Research: Malaria Vaccine and Development

1
Research Malaria Vaccine and Development

• Baraka Amuri
• Ifakara Health Institute (IHI)

2
Presentation Outline

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

3
Research Development
Identify Antigens
Produce Antigens
Test in Animals
Proof of Concept
Phase I
III
File
Registration/Post marktng
II
Research (Inc. Immunology)
Preclinical Development (Inc. Formulation Science)
Clinical Development (Inc Post Marketing
Surveillance
Transfer Process to Manufacturing
Build Facility
x
x
up to 10-20M
up to 50-100M
up to 500-1B
x
x
x
1-10 yrs
2-3yrs 2-4 yrs ? 1 yr
4
Vaccine/Drug Development Model

• Stage of Development
• Discovery and Pre-clinical Stages

• Clinical Phases/stages
• Phase I
• Phase II
• Phase II
• Phase IV

5
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

6
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

7
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

8
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
9
Clinical trial of Malaria vaccine
PHASE 0 Preclinical
Safety, immunogenicity, tolerability, efficacy
Animal models
Non-immune human volunteers in non-malarious
areas. Clinical setting
PHASE 1 Clinical
Safety, immunogenicity, tolerability
Human volunteers. Experimental challenge with
infected mosquitos. Clinical setting
Phase IIa non-immune volunteers Phase IIb
Immune volunteers Vaccine efficacy, safety,
tolerability, acceptance
PHASE II Clinical
Semi-immune residents of malarious areas (all
endemicities). Small target population, special
groups. Natural challenge
Vaccine efficacy, safety, tolerability, acceptance
PHASE III
Vaccine efficacy, safety, tolerability,
acceptance, vaccination strategy, effectiveness
Semi-immune residents of malarious areas.Large
target population, whole communities Natural
Challenge
PHASE IV
10
Developing any vaccine is hard
Laboratory
Can take 10-20 years to develop a product. Cost
hundreds of millions of dollars
11
Sporozoites
Gametocytes
Liver Stage
Blood Stage
Merozoites
12
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.
Sporozoites
Pre-erythrocytic Stage
Liver Stage
13
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

14
Asexual Erythrocytic Stage
Blood Stage
Merozoites
15
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

16
Sexual Stage
Gametocytes
17
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

18
Vaccine Portfolio
Pre-Clinical Evaluation
Phase 1 /- Challenge
Phase 1b endemic
Phase 2b endemic
Development Manufacture
Phase 3
Ad5 CSP/ LSA/TRAP
PvR II in ASO2
RTS,S in ASO1
RTS,S in ASO2
LSA-1 in ASO1
RTS,S in ASO2
Ad5 MSP- AMA 1
CP2.9 in ISA 720
PvR II in AlOH
MSP-4
MSP-2 in ISCOM
MSP-1C in Alum-CPG
MSP-5
MSP-2 in ISA 720
LSA-1 in ASO 2
AMA-1C in ISA 720
Pfs-16
AMA-1 in ASO2
AMA-1 in ASO1
19
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.

20
(No Transcript)
21
(No Transcript)
22
Efficacy in Double Blind Phase
Cohort 1
29.9 95 CI 11-45 p 0.004
0.7
0.6
0.5
0.4
Proportion
0.3
0.2
0.1
0.0
Clinical Malaria
ATP analyses
23
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

24

• Asante Sana