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Table of Contents   
REVIEW ARTICLE  
Year : 2013  |  Volume : 6  |  Issue : 3  |  Page : 274-279
Malaria vaccine: A myth or a reality


Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India

Click here for correspondence address and email

Date of Web Publication7-Nov-2013
 

   Abstract 

Malaria is a common parasitic disease caused by Plasmodium spp. and transmitted by anopheles mosquito. Every year several million people are affected and killed due to this infection in the endemic regions of the world. Recently, drug resistance to the common antimalarial drugs has pressurized upon the development of an effective vaccine for the elimination of malaria along with other control measures. A number of vaccine trials are in the pipeline. Indeed, some were proven to have potential efficacy as therapeutic vaccine. We searched all the articles in heading malaria vaccine, recent advances in malaria vaccine, review on malaria vaccine, efficacy trials on malaria vaccine published in pubmed and google website and, review the current status and the unresolved challenges regarding malaria vaccine.

Keywords: Malaria, Plasmodium spp., vaccine

How to cite this article:
Mohapatra S. Malaria vaccine: A myth or a reality. Ann Trop Med Public Health 2013;6:274-9

How to cite this URL:
Mohapatra S. Malaria vaccine: A myth or a reality. Ann Trop Med Public Health [serial online] 2013 [cited 2020 Jan 23];6:274-9. Available from: http://www.atmph.org/text.asp?2013/6/3/274/120982

   Introduction Top


Malaria is thought to be one of the leading causes of mortality and morbidity worldwide. It is caused by any of the five species of plasmodium, i.e. P. falciparum, P. vivax, P. ovale, P. malarae, and P. knowlesi. Out of these, P. falciparum and P. vivax are most widely distributed and cause maximum host suffering. P. falciparum is the most deadly amongst the five causing more than 95% of malarial death followed by P. vivax. As per the WHO report, 600,000-900,000 deaths reported in 2009 were due to malaria alone. [1] Early diagnosis and prompt treatment are the two main life-saving tools for this infection. Due to the procurement of good interventional strategies (such as artesunate combination therapy (ACT), antimalarial insecticide-treated mosquito net (ITN)), the incidence of malarial cases in the endemic areas of Africa was declared to be reduced by 50%. [2],[3] Later on the incidence was found to be static or increased in other areas of Africa and regions like Amazonia. [3],[4] There are several explanations for these observations. But the most important reason is the emergence of resistance to artesunate compounds. It is proven that P. falciparum acquire and spread resistance very quickly. More ever, chloroquine which is used for the treatment and prophylaxis of malaria is found to be resistant by both P. falciparum and P. vivax. So with the failure of malarial control program, an effective vaccine remains the main avenue for control, elimination, and eradication of malaria in conjunction with antimalarial drugs and vector control. Here we reviewed the literatures available regarding the current status of malaria vaccine and its challenges. All the articles about recent advances in malaria vaccine, reviews on malaria vaccine, efficacy and pipeline trials on malaria vaccine, pre-erythrocytic vaccine, blood stage vaccine, gametocyte stage vaccine, etc. in pubmed and google website were searched and compiled.


   The Parasite's Life Cycle Top


Malaria is transmitted by female anopheles mosquito. The life cycle of Plasmodium spp. is completed in two hosts which gives several clues for interruption. The disease is acquired when female anophiline mosquito bites injecting sporozoites into blood. The sporozoites take around 60 min to reach the hepatocytes. Once it reaches inside the hepatocytes, it undergoes asexual multiplication forming merozoites. This amplification takes place for about 1-2 weeks. Some merozoites (hypnozoites in P. vivax and P. ovale) stay within the hepatocyte causing relapses. Release of merozoites into the blood stream is the end of the pre-erythrocytic cycle. The merozoites from the hepatocyte immediately invade the erythrocytes and continue asexual amplification forming trophozoites, schizonts, and merozoites. With the rupture of schizonts, various parasitic components are released into blood and the illness begins with different signs and symptoms. Some of the merozoites develop into male and female gametocytes and are picked up by the mosquito during blood meal. In a mosquito, the exflagellation occurs. The fusion of male and female gametes forms the zygote, which further develops to ookinete and oocyst in the midgut of the mosquito. From the oocyst, several sporozoites will develop and migrate to the salivary glands of the mosquito.


