Malaria is a major global health problem, killing over 700,000 people annually. Developing an effective vaccine is challenging due to the parasite's complex life cycle and ability to evade the immune system. Current vaccine approaches include protein-adjuvant vaccines targeting specific stages, viral vectored vaccines to induce cellular immunity, and whole parasite vaccines. Significant progress has been made, but partial efficacy has required unprecedented immunogenicity. A multi-component vaccine targeting multiple stages may be needed for high efficacy.

1. Malaria Vaccines
Adrian Hill
The Jenner Institute, Oxford University

2. How to Make a Vaccine
1790s pub, pustule, publish
1890s isolate, inactivate, inject
21st Century sequence, select, synthesize

3. Malaria Mortality and Morbidity
• Currently about 700,000 deaths each year from
Plasmodium falciparum
– Mostly in young children
– Mostly in Africa
• About 250,000,000 clinical cases a year
• Malaria control now costing $1.5 billion annually
– Tools such as spraying, drugs and impregnated bed nets
have a finite period of utility
– Current economic cost of malaria to Africa : ~$12bn

4. A Complex Parasite Life-Cycle
Many Target Antigens

5. Some Difficulties in Malaria
Vaccine Development
• Stage-specificity of antigen expression
• Antigenic variation
• Extensive genetic diversity
• Exceptional immunogenicity required

6. Main Approaches to Malaria
Vaccine Development
1. Protein-adjuvant vaccines
• RTS,S/AS01
antibodies
• AMA1/AS02
• MSP3/alum
2. Vectored vaccines
• Adenovirus-MVA cellular immunity
• DNA-Adenovirus
3. Whole parasite vaccines
• Irradiated sporozoites
• Genetically attenuated parasites both to multiple antigens
• Low dose blood-stage parasites

7. SANARIA
The quest for a whole sporozoite vaccine

8. Efficacy of Sporozoites Administered
by the Bites of Irradiated Mosquitoes
Courtesy S Hoffman

9. Difficulties for the Whole Irradiated
Sporozoite Vaccine Approach
• Manufacturing
– One batch per day
• Storage
– Liquid nitrogen required
• Lack of efficacy
– Only 2 / 44 vaccinees protected
– 137,000 parasites x 6 in high dose group
– Implications for genetically-attenuated parasites

10. Viral Vector Vaccines
to Maximise Cellular Immunogenicity
8 weeks
Adenovirus Prime MVA Boost
Malaria, HCV, HIV, influenza, TB...

11. Vaccine Efficacy in Murine Malaria
Photon Imaging
ChAd63-MVA
ChAd63 alone
controls

12. A PolyEpitope-Protein Construct
pSG.ME.TRAP
ME: Malaria Epitopes
TRAP: Thrombospondin-
Related Adhesion Protein
TRAP strain is T9/96
in this vaccine

13. Clinical BioManufacturing Facility
University of Oxford

14. ME-TRAP T Cell Immunogenicity
in the Clinic
VACCINE T CELL RESPONSE ANTIGEN
mean cells/ million PBMCs
DNA x 3 48 ME-TRAP
Fowlpox x 2 50 ME-TRAP
MVA x 3 41 ME-TRAP
ChAd63 x 1 850 ME-TRAP
DNA x 2 - MVA boost 430 ME-TRAP
Fowlpox x 2 - MVA boost 475 ME-TRAP
ChAd63 x 1 - MVA boost 2800 ME-TRAP

15. Induced CD8 and CD4 Cells Show
Substantial Polyfunctionality

16. Responses are Durable and Can Be
Re-Boosted at 6-30 Months Post-MVA

19. Vectored Liver-Stage Vaccines
for Malaria
• Efficacy correlates with induced CD8+ T cell numbers in
phase II trials
– First example for any vaccine
– Correlate is with mono-functional effectors secreting g-interferon
• Excellent safety data for both ChAd63 and MVA vectored
vaccines
– About 500 and 3000 vaccinees, respectively, in malaria, TB, HIV
– Re-boosting with each vector demonstrated
• Phase I trials of ChAd63-MVA completed successfully in
African adults, children and infants

20. Sukuta Vaccine Clinic
The Gambia

21. The Malaria Vectored Vaccine Consortium
African Prime-Boost Trials
• EDCTP funded: ChAd63-MVA MeTRAP
– Kenya, Gambia, Burkina Faso, Senegal
• Phase I trials in adults, children and infants
– 164 adults in The Gambia, Kenya, Senegal
– 24 children and 48 infants in The Gambia
– Excellent safety and immunogenicity
• Phase IIb efficacy trials underway
– 2012: Adults in Kenya and Senegal (Q2 and Q3)
– 2013: 5-17 month olds in Burkina Faso
MVVC

