Dr iwalokun presentation_amls_lagosstate_2018

Research in Vaccine Development to
Address Disease of Public Health Importance
in Nigeria: A Case Study of Malaria Vaccine
Dr. Iwalokun, B.A.
NIMR, Lagos, Nigeria

Presentation Overview
• Vaccine
– Action, Benefits, Developmental milestone & Types.
• Global Disease Burden
– Africa and Nigeria perspectives
• Research in Vaccine Development
– Technique evolution & Road Map
• Malaria Vaccine
– Need assessment and requirement
• Malaria vaccine development
• Malaria vaccine research in Nigeria
• Conclusion & Recommendation

A substance used to stimulate the production of antibodies and
provide immunity or protection against one or several diseases,
prepared from the causative agent of a disease, its product or a
synthetic substitute, treated to act as an antigen without inducing the
disease.
A preparation of a killed or weakened microorganism that is given to
a person orally or injected in order to prevent disease.
Edward Jenner (1796-Cowpox inoculation)
Louis Pasteur (1881) coined the name Vaccination and Vaccine
What is a Vaccine?

Edward Jenner –
Small pox (1796)
Louis Pasteur-Vaccinology
George Hilleman-MMR
Polio
The Vaccine Apostles
Robert Koch – TB,
Anthrax, Koch
Postulate-1876

Raises IQ and
improves cognition
function.
Reduces infant and
child mortality and
fertility rate.
Lowers cost of health
care system (6 b
USD saved annually
for treatment.
Improves family
savings (1 billion
USD annually)
Vaccines are the most cost effective public health tools

FIG1. Vaccine Development Milestone

FIG2: Classification of Vaccines

A protein antigen vaccine (part or whole protein) with an
adjuvant : single antigen (AMA1-alum/AS01), dual antigen
(AMA1-MSP1-AS01), triple antigen, multi-antigen (MSP1-
MSP2-RESA-Motanide)
Subunit
A vaccine made from antigenic parts (polysaccharide,
protein, DNA) of an organism in combination with a carrier
protein with or without an adjuvant: Subunit or whole protein,
DNA and conjugate vaccines
Recombinant
Vaccine
A vaccine subcloned in a plasmid or viral vector such as
MVA, fowlpox virus, Vaccinia virus (serotype 5) (e.g LSA-
1&3-MVA)
DNA
A polysaccharide vaccine combined with a carrier protein
(E.g. MenA vaccine)
Conjugate
vaccine
A vaccine made from an organism killed by heat or irradiation
in the lab
Inactivated
vaccine
A vaccine made from a living organism that has been
rendered avirulent in the lab
Live attenuated
Vaccine
DefinitionVaccine Type
Vaccine Definition

SubunitvirusHPVHuman Papilloma virus
SubunitvirusHepBHepatitis B
ConjugateBacteriaHibHaemophilus
influenzae type b
Inactivated
toxin
BacteriaDPTDiptheria
Live,
Attenuated
VirusYellow fever
Live,
attenuated
virusVaricellaChicken pox
SubunitBacteriaAnthrax
TypeTarget
pathogen
Common
name
Vaccine
Over 50 vaccines are currently available globally for commercial use

Live,
Attenuated
BacteriaBCGTuberculosis
Live, attenuatedvirusRotarix,
Rotateq
Rotavirus
Attenuated
(Sabin)
Inactivated
(Salk)
virusOPV, IPVPolio
ConjugateBacteriaMenAfriVacMeningococcal A vaccine
ConjugateBacteriaPCV-7/10/13Pneumococal conjugate
vaccine
SubunitBacteriaWhopping
cough (DPT)
Pertusis
Live, attenuatedvirusMMRMeasles
TypeTarget
pathogen
Common nameVaccine
SOME OF THE VACCINES CURRENTLY RECCOMMENDED FOR USE
GLOBALLY.

A Typical Vaccine schedule implemented by the
National Programme of immunisation of a country.

Despite availability of vaccines, vaccine preventable diseases remain a
major barrier to global health and development.

TB : New Cases per, 100,000 population in the 22 High burden Countries of
the World, 2015

21
Living
with
AIDS
in
Africa
(000s.)
8,500 people
in sub-
Saharan
Africa
contract HIV
every day.

29%
Nigeria with a population of 186 m is a major contributor
to global malaria burden

FIG. Population Projection of countries by 2050. Nigeria will be 6th.
UN Population Division

SDG; A guide to global development in the next 15 years: 2016 –
2030: 17 goals, 169 indicators; 15 years.

