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CURRENT STATUS OF MALARIA VACCINOLOGY
In order to assess the current status of malaria vaccinology one must first take an overview of the whole of the whole disease. One must understand the disease and its enormity on a global basis. Malaria is a protozoan disease of which over 150 million cases are reported per annum. In tropical Africa alone more than 1 million children under the age of fourteen die each year from Malaria. From these figures it is easy to see that eradication of this disease is of the utmost importance. The disease is caused by one of four species of Plasmodium These four are P. falciparium, P .malariae, P .vivax and P .ovale. Malaria does not only effect humans, but can also infect a variety of hosts ranging from reptiles to monkeys. It is therefore necessary to look at all the aspects in order to assess the possibility of a vaccine. The disease has a long and complex life cycle which creates problems for immunologists. The vector for Malaria is the Anophels Mosquito in which the life cycle of Malaria both begins and ends. The parasitic protozoan enters the bloodstream via the bite of an infected female mosquito. During her feeding she transmits a small amount of anticoagulant and haploid sporozoites along with saliva. The sporozoites head directly for the hepatic cells of the liver where they multiply by asexual fission to produce merozoites. These merozoites can now travel one of two paths. They can go to infect more hepatic liver cells or they can attach to and penetrate erytherocytes. When inside the erythrocytes the plasmodium enlarges into uninucleated cells called trophozites The nucleus of this newly formed cell then divides asexually to produce a schizont, which has 6-24 nuclei. Now the multinucleated schizont then divides to produce mononucleated merozoites . Eventually the erythrocytes reaches lysis and as result the merozoites enter the bloodstream and infect more erythrocytes. This cycle repeats itself every 48-72 hours (depending on the species of plasmodium involved in the original infection) The sudden release of merozoites toxins and erythrocytes debris is what causes the fever and chills associated with Malaria. Of course the disease must be able to transmit itself for survival. This is done at the erythrocytic stage of the life cycle. Occasionally merozoites differentiate into macrogametocytes and microgametocytes. This process does not cause lysis and there fore the erythrocyte remains stable and when the infected host is bitten by a mosquito the gametocytes can enter its digestive system where they mature in to sporozoites, thus the life cycle of the plasmodium is begun again waiting to infect its next host. At present people infected with Malaria are treated with drugs such as Chloroquine, Amodiaquine or Mefloquine. These drugs are effective at eradicating the exoethrocytic stages but resistance to them is becoming increasing common. Therefore a vaccine looks like the only viable option. The wiping out of the vector i.e. Anophels mosquito would also prove as an effective way of stopping disease transmission but the mosquito are also becoming resistant to insecticides and so again we must look to a vaccine as a solution Having read certain attempts at creating a malaria vaccine several points become clear. The first is that is the theory of Malaria vaccinology a viable concept? I found the answer to this in an article published in Nature from July 1994 by Christopher Dye and Geoffrey Targett. They used the MMR (Measles Mumps and Rubella) vaccine as an example to which they could compare a possible Malaria vaccine Their article said that "simple epidemiological theory states that the critical fraction (p) of all people to be immunised with a combined vaccine (MMR) to ensure eradication of all three pathogens is determined by the infection that spreads most quickly through the population; that is by the age of one with the largest basic case reproduction number Ro. In case the of MMR this is measles with Ro of around 15 which implies that p> 1-1/Ro » 0.93 Gupta et al points out that if a population of malaria parasite consists of a collection of pathogens or strains that have the same properties as common childhood viruses, the vaccine coverage would be determined by the strain with the largest Ro rather than the Ro of the whole parasite population. While estimates of the latter have been as high as 100, the former could be much lower. The above shows us that if a vaccine can be made against the strain with the highest Ro it could provide immunity to all malaria plasmodium " Another problem faced by immunologists is the difficulty in identifying the exact antigens which are targeted by a protective immune response. Isolating the specific antigen is impeded by the fact that several cellular and humoral mechanisms probably play a role in natural immunity to malaria - but as is shown later there may be an answer to the dilemma. While researching current candidate vaccines I came across some which seemed more viable than others and I will briefly look at a few of these in this essay. The first is one which is a study carried out in the Gambia from 1992 to 1995.(taken from the Lancet of April 1995).The subjects were 63 healthy adults and 56 malaria identified children from an out patient clinic Their test was based on the fact that experimental models of malaria have shown that Cytotoxic T Lymphocytes which kill parasite infected hepatocytes can provide complete protective immunity from certain species of plasmodium in mice. From the tests they carried out in the Gambia they have provided, what they see to be indirect evidence that cytotoxic T lymphocytes play a role against P falciparium in humans Using a human leucocyte antigen based approach termed reversed immunogenetics they previously identified peptide epitopes for CTL in liver stage antigen-1 and the circumsporozoite protein of P falciparium which is most lethal of the falciparium to infect humans. Having these identified they then went on to identify CTL epitopes for HLA class 1 antigens that are found in most individuals from Caucasian and African populations. Most of these epidopes are in conserved regions of P. falciparium. They also found CTL peptide epitopes in a further two antigens trombospodin related anonymous protein and sporozoite threonine and asparagine rich protein. This indicated that a subunit vaccine designed to induce a protective CTL response may need to include parts of several parasite antigens. In the tests they carried out they found, CTL levels in both children with malaria and in semi-immune adults from an endemic area were low suggesting that boosting these low levels by immunisation may provide substantial or even complete protection against infection and disease. Although these