This document discusses malaria, its transmission by mosquitoes, and the various Plasmodium species causing the disease. It emphasizes the urgent need for malaria vaccines, outlines current vaccine development strategies, and highlights challenges such as antigenic variation and the complexities of immune response. The document also details specific vaccine candidates, such as RTS,S and VMP001, and the international efforts to enhance vaccine efficacy and accessibility.

1. Presented by-
Nayan Gupta
M.G.M Medical college, Indore

2. Malaria vaccines are an area of intensive research.
 Malaria is a protozoan disease caused by Plasmodium species
of the phylum Apicomplexa.
 Transmitted by the bite of infected female anophelese
mosquitoes.
 It is characterized by periodic paroxysm with shaking chills,
high fever, heavy sweating.
oFour species of Plasmodium cause malaria in human.
 P. vivax (benign tertian malaria)
 P. ovale (benign tertian malaria)
 P. malariae (quartan malaria)
 P. falciparum (malignant tertian malaria)

3.  According to WHO fact sheet on malaria report
 In 2014, 97 countries and territories had ongoing
Malaria transmission.
 3.3 billion people are at risk of malaria {1.2 billion
at high risk}
 Disease burden in 2013
 Total 198 million cases of malaria worldwide
 Estimated 584000 deaths [90 percent in Africa] in
which approx. 4 lakh African children died before
their fifth birthday due to malaria

5.  Shortfalls of control measures and continuing prevalence
of malaria, the focus has shifted
 WHO identified vaccines as a cost effective method to
reduce the burden of this disease
 Artimisinin based Combination Therapy (ACT) has
limiting factors:
limited knowledge on safety in pregnancy,
and the imbalance between demand and supply
Recently WHO has recommended that a ban be placed
on oral artimisinin bases monotherapies due to emergence
and spread of drug resistance.

6.  International Health organization have developed a
global strategy or plan for accelerating the development
and licensing of a highly effective malaria vaccine .
 This plan is known as Malaria Vaccine Technology
Roadmap.
 Developing and licensing a first-generation vaccine by
2015 with 50 percent protective efficacy against severe
disease and death.
 Developing a malaria vaccine by 2025 that would have a
protective efficacy of mare than 80 percent against
clinical disease and that would provide protection for
longer than 4 years

9. Preerthyrocytic phase
 Hepatocyte invasion
 Direct anti sporozoite
 Direct anti hepatozoite
How they work:
Generates Ab response against sporozoites and
prevents them from invading the liver
Prevents intra-hepatic multiplication by killing
parasite-infected hepatocytes

10. Targets
 Anti host erythrocyte
 Binding of merozoite in to host erythrocyte
 Invasion of merozoite in erythrocyte
 Antibody mediated cellular inhibition of parasite
How they work
 Erythrocytic stage vaccine Elicit antibodies that will
inactivate merozoites and/or target malarial Ag
expressed on RBC surface
 Inhibit development of parasite in RBCs

11.  Targets
 Anti gametocyte
 Antibodies blocking fertilization
 How they work:
 Induces Ab against sexual stage Ag
 Prevents development of infectious sporozoites in
salivary glands of mosquitoes
• Not give any protective benefits to the individual
inoculated
• Prevent further transmission of the parasite by preventing
the gametocytes from producing multiple sporozoites in the
gut wall of the mosquito.

12.  Prevent the infection at the first instance and if
this is not possible, should decrease the intensity
of infection.
 Reduce the clinical disease severity.
 Should be successful in preventing or reducing
the malaria transmission.

13.  Difficulty of evaluation
 Parasite’s ingenious ways of avoiding host’s
immune response
 Complexity of conducting clinical and field trials
 Antigenic variations e.g. MSA-I has 8 variants,
MSA-2 has 10 and CSP has 6 variants
 Multiple antigens, specific to species and stage

14.  P. falciparum has a very high degree of antigenic variation,
making it difficult for the immune system to recognize malaria.
 P. falciparum has two different ways for variation in antigen
which they express.
 The first way in which this might occur is during the sexually
reproducing stage in the lifecycle when P. Falciparum
recombines genetic material. This has unlimited potential to
change the genome of P. Falciparum.
 The second way in which antigenic variation can occur is
through variable genes and point mutations during asexually
reproducing stages of the lifecycle. P. Falciparum o has several
families of variable antigenic genes.
 These are var family, the rosettin/ rif family, and the p60 family.

15. Pre erythrocytic phase
 Circum sporozoite protein [CS Protein]
 TRAP- Thrombospondin Related Adhesion Protein
 LSA-1 – Liver Stage Antigen 1
Erythrocytic phase
 SERA- Serine Repeat Antigen
 EBA175- Erythrocyte Binding Antigen
 AMA1- Apical Membrane Antigen
 MSP1 & 3- Merozoite surface protein
Sexual Stage
 Pfs 25, pfs 30

16.  The Plasmodium circumsporozoite protein (CS) is
expressed during the sporozoite and early liver stages
of parasitic infection.
 This protein is involved in the adhesion of the
sporozoite to the hepatocyte and invasion of the
hepatocyte.
 Anti-CS antibodies have been shown to inhibit
parasite invasion and are also associated with a
reduced risk of clinical malaria.
TRAP- expressed both on the surface of sporozoites and
within infected hepatocytes

17. • MSP-1
 expressed from the onset of schizogony and is involved in
erythrocyte invasion by merozoites.
 Anti-MSP-1 antibodies have also been associated with
decreased risk of clinical malaria.
 IgG induction is more important for MSP1 than cell
mediated
effector responses
• MSP-3
 associated with reduced disease via antibody dependent cell
mediated inhibition (ADCI).

