Transmission heterogeneity has consequences on malaria vaccine researches - Conférence du 5e édition du Cours international « Atelier Paludisme » - Vincent ROBERT - Institut de Recherche pour le Developpement, Paris - v.robert@mnhn.fr

1. Atelier Paludisme 2007
Institut Pasteur de Madagascar
19 Février - 30 Mars
Vincent ROBERT
Institut de recherche pour le développement (IRD) UR 077 Paludologie afro-tropicale
Muséum national d’histoire naturelle (MNHN) USM-504 Biologie fonctionnelle des protozoaires
L’hétérogénéité de la transmission
doit être prise en compte
dans les recherches vaccinales contre le paludisme

2. Transmission
vectorielle
Transmission des Plasmodium
Anopheles
Aedes
phlébotomes
Bio-écologie
Gamétocytes
Santé publique
Antipaludiques
Résistance
Prévention de
l’impaludation
Lutte
antivectorielle
Insecticides
Résistance
Sahara Sahel
Savane Forêt
Madagascar
Villes
Guyane
Transmission des arbovirus
Enseignement
professionnel
supérieur
enfants
Epidémiologie
Evolution
Génétique
Immunologie
VaccinsMoustiquaires
Répulsifs
Plasmodium
animaux
Apicomplexa Piégeage Diagnose Laboratoire
Sporogonie
Mesure de la transmission

3. Atelier Paludisme
Institut Pasteur de Madagascar
February 29, 2007
Transmission heterogeneity has
consequences on malaria vaccine researches
1 /18

4. Three modes of transmission :
Transmission • vectorial
• transfusion
• placental
2 /18

5. MOSQUITO-HUMAN
TRANSMISSION
MOSQUITO
HUMAN
The transmission
HUMAN-MOSQUITO
TRANSMISSSION
? or the two transmissions ?
Vaccines
Inhibition of sporozoite invasion
Inhibition of merozoite invasion
Inhibition of infected red blood cells cyto-adherence
Immunity regulation
Inhibition of sporogonic development
Transmission
blocking vaccines
3 /18

6. transmission morbidity mortality
the malaria in one slide
Human
uninfected
Human
infected
Human
sick
Human
dead
natural immunity
- --
vector controlprevention of
infection
drug treatment
--- - -
and / or vaccines
4 /18

7. Transmission and natural immunity are highly linked
If the vaccine would have nothing to deal with the stimulation of natural immunity and only induces new
immunological mechanism of protection (fully different from natural situations), one may speculate :
- the induction of protective immunity by a vaccine is not linked to transmission intensity,
- but the duration of protection might be.
Transmission intensity has important consequences for the
artificial induction of protective immunity by a vaccine
Transmission may act positively, as additional boosters
New infections may act negatively, overwhelming the protective immunity
The development of the vaccine must document transmission intensity,
(except during phases testing safety), as soon as the first phases
testing immunogenicity and efficacy in endemic zones
Infants do not constitute a special issue
5 /18

8. The measure ofThe measure of PlasmodiumPlasmodium transmissiontransmission
≠≠ number of inoculation ofnumber of inoculation of PlasmodiumPlasmodium
per person : ordinary, an adultper person : ordinary, an adult
per unit of time : night, month, year, lifeper unit of time : night, month, year, life
Definition
E I R : Entomological Inoculation Rate
EIR = ma x s
ma = biting rate
s = sporozoite index
Unit : Nb of bites of infected anopheline per human and per unit of time
6 /18

9. Does EIR measure transmission ?
• Mean on a sample of persons : what about individual variations
for an adult human ?
in a mean environment ?
• Mean on a period time : what about the temporal variations ?
==> specify if transmission is seasonal or permanent,
(duration of season without transmission)
• Measure established from awaked voluntaries
• Give the Nb of bites of infected anophelines
(about double of the Nb of bites that induce blood parasite infection )
EIR is a proxy of malaria transmission
7 /18

10. 8 /18

11. Incidence ofIncidence of P. falciparumP. falciparum simple malaria attackssimple malaria attacks
in relation to age and intensity of transmissionin relation to age and intensity of transmission
AnnualAnnualNbNbofmalariaattacksofmalariaattacks
00
11
22
33
44
55
66
00 55 1010 1515 2020 2525 3030 3535 4040 4545 5050
Age (years)Age (years)
DananéDanané, Côte d'Ivoire:, Côte d'Ivoire: ≥≥≥≥≥≥≥≥ 300300 b.i.ab.i.a./human/year./human/year
DielmoDielmo,, SénégalSénégal: 100: 100--300300 b.i.ab.i.a./human/year./human/year
NdiopNdiop,, SénégalSénégal: 10: 10--3030 b.i.ab.i.a./human/year./human/year
PikinePikine,, SénégalSénégal:: ≤≤≤≤≤≤≤≤11 b.i.ab.i.a./human/year./human/year
TotalTotal NbNb of attacksof attacks
at 60 years oldat 60 years old
2525
4343
6262
2525
% within% within
adultsadults
10%10%
23%23%
41%41%
50%50%
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12. NonNon--entomological methods to measure transmissionentomological methods to measure transmission
Parasitological (Parasitological (presence of parasites)presence of parasites)
Longitudinal or transversal surveysLongitudinal or transversal surveys
Incidence of the disease (Detection of new clinical cases;Detection of new clinical cases;
with parasiwith parasitological confirmation)tological confirmation)
Serological (Serological (AbAb :: indirect markers of the presence of parasiteindirect markers of the presence of parasite))
10 /18

