide-Treated Bed Nets• Treat Symptoms


Malaria Transmission Cycle

indices and parameters; these are the EIR, the PR, thevectorial capacity, V, which measures the number ofinfectious bites that arise from all the mosquitoes that areinfected by a single infectious person on a single day [24], theinfectivity of humans to mosquitoes, c, and the stability index,S, which measures the number of human bites taken by avector during its lifetime [25]. The classical parameters andseveral malaria transmission indices are described in Tables 1and 2. At the equilibrium, the relationship between theseindices is given by a simple formula (Methods):

V ! E"1# cSX$cX

: "1$

A simple relationship exists between R0 and vectorialcapacity. R0 sums vectorial capacity, discounted for imperfecttransmission efficiency, over the average infectious period[26,27]. In a population with heterogeneous biting, where thesquared coefficient of variation in biting rates is a, R0 islarger by the factor 1# a, because the humans who are bittenmost amplify transmission [15,16]; we call a the index ofbiting disparity. The relationship between R0, vectorialcapacity, and the other indices is given by the formula

R0 !bcrV"1# a$ ! E

br"1# cSX$

X"1# a$: "2$

These formulas are based on the classic assumptions:mosquito lifespan and the duration of human infections areassumed to be exponentially distributed, and R0 is computedfor a single parasite type (for a longer discussion of theassumptions, see the Methods).Using equation 2, estimates of annual EIR and PR from

studies of 121 African populations [3], and parameterestimates from other studies, we generated 121 estimates ofR0 (Figure 2). Parameter estimates for b/r and a were takenfrom 91 of these studies that included only children less than15 y old [14]. Published estimates of the stability index rangefrom less than one up to five [9,28]; we use the estimate S ’ 1,at the low end of published studies. For the infectivity, we usethe value c ! 0.5, a number that agrees with estimates fromdirect-feeding experiments [29].The R0 estimates range from near one to more than 3,000.

The median was 115 and the interquartile range was 30%815.These values are consistent with previous estimates, includingone estimate of 1,600 [20] in Mngeza, in northwest Tanzania,and another of 2,000–5,000 [19] in Lira township, in centralUganda. Had these studies considered heterogeneous biting,they would have exceeded our highest estimates.In an area around Madang, Papua New Guinea, where

entomological surveys have shown that annual EIR isapproximately 150 [30], and where our methods wouldsuggest that R0 is larger than 500, an estimate based on ageseroprevalence was R0 ’ 7. The biological basis for the largediscrepancy remains unresolved; one possibility is the straintheory of transmission [31].

Immunity and Sampling BiasEquilibrium methods for estimating R0 are based on the

simple assumptions of mathematical models; the differencebetween these simple assumptions and variance in realpopulations can introduce a large bias. When biting ratesare heterogeneous, for example, mosquitoes bite infectedhumans at a different frequency than when humans aresampled in a study. Thus, PR may be a biased measure of theprobability a mosquito becomes infected after biting ahuman. In addition, the intensity of transmission at equili-brium may be lower than it would be in that same populationwithout immunity; immunity would reduce the infectivity of

Table 2. The Parameters

a Human feeding rate: the number of bites on a human, per mosquito, per day. Let f denote the feeding rate, i.e., thenumber of bites, per mosquito, per day, and Q the proportion of bites on humans. The human feeding rate is the pro-duct a ! fQ.

b Infectivity of mosquitoes to humans: the probability that a human becomes infected from a bite by an infectious mosqui-to. With pre-erythrocytic immunity, the infectivity of mosquitoes may depend on EIR, bE.

c Infectivity of humans to mosquitoes: the probability that a mosquito becomes infected from a bite on an infected hu-man. Infected humans are not infectious all the time, and infectious bites transmit less than perfectly. With transmission-blocking immunity, infectivity of humans may depend on EIR, cE.

g Death rate of mosquitoes. The probability a mosquito survives one day is p ! e%g, so g ! %ln p. The expected lifespanof a mosquito is 1/g.

m Number of mosquitoes per human. Assuming adult mosquitoes emerge at a constant rate k, per human, then m ! k/g.n Number of days required for a mosquito to complete sporogony.1/r Expected waiting time to naturally clear a simple infection.

doi:10.1371/journal.pbio.0050042.t002

Figure 1. The Life Cycle Model and R0The basic reproductive number, R0, is derived by computing theexpected number of vertebrate hosts or vectors that would be infectedthrough one complete generation of the parasite by a single infectedmosquito or a single infected human. The underlying mathematicalmodel, by Ross [11] and Macdonald [12] and with a slight modificationby Smith and McKenzie [27], is a quantitative description of the idealizedlife cycle. This diagram follows one by Macdonald et al. [23]. Theparameters are described in Table 2.doi:10.1371/journal.pbio.0050042.g001

