Current Status of Malaria Vaccinology

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 effectiv eateradicating 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. 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