Research: Malaria Vaccine and Development

Baraka AmuriIfakara Health Institute (IHI)

Presentation Outline

•Research and Development•Clinical phases•Target sites for malaria

vaccines•Challenges

Research & DevelopmentIdentify Antigens

Produce Antigens

Test in Animals

Proof of Concept

Phase I III File

x

Registration/Post marktng

xup to 10-20M$

up to 50-100M$ up to 500-1B$

x x 1-10 yrs 2-3yrs 2-4 yrs 1 yr

x

Transfer Process to Manufacturing

Build Facility

II

Research (Inc. Immunology)

Preclinical Development (Inc. Formulation Science)

Clinical Development (Inc Post Marketing Surveillance

Vaccine/Drug Development Model

Stage 1a Discovery per se

Stage 1b Transitional research

Stage 1c Non-regulated

Non-clinical research

Stage of Development:A. Discovery and Pre-clinical Stages

B. Clinical Phases/stagesi. Phase Iii. Phase IIiii. Phase IIiv. Phase IV

Stage 1a: Discovery per se• Researcher/scientist identifies a possible new

vaccine/drug candidate• Identifying signs that a compound may have a

therapeutic potential• Idea come from:

• Direct observation• Scientific literature• Knowledge of traditional practices• Systematic screening

• Unlikely the research progress smoothly; researcher meet many dead ends and may collect inconclusive results

Stage 1b: Transitional research• Researcher tries to characterize the active

pharmaceutical ingredient (API)

• Investigate on how to produce and analyze the API

• Biological experimentation to investigate its actions in cells, tissues or the whole body

Stage 1c: Non-regulated, non-clinical research• Biological tests on subcellular systems, tissues

and/or animals provide evidence for efficacy – i.e. ‘proof of principle’ (POP)

• Rigorously controlled studies with biological models• Indicates whether the compound is biologically

active• Whether it is likely to be efficacious in man

• A sufficient supply of well-characterized test compound has to be ensured

Example

Stage 1a Discovery per se

Stage 1b Transitional research

Stage 1c Non-regulated

Non-clinical research

A researcher knows that a population

traditionally uses a local herb to alleviate an affective disorder. But the herb contains dozens of interesting compounds of which several might be the

active principle

Isolation of the most promising API,

further exploration of the biological activity in cell, tissues and/or

animal model. Methods of

producing and analyzing the

compound

Receptor binding studies and animal behavioral models are most useful for

establishing potential for efficacy

Clinical trial of Malaria vaccine

Animal modelsSafety, immunogenicity, tolerability, efficacy

Safety, immunogenicity, tolerability

Non-immune human volunteers in non-malarious areas. Clinical setting

Human volunteers. Experimental challenge with infected mosquitos.Clinical setting

Phase IIa: non-immune volunteersPhase IIb: Immune volunteersVaccine efficacy, safety, tolerability, acceptance

Semi-immune residents of malarious areas (all endemicities). Small target population, special groups.Natural challenge

Semi-immune residents of malarious areas.Large target population, whole communitiesNatural Challenge

Vaccine efficacy, safety, tolerability, acceptance

Vaccine efficacy, safety, tolerability, acceptance, vaccination strategy, effectiveness

PHASE 0Preclinical

PHASE 1Clinical

PHASE IIClinical

PHASE III

PHASE IV

Developing any vaccine is hard

Can take 10-20 years to develop a product. Cost hundreds of millions of dollars

Phase 3 Phase 2

Phase 1aPre-clinicalLaboratory

Phase 1b

Malaria: Plasmodium Life Cycle

Liver Stage

Blood Stage

Sporozoites

Merozoites

Gametocytes

Malaria: Plasmodium Life Cycle

Liver Stage

SporozoitesPre-erythrocytic

Stage

Pre-erythrocytic stage, that is the stage that takes place shortly after being bitten by an infected mosquito up to and including the liver stage.

Pre-erythrocytic stage, that is the stage that takes place shortly after being bitten by an infected mosquito up to and including the liver stage.

Pre-erythrocytic Stage Vaccines• How they work:

• Generates Ab response against sporozoites and prevents them from invading the liver

• Prevents intra-hepatic multiplication by killing parasite-infected hepatocytes

• Intended Use: • Ideal for travelers - protects against

malaria infection

Malaria: Plasmodium Life Cycle

Blood Stage

Merozoites

Asexual Erythrocytic

Stage

Asexual Erythrocytic Stage Vaccines• How they work:

• Elicit antibodies that will inactivate merozoites and/or target malarial Ag expressed on RBC surface

• Inhibit development of parasite in RBCs• Intended Use:

• Morbidity reduction in endemic countries

Malaria: Plasmodium Life Cycle

Gametocytes

SexualStage

Sexual Stage Vaccines• How they work:

• Induces Ab against sexual stage Ag• Prevents development of infectious

sporozoites in salivary glands of mosquitoes• Prevent or decrease transmission of parasite

to new hosts• Intended Use:

• Decreased malaria transmission

Vaccine Portfolio

Ad5 CSP/LSA/TRAP

DevelopmentManufacture

Pre-ClinicalEvaluation

Phase 1+/- Challenge

Phase 1bendemic

Phase 2bendemic Phase 3

AMA-1Cin ISA 720

MSP-2in ISCOM

PvR IIin AlOH

PvR IIin ASO2

MSP-2in ISA 720

RTS,Sin ASO1

RTS,S in ASO2

Pfs-16

MSP-5

Ad5 MSP-AMA 1

MSP-4

LSA-1in ASO1

LSA-1in ASO 2

MSP-1Cin Alum-CPG

CP2.9in ISA 720

AMA-1in ASO1

AMA-1in ASO2

RTS,S in ASO2

RTS,S vaccine - Pre erythrocytic vaccine• Hybrid containing the central repeats

and most of the C-terminal of the CSP fused with hepatitis B surface antigen

• Complex adjuvant mixture AS02• Completely protected six out of seven

volunteers • Field study in The Gambia showed good short-term

protection• A clinical trial in Mozambique and Tanzania showed

delay of infection and reduction in incidence of severe malaria in young children

• The vaccine advanced to Phase III trial.

Efficacy in Double Blind Phase

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

29.9%

95% CI 11-45

p = 0.004

ATP analyses

Pro

port

ion

Cohort 1

0.00

0.01

0.08

0.07

0.06

0.05

0.04

0.03

0.02

Severemalaria

Hospitalizedmalaria

57.7%

95% CI 15-79

p = 0.019

32.3%

95% CI 1-54

p = 0.053

Rate

Exploratory cohort 1

0

1

2

3

4

5

6

7

Infection

44.9%

95% CI 31-56

p < 0.001

Even

ts

Cohort 2

Control

RTS,S/AS02

Clinical Malaria

Challenges for Malaria Vaccine

• Four antigenetically distinct malaria species• Each has ~6,000 genes• First gene only identified in 1983

• Immunity in malaria is complex and immunological responses and correlates of protection are incompletely understood.

• Identifying and assessing vaccine candidates takes time and is expensive

• There is no clear ‘best approach’ for designing a malaria vaccine

Asante Sana