Sunteți pe pagina 1din 14

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 Vaccine Efficacy tested progress
candidate
glycophosphatidylinositol (GPI)- MSPI(42- Ellis et al in 2010 recorded a 49 fold increase in antibody titre Phase1
anchored proteins 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
Peripheral surface proteins 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

Microneme proteins released onto AMAI- 54% increase in IgG Absfrom volunteers showed reactivity Phase 1
merozoites surface 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 Efficacy


Multi antigenic Whole organism: chemically in vivo mice immunized with Blood stage malaria parasites
attenuated with seco‐cyclopropyl pyrrolo indole (CPI)
attenuated Pf asexual blood stage induce robust T cells offered complete protective immunity
parasites in the recipient mice (Reiman et al., 2018)

PRBCs Model applied in ascertaining immunogenicity and safety


of PfRBCs, IFN-γ and TNF, and CD3+CD45RO+ memory T
cells

Multi allele Combination B: compose of Phase II


MSP1, MSP2 and RESA Significant reduction in parasitaemia
absorbed in ISA720 adjuvant Genton et al., 2002)

multistage NYVAC-PFT: combination of Phase II


CSP, SSP AND LSAI from Poor antibody response
preerythrocytic stage, MSP1, >90% increase in cellular respone
AMA1 and SERA from Delay time to parasite patency
erythrocytic stage and Pfs25
from mosquitoe sexual stage
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
• Genton B, Betuela I, Felger I. A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective
pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis. 2002;185:820–827
• Ockenhouse CF, Sun PF, Lanar DE, Wellde BT, Hall BT, Kester K, Stoute JA, Magill A, Krzych U, Farley L, Wirtz RA, Sadoff JC, Kaslow DC, Kumar
S, Church LW, Crutcher JM, Wizel B, Hoffman S, Lalvani A, Hill AV, Tine JA, Guito KP, de Taisne C, Anders R, Ballou WR
• J Infect Dis. 1998 Jun; 177(6):1664-73. Bernstein, A., Pulendran, B., Rappuoli, R. (2011) Systems vaccinomics: the road ahead for
vaccinology.15(9):529-31.
• Cousens S. B. and Druilhe, C. P .( 2011). Protection against malaria by MSP3 candidate vaccine New Engl J Med 365(1062):4
• Douglas, A. D. et al. A PfRH5-based vaccine is efficacious against heterologous strain blood-stage Plasmodium falciparum infection in aotus
monkeys. Cell Host. Microbe. 17, 130–139 (2015).
• Ellis, R. D, Martin L. B, Shaffer, D., Long, C. A, Miura, K., Fay, M.P., Narum, D. L, Zhu D., Mullen, G. E., Mahanty, S., Miller, L. H., Durbin, A. P.
(2010). Phase 1 trial of the Plasmodium falciparum blood stage vaccine MSP1(42)-C1/Alhydrogel with and without CPG 7909 in malaria
naïve adults. PLoS One; 5(1):e8787
• James G. Beeson, Damien R. Drew, Michelle J. Boyle, Gaoqian Feng, Freya J.I. Fowkes, Jack S. Richards; Merozoite surface proteins in red
blood cell invasion, immunity and vaccines against malaria, FEMS Microbiology Reviews; 40(30): 343-372
• Malkin, D. J., Diemert, J. H., McArthur,J.R., Perreault,A. P. Miles,B.K. Giersing, G.E., Mullen, A., Orcutt,O, Muratova, MA., Hong, Z.J.,
Wang,A., Stowers,C.A.,. Long,S.T., Louis H.M., Allan, I and Anna P. Durbin, M. (2005). Phase 1 Clinical Trial of Apical Membrane Antigen 1: an
Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria. American Society for Microbiology 73(6): 3677–3685
• Malkin, D. J., Diemert, J. H., McArthur,J.R., Perreault,A. P. Miles,B.K. Giersing, G.E., Mullen, A., Orcutt,O, Muratova, MA., Hong, Z.J.,
Wang,A., Stowers,C.A.,. Long,S.T., Louis H.M., Allan, I and Anna P. Durbin, M. (2005). Phase 1 Clinical Trial of Apical Membrane Antigen 1: an
Asexual Blood-Stage Vaccine for Plasmodium falciparum Malaria. American Society for Microbiology 73(6): 3677–3685
• McCarthy, J. S., Marjason, J., Elliott, S., Fahey, P., Bang, G., Malkin, E., Tierney, E., Aked-Hurditch, H., Adda, C., Cross, N., Richards, J. S.,
Fowkes, F. J., Boyle, M. J., Long, C., Druilhe, P., Beeson, J. G., … Anders, R. F. (2011). A phase 1 trial of MSP2-C1, a blood-stage malaria
vaccine containing 2 isoforms of MSP2 formulated with Montanide® ISA 720. PloS one, 6(9), e24413.
• Osier, F. H., Mackinnon, M. J., Crosnier, C., Fegan, G., Kamuyu, G., Wanaguru, M., Ogada, E., McDade, B., Rayner, J. C., Wright, G. J., …
Marsh, K. (2014). New antigens for multicomponent blood-stage malaria vaccine. Science translational medicine, 6(247): 247ra102.
• Ouattara, A., Barry, A. E., Dutta, S., Remarque, E. J., Beeson, J. G., & Plowe, C. V. (2015). Designing malaria vaccines to circumvent antigen
variability. Vaccine, 33(52), 7506-12.
• Reiman, J. M., Kumar, S., Rodriguez B. M., Gnidehou, S., Ito, K., Stanisic, D., Lee, M., McPhun, V., Majam, V. and Willemsen, N. M.(
2018) Induction of immunity following vaccination with a chemically attenuated malaria vaccine correlates with persistent antigenic
stimulationclinical and translational immunology 7(4) .
• Srinivasana, P. E., Ababacar, E., Michelle, D., Kazutoyo, L.T. Martin, M., Boulangerc , J., Longa , C. A. Narumb D, and Millera, L.H.
Immunization with a functional protein complex required for erythrocyte invasion protects against lethal malaria 111(28):10311–10316.
Thank you for listening