Course code and Title: PAR 707:

Current topics on the control of

malaria

Seminar Topic: Progress in the Development of

blood stage vaccine against malaria

NGONG INNOCENTIA NJI

(SC18P290)

Lecturer: Prof. ACHIDI E.

March, 2019
 outline
• Introduction

• Antigens explored in production of blood stage

malaria vaccine

• Mechanism of action of blood stage vaccine

candidates

• Current blood stage vaccine development

• Challenges face in the development of blood stage

malaria vaccine

• Development of blood stage vaccine to target

antigenic polymorphism
 Introduction

The schizonts burst,

producing the
characteristic fever In 48hrs, mitotic replication, progressing
cycle thus clinical an average of 16 new daughter
manifestations. merozoites per schizont.

begins with the rupture of

liver schizonts, releasing some merozoites,
thousands of merozoites into develop into
gametocytes bringing
the blood
to end the cycle in the
some of the merozoites, instead of producing new definitive host
merozoites, develop into gametocytes bringing to end the
cycle in the definitive host (Beeson et al., 2016).
(Beeson et al., 2016).
 Introduction
• The eythrocytic stage of the plasmodium life cycle is responsible for the symptoms
experienced in malaria

• in the erythrocyte, numerous known and unknown waste substances such as

hemozoin pigment and other toxic factors accumulate in the infected red blood cell

• . These are dumped into the bloodstream when the infected cells lyse, stimulating
macrophages

• cytokines and other soluble factors which act to produce fever and rigors or even
death (CDC, 2019).

• Thus a vaccine at this stage is aimed at inhibiting erythrocyte invasion and reducing
symptoms. Because completely blocking merozoites replication is almost imposible.
Antigens explored in production of blood stage malaria vaccine
•merozoite surface proteins,
tethered with
glycophosphatidylinositol
(GPI)-anchored proteins,
integral membrane proteins or
as peripherally-associated
proteins

contained within
organelles known merozoites
as rhoptries and

•micronemes at the apex of the

merozoite. (Beeson et al., 2016).
 candidates explored in production of blood stage malaria vaccine
• Serim repeat antigen-SERA;
enables the parasite to fully utilize
the whole age repertoire of
circulating erythrocytes Houang et
al., 2013) • Apical memebrabe antigen-
AMAI; Mitchel et al., 2004)
• Rhoptry associated protein-
RAP (Ghosh et al., 2017)

• Erythrocyte bind
protein- EBA
175
• Merozoite P f E M P – 1,
surface antigen Pf332,
1 and (Beeson
et al., 2016). Rosettin,
• Ring infected erythrocyte
RAP and AMAI
surface antigen-RESA;
prevents further invasion
of already infected cell
and protects against
thermal damage Pei et
al., 2007)
Mechanism of action of blood stage vaccine
 Inhibition of
merozoites invasion
into erythrocytes
through glycoprotein
A e.g EBA-175.

 Inhibition of
merozoites invasion
into erythrocytes
 Inhibit merozoites through band A anion
interaction with exchanger of RBCs)
RBCs e.g. AMAI e.g MSP 1
Current blood stage vaccine development
Location of protein
glycophosphatidylinositol
anchored proteins
Peripheral surface proteins
Microneme proteins released onto AMAI-
merozoites surface
Vaccine Efficacy tested progress
candidate
(GPI)- MSPI(42- Ellis et al in 2010 recorded a 49 fold increase in antibody titre Phase1
C1/ALHYDROGE 2weeks after inoculation of 30 malari-naïve adults. Thus
L) optimal Ab respone but protection and durability not
guaranteed
MSP2 (McCarthy et al.2011) : induction of Ab reponse that mediated Phase
ADCI. problems with reactogenity with variable adjuvants thus I/IIb
require further refinement
MSP3 Complexex Reduction in incidence upon immunization with MSP3 as Phase 1
With MSP1 compared to control group. Short term protection against
clinical malaria (Cousens and Druilhe)
PfRH5 Induced Abs and conferred protection against a virulent Phase 1
heterologous Pf challenge. In vivi testing revealed expression
of 10different Pf Ags with ability to induce IgG Abs that were
able to recognize naïve malaria parasite assessed by IFA
54% increase in IgG Absfrom volunteers showed reactivity Phase 1
C/alhydrogel. with schizonts of Pf (malkin et al., 2005)
Combine with
protein base gene
FVO and 3D7
AMAI-RON2 In vivo mice model revealed induction Ab mediated complete Preclinical
infection against lethal P. yoelli. If successful in animals, this phase
will be a solution to overcome antigenic polymorphism.
(srinivasan et al., 2014)
Challenges face in the development of blood stage malaria vaccine

Antigenic polymorphism
of both merozoites as well as
infected erythrocyte surface
proteins.

Overwhelming number of merozoites

from each hepatocyte

Rapid time of RBC invasion

Redundancy in the merozoite invasion pathways including

both sialic acid-dependent and sialic acid-independent
pathways, (Satchwell et al.., 2016)
Vaccine candidates targeting antigenic polymorphism of MP

The development of a single broadly efficacious

vaccine regimen containing all the antigenic variants
known to be most prevalent in the target populations
will be a step ahead to tackle antigenic polymorphism
of MP

advances in bioinformatics, genomics and the

availability of the parasite genome have employed
new approaches for the production of diverse malaria
vaccine candidates (Ouattara et al., 2015).

Production of multti-allel, multi-antigen or multi-

stage vaccines
Vaccine candidates targeting antigenic polymorphism of MP
Strategy Vaccine cnadidate
Multi antigenic Whole organism: chemically
attenuated Pf asexual blood stage
parasites
PRBCs
Multi allele Combination B: compose of
MSP1, MSP2 and RESA
absorbed in ISA720 adjuvant
multistage NYVAC-PFT: combination of
CSP, SSP AND LSAI from
preerythrocytic stage, MSP1,
AMA1 and SERA from
erythrocytic stage and Pfs25
from mosquitoe sexual stage
Efficacy
in vivo mice immunized with Blood stage malaria parasites
attenuated with seco‐cyclopropyl pyrrolo indole (CPI)
induce robust T cells offered complete protective immunity
in the recipient mice (Reiman et al., 2018)
Model applied in ascertaining immunogenicity and safety
of PfRBCs, IFN-γ and TNF, and CD3+CD45RO+ memory T
cells
Phase II
Significant reduction in parasitaemia
Genton et al., 2002)
Phase II
Poor antibody response
>90% increase in cellular respone
Delay time to parasite patency
 conclusions
• Vaccine development for blood stage plasmodium parasite are
directed toward merozoite proteins which are very diverse in
antigenicity thus making success in the development of vaccine at
this stage very challenging.

• Many of these proteins have been accessed either in clinical trial

phase I or II yet efficacy and durability has not been established

• Due to these challenges, new techniques have been developed to

enable the production of multivalent antigens , multi stage or multi
allele vaccine cocktails to overcome the problem of antigenic
polymorphism.
 References
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