malarial vaccine
TRANSCRIPT
MALARIA VACCINE
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)
INTRODUCTION
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.
Malaria vaccine initiative (MVI)
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.
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MVI mission, vision, and goal
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
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
PROBLEMS IN DEVELOPING MALARIA VACCINE
Circum-sporozoite
protein (CSP)
1. Liver stage antigen 1(LSA-1)
2. Liver stage antigen 3 (LSA-3)
1.MSP-12. MSP-23. MSP-34. AMA-15. SRA
6. GLURP7. EBA-175
8. RESA
Pfs25Pfs28
Pfs48/45Pfs230
Malaria antigens
1. Pre-erythrocytic vaccines2. Blood stage vaccines3. Transmission blocking vaccines4. Anti disease vaccines
Types of malaria vaccine
Classification of malaria vaccineStage of plasmodium
Antigens Salient features
Pre-erythrocytic Irradiated sporozoites , Circum Sporozoite Protein (CSP) or peptides, Liver stage Antigens -1 (LSA-1)
Stage/species specific; antibody blocks infection of liver; large immunising dose required; can abort an infection
Merozoite and Erythrocytes
Erythrocyte Binding Antigen (EBA-175), Merozoite Surface Antigen 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
Pre- Erythrocytic Stage Vaccines 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
Pre- erythrocytic stage:that is the stage that takes place shortly after being bitten by an infected mosquito up to and including the liver stage.
Asexual Erythrocytic Stage Vaccines
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
Sexual Stage Vaccines
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
Anti-disease Vaccines
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
Vaccine formats
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
spf66 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
Csp 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
NYVAC - Pf. 7 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
NANP 19-5.1
RTS,S /AS02 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
DNA Vaccine
VACCINATING MOSQUITOES 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.
Thank you.