   Immunological mechanisms at various stages of the life cycle Top


The three stages play a major role in the pathogenesis of malaria, i.e. the pre-erythrocytic cycle (free sporozoites and liver stages), erythrocytic cycle (trophozoites, schizonts, and merozoites), and the gametocytic cycle. Both humoral and cell-mediated immune responses play a role in the induction of immunity in malaria. Sporozoite is the first stage, which stays in blood for up to 60 min. Pre-existing antibodies against sporozoite can bind and block the invasion into hepatocytes. It has been observed that about 90% of volunteers achieved sterile protection when injected with irradiated sporozoites. [5],[6],[7] With the start of liver stage, the infected hepatocytes become the prime targets for CD4 and CD8 T cells. The malarial antigens which are expressed on the surface of the hepatocytes along with the MHC molecules are targeted by these cells. Several mechanisms were described for the clearance of infected hepatocytes out of which necrotic cell death, apoptotic cell death, death due to NK cell by antibody-dependent cell cytotoxicity (ADCC), release of cytokine (e.g. IFNγ and nitric oxide) leading to death, etc. are common. [8] Merozoites are of the free stage and liable to bind with the pre-existing antibody. This leads to opsonization and clearing of the parasite by neutralization or phagocytosis. RBCs do not possess major histocompatibility complex (MHC) molecules. Hence, antibody-mediated opsonization (ADCC) is the main mode of defence during the erythrocytic stage.


   Targets of malaria vaccine Top


Sporozoites and merozoites are the two free stages targeted for malaria vaccine development. Vaccines trials are in the pipeline targeting antigens of pre-erythrocytic stage, erythrocytic stage, sexual stage, and malarial toxins. Vaccines designed against erythrocytic stage antigens mainly reduce the severity of disease. Hence, it is otherwise known as an anti-disease vaccine. The vaccines targeting the sexual stage are able to produce antibodies against antigens on gametes/zygotes/ookinetes, which further block the development of malaria parasite in the mosquito. These are called transmission-blocking vaccines.

Vaccine candidates from the different phases of the plasmodium life cycle

Sporozoite

  1. Circumsporozoite antigen (CSP)
  2. Thrombospondin-related anonymous protein (TRAP)
  3. Sporozoite threonine and asparagine-rich protein (STRAP)


Merozoite

P. falciparum

  1. Merozoite surface antigen (MSP)-1, 2, 3, 4, and 5
  2. Erythrocyte binding antigen (ERA)-175
  3. Apical membrane antigen (AMA)-1
  4. Rhoptry-associated protein (RAP)-1 and 2
  5. Acidic-basic repeat region (ABRA)


P. vivax

  1. Merozoite surface protein-1
  2. Apical membrane antigen-1
  3. Duffy-binding protein (DBP)


Liver stage

  1. Liver stage antigen (LSA)-1 and 3
  2. Sporozoite and liver stage antigen (SALSA)
  3. Sporozoite threonine and asparagines rich protein (STRAP)


Blood stage

  1. Ring erythrocyte surface antigen (RESA)
  2. Serine rich protein (SERP)
  3. Erythrocyte membrane protein (EMP)-1, 2, and 3 Glutamate rich protein (GLURP)


Sexual stage

Pfs48/45, Pfs230, Pfs40, Pfs16, Pfs10, Pfs25, Pfs28, Pvs25

Toxins

Glycophospatidyl inositol (GPI)


   Malaria Vaccine Technology Roadmap Top


Thus, we do not have any malaria vaccine and the picture of an effective malaria vaccine in the pipeline is also not clear so far. Several bottlenecks in the development of malaria vaccine have been postulated. These are extensive antigenic variation of parasite from place to place, genetic polymorphism, complex life cycle (completed in two hosts), lack of lifelong immunity, multiple stages of development, lack of proper animal model, etc. Hence, the strategic goal of vaccine technology is to develop and license a malaria vaccine that has a protective efficacy of more than 80% against clinical disease and lasts longer than 4 years. However, the milestone of vaccine development is to develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts longer than 1 year. [9]