22. Pre-Erythrocytic Vaccine Efficacy
Sporozoite Challenge Trials
Vectors encode ME-TRAP; RTS,S encodes CSP
80%
70%
60%
50%
40%
30%
20%
10%
0%
Controls Other DNA-MVA* FP9-MVA* Ad-MVA* RTS,S*
n = 68 candidates n = 22 n =16 n = 14 n >100
n = 104
+
Sterile Protection Partial Protection
*Vaccine groups differing significantly from controls
+
Delay to day 14 or beyond = > 95% reduction in liver parasite burden

23. Options for Better
Pre-Erythrocytic Efficacy
1. Assess alternative antigens
– ChAd-MVA encoding AMA1, MSP1, CSP assessed
so far
– None better than TRAP
2. Add an encoded adjuvant to vectors
3. Add an RTS,S biosimilar = R21

24. A Sporozoite and Liver-Stage Vaccine
a combination two-hit approach
Sporozoite Stage:
Antibodies clear
most sporozoites
schizonts Liver Stage:
T Cells clear the
remaining liver
RBC cells
CONFIDENTIAL

27. RTS,S Immunogenicity and Efficacy
• Exceptional antibody titres to the central repeat of
the circumsporozoite protein
– 70-600 mg per ml
– No CD8+ T cell response induced
• 45% sterile efficacy on sporozoite challenge
• 35% reduction in malaria clinical episodes
– over 12 months follow-up
– in older infants

28. Multi-Component Malaria
Vaccine Strategy
• A Four-Stage High Efficacy Modular Vaccine
against P. falciparum malaria
– Sporozoite Stage: R21
– Liver Stage: TRAP
– Blood Stage: PfRH5
– Mosquito Stage: Pfs25

29. Screening for Better P. falciparum
Blood-Stage Antigens
8wk
AdHu5 Prime MVA Boost
Douglas AD (2011) Nat Commun 2, 601

30. PfRH5: a promising novel
blood-stage vaccine antigen
• PfRH5 is essential for invasion of human and Aotus RBCs
– Interacts with the basigin receptor on RBCs
Hayton et al, CHM 2008; Baum et al, IJP 2008; Crosnier et al, Nature 2011
• Vaccination of rabbits with PfRH5 elicits antibodies which
neutralise all tested strains of P falciparum.
Douglas et al, Nature Comms 2011
• RH5 sequence is highly conserved
– among circulating parasites in the field: <1% amino acid variation
Williams & Douglas et al, submitted
• Not very immunogenic during natural infection
– a target for non-natural vaccine-induced immunity
Douglas et al, Nature Comms 2011

31. Transmission-Blocking Vaccines:
Leading Target Antigens – Parasitic and Mosquito
Pfs48/45 and Pfs 230
PfsHAP2
Pfs25
HUMAN HOST VECTOR HOST
Alanyl Aminopeptidase N1
(AgAPN1)

32. Standard Membrane Feeding Assay
Cardiac bled two weeks after
immunization for serum
Plasmodium oocysts in mosquito
midgut are counted 12 days later
Serum (at different dilutions)
mixed with P. falciparum
gametocyte culture and put in
membrane feeders
A pot of 50 mosquitoes (starved 5-6 hrs
prior to the feed) via mini-feeders

33. Summary
• There is considerable progress in vaccine
development for malaria
– RTS,S could be licensed by 2015
– Further components should increase efficacy
• Partial efficacy has required unprecedented
immunogenicity
• Access to challenge models and functional assays
has been crucial

34. Pre-Erythrocytic Acknowledgements
Malaria Pre-Clinical BioManufacturing Clinical Trials
Arturo Reyes-Sandoval Sarah Moyle Geraldine O’Hara
Katharine Collins Eleanor Berrie Susanne Sheehy
Alex Spencer Chris Duncan
Migena Bregu Nick Anagnostou
Anita Milicic Carly Bliss
Sarah Gilbert Alfredo Nicosia Katie Ewer
Matt Cottingham Stefano Colloca Ian Poulton
Riccardo Cortese Nick Edwards
The Gambia Alison Lawrie
Kalifa Bojang Kilifi, Kenya Bob Sinden
Muhammed Afolabi Roma Chilengi
Jenny Mueller Caroline Ogwang
Britta Urban Rino Rappuoli
European Vaccine Initiative Kevin Marsh Giuseppe del Giudice
Egeruan Imoukhuede

35. Blood-Stage and Mosquito-Stage
Vaccine Acknowledgements
Oxford Oxford NIH
Simon Draper Sumi Biswas Carole Long
Sandy Douglas Melissa Kapulu Sam Moretz
Andrew Williams Bob Sinden Kazutoyo Miura
Joe Illingworth Lynn Lambert
Prateek Choudhary
NAMRU, Lima Sanger Centre
Linda Murungi
Sara Zakutansky Gavin Wright
Ali Turner Willy Lescano
Cecile Crosnier
Vector Core Luis Lugo
Julie Furze Jeremy Moorhead
Drew Worth