Current Status of Malaria VaccinologyannonIn order to assess the current status of malaria vaccinology one mustfirst take an overview of the whole of the whole disease. One mustunderstand the disease and its enormity on a global basis. Malaria is a protozoan disease of which over 150 million cases arereported per annum. In tropical Africa alone more than 1 millionchildren under the age of fourteen die each year from Malaria.
Fromthese figures it is easy to see that eradication of this disease is ofthe utmost importance. The disease is caused by one of four species of Plasmodium These fourare P. falciparium, P . malariae, P .
vivax and P . ovale. Malaria does notonly effect humans, but can also infect a variety of hosts ranging fromreptiles to monkeys. It is therefore necessary to look at all theaspects in order to assess the possibility of a vaccine. The disease has a long and complex life cycle which creates problems forimmunologists. The vector for Malaria is the Anophels Mosquito in whichthe life cycle of Malaria both begins and ends.Order now
The parasitic protozoanenters the bloodstream via the bite of an infected female mosquito. During her feeding she transmits a small amount of anticoagulant andhaploid sporozoites along with saliva. The sporozoites head directly forthe hepatic cells of the liver where they multiply by asexual fission toproduce merozoites. These merozoites can now travel one of two paths.
They can go to infect more hepatic liver cells or they can attach to andpenetrate erytherocytes. When inside the erythrocytes the plasmodiumenlarges into uninucleated cells called trophozites The nucleus of thisnewly formed cell then divides asexually to produce a schizont, whichhas 6-24 nuclei. Now the multinucleated schizont then divides to produce mononucleatedmerozoites . Eventually the erythrocytes reaches lysis and as result themerozoites enter the bloodstream and infect more erythrocytes. Thiscycle repeats itself every 48-72 hours (depending on the species ofplasmodium involved in the original infection) The sudden release ofmerozoites toxins and erythrocytes debris is what causes the fever andchills associated with Malaria. Of course the disease must be able to transmit itself for survival.
Thisis done at the erythrocytic stage of the life cycle. Occasionallymerozoites differentiate into macrogametocytes and microgametocytes. This process does not cause lysis and there fore the erythrocyte remainsstable and when the infected host is bitten by a mosquito thegametocytes can enter its digestive system where they mature in tosporozoites, thus the life cycle of the plasmodium is begun againwaiting to infect its next host. At present people infected with Malaria are treated with drugs such asChloroquine, Amodiaquine or Mefloquine. These drugs are effective ateradicating the exoethrocytic stages but resistance to them is becomingincreasing common.
Therefore a vaccine looks like the only viableoption. The wiping out of the vector i. e. Anophels mosquito would also prove asan effective way of stopping disease transmission but the mosquito arealso becoming resistant to insecticides and so again we must look to avaccine as a solutionHaving read certain attempts at creating a malaria vaccine severalpoints become clear.
The first is that is the theory of Malariavaccinology a viable concept? I found the answer to this in an articlepublished in Nature from July 1994 by Christopher Dye and GeoffreyTargett. They used the MMR (Measles Mumps and Rubella) vaccine as anexample to which they could compare a possible Malaria vaccine Theirarticle said that “simple epidemiological theory states that thecritical fraction (p) of all people to be immunised with a combinedvaccine (MMR) to ensure eradication of all three pathogens is determinedby the infection that spreads most quickly through the population; thatis 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 impliesthat p> 1-1/Ro ? 0. 93 Gupta et al points out that if a populationof malaria parasite consists of a collection of pathogens or strainsthat have the same properties as common childhood viruses, the vaccinecoverage would be determined by the strain with the largest Ro ratherthan the Ro of the whole parasite population.
While estimates of thelatter 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 withthe highest Ro it could provide immunity to all malaria plasmodium “Another problem faced by immunologists is the difficulty in identifyingthe exact antigens which are targeted by a protective immune response. Isolating the specific antigen is impeded by the fact that severalcellular and humoral mechanisms probably play a role in natural immunityto malaria – but as is shown later there may be an answer to thedilemma. While researching current candidate vaccines I came across some whichseemed more viable than others and I will briefly look at a few of thesein this essay.
The first is one which is a study carried out in the Gambia from 1992 to1995. (taken from the Lancet of April 1995). The subjects were 63 healthyadults and 56 malaria identified children from an out patient clinicTheir test was based on the fact that experimental models of malariahave shown that Cytotoxic T Lymphocytes which kill parasite infectedhepatocytes can provide complete protective immunity from certainspecies of plasmodium in mice. From the tests they carried out in theGambia they have provided, what they see to be indirect evidence thatcytotoxic T lymphocytes play a role against P falciparium in humansUsing a human leucocyte antigen based approach termed reversedimmunogenetics they previously identified peptide epitopes for CTL inliver stage antigen-1 and the circumsporozoite protein of P falcipariumwhich is most lethal of the falciparium to infect humans.
Having theseidentified they then went on to identify CTL epitopes for HLA class 1antigens that are found in most individuals from Caucasian and Africanpopulations. Most of these epidopes are in conserved regions of P. falciparium. They also found CTL peptide epitopes in a further two antigenstrombospodin related anonymous protein and sporozoite threonine andasparagine rich protein. This indicated that a subunit vaccine designedto induce a protective CTL response may need to include parts of severalparasite antigens.