test were not a huge success they do show that a CTL inducing vaccine may be the road to take in looking for an effective malaria vaccine. There is now accumulating evidence that CTL may be protective against malaria and that levels of these cells are low in naturally infected people. This evidence suggests that malaria may be an attractive target for a new generation of CTL inducing vaccines. The next candidate vaccine that caught my attention was one which I read about in Vaccine vol 12 1994. This was a study of the safety, immunogenicity and limited efficacy of a recombinant Plasmodium falciparium circumsporozoite vaccine. The study was carried out in the early nineties using healthy male Thai rangers between the ages of 18 and 45. The vaccine named R32 Tox-A was produced by the Walter Reed Army Institute of Research, Smithkline Pharmaceuticals and the Swiss Serum and Vaccine Institute all working together. R32 Tox-A consisted of the recombinantly produced protein R32LR, amino acid sequence [(NANP)15 (NVDP)]2 LR, chemically conjugated to Toxin A (detoxified) if Pseudomanas aeruginosa. Each 0.4 ml dose of R32 Tox-A contained 320mg of the R32 LR-Toxin-A conjugate (molar ratio 6.6:1), absorbed to aluminium hydroxide (0.4 % w/v), with merthiolate (0.01 %) as a preservative. The Thai test was based on specific humoral immune responses to sporozoites are stimulated by natural infection and are directly predominantly against the central repeat region of the major surface molecule, the circumsporozoite (CS) protein. Monoclonal CS antibodies given prior to sporozoite challenge have achieved passive protection in animals. Immunisation with irradiated sporozoites has produced protection associated with the development of high levels of polyclonal CS antibodies which have been shown to inhibit sporozoite invasion of human hepatoma cells. Despite such encouraging animal and in vitro data, evidence linking protective immunity in humans to levels of CS antibody elicited by natural infection have been inconclusive possibly this is because of the short serum half-life of the antibodies. This study involved the volunteering of 199 Thai soldiers. X percentage of these were vaccinated using R32 Tox -A prepared in the way previously mentioned and as mentioned before this was done to evaluate its safety, immunogenicity and efficacy. This was done in a double blind manner all of the 199 volunteers either received R32Tox-A or a control vaccine (tetanus/diptheria toxiods (10 and 1 Lf units respectively) at 0, 8 and 16 weeks. Immunisation was performed in a malaria non-transmission area, after completion of which volunteers were deployed to an endemic border area and monitored closely to allow early detection and treatment of infection. The vaccine was found to be safe and elicit an antibody response in all vaccinees. Peak CS antibody (IgG) concentrated in malaria-experienced vaccinees exceeded those in malaria-naïve vaccinees (mean 40.6 versus 16.1 mg ml-1; p = 0.005) as well as those induced by previous CS protein derived vaccines and observed in association with natural infections. A log rank comparison of time to falciparium malaria revealed no differences between vaccinated and non-vaccinated subjects. Secondary analyses revealed that CS antibody levels were lower in vaccinee malaria cases than in non-cases, 3 and 5 months after the third dose of vaccine. Because antibody levels had fallen substantially before peak malaria transmission occurred, the question of whether or not high levels of CS antibody are protective still remains to be seen. So at the end we are once again left without conclusive evidence, but are now even closer to creating the sought after malaria vaccine. Finally we reach the last and by far the most promising, prevalent and controversial candidate vaccine. This I found continually mentioned throughout several scientific magazines. "Science" (Jan 95) and "Vaccine" (95) were two which had no bias reviews and so the following information is taken from these. The vaccine to which I am referring to is the SPf66 vaccine. This vaccine has caused much controversy and raised certain dilemmas. It was invented by a Colombian physician and chemist called Manual Elkin Patarroyo and it is the first of its kind. His vaccine could prove to be one the few effective weapons against malaria, but has run into a lot of criticism and has split the malaria research community. Some see it as an effective vaccine that has proven itself in various tests whereas others view as of marginal significance and say more study needs to be done before a decision can be reached on its widespread use. Recent trials have shown some promise. One trial carried by Patarroyo and his group in Columbia during 1990 and 1991 showed that the vaccine cut malaria episodes by over 39 % and first episodes by 34%. Another trail which was completed in 1994 on Tanzanian children showed that it cut the incidence of first episodes by 31%. It is these results that have caused the rift within research areas. Over the past 20 years, vaccine researchers have concentrated mainly on the early stages of the parasite after it enters the body in an attempt to block infection at the outset (as mentioned earlier). Patarroyo however, took a more complex approach. He spent his time designing a vaccine against the more complex blood stage of the parasite - stopping the disease not the infection. His decision to try and create synthetic peptides raised much interest. At the time peptides were thought capable of stimulating only one part of the immune system; the antibody producing B cells whereas the prevailing wisdom required T cells as well in order to achieve protective immunity. Sceptics also pounced on the elaborate and painstaking process of elimination Patarroyo used to find the right peptides. He took 22 "immunologically interesting" proteins from the malaria parrasite, which he identified using antibodies from people immune to malaria, and injected these antigens into monkeys and eventually found four that provided some immunity to malaria. He then sequenced these four antigens and reconstructed dozens of short fragments of them. Again using monkeys (more than a thousand) he tested these peptides individually and in combination until he hit on what he considered to be the jackpot vaccine. But the WHO a 31% rate to be in the grey area and so there is still no decision on its use. In conclusion it is obvious that malaria is proving a difficult disease to establish an effective and cheap vaccine for in that some tests and inconclusive and others while they seem to work do not reach a high enough standard. But having said that I hope that a viable vaccine will present itself in the near future (with a little help from the scientific world of course).

 



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