PLoS Biology | www.plosbiology.org March 2007 | Volume 5 | Issue 3 | e420533

Revisiting R0 for Malaria Control

from Smith et al. (2007)



On Vectorial Capacity

Vecotrial capacity (C) is a measure frequently used inmalaria epidemiologyIt is very similar to R0 in the sense that it assumes acompletely susceptible human populationWhere it differs is that it does not consider transmissibilityof the PlasmodiumC measures the potential of an environment for malariatransmission neglecting both the state of the hosts and thetransmissibility



The Components of C

C is the product of three quantities:1 the emergence rate of mosquitoes per human per day2 the squared number of mosquito bites on humans after

mosquitoes become infectious3 the probability of a mosquito surviving the Plasmodium

incubation periodC ! (Emergence Rate) · (Number of Bites)2 · (Mosquito Survival)



Vectorial Capacity, C

Define the following quantities:a Expected number of bites on humans per

mosquitom Equilibrium mosquito density per humann Length of incubation periodp Daily survival probability of mosquitoes (= e!g)

Vectorial capacity is then

C = mg!

ag

"2

e!gn =ma2pn

! log(p)



Sensitivities

0 20 40 60 80 100

0e+

00

4e+

05

8e+

05

Expected Bites per Day (a)

Vecto

rial C

apacity

a

0.4 0.5 0.6 0.7 0.8 0.9 1.0

0e+

00

4e+

05

8e+

05

Mosquito Survival Probability (p)

Vecto

rial C

apacity

p

0 5 10 15 20 25 30

0e+

00

4e+

05

8e+

05

Length of Incubation Period (n)

Vecto

rial C

apacity

n

0 20 40 60 80 100

0e+

00

4e+

05

8e+

05

Density of Mosquitoes per Person (m)

Vecto

rial C

apacity

m



The Importance of Mosquito Mortality

0 5 10 15 20

0.0

0.2

0.4

0.6

0.8

1.0

Age (d)

Fra

ctio

n A

live p=0.95

p=0.9


Implications for Malaria Control

• Reducing adult mosquito survival (p) has the largest effect on C

• Reducing the biting rate (a) also has a strong effect, but it is considerably more shallow that reducing p

• This means that residual spraying (e.g., with DDT) will have a greater impact on outbreak control than employing bednets


Estimating R0 From Data

R0 is difficult to estimate because some of the parametersare difficult to measureIt is much more common to find measurements of C or E,the entomological inoculation rateFortunately, we can measure R0 from the entomologicalinoculation rate



The Entomological Inoculation Rate, E

The Entomological Inoculation Rate, E is the averagenumber of infectious bites a person receives in a yearIt is commonly measuredIt is the product of three things

1 The human feeding rate a2 The number of mosquitoes per person m3 The sporozoite rate Y (the fraction of mosquitoes that are

infectious)

At equilibrium, vectorial capacity (C) is related to to E bythe following relationship:

C =E(1+ cSX)

cX(1)

where S = a/g is the expected number of bites a mosquitomakes over its life (“the stability index”)



Estimating R0 From E

The formula for R0 is:

R0 =bcr

C (2)

Note the resemblance to the general formula for R0

It is the product of1 Transmissibility, bc, where transmissibility has two

components: humans! mosquitoes and mosquitoes!humans

2 The duration of infectiousness 1/r3 The contact rate between infectious and susceptible

individuals, C


Smith et al. 2007

Persistence

2

S1

N2

N1

Exclusion

S

Multi-Species Epidemic:

Complementary?

Exclusion

2

S1

N1

Persistence

S

Or Inhibitory?

Evolution of Virulence in Multi-Host Infections

Malaria Virulence Evolution

Plasmodium falciparum only infects humansYet we know that it once infected multiple speciesP. falciparum is also extremely virulentIs there a relationship between host species richness andthe evolution of virulence?The simple answer is: yesThe complicated answer is: it’s complicated



How Can Species Richness Decrease EpidemicPotential?

from Keesing, Holt & Ostfeld (2006)



Evolving Virulence: Conceptual Model I

Mortalityµ

Transmission

Efficiency



Evolving Virulence: Conceptual Model II

Mortality

!

(x*)"µ

Transmission

Efficiency

(x*)



Evolving Virulence: Conceptual Model II

This increases virulence

!

(x*)"

Reduction in SpeciesRichness Decreases

Transmission Efficiency

(x**)"

(x**)!

µ

Transmission

Efficiency

Mortality

(x*)


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Malaria - NCEASsjryan/PPP/lectures/zoonotic_malaria.pdf · Malaria Epidemiology Global Burden of Malaria 300-500 million worldwide cases of acute malaria annually (see UN Millenium