   Pre-Erythrocytic Stage Vaccine Top


In the early 1960, Nussenzweig et al. first performed the experiment for immunization of animals with the bites of mosquitoes infected with irradiated sporozoites. [10] The animals were found to be protected against challenge with infectious sporozoites. This was the benchmark in the field of high level (>90%) sterile protection. Later on, this experiment was extended to human volunteers, which showed high-grade protection. Several studies and animal models proved that an effective sporozoite vaccine not only gives protection by clearing the sporozoites, but they also induce an immune response that would prevent sporozoite from further amplification. [8] Despite such high sterile protection against malaria, this vaccine remained ill popular because of its complex method of preparation and vaccination through mosquito bite. But with this experiment, the identification of circumsporozoite (CS) protein was made, which put forward light in the path of malaria vaccine development.

Circumsporozoite protein

This protein has a molecular weight of 40-66 kDa and expressed on the surface of sporozoites. It is present in all the Plasmodium spp. It has a central area of repeated amino acid sequences, which are highly immunogenic and varies from strain to strain. A number of studies showed that immunization with CSP induces adequate T-cell response (CD8 cell and CD4 cell) and antibody-dependent protection. [8] Hence, it was found to be an excellent candidate for malaria vaccine.

Thrombospondin-related anonymous protein (TRAP)

TRAP is located on the surfaces and micronemes of sporozoites and lasts upto first 4 days in the liver stage. It has a molecular weight of 90 kDa. It generates humoral as well as cytotoxic T-lymphocyte response in rodent models. It is mainly used in multi antigen constructs.

Liver stage antigen-1

Liver stage antigen-1 is another surface antigen having molecular weight of 230 kDa. This antigen is actively synthesized throughout the liver schizogony. Some studies have shown that there is a 9-aminoacid peptide region with association with HLAbw53. [11],[12] This region protects from severe malaria. [11],[12] Hence, this is considered as an ideal target for vaccine preparation.

RTS,S malaria vaccine

The reality of malaria vaccine in the near future remains a big question mark. However, with the discovery of CSP, a great hope was made for the successful build of malaria vaccine. After an effective vaccine for hepatitis B, Rutgers et al. at Glasko-Smith-Kline (GSK) in collaboration with WRAIR (Walter Reed Army Institute of Research) implemented a similar type of hypothesis for malaria vaccine preparation. They used hepatitis B surface antigen (HBs Ag) as a carrier molecule for P. falciparum CS protein. This would increase its immunogenicity and achieve a high level of protection against malaria. This new formulation of CSP is popularly known as RTS,S vaccine. [13],[14] RTS,S is a recombinant protein consisting of CSP from the P. falciparaum strain NF54, clone 3D7 and hepatitis B surface antigen. [15] The CSP of this strain is composed of an N-terminal region (RI), a central area of repeated aminoacids NANP (N: asparagines, A: alanine, P: proline (approx. 41 repeats) and a C-terminal region (RII). The N terminal of CSP (R1) is highly conserved and contains a motif of 5 amino acids. [16] It binds with the heparin sulfate proteoglycans. This region is shared by most of the mammalian sporozoites and is responsible for the invasion into the mosquito salivary gland and hepatocytes. [17],[18] The central region of CS protein is an immunodominant region for the B-cell epitope. The RII region is the C terminal flanking region containing last 16 NANP repeats. The C terminal binds with 25% of the total HbS antigen. It contains both B- and T-cell epitopes and is highly variable from species to species. So, the final composition of RTS,S comprised of 25% fusion protein RTS (B-cell epitope + T-cell epitope + HBsAg (S) antigen) and 75% wild-type HBsAg(S) antigen. After vaccination, the central region of the RTS,S vaccine induces antibodies formation protecting from P. falciparum infection. However, this vaccine does not give any protection from the clinical disease (signs and symptoms). [15]