We will need an optimally effective health system to achieve SDG 3 by 2030.

Development of a new vaccine a priority
1. To accelerate global reduction in diseases of public health
importance and high DALY
2. To enable the achievement of SDG 3 in many countries of
world by 2030.
3. To foster global economic growth and development
4. To boast human productivity
5. To achieve targets set in
Agenda 2063 for Africa.

Vaccine Development
The process of discovering a vaccine candidate and advancing it through
refinement, production, preclinical and clinical testing to confirm its safety,
tolerability, immunogenicity, efficacy before licensure and subsequent
none for profit or commercial use by the public.

Like drugs, Vaccine
development takes ~ 12 yr

Research (especially at the discovery stage) has become the
most important tool for reducing vaccine development time.

Research:
A systematic way of making scientific and social enquiries with appropriate
methods to generate empirical data analyzed to obtain new information on
which decision is made or strengthened.

Vaccine Development is no longer Business as Usual. Every
Vaccine Development Portfolio must have a Road Map
Roadmap refers to specific action areas in vaccine development: Very
critical for vaccine investment by funders and Phamarceutical Industry and
Public acceptability:
Clinical Trial
Update on global disease burden
Immuno-Epidemiological Surveys
Modelling Vaccine impact
Defining Vaccine Characteristics
Encouraging Vaccine investment
Basic Research: Molecular Epidemiology,
improved diagnostics: genomics,
proteomics, metabolomics, system biology;
Basic Research: immunology,
immunogenetics
Cross-cutting: Mathemathical assumptions;
equations; environmental simulation,
scenarios injections
Preclinical, translational, toxicology,
pharmacogenetics, pharmacokinetics
Implementation research
Clinical Research
Roadmap vs. Research

The Push and Pull Drivers of Vaccine Development.

Evolution of Techniques used in Vaccine Development.
Comparative RV
Louis Pasteur Model
Genetic Engineering
Genomic Technology-Reverse Vaccinology (RV)
Pan Genome RV
•Genome Sequencing
•Bioinformatics
•Epitope prediction (B cell, T cell)
•Vaccine candidate antigen
Vaccinomics
1st Revolution
19th/20th Century
2nd Revolution
20th/21st Century

Vaccinomics
1. A new branch of Bioinformatics for discovering a candidate vaccine
antigen against a pathogen in a lesser time than conventional
Vaccinology (culture-based)
2. It involves the use of Reverse Vaccinology, which entails genome
sequencing, epitope prediction and structural proteomics.
3. Vaccinomics has been used to design vaccines against Malaria,
Anthrax, Endocarditis, Meningitidis (serogroup B), HIV etc
What is Vaccinomics?

Pan Genomic Reverse Vaccinology
Here genomes of different organisms of the same species are compared using
Computational Biology

Comparative Reverse Vaccinology
Comparing pathogenic and non-pathogenic strains of the same species
Hit Lead Vaccine Candidate
FIG. Comparative Genomics Approach for identifying vaccine targets.

Epitopes
Surface protein amino acid sequences of a vaccine candidate antigen.
They can be detected by antibodies and Reverse Vaccinology can also
used to detect them

Epitope Epitope Immune epitope Database &
analysis Resources. (IEDB)
Algorithms: E.g. EpiMatrix, Conservatrix,
Clustimer (Tcell); PREDITOPE, PEOPLE,
BEPITOPE (Bcell)
Immunology
Key Players in B cell and T cell Epitope Mapping

New TB Vaccine developmental pipeline to replace BCG of 1921

Setting Priority is key –The work of the Portfolio
Management Committee
Green = Criteria met; orange = Criteria may be met; red = criteria
cannot be met. So, P1 and P2 should be prioritized

Clinical cases: 214m (149-303m): Afr (88%), SEA (10%), EM (2%)
Death : 438,000 (235,000-635,000): Afr (90%), SEA (7%), EM (2%)
The Malaria Problem – 2015- A need for a malaria vaccine.

Malaria death disparity: Africa remains in big trouble.

Why do we need a malaria vaccine?

Like HIV, malaria is the fourth leading cause of death in Africa
for which no vaccine is available for commercial use.

