Vaccines are considered the most cost-effective means of control, prevention, elimination, eradication of infectious diseases: for this reason, a malaria vaccine would greatly assist in the drive to eradicate malaria from the world. Professor Flanagan presents in this slideset the current status and challenges of developing malaria vaccines. To learn more, visit www.waidid.org!

1. Malaria vaccines: Current status
and challenges
A/Prof Katie Flanagan
Clinical Associate Professor & Head of Infectious Diseases, NorthernTasmania
Director of SystemsVaccinologyTrial Centre, Clifford Craig Medical ResearchTrust,Tasmania
Adjunct , Dept of Immunology and Pathology, Monash University, Melbourne

2. Cases
214 million cases
in 2015
Incidence
37% decrease
in incidence
between 2000
and 2015
Mortality
60% decrease in
deaths between
2000 and 2015
(>98% of deaths
from P. falciparum)
Malaria elimination is now considered feasible

3.  3.2 billion people at risk per year
 200-300 million cases per year world wide
 ~0.5 million fatalities – mainly in children and pregnant women
 Malaria poses a huge economic burden 1-6% of GDP
 Control measures such as ITNs, spraying, prophylaxis, early diagnosis & Rx
o are not sufficient alone
o failing due to insecticide resistance, drug resistant parasites
o expensive (>$2.6 billion spent on malaria control in 2013)
 A malaria vaccine would greatly assist in the drive to eradicate malaria from
the world since vaccines are considered the most cost-effective means of
control, prevention, elimination, eradication of infectious diseases

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Liver or
Pre-erythrocytic
Stage
Blood Stage
Sexual Stage
Complex
parasite with
multiple life
cycle stages
making vaccine
development
challenging

5. From Barry & Arnott, Front Immunol 2014; 5(359): 4

6. Immune Response to Malaria Infection
From Crompton et al, Annu Rev Immunol 2014; 32: 157
 Successful
vaccine
probably needs
to induce
cellular (CD4
and CD8T cells)
andAb
responses
 Multi-stage
vaccine
preferable for
inducing
sterilising
immunity

7. Crompton et al, Annu Rev Immunol 2014; 32: 157
Acquired Natural Immunity
TakesYears to Develop

8. Conway,Trends in Genomics 2015;31(2):97
Barry & Arnott, Front Immunol 2014;5(359):4

9.  UK adults Phase I – safety, dose finding and immunogenicity
 UK adults Phase IIa – sporozoite challenge study (CHMI)
 African adults Phase I – safety and immunogenicity
 African age de-escalation Phase I – safety, dose finding and
immunogenicity (2-5 years  5-12 months  10 weeks)
 African adults Phase IIb – efficacy (time to infection by blood film+ fever or
PCR)
 African infants Phase I / IIb – efficacy (time to infection)
 African infants Phase I - EPI immunogenicity
 African infants Phase III – efficacy
 File for license

10. From Conway,Trends in Genomics 2015;31(2):97

11. Regulatory requirements
 Time
 Certification
 Testing each adjuvant/antigen to complete product development
 Increasing inflexibility along the translational path
Costs
 Large investment (RTS,S investment from GSK and BMGF $610 million)
 Requires partnerships
 Vaccine production costs high
 Technological innovation/QC commitment to a limited number of products
 Risk aversion - old technologies (e.g.VLPs) preferred

12. Ouattara and Laurens, CID 2015;60:930

13.  Consists of a fusion protein of pre-erythrocytic circumsporozoite protein (CS)
antigen repeat region, CST cell epitopes and HBsAg
 Hybrid particle vaccine in AS01B adjuvant produced by GSK
 Only malaria vaccine to reach phase III clinical trials
 Induces CD4T cells but not CD8T cells in humans
 Strain/variant specific protection (consists of 1 of 10 natural variants of CS)
Kaslow and Biernaux.Vaccine 2015;33:7425

14.  Efficacy against clinical malaria in phase III trials (to 14m post vaccination)
 50.4% (95% CI 45.8-54.6) in 5-17 month old children (n=6,000)
 30.1% (95% CI 23.6-36.1) in 6-12 week old infants (n=6,537)
 This efficacy is too low for deployment in the field
 Efficacy mediated by high titre anti-CS antibody responses
Kaslow & Biernaux.
Vaccine 2015;33:7425

15. To facilitate malaria elimination it is estimated that a vaccine should induce
>85% sterile protection for >6 months (Hoffman. Vaccine 2015;33:D13)
Kaslow & Biernaux.
Vaccine 2015;33:7425

