Current Status Of Malaria Vaccinology

.. est 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.

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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-nave 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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