Annals of Community Health (ISSN 2347-5455, eISSN 2347-5714), Peer Reviewed, Indexed Journal focusing exclusively on Community Medicine and Public Health

Malaria Vaccines

Plan of presentation

  • Introduction
  • Life cycle of malaria parasite
  • Antigens, immune response, vaccine effects.
  • Difficulties in vaccine research.
  • Steps in Malaria vaccine development
  • Vaccines acting at different stages.
  • vaccines under trial.

Introduction

  • Malaria continues to be a major health problem. It is the most prevalent vector-borne disease in the world. Malaria is estimated to cause up to 500 million clinical cases and 2.7 million deaths each year. The emergence of drug resistance in the malaria parasite and the widespread insecticide resistance of the mosquitoes has increased the burden.
  • Development of a vaccine against malaria is recognized as one of the most promising and cost-effective control measures. Malaria vaccine development has been an active field of research for over 2 decades. Clinical and animal studies have shown that experimental vaccination has some degree of success when using attenuated sporozoites and using the RTS,S/AS01 malaria vaccine candidate.

WHO has identified more than 80 vaccines which are at the preclinical development stage and more than 30 malaria vaccines have entered clinical testing. Malaria vaccine development strategies are based on the complex life cycle of the parasite.

MALARIA PARASITE LIFE CYCLE

Human genetic disorders which is associated with resistance to malaria as in the cases of a and b thalassemia, haemoglobin C, G6PD deficiency, haemoglobin S and haemoglobin E, ABO blood groups (Fya and Fyb).

  • Premunition a state resistance in a infected host, which is associated with continued asymptomatic parasitemia.

Reasons for incomplete protection against malaria:

  • Polymorphism and clonal variation in antigens of plasmodium.
  • Parasite induced immunosuppression.
  • Intracellular parasites.
  • Lack of MS proteins on infected RBCs.

Difficulties in vaccine research

  • Problems in vaccine production including not being able to grow the parasite in large quantities
  • Absence of MHC antigens on the surface of infected RBCs
  • Difficulty of evaluation
  • Parasites’ ingenious ways of avoiding hosts’ immune response
  • Complexity of conducting clinical and field trials
  • Mutation of the parasites .
  • Antigenic variations e.g. MSA-I has 8 variants, MSA-2 has 10 and CSP has 6 variants (Orissa)
  • Multiple antigens, specific to species and stage
  • Difficulty in expressing recombinant products in immunogenic form.
  • Some are large molecules it is difficult to determine which regions would be effective in a vaccine.
  • For TBV some antigens are not expressed in human beings.
  • Pharmaceutical research and development (R&D) is so expensive.
  • Vaccines based on a single antigen have a limited role.
  • Multi-stage, multi-component vaccine, incorporating multi-antigenic sequences from different asexual and sexual stages of plasmodia are effective.
  • Vaccines have been found successful in simian malaria caused by isolated merozoites of P. knowlesi.

Steps in Malaria Vaccine Development

  • Research and development: Identify useful antigens and create vaccine concept, evaluate in animals, and validate product manufacturingProcess.
  • Phase 1 clinical trials: Establish a safe dosage, observe how the product affects the human body, and measure immune response.
  • Phase 2 clinical trials: Monitor safety and potential side effects: measure immune response, measure preliminary efficacy against infection, and determine optimum dosage andschedule.
  • Phase 3 clinical trials: Continue to monitor safety, potential side effects, and efficacy.
    • Licensure: Obtain regulatory approval for distribution.
    • Introduction: Begin vaccine use.
  • Phase 4 clinical trials: Follow up safety monitoring; measure duration of protection and assess public acceptance.

Attenuated sporozoite vaccine

  • Sporozoites have been attenuated (weakened) with irradiation, and injection of such sporozoites provided complete protection.
  • Genetic attenuation of sporozoites is also used to produce mutant strains unable to complete their life cycle.
  • Attenuated sporozoite vaccines are attractive for protection against malaria but difficult and costly to produce on a global scale.

Subunit vaccines

  • Synthetic and genetically engineered sub-unit vaccines are usually based on either of two sporozoite surface proteins: circumsporozoite protein (CSP), and thrombospondin related anonymous protein (TRAP) .
  • The RTS,S vaccines, produced in yeast cells, are made up of the tandem repeat tetrapeptide (R) and the C terminal T-cell epitope (antigenic unit) containing (T) regions of CSP fused to hepatitis B surface antigen (S), plus the unfused S antigen .
  • The vaccine contains an adjuvant.ASO2, oil in water emulsion of the immunostimulants monophosphoryl lipid A and QS-21, a fraction of China bark extract (Quillaia saponara).
  • The RTS,S vaccine is the farthest advanced of the malaria vaccines.

Viral vector vaccines

  • Pre-red cell stage vaccines are based on CSP, TRAP and other liver stage antigens are being developed using viral vector delivery systems.
  • Antigens from the different stages of the parasite were chemically linked to the surface of the virosome to enhance their immune activity.
  • A replication –defective adenovirus strain 35 (Ad35) with chromosome deletions is grown in human embryo cells (PER,C6/55k).
  • P. falciparum CSP is inserted into the viral vector, and placed under the control of a cytomegalovirus promoter and a simian virus 40 terminator signal.
  • The vaccine protected against the liver stages of the parasite as well as the blood stages
  • protein vaccines that do not contain viral or other recombinant nucleic acid sequences are preferable, because there is little risk from horizontal gene transfer and recombination that can create more lethal parasites as well as viral and bacterial pathogens.

