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.