RTS,S along with adjuvant

Unlike the conventional hepatitis vaccine, RTS,S alone was not found to be immunogenic. Hence, several adjuvants (adjuvant series (AS)) were planed and developed by the GSK group. Around 11 different adjuvants were tested in animals for their immunogenicity. In Stoute's trial, RTS,S along with adjuvant AS02 confers significant protection in 85.7% (6/7) of volunteers. [19],[20] Adjuvant AS02 is made up of monophosphoril lipid A (MPL) and QS21. QS21 is a saponin derivative derived from the bark of a plant. Because of its hydrophobic nature, it allows the slow and sustained release vaccine component to into the immune system. [21] Several field trials had been conducted to see the efficacy of this vaccine in adult as well as in pediatric population. The other variables which are included in studies are bed net use, geographical area, and distance from the health center. [22],[23],[24],[25],[26] The outcome of the vaccine efficacy is also calculated in terms of time to event analysis, i.e. severity of disease, first malarial infection, multiple clinical episode, etc. So this vaccine is targeted toward achieving partial protection to most of the vaccines rather than complete protection to few. [27] Overall protection of RTS,S with adjuvant ASO2 was 40-57.3% and found to be more efficacious in low malaria transmission areas. [15] Afterward, RTS,S vaccine was tested in Kenya and Tanzania among 5-17 months of infants with a new formulation of adjuvant AS01B (termed as AS01E). [28] The antibody titer against hepatitis B in all the trials was found to be optimum to reach the protection level. Moreover, in some studies it was co-administered along with the DPT and Hib vaccine. RTS,S vaccine showed its efficacy without altering the seroconversion of other vaccines. [29],[30],[31] So the end result of the phase II study of RTS,S vaccine was proven to be more efficacious low-malaria-transmission areas which can protect a specific group of population (targeting infants and children only). A double-blind randomized multicentric malaria vaccine trial (Phase III) was going on in 11 clinical trial sites involving 7 countries and 16,000 children. [32] The primary objective of the phase III trial was to see the efficacy of this vaccine against clinical malaria. The secondary objectives were to see the efficacy against severity, duration of protection, requirement of booster dose, etc. The study of phase III will end in 2012. However, as per the result of phase II, the RTS,S vaccine was proved to be a better vaccine for preventing clinical and severe malaria rather than giving complete protection.


   Erythrocytic Stage Vaccine (Blood Stage Vaccine) Top


The vaccine against blood stage antigens of the parasite is found on erythrocyte after leaving hepatocytes (i.e. merozoites, schizonts, and trophozoites). Since RBCs lack MHC molecule, the predokinant mode of action of vaccine is the antibody mediated by inactivation of the free merozoites or the antigens expressed on the surface of RBCs. Hence, these vaccines serve as a selfish vaccine reducing the disease signs and symptoms of the vaccine, but does not completely protect from disease or its transmission.


   Merozoite Surface Protein Top


Merozoite surface protein (MSP) is one of the predominant constituents of merozoite. It consists of several proteins out of which MSP-1, MSP-2, MSP-3, and MSP-6 are important. [8],[33] MSP-1 is a 195 kDa protein, which helps the parasite to invade into the RBC surface. [8] Mice were immunized with MSP-1 (derived from P. yoelii) found to be protected against malarial infection. [34] Although other proteins (MSP-2 and MSP-3) were immunogenic, but do not induce sufficient immunity alone. [8],[35] Hence, they are used as candidate antigens of cocktail vaccine. Sequence diversity is the main drawback of all these surface proteins. [36] Recently, pfMSP6 (Plasmodium falciparum merozoite surface protein6) was proven to be a potential candidate for blood stage vaccine. [37] After several epidemiological study, it was concluded that the sequence diversity of pfMSP6 was conserved there is no intra-allelic class sequence variation. [37]


   Erythrocyte Binding Antigen Top


Erythrocyte binding antigens are group of proteins present on the surface of merozoite and have a major role in erythrocyte invasion. [8] Their presence is served as a ligand to attach the merozoites with the specific receptors of RBCs. [38] Among the different EBAs, EBA-175, EBA-140, and EBA-181 were found to have a major role in RBC invasion. [39],[40],[41] Studies showed that patients with malaria infection have raised IgM and IgG antibodies against these antigens. [42] These antibodies are mainly responsible to protect from clinical symptoms and severe malaria. Therefore, they were proven to be helpful for the protection of symptomatic patients rather than prevention of infection. [42]


