Review work on vaccine development towards malaria parasite

Presented BY

SWARNENDU BASAKDEPARTMENT OF ZOOLOGY

VISVA-BHARATI

General Introduction Malaria is one of the most important and tropical parasitic disease

especially in Africa.

Causative agent- protozoan parasite Plasmodium sp.

Four species of plasmodium, including P. falciparum (responsible for high mortality), P. vivax , P. ovale, P. malariae.

In the year 1973 pre-erythrocytic (sporozoite) vaccine develop from P. falciparum, protection sustained for 7 months (species specific but not strain specific).

Theree types of potential malaria vaccine, each attacking a different stage of their life cycle, include pre-erythrocytic, blood stage vaccine, transmission blocking vaccine.

RTS,S/AS02 has reached the stage of phaseIII clinical trials.

What is vaccine?

A biological preparation or combination which is work as stimulating agent and provides an active acquired immunity to a particular disease.

Vaccine consists of some agent that resembles a disease-causing micro-organism, weakened or killed form of microbe, its toxins or one of its surface proteins.

Vaccine is used for stimulation of immune system for future recognition of these agents as a pathogen finally destroy it and keep a record of it .

Life cycle of Plasmodium sp.

SPOROZOITE

LIVER STAGE

ASEXUAL STAGE

SEXUAL STAGE

ANOPHELES MOSQUITO Vaccine

Candidate

CSP, SSP2

CS, TRAP, EXP-1, LSA-1 , LSA-3

MSP-1, MSP-2, MSP-3, AMA-1

Pfs-25, Pvs-25

Malaria Vaccine Target

Pre erythrocytic vaccine Pre-erythrocytic vaccine strategies aim to generate an

antibody response able to neutralize sporozoites and prevent them from invading the hepatocyte, as well as to elicit a cell-mediated immuneresponse able to interfere with the intra-hepatic multiplication cycle of the parasites.

CD4+ and CD8+ cytotoxic T cells (CTL), NK T cells have been implicated in such a control .

CSP vaccine RTS,S/AS02A DNA vaccine and live recombinant vaccine.

RTS,S This candidate vaccine was developed by Glaxo Smith

Kline (GSK) in collaboration with the Walter Reed Army Institute of Research (WRAIR).

Composition- The C-terminus (amino acids 207–395) of the CSP

from P. falciparum fused to the hepatitis B surface antigen and expressed in the form of virus-like particles (VLPs) in Saccharomyces cerevisiae.

Initial Phase I clinical trials of RTS,S formulated with GSK AS02 adjuvant, showed protection against malaria challenge in six out of seven volunteers.(trials in the Gambia demonstrated )

The RTS,S candidate vaccine has continued in partnership with PATH MVI, at phase-III study efficacy of RTS,S/AS02 at preventing a first malaria attack in 1–4 years old children was about 30% .

Other DNA and live recombinant vaccine

Based on CSP antigen include plasmid DNA vaccine and live recombinant vaccines that use (MVA),(FPV), Adenovirus, Sindbis virus, yellow fever virus or a cold-adapted attenuated influenza virus strain as a vector.

vaccine was tested in a “proof-of-concept” Phase I study carried out by the US Navy Malaria Program. The vaccine elicited cell-mediated immune responses but only modest antibody responses and no protection against experimental challenge in human volunteers .

Multiple –antigen DNA vaccine Encode five different liver-stage antigens:

CSP, liver stage antigens 1 and 3 (LSA-1 and -3), exported protein 1 (EXP1), and the sporozoite surface protein 2(TRAP).

Induction of IFN-Ƴ secreting CD4+ and CD8+T-cell responses .

ASEXUAL BLOOD STAGE VACCINE

A number of parasite protein including MSP-1, MSP-2, MSP-3, AMA-1, GLURP transiently accessible to circulating antibodies and other responses.

