An overview of vaccines against malaria

IN THE NEWS

On 9 August 2013, CNN reported a breakthrough in malaria vaccinology. A new radiation attenuated intravenous vaccine has shown to be 100 % efficacious if injected in multiple doses. In about eight to ten years, this vaccine would be readily available at any pharmacy store. Before that, it has to pass rigorous tests of safety and must be approved by the FDA.

ARE WE THERE YET ?

Although it is relatively easy to produce updated flu vaccines every year, malaria vaccines have eluded decades of research. There have been many hurdles along the way. Some of these have been discussed in a paper by Thera and Plowe, titled "Vaccines for Malaria: How close are we? " published in the Annual Reviews in Medicine in November 2011.

The first obstacle is the size of the parasite's genome. The 5000 genes in Plasmodium falciparum's genome are organized into 14 chromosomes and there are roughly 23 million bases. This precludes the development of an efficient DNA vaccine. Successful DNA vaccines have so far only been developed against viruses and bacteria with much smaller genomes.

The complex lifecycle of Plasmodium also allows for differential gene expression. Like the Lyme disease parasite that shows antigenic (and phase variation), Plasmodium expresses highly variant antigens such as PfEMP1s that are coded by up to 60 var genes in the genome.

In the haploid liver stages and blood stages of the parasite, mutations occur during mitotic replication. Genetic recombination commonly occurs during the diploid sexual stages. Drugs used against Plasmodium also provide some amount of selection pressure and drive mutation of the parasite. From a single geographical location, it is possible to isolate up to 18 different forms of a