Defeating malaria will save million of lives and boost
the global economy by 2 trillion USD

663
million
60 37
66% in Africa 44% in Africa
188m
household
sprayed
-IRS
35%
34%
27%
16%
8%
4%
IPTp1
IPTp2
IPTp3
337 m11 mACT
304 m50 mRDT
Roll out
2014/15
Roll out
2001
Inter-
vention
SUFI
LLIN (69%); ACT (21%), IRS (10%)
To Sustain and Accelerate Progress to Eliminate malaria by 2040.

More Scale-Up of LLIN and IPTp-SP is needed to attain 100% ownership
and use and meet the rising population of endemic countries in Sub-
Saharan Africa (e.g. Nigeria)
Funds are limited:
Africa contribution =
800m
Malaria Vaccine
R & D is receiving
improved funding
attention, though still
limited

New Interventions are needed to ward off threat to LLIN ,
ACT, IRS and IPTp efficacy.

Resistance to pyrethroid, carbamate, organophosphates/organochlorides
are spreading rapidly in Sub-Saharan Africa.

Artemisinin Resistance is already a problem in South-East Asia-A
reminder of how CQ and SP resistance emerged and eventually got
to Africa in the 70s and 90s

Kelch 13 gene Polymorphism Concern.

Multiple Haplotypes in 25 nucleotide sequence Entries in UniProt-
impact on Fitness Cost?? And evolution of novel functional SNPs.

The progress to eliminate malaria has stalled: more cases in 2016 (216m) &
serious funding gap (Expectation 6.5b USD /year; Reality 2.7b USD in 2016

To achieve Malaria elimination Vision by 2040.
A malaria free world by 2040

To be able to achieve the milestones and goals set in
the global malaria technical strategy.

WHO has already set the stage for African countries especially
to fight malaria. Act as a referee and gives clues for victory.

FIG. Malaria Elimination Milestone.

What do we need to know to be able to
develop a malaria vaccine?

• 23–27 million bases
• 14 chromosomes
• ~5,500 genes
• Rich in low-complexity regions
• High A+T content
– P. falciparum: 79.6%
– P. vivax: 67.7%
• Immune evasion multigene families located in the
telomere.
• 77% of proteins are conserved.
• Genomics>Functional Genomics or Transcriptomics
• Genomics > Cell Biology (e.g. Maurer’s cleft proteins,
PfEMP1, KAHRP2, Pfhsp70-x etc
74
Understand Plasmodium falciparum Genomic Structure and as
the source of Vaccine targets, Drug targets & Diagnostics.
Expression profile
Liver : LSA1, LSA3, TRAP
RBC: MSP1, MSP2
Mosquito: pfs25, Pfs47/48

1. Maternally inherited
2. No recombination
3. Haploid
4. 3 coding genes
(cytochrome c oxidase 1
(cox1), cytochrome c
oxidase III ( coxIII) &
cytochrome b (cytb)
5. Small size (~6kb)
6. Cellular Process:
1. Membrane potential
2. Heme COQ
synthesis
3. Oxidative
phosphorylation
4. Cytb<Atovaquone
Pf Mitochondria Genome at a glance.

Knowing tha five species of Plasmodium cause malaria in human and P.
falciparum is responsible for over 97% of malaria mortality in Africa.

Knowing that different life forms of malaria parasite exists and P.
falciparum & other species are most susceptible at sporozoite and
merozoite life forms

Each life form presents with distinct antigenic targets.

Plasmodium merozoites.
Each life form presents with distinct antigenic targets.

Knowing that the malaria parasite has a complex life cycle

The different stages of development of the malaria parasite presents the
human immune system with distinct antigens, which are vaccine targets.

Antimalarial drugs do not target sporozoites. But vaccines do.

Understand the mechanisms of immune response to the malaria
parasite.

Protective immunity against the liver stage malaria parasite.

Malaria parasite immune evasion mechanism in the Liver.

Functional Antibodies and Protection Against blood stage parasite.

Is developing a malaria vaccine feasible?

White et al, 2014
The Lancet. 383; 723-735
Yes. Evidence 1: Immunity to malaria is acquired overtime, requiring
repeated parasite bites to attain a state of premunition.

Anti-malarial antibodies against blood stage parasite vary in levels with age

Yes. Evidence 2. Newborns and infants in their first 6 months of life are
often protected from severe and clinical malaria due to acquired
antibodies from their immune mothers.

Yes. Evidence 3a. in the 1970s : Human volunteers immunized with
irradiation attenuated sporozoite are protected by sterilizing immunity
(though short lived) against infection by natural parasite population
Yes. Evidence 3b. Recent research, using genetically modified
Plasmodium parasite (UIS3 defiecient) revealed a possible replication
of the human experiment in rodents.