   Apical Membrane Antigen-1 Top


Apical membrane antigen-1 helps the parasite to bind with the erythrocytic surface allowing further growth. It is 83 kDa and a leading antigen for vaccine preparation. It consists of three domains (domain I, domain II, and domain III) out of which domain III is the most immunogenic and has a major role in binding. [43],[44],[45],[46] Studies showed that antibodies against this region are protective, preventing the invasion of merozoites into RBC. Several challenges with parasite-derived and recombinant AMA-1 achieved a high level of protection successfully in different animal models. [47],[48]

Other blood stage antigens which are being used for malaria vaccine are serine erythrocyte ring antigen (SERA), ring erythrocyte surface antigen (RESA), etc. Although most of the antigens proved to be good in animal models, antigenic variation is the main limitation of these vaccines. However, these groups of antigen will be more useful in combination with a preventive vaccine, i.e. with the pre-erythrocytic vaccine.


   Transmission Blocking Vaccine Top


As the name suggest, this group of vaccine prevents the transmission by inhibiting the parasitic development in the mosquito. The antigens targeted here are present on the surface of gamete, zygote, or ookinete. [49] During the intake of blood meal, antibodies (formed after vaccination) were taken up by the mosquito along with the malaria parasite. These antibodies prevent the sporogonic cycle in mosquito and thereby block further transmission. Both antibody and complement-mediated immune response are responsible for the action of this vaccine. It does not protect the individual who received the vaccine per se, but would prevent further transmission of disease to another person. Thus, it will be effective in eliminating malaria in the low transmission area. For P. falciparum, Pfs25, Pfs48/45 and Pfs230 and for P. vivax, Pvs25, Pvs48/45, and Pvs230 antigens are in the pipeline of vaccine trial. Pfs25 is the first sexual antigen to be cloned. This is highly conserved and completely blocks the parasitic development in the midgut of mosquito. Antigenic polymorphism is the major drawback of these targets. However, among the antigens of P. vivax, Pvs230 was found to be highly conserved and suggested as a better candidate for vaccine trial. [50] Transmission blocking vaccine strategy (which protects the mosquito not the human) is difficult to develop and implement. Firstly, we need sufficient levels of antibody in the patient's blood, which inhibit the mosquito cycle and secondly has no role in the prevention or symptomatic relief in the vaccine. Hence, this will be more popular and useful if a combination of pre-erythrocytic vaccine using the CSP region will be combined to transmission-blocking vaccine. [51]


   Summary Top


Although a number of vaccine trials are going on worldwide, we do not have any registered malaria vaccine. The recombinant subunit vaccine (RTS,S) is the only vaccine entered into the phase-III trial. But rethinking of the criteria regarding this vaccine has already started. The vaccine approach can be improved by using other approaches like DNA vaccination (pre-erythrocytic and blood stage antigens), using viral vectors (Adeno virus, Vaccinia, etc.), recombinant proteins with blood stage antigen. Polymorphism of the target antigens remains the main limitation in designing malaria vaccine. Despite the drawbacks, we are still hopeful for a better malaria vaccine which will not only give protection but also symptomatic relief.

 
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43.Hodder AN, Crewther PE, Matthew ML, Reid GE, Moritz RL, Simpson RJ, et al. The disulfide bond structure of Plasmodium apical membrane antigen-1. J Biol Chem 1996;271:29446-52.  Back to cited text no. 43
    
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Correspondence Address:
Sarita Mohapatra
Pool Officer, Department of Microbiology, A.I.I.M.S., New Delhi 110029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1755-6783.120982

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    Abstract
   Introduction
    The Parasite's L...
    Immunological me...
    Targets of malar...
    Malaria Vaccine ...
    Pre-Erythrocytic...
    Erythrocytic Sta...
    Merozoite Surfac...
    Erythrocyte Bind...
    Apical Membrane ...
    Transmission Blo...
   Summary
    References

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