Transmission blocking vaccines

  • Vaccines that block transmission of the malaria parasite to human victims have been developed.
  • A recombinant vaccine was produced in yeast that went through a phase I clinical trial and no vaccine-related serious adverse events were observed.
  • A recombinant transmission-blocking vaccine directed at Plasmodium falciparum was produced in the bacterium E. coli.
  • The vaccine Pfs 48/45 contains part of the protozoan proteins 48/45, which required four bacterial folding proteins because the vaccine protein had to be folded properly to elicit antibodies.

Malaria vaccines under trial

C.S.P. Vaccine

Kenyan study concluded that CSP vaccine induced antisporozoite antibody is not protective. Encouraging results have been reported with a CSP-HBs Ag Hybrid Vaccine (U.S. Army and SKB).

NYVAC - Pf. 7

This vaccine 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 Plasmodium falciparum antigens derived from the sporozoite (CSP and SSP 2), Liver (LSA1), blood (MSA 1, SRA, AMA 1), and sexual (25-kDa sexual-stage antigen) stages of the parasite life cycle were inserted into a single NYVAC genome to generate NYVAC-Pf7.
  • Each of the seven antigens was expressed in NYVAC-Pf7-infected culture cells, and the genotypic and phenotypic stability of the recombinant virus was demonstrated. When inoculated into rhesus monkeys, NYVAC-Pf7 was safe and well tolerated.
  • Antibodies that recognize sporozoites, liver, blood, and sexual stages of P. falciparum were elicited.
  • Specific antibody responses against four of the P. falciparum antigens (circumsporozoite protein, sporozoite surface protein 2, merozoite surface protein 1, and 25-kDa sexual-stage antigen) were characterized. The results demonstrate that NYVAC-Pf7 is an appropriate candidate vaccine for further evaluation in human clinical trials.

Recombinant Vaccine

Against P. vivax blood stage infection, a recombinant C- terminal fragment of MSP-1 in block co-polymer adjuvant with T- helper epitopes, the yeast expressed P2 P30 PV20019 recombinant vaccine offers partial protection in Saimiri monkeys.

Combination of malarial antigens with immune boosting adjuvants and hepatitis B surface antigens have been reported. Liver stage vaccine may hold the key to reduce relapse/ re-infections in malaria prone individuals.

Gamete Vaccine

When the antibodies are taken up by the mosquitoes, gametes escaping the RBCs will be neutralised, thus preventing fertilisation and reducing transmission.

DNA Vaccine

Based on a synthetic gene, made by adding 21 epitopes of 9 different antigens present in P. faciparum.

  • Epitopes are small regions in proteins, which are recognised by immune cells.
  • This has been developed by CDC with National Institute of Immunology.
  • Example - Pf 155/RESA (Ring Infected Erythrocyte Surface Antigen).

CDC/NII MLVAC-1

It is a candidate vaccine that codes for nine different antigens that the plasmodium expresses during its development is liver, blood and circulation in the hosts.

The vaccine stood the challenge on rabbit trial.

Patorraya Vaccine (Cocktail vaccine)

  • Based on incorporation of antigens from different stages into one vaccine to produce an immune response, blocking all stages of the parasite development.
  • synthetic or recombinant subunit vaccine such as the synthetic Colombian Malaria vaccine SPf 66. SPf 66 which consists of 3 peptide epitopes from 3 blood stage proteins intercalated with NANP sequence is used.
  • Field trials under both low and high malaria endemicity areas in Latin America and Africa have been carried out, at a dosage of 1 mg for children < 5 years and 2 mg for adults over deltoid on days zero, 30 and 180 days.
  • Results from these studies showed a protective efficacy ranging between 38.8 and 60.2% against Plasmodium falciparum malaria.
  • In Tanzania, the efficacy has been 31% in children (1-5 yrs old), while protective efficacy in Gambia was 8% (in infants 6-11months old).
  • SPf 66 with QS - 21 adjuvant is also undergoing trials.

The RTS, S Candidate Malaria Vaccine

The RTS,S candidate malaria vaccine was created in 1987. Its early development was undertaken by GlaxoSmithKline, in close collaboration with the Walter Reed Army Institute of Research (WRAIR).

RTS,S induces the production of antibodies and white blood cells that are believed to diminish the capacity of the malaria parasite to infect, survive, and develop in the human liver.

  • In addition to inducing partial protection against malaria, the RTS,S vaccine candidate stimulates a protective immune response to hepatitis B.
  • trial of RTS,S, malaria vaccine candidate, is now underway in seven African countries: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania.
  • The candidate vaccine developed by ICGEB in India targets the parasites “Duffy binding protein”.
  • This vaccine is designed to thwart invasion of red cells, it may be able to prevent disease caused by P.vivax.

Side effects: The most frequent serious adverse event was pneumonia, followed by anaemia, and gastroenteritis.Others like joint pain, muscle pain, head ache, and malaise.

Malaria vaccine funders' group

  • WHO, PATH MVI, the Bill & Melinda Gates Foundation
  • Wellcome Trust
  • European and Developing Countries Clinical Trials Partnership (EDCTP),
  • European Malaria Vaccine Initiative (EMVI),
  • European Commission (Directorate General for Research), t
  • United States National Institute for Allergy and Infectious Diseases (NIAID),
  • United States Agency for International Development (USAID)
  • The International Centre for Genetic Engineering and Biotechnology(ICGEB)
  • Government of India.


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