Yes. Evidence 4. Clinical trials, showing efficacy of experimental
malaria vaccines in infants, children and adults.

What are the strategies for malaria vaccine design?

Malaria Vaccine Strategic Goal by 2025
To develop a malaria vaccine that will be > 80% efficacious in high
risk populations for a minimum of 4 years.
Malaria Vaccine Design strategy 1. Based on life cycle
Anti-
Pfs25/230/47/48
Antibodies.
Kill gametocytes; prevents sexual
reproduction, ookinete development and
sporozoite formation. Blocks tranmission
Transmission
blocking vaccine
(TBV)
Innate, Antibodies,
(e.g. Anti-MSP1,
MSP2, RESA),
CD4 T cells.
Inhibits merrozoite binding & invasion of the
RBC; meroxoite growth inhibition in the iRBC;
inhibit gametocytogenesis; prevents severe
malaria
Erythrocytic
vaccine (WV)
CTL, IFN-y
Anti-CSP
antibodies.
Inhibit sporozoite invasion of the liver
Arrest parasite development in the liver.
Kill infected hepatocytes
Prevent patency & clinical malaria
Pre-erythrocytic
vaccine (PEV)
ImmunityFunctionVaccine Type

Malaria Vaccine Landmark Goal by 2025
To develop a malaria vaccine that will be > 50% protective against
death and clinical malaria in high risk populations for a minimum of
1 year.
Malaria Vaccine Design strategy 2. Based on target population
100%Non-immune children and non-pregnant adultsPEV (whole
sporozoite) + TBV
< 100%Children in malaria endemic settingsPre-erythrocytic
vaccine (PEV) or
EB or both
EfficacyTarget PopulationVaccine Type

Malaria Vaccine Design strategy 3. Based on formulating an ideal malaria
vaccine.
1. Safe
2. Tolerable
3. Stable
4. Cost-effective
5. Immunogenic
6. Efficacious
7. Ease of administration
8. Adaptable to the routine vaccination schedules of the National
Programme on Immunisation (NPI).
9. Not affected by co-administered vaccines.

Laboratory of Malaria Immunology and Vaccinology, Vaccine Development Pipeline
1. Identify disease targets
2. Identify antigens
3. Design the vaccine
4. Characterized the
vaccine. (FFIPS)
5. Conduct preclinical study
(Potency, Safety)
6. Vaccine production (GCP,
cGMP, Sterility, QC).
7. IND Application (FDA,
NAFDAC)
8. Clinical trials 1 - 3) - 10
11.BLA
12.FDA Approval
13.Phase IV

Malaria Vaccine in Clinical Development.

Malaria Vaccine Research Activities in Nigeria: A
Systematic Review
0Cloning, gene-expression,
Bioinformatics
2Immunopathology
0Clinical (Phase 1 – 3)
0Pre-clinical
2Translational
5ImmunoEpidemiology
5Innate immunity
1Pf diversity-Microsatelite level
17Genomics/Vaccine candidate
Gene diversity studies msp1,
msp2, glurp
No. of Publication in
peer reviewed journals
the last 5 years
Research area

Conclusion
• Vaccine Preventable diseases such as rotavirus diarrhea,
pneumonia and tuberculosis remain a major public health challenge
in Nigeria.
• Nigeria also bears significant burden of diseases in dire need of
vaccine for public health use such as HIV and malaria
• Involvement of the country in vaccine development programmes for
malaria, HIV etc is unacceptably poor.
• RTS, S, a pre-erythrocytic stage malaria vaccine is the only
advanced malaria vaccine in phase III clinical trial and ready for pilot
implementation in Ghana, Kenya and Malawi from June, 2018
• Malaria vaccine research at discovery, pre-clinical stages of
development is highly inadequate in the country.

1. Need for immuno-Epidemiological surveys of new vaccine candidates
for malaria, TB and HIV in Nigeria.
2. The county should as a matter or urgency generate updated evidence
on genotypes of rotavirus virus circulating in the country and accelerate
the integration of appropriate rotavirus vaccine into her National
Immunization Programme
3. Need to set up of a National Vaccine Development Plan & Inter-
Agency Collaboration.
4. Need to set up Vaccine Development Steering Committee that will
interface with Regional WHO (PD- VAC).
5. Need to strengthen basic science research in malaria vaccinology and
immunology in Nigeria.
Recommendations

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