In the tests they carried out they found, CTL levels in both childrenwith malaria and in semi-immune adults from an endemic area were lowsuggesting that boosting these low levels by immunisation may providesubstantial or even complete protection against infection and disease. Although these test were not a huge success they do show that a CTLinducing vaccine may be the road to take in looking for an effectivemalaria vaccine. There is now accumulating evidence that CTL may beprotective against malaria and that levels of these cells are low innaturally infected people. This evidence suggests that malaria may be anattractive target for a new generation of CTL inducing vaccines. The next candidate vaccine that caught my attention was one which I readabout in Vaccine vol 12 1994. This was a study of the safety,immunogenicity and limited efficacy of a recombinant Plasmodiumfalciparium circumsporozoite vaccine.
The study was carried out in theearly nineties using healthy male Thai rangers between the ages of 18and 45. The vaccine named R32 Tox-A was produced by the Walter Reed ArmyInstitute of Research, Smithkline Pharmaceuticals and the Swiss Serumand Vaccine Institute all working together. R32 Tox-A consisted of therecombinantly produced protein R32LR, amino acid sequence 2 LR, chemically conjugated to Toxin A (detoxified) ifPseudomanas aeruginosa. Each 0.
4 ml dose of R32 Tox-A contained 320mg ofthe R32 LR-Toxin-A conjugate (molar ratio 6. 6:1), absorbed to aluminiumhydroxide (0. 4 % w/v), with merthiolate (0. 01 %) as a preservative. The Thai test was based on specific humoral immune responses tosporozoites are stimulated by natural infection and are directlypredominantly against the central repeat region of the major surfacemolecule, the circumsporozoite (CS) protein.
Monoclonal CS antibodiesgiven prior to sporozoite challenge have achieved passive protection inanimals. Immunisation with irradiated sporozoites has producedprotection associated with the development of high levels of polyclonalCS antibodies which have been shown to inhibit sporozoite invasion ofhuman hepatoma cells. Despite such encouraging animal and in vitro data,evidence linking protective immunity in humans to levels of CS antibodyelicited by natural infection have been inconclusive possibly this isbecause of the short serum half-life of the antibodies. This study involved the volunteering of 199 Thai soldiers.
X percentageof these were vaccinated using R32 Tox -A prepared in the way previouslymentioned and as mentioned before this was done to evaluate its safety,immunogenicity and efficacy. This was done in a double blind manner allof the 199 volunteers either received R32Tox-A or a control vaccine(tetanus/diptheria toxiods (10 and 1 Lf units respectively) at 0, 8 and16 weeks. Immunisation was performed in a malaria non-transmission area,after completion of which volunteers were deployed to an endemic borderarea and monitored closely to allow early detection and treatment ofinfection. The vaccine was found to be safe and elicit an antibodyresponse in all vaccinees. Peak CS antibody (IgG) concentrated inmalaria-experienced vaccinees exceeded those in malaria-na?ve vaccinees(mean 40.
6 versus 16. 1 mg ml-1; p = 0. 005) as well as those induced byprevious CS protein derived vaccines and observed in association withnatural infections. A log rank comparison of time to falciparium malariarevealed no differences between vaccinated and non-vaccinated subjects. Secondary analyses revealed that CS antibody levels were lower invaccinee malaria cases than in non-cases, 3 and 5 months after the thirddose of vaccine. Because antibody levels had fallen substantially beforepeak malaria transmission occurred, the question of whether or not highlevels of CS antibody are protective still remains to be seen.
So at theend we are once again left without conclusive evidence, but are now evencloser to creating the sought after malaria vaccine. Finally we reach the last and by far the most promising, prevalent andcontroversial candidate vaccine. This I found continually mentionedthroughout several scientific magazines. “Science” (Jan 95) and”Vaccine” (95) were two which had no bias reviews and so the followinginformation is taken from these. The vaccine to which I am referring tois the SPf66 vaccine.
This vaccine has caused much controversy andraised certain dilemmas. It was invented by a Colombian physician andchemist called Manual Elkin Patarroyo and it is the first of its kind. His vaccine could prove to be one the few effective weapons againstmalaria, but has run into a lot of criticism and has split the malariaresearch community. Some see it as an effective vaccine that has provenitself in various tests whereas others view as of marginal significanceand say more study needs to be done before a decision can be reached onits widespread use.
Recent trials have shown some promise. One trial carried by Patarroyoand his group in Columbia during 1990 and 1991 showed that the vaccinecut malaria episodes by over 39 % and first episodes by 34%. Anothertrail which was completed in 1994 on Tanzanian children showed that itcut the incidence of first episodes by 31%. It is these results thathave caused the rift within research areas. Over the past 20 years, vaccine researchers have concentrated mainly onthe early stages of the parasite after it enters the body in an attemptto block infection at the outset (as mentioned earlier). Patarroyohowever, took a more complex approach.
He spent his time designing avaccine against the more complex blood stage of the parasite – stoppingthe disease not the infection. His decision to try and create syntheticpeptides raised much interest. At the time peptides were thought capableof stimulating only one part of the immune system; the antibodyproducing B cells whereas the prevailing wisdom required T cells as wellin order to achieve protective immunity. Sceptics also pounced on the elaborate and painstaking process ofelimination Patarroyo used to find the right peptides.
He took 22″immunologically interesting” proteins from the malaria parrasite, whichhe identified using antibodies from people immune to malaria, andinjected these antigens into monkeys and eventually found four thatprovided some immunity to malaria. He then sequenced these four antigensand reconstructed dozens of short fragments of them. Again using monkeys(more than a thousand) he tested these peptides individually and incombination until he hit on what he considered to be the jackpotvaccine. But the WHO a 31% rate to be in the grey area and so there isstill no decision on its use. In conclusion it is obvious that malaria is proving a difficult diseaseto establish an effective and cheap vaccine for in that some tests andinconclusive and others while they seem to work do not reach a highenough standard.
But having said that I hope that a viable vaccine willpresent itself in the near future (with a little help from thescientific world of course).