18. • AMA-1
 also associated with erythrocyte invasion by merozoite
• EBA175
 also blood stage antigen that aids binding of the
merozoite to host erythrocytes
• SERA5
 blood stage antigen is expressed during the trophozoite
and schizont stages.

19.  involve ookinete antigens; Pfs25 from P. falciparum and
Pvs25 from P. vivax.
 Pfs25 is expressed on the surface of zygote and
ookinete form of parasite.
 Monoclonal antibodies directed against native Pfs 25
can block completely the development of Plasmodium
Falciparum oocyst in the midgut of the mosquito vector.

20.  PfSPZ: metabolically active, non-replicating malaria
sporozoite vaccine.
 A biotech company has developed an approach using
injection of metabolically active, non-replicating whole
P. falciparum sporozoites thawed from long-term storage
in liquid nitrogen.

21.  Recombinant protien- based malaria vaccine
 The RTS,S attempted by fusing the protein CPS with a
surface antigen from Hepatitis B, hence creating a more
potent and immunogenic vaccine.
 5 different types of adjuvants used in the formulation
RTS,S AS01, AS02, AS03, AS04 and Alum.
 RTS,S/AS01E – most advanced candidate malaria vaccine,
is the only one in Phase 3 evaluation
 The EMA approved the RTS,S vaccine in july 2015, with a
recommendation that it be used in Africa for babies at risk
of getting malaria
 RTS,S was the world first malaria vaccine to get approval
for this use.

22. VMP001/AS01B
 VMP001/AS01B is currently the only vaccine in
clinical evaluation that is designed to protect
against P. vivax.

23. MVI is working with the International Centre for Genetic
Engineering and Biotechnology (ICGEB) in New Delhi,
India, to develop a vaccine against Plasmodium vivax.
This development effort includes Bharat Biotech
International Ltd. (Hyderabad), which will manufacture
the vaccine for preclinical testing followed by initial
safety trials in adults.
Vaccine is ChAd63/MVA Pv DBP

24.  Polymorphism and clonal variation in antigens of
plasmodium
 Parasite induced immuno-suppression
 Intracellular parasites

25.  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

26. Stage of plasmodium Antigens Salient features
Pre-erythrocytic Irradiated sporozoites , Circum Sporozoite Protein
(CSP) or peptides, Liver stageAntigens -1 (LSA-1)
Stage/species specific; antibody blocks
infection of liver; large immunising
dose required; can abort an infection
Merozoite and
Erythrocytes
Erythrocyte BindingAntigen (EBA-175), Merozoite
SurfaceAntigen 1&2 (MSA-1&2) ; Ring Infected
Erythrocyte Surface Antigen (RESA); Serine Repeat
Antigen (SERA); Rhoptry Associated Protein (RAP);
Histidine Rich Protein (HRP); Apical Membrane
Antigen-1 (AMA-1)
Specific for species and stage;Cannot
abort an infection; Prevents invasion of
erythrocytes, thus reducing severity of
infection
Gametocytes &
gametes
Pfs 25, 48/45k, Pfs 230 Prevents infection of mosquitoes;
antibody to this antigen prevents either
fertilization or maturation of
gametocytes, zygotes or ookinetes; is of
use in endemic areas but not suited for
travelers; antibody blocks transmission
cycle
Combined vaccine
(cocktail)
SPf 66 (based on pre-erythrocytic and asexual
blood stage proteins of Pf)
Based on incorporation of antigens from
different stages into one vaccine to
produce an immune response, blocking
all stages of the parasite development

28.  Several antigens expressed during the blood stream and
liver stage of P. falciparum have been shown to elicit an
immune response in humans.
 The study showed that liver stage antigen 3 was highly
immunogenic and a good candidate for use in a vaccine
to prevent the invasion of RBC by P. falciparum.
Immune memory of the antigens (especially LSA3)
lasted up to 9 months when tested in chimpanzees.

29. 1. L, Schwartz and B, Graham.(2012). A Review of Malaria Vaccine
Clinical Projects Based on the WHO Rainbow Table. Malaria
Journal 11.11.
2. Global_malaria_vaccine_pipeline_2014March
3. Rainbow_Table_Detailed_Version_January2015, given by WHO
4. "PATH Malaria Vaccine Initiative: The need for a vaccine." PATH
Malaria Vaccine Initiative. N.p., n.d. Web. 28 Nov. 2012
5. http://www.medscape.com/viewarticle/717152_1-4
6. Wikipedia
7. Malaria vaccine http://www.slideshare.com
8. WHO | Malaria. (n.d.). Retrieved from
http:// www.who.int/mediacentre/factsheets/fs094/en/
9. Guidance by:- Dr. Manish Purohit sir