13. Efficacy of bites of infected anopheline
Rickman et al., 1990
No appropriate animal model
In human
An. stephensi with P. falciparum sporozoites
in their salivary glands
3 / 5 volunteers
Parasitaemia
in American
volunteers
10 / 10 volunteers
2 / 5 volunteers
1 bite
2 simultaneous bites
5 simultaneous bites
What is the fraction of bite of infected anophelines that develop parasitaemia ?
About half bites of infected anophelines induces blood parasite infection
Challenges after vaccination are made usualy using 5 simultaneous bites
Reminder : these voluntaries were non immune
11 /18

14. Sporozoites injected per bite of infected anophelines
Where and when ?
How many ?
Into the avascular skin tissue (of mice), during the probing
Sprozoites injected during the feeding, in the blood vessel,
are re-injested with the bloodmeal. They can be numbered in
the midgut of a fed mosquito.
Sidjanski & Vanderberg, 1997
Kebaier & Vanderberg, 2006
by the way of the stream of mosquito saliva
Sporozoites delivered represent only a tiny %age of the sporozoites
within the salivary glands of the mosquito (±1%)
Range : 0 - 1000
Beier et al, 1992
Ponnudurai et al, 1991
Rosenberg et al, 1990
Mean : 10 to 20
12 /18

15. 0
Nb of bites of
infected anophelines
Boundary min Boundary max
1 10 100 103 104 105
Evidence of heterogeneity in malaria transmission
= 10 bites of infected anophelines= 1 bite of infected anophelines
per human, per year, during 100 years
This heterogeneity in transmission results in a variation :
in the acquisition of immunity (efficient against the disease)Impossible <100
Need ± 10 years if
103
Need ± 2 years if 104
in the challenge to the immune system ; but natural infections following
vaccination may either reinforce the immunity or overwhelm it
13 /18

16. Source 2002
Population Reference Bureau
Africa
Sub-saharan Africa, except southern Africa
North America
Central + The West indies
South
Amazonia s.l. + Haïti
Asia
Europa
Oceania
Population
(millions)
Population who get malaria
at least one / life
840
630
319
140
354
3766
728
32
WORLD 6200 1740
600
30
104
1000
5
Malaria transmission depends mainly on
Altitude
Climate
Urbanisation
Water surface (eg: rice field)
Personal protection and vector control
Journey (eg: tourism)
1
28%
14 /18

17. Human population (millions)
0
1 000
2 000
3 000
4 000
5 000
Human population and the number of bites of infected anophelines
0
Nb of bites
of infected
anophelines
Boundary min Boundary max
1 10 100 103 104 105
700
300
1 740
Total world population
infected at least once
15 /18

18. % of the world population
as potential target
for malaria vaccine
60%
23%
17%
Transmission
intensity
low
medium
hight
Risk of
overwhelming
vaccinal efficacy
—
+
+++
Annual
EIR
≤ 1
1 -10
> 10
Tropical Africa + Papua-New-Guinea
Because high number of new infections may overwhelm any protective
immunity (natural or vaccinal), it is conceivable that some malaria vaccines may
have various efficacy at the different transmission levels.
Human population and the number of bites of infected anophelines (2)
If it is right, world population mainly
needs vaccine efficient at low transmission level
16 /18

19. Transmission intensity :
CONCLUSIONS
This heterogeneity :
That must be taken into account in any malaria vaccine research
(except in phase 1)
- ranges from 0 to 105 bites of infected anophelines per man and per life
- varies by a factor of 100 000 fold across tropical Africa
(some downtowns vs. some humid rural savannahs)
- has huge consequences for acquisition of natural immunity
- may have important consequences for the success and longevity
of artificial induction of protective immunity by a vaccine
1
2
4
It is conceivable that some malaria vaccines may have various
efficacy at the different transmission levels
3
17 /18

20. Bibliography
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Four years' entomological study of the transmission of seasonal malaria in Senegal and the bionomics of
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Filion GJP, Paul REL & Robert V
transmission and immunity : the importance of heterogeneity in the fight agaisnt malaria.
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Re-ingestion of Plasmodium berghei sporozoites after delivery into the host by mosquitoes.
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The global distribution of clinical episodes of Plasmodium falciparum malaria.
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Sidjanski S & Vanderberg JP
Deleyed migration of Plasmodium sporozoites from the mosquito bite site to the blood.
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Combating malaria morbidity and mortality by reducing transmission.
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