Malaria vaccines: Current status and challenges

A/Prof Katie Flanagan

Clinical Associate Professor & Head of Infectious Diseases, Northern Tasmania

Director of Systems Vaccinology Trial Centre, Clifford Craig Medical Research Trust, Tasmania

Adjunct , Dept of Immunology and Pathology, Monash University, Melbourne

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

3.2 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

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

Immune Response to Malaria Infection

From Crompton et al, Annu Rev Immunol 2014; 32: 157

Successful vaccine probably needs to induce cellular (CD4 and CD8 T cells) and Ab responses

Multi-stage vaccine preferable for inducing sterilising immunity

Crompton et al, Annu Rev Immunol 2014; 32: 157

Acquired Natural Immunity Takes Years to Develop

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

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

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

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

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

Ouattara and Laurens, CID 2015;60:930

Consists of a fusion protein of pre-erythrocytic circumsporozoite protein (CS)

antigen repeat region, CS T cell epitopes and HBsAg

Hybrid particle vaccine in AS01B adjuvant produced by GSK

Only malaria vaccine to reach phase III clinical trials

Induces CD4 T cells but not CD8 T cells in humans

Strain/variant specific protection (consists of 1 of 10 natural variants of CS)

Kaslow and Biernaux. Vaccine 2015;33:7425

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

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

Potent T cell responses

Adenovirus Prime Modified Vaccinia Ankara (MVA) Boost

Main Ags - 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

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 CD8 T cells, NK cells, γδ T

cells

Protection lasts >1 year (VE of 55% at 59 weeks)

Early efficacy correlates with antibody and γδ T cell responses

Later efficacy probably requires tissue resident CD8 T 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

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

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

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 monoclonal Abs 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

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: from VLPs to synthetic NPs Positive short and long-term effects Some can increase immunity without inflammation (or Treg) NSEs Beneficial NPs (PS, silver) ↑resistance to asthma and influenza

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 CD8 T 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