MSP-1, MSP-2 AND RESA combination

o This vaccine combined the merozoite surface proteins MSP-1 andMSP-2 with P. falciparum ring-stage infected-erythrocyte surface antigen (RESA) in a Montanide adjuvant formulation.

o A Phase I/IIb trial in 5–9 years old children in

Papua New Guinea showed a 62% reduction in parasite density.

AMA-1/MSP-1 chimera Developed by the Second Military Medical

University in Shanghai in partnership with the WHO

A chimeric fusion of domain III ofAMA-1 and

the 19-kD portion of MSP-1 called P. falciparum chimeric protein 2 (PfCP-2.9).

efficiently block parasitic growth

GLURP VACCINE

GLUP present on parasitophorous membrane of mature schizont .

Induce ADCC pathway.

Transmission blocking vaccine

induce antibodies against the sexual stage antigen.

Prevent the development of infectious sporozoite in salivery gland of anopheles mosquito.

Protect communities from infection not individually.

Develop from P. falciparum ookinete surface antigens.

Pfs25

After vaccination secondary immune response

 After vaccination

secondary immune response

Antigen

MP DC

APC cell NK

CD-4 T

CELL

MHC II MHC I

CTL

INF-Ƴ

B CEL

L

IgG-2aIgG-3

Ag-Ab mediatedkilling

Production of NOS

NO

KILL

CD-8 T CELL

IL-4

B CEL

LIgG-1 , IgG-2h,

IgG-2

IL-16

T CELL REGULATOR

OR SUPPRESSOR

IL-10

TNF-α

IL-β

FAS

FADD

CASPASE APOPTOSI

S

after vaccination secondary immune

response of erythrocytic pathway

same pathway like pre-

erythrocytic vaccine pathway

Antibody produce IgG-2a,

IgG-3, IgG-2, IgG-2h

Ag-Ab mediated killing

Blocking interaction of endothelial cell receptor

CD-36 with CIDR region of EMP-1, Antibody binds with CIDR region cause cytoadhesion blocking

NK CELL

.

Infected RBC

FC REGIO

N

NK CELL

FC RECEPTOR

ADDC

Conclusion An ideal malaria vaccine should be safe, highly

effective, and provide long-term immunity, besides being stable, easy to administer.

We hope in near future successful low expensive malaria candidate vaccine can be developed which will affordable in all endemic countries.

References • Egan, J.E., Hoffman, S.L., Haynes, J.D., Sadoff, J.C., Schneider, I., Grau,

G.E. et al. Humoral immune responses in volunteers immunized with irradiated Plasmodium falciparum sporozoites. Am. J. Trop. Med. Hyg., 1993, 49, 166–173

• Hoffman, S.L., Goh, L.M., Luke, T.C., Schneider, I., Le, T.P., Doolan, D.L.,et al. Protection of humans against malaria by immunization withradiation-attenuated Plasmodium falciparum sporozoites. J. Infect. Dis., 2002, 185, 1155–1164

• Smith, T.A., Leuenberger, R., Lengeler, C. Child mortality and malaria transmission intensity in Africa. Trends Parasitol., 2001, 17, 145–149.

• Gonzalez-Aseguinolaza, G., de Oliveira, C., Tomaska M, Hong S,Bruna-Romero O, Nakayama T, et al. Alpha-galactosylceramide activated Valpha 14 natural killer T cells mediate protection againstmurine malaria. Proc. NatlAcad. Sci., 2000, 97, 8461–8466.

• Bojang, K.A., Milligan, P.J., Pinder, M., Vigneron, L., Alloueche, A., Kester, K.E., et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia:a randomised trial. Lancet., 2001, 358, 1927–1934.

• Walther, M., Thompson, F.M., Dunachie, S., Keating, S., Todryk, S., Berthoud, T., et al. Safety, immunogenicity, and efficacy of prime-boostimmunization with recombinant poxvirus FP9 and modified vaccinia virus Ankara encoding the full-length Plasmodium falciparum circumsporozoite protein. Infect. Immunl. 2006, 74, 2706–2716.

Thank you