Dr.

Ruqaiyah
 One of the oldest known diseases.
 40% of the world’s population lives in endemic areas.

 WHO, estimates that there are 350 - 500 million cases

of malaria worldwide.

 1.5-2.7 million deaths (90% Africa)

 Increasing problem (re-emerging disease)

resurgence in some areas
drug resistance (↑mortality)
 Malaria kills in one year what AIDS kills in 15 years.
 For every death due to HIV/AIDS there are about 50
deaths due to malaria.
 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.
  Mission: To accelerate the
development of malaria
vaccines and ensure their
availability and accessibility
in the developing world
 Vision: A world free from
malaria
 Goal: To develop by 2025 a
malaria vaccine with 80% or
greater efficacy that lasts
for at least four years

MVI was established in 1999 as a program of PATH,

an international nonprofit organization that creates sustainable,
culturally relevant solutions, enabling communities worldwide to
5
break longstanding cycles of poor health.
 Difficult to grow in artificial medium
 Mutation of parasites
 Antigenic variation
 Multiple antigens
 Lack of suitable animal model
 Lack of effective adjuvants
 Lack of proven delivery system
 Lack of volunteers & expense in carrying
trials
 1.MSP-1
Circum- 1. Liver stage Pfs25
sporozoite antigen 2. MSP-2
Pfs28
protein (CSP) 1(LSA-1) 3. MSP-3
4. AMA-1 Pfs48/45
2. Liver stage
5. SRA
antigen 3 Pfs230
6. GLURP
(LSA-3)
7. EBA-175
8. RESA
1. Pre-erythrocytic vaccines
2. Blood stage vaccines
3. Transmission blocking vaccines
4. Anti disease vaccines
Stage of Antigens Salient features
plasmodium
Pre-erythrocytic Irradiated sporozoites , Circum Sporozoite Stage/species specific; antibody
Protein (CSP) or peptides, Liver stage blocks infection of liver; large
Antigens -1 (LSA-1) immunising dose required; can
abort an infection
Merozoite and Erythrocyte Binding Antigen (EBA-175), Specific for species and stage;
Erythrocytes Merozoite Surface Antigen 1&2 (MSA-1&2) Cannot abort an infection;
; Ring Infected Erythrocyte Surface Antigen Prevents invasion of
(RESA); Serine Repeat Antigen (SERA); erythrocytes, thus reducing
Rhoptry Associated Protein (RAP); Histidine severity of infection
Rich Protein (HRP); Apical Membrane
Antigen-1 (AMA-1)
Gametocytes & Pfs 25, 48/45k, Pfs 230 Prevents infection of mosquitoes;
gametes 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 SPf 66 (based on pre-erythrocytic and Based on incorporation of
(cocktail) asexual blood stage proteins of Pf) antigens from different stages
into one vaccine to produce an
immune response, blocking all
stages of the parasite
development
 How they work:
◦ Generates Ab response against sporozoites and prevents them
from invading the liver
◦ Prevents intra-hepatic multiplication by killing parasite-infected
hepatocytes
 Intended Use:
◦ Ideal for travelers - protects against malaria infection
 How they work:
◦ Elicit antibodies that will inactivate merozoites and/or target
malarial Ag expressed on RBC surface
◦ Inhibit development of parasite in RBCs
 Intended Use:
◦ Morbidity reduction in endemic countries
 How they work:
◦ Induces Ab against sexual stage Ag
◦ Prevents development of infectious sporozoites in
salivary glands of mosquitoes
◦ Prevent or decrease transmission of parasite to new
hosts
 Intended Use:
◦ Decreased malaria transmission
 Aim: To reduce pathological consequences of infection

 In highly endemic areas older children often present with high

parasitemia & little evidence of clinical disease.

 TNF-α causes clinical manifestations, so vaccines directed

against TNF inducing Ags may be effective in preventing
pathological consequences.
1. Attenuated whole parasites
◦ Deliver a vast array of antigens
◦ Multiepitope vaccine

2. Sub-unit vaccines
◦ Polyvalent, multicomponent vaccine
◦ Targeting different protiens in different stages
◦ Recombinant antigens or long synthetic peptides
1. Whole cell sporozoite vaccine
◦ Using inactivated sporozoites
◦ 1910 – avian malaria
◦ 1941- fowls
◦ 1967- mice
◦ 1970s- human volunteers
 Limitation- precise irradiation

Genetically attenuated parasites

 P.berghei- with deletion UIS3, UIS4, P36p
 P.falciparum- with deletion of p52, p36
 The first vaccine developed that has undergone field trials
 Developed by Manuel Elkin Patarroyo in 1987.
 It presents a combination of antigens from the sporozoite (using CS
repeats) and merozoite parasites.
 During phase I trials a 75% efficacy rate was demonstrated and the
vaccine appeared to be well tolerated by subjects and
immunogenic.
 The phase IIb and III trials were less promising, with the efficacy
falling to between 38.8% and 60.2%.
 Despite the relatively long trial periods and the number of studies
carried out, it is still not known how the SPf66 vaccine confers
immunity
 Based on the circumsporoziote protein, but additionally has
the recombinant protein covalently bound to a purified
Pseudomonas aeruginosa toxin (A9).

 A complete lack of protective immunity was demonstrated in

those inoculated at early stage.

 The study group used in Kenya had an 82% incidence of

parasitaemia whilst the control group only had an 89%
incidence.

 Intended to elicits a cellular response enabling the

destruction of infected hepatocytes was also not observed
  Blocks transmission of the parasite from vertebrate host to mosquitoes.
 The highly attenuated NYVAC vaccinia virus strain has been utilized to
develop a multiantigen , multistage vaccine candidate for malaria.
 Genes encoding seven Pf antigens derived from the
1. sporozoite (CSP and sporozoite surface protein 2),
2. Liver (liver stage antigen 1),
3. blood (merozoite surface protein 1, serine repeat antigen, and apical
membrane antigen 1),
4. sexual (Pfs25 , 25-kDa sexual-stage antigen)
 inserted into a single NYVAC genome to generate NYVAC-Pf7.
 safe and well tolerated.
 Specific antibody responses against four of the P. falciparum antigens
were characterized during 1a clinical trial. ( CSP,PfSSP2,MSP1,Pfs25)
 Shizont export protein (5.1)
 19 repeats of sporozoite surface protein
(NANP)
 Low immunogenicity
 Does not contain any T-cell epitopes
 Most recently developed recombinant 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.
 Adjuvant- emulsion of oil in water and the added adjuvants of
monophosphoryl A & QS21
 the vaccine gave 7 out of 8 volunteers challenged with P.
falciparum protective immunity
 Removing sections of DNA from parasitic genome

 Inserting into vector (plasmid,DNA viral

genome,liposomes, proteoliposomes)

 When plasmid is inoculated, DNA sequence is

incorporated into host DNA

 Protein synthesised- expressed on cell surface of

infected cells

 Bind to HLA molecule and produce memory T-cells

 In mosquitoes, there are proteins on the surface of
gametes and ookinets that may prove useful in
formulating a vaccine that protects mosquitoes from
infection.

 Antibodies to these proteins prevent the parasite from

taking up residence in the mid-gut of mosquitoes and
forming oocysts. However, in order for such vaccines to
reach mosquitoes they must be combined with efforts
to vaccinate people living in endemic areas.
 "It is now clear that administering the PfSPZ
Vaccine intravenously confers long-term,
sterile protection in a small number of
participants, which has not been achieved
with other current vaccine approaches," said
principal investigator of the trial Robert Seder
from National Institute of Allergy and
Infectious Diseases (NIAID), part of the US
National Institutes of Health.