16. Potent T cell responses
Adenovirus Prime Modified Vaccinia Ankara
(MVA) Boost
 MainAgs - CS protein and thromobospondin related adhesion protein (TRAP)
 Inhibit sporozoite motility and hepatocyte invasion
 Prime-boost strategies with DNA and viral vector vaccines
 US Navy
 DNA prime, AdHu5 boost +/- AMA-1
 Jenner Centre, Oxford, UK (Prof Adrian Hill)
 Fowlpox prime, MVA boost with full-length CS
 DNA prime, MVA boost with full-length CS
 Chimp adenovirus prime (ChAd63), MVA boost with TRAP
 Highly potent CD8 T cell responses and Abs
 Being tested in combination with RST,S
Disappointing results
in challenge studies

17.  It has long been known that injecting humans with irradiated sprorozoites
confers complete protection against malaria challenge
 Hoffman et al. have shown 100% efficacy after 4-6 i.v. doses of 1.35x105 spz
(4 mosquitoes per dose)
 Broad ranging immunity induced - Abs, CD4 and CD8T cells, NK cells, γδT
cells
 Protection lasts >1 year (VE of 55% at 59 weeks)
 Early efficacy correlates with antibody and γδT cell responses
 Later efficacy probably requires tissue resident CD8T cells
 Safe, well tolerated, meets regulatory standards
 Feasibility concerns –
 Large scale manufacture - new sporozoite culture techniques being developed
 IV vaccination required
 Stored in liquid N2
 Attenuated sporozoites may revert to virulent forms or be under-attenuated

18. 3 weeks
3 weeks 21-25 weeks 21-25 weeks 59 weeks
 100% sterile protection against controlled human malaria infection at 59
weeks in n=5 subjects (f) (Ishizuka et al. Nat Med 2016;22(6):614)
 Recently granted FDA fast track approval
 Other whole parasite approaches are being pursued including sporozoites +
chemoprophylaxis, genetic and chemical attenuation

19. Beeson et al. FEMS
Microbiol Rev
2016;40(3):343
 Various blood stage vaccines are being tested in human clinical trials
 Target merozoites to inhibit RBC invasion
 Infection still occurs but is blocked at the blood stage
 Merozoites express multiple antigens so identifying the ideal target(s) is
challenging
 Leading targets include MSP1, MSP2, MSP3, AMA1, EBA175, PfRH5
 Significant polymorphism of Ag targets
 Abs and CMI responses thought to be required for protection
 Human efficacy trials have been disappointing
 No in vitro assays or challenge models that provide correlates of protection in
human studies
 Live attenuated whole blood stage vaccines are being developed

20. Crompton et al, Ann
Rev Immunol 2014;
32: 157
 Also called SSM-VIMT – vaccines that target sexual, sporogenic, and /or
mosquito stage antigens to interrupt malaria transmission
 Inhibit ookinite development in the mosquito midgut thereby blocking
transmission – do not prevent infection / clinical disease
 A handful of antigenic targets currently being developed as vaccines
 Humans produce Abs to Ags expressed during the human sexual stage &/or
mosquito life-cycle
 Abs are ingested by the mosquito and prevent parasite development
 Passive immunisation with monoclonalAbs also being explored
 Challenges:
 Expressing and purifying appropriately folded
target proteins
 Low level Ab titres induced by current candidate
vaccines
 Lack of assays for correlating efficacy in the field

21. TLRs, PRRs, PAMPs, inflammasome activators (Alum)
 Positive short term effects
 Increase immunity; modulate type of immunity
 Negative long term effects
 Pro-inflammatory Tregs
 NSEs (sex differential)
Nanoparticle based vaccines: fromVLPs to synthetic NPs
 Positive short and long-term effects
 Some can increase immunity without inflammation (orTreg)
 NSEs
 Beneficial NPs (PS, silver) ↑resistance to asthma and influenza

22.  Despite >30 years of intense efforts we still don’t have an effective malaria
vaccine
 The vaccine development pathway is very slow and very expensive
 The parasite has multiple stages where it expresses different antigens and a
multistage and multi-antigen vaccine may be preferable
 Most major antigenic sites are highly polymorphic (but do have conserved
regions) thus an ideal vaccine needs to be strain transcending
 An ideal vaccine would induce Abs, CD4 and CD8T cells
 T cell inducing vaccines need to cover multiple HLA haplotypes to be effective
in different regions of the world
 Models for surrogates of protection are lacking for human trials
 Results of subunit vaccine studies have been disappointing
 The whole sporozoite vaccine approach is highly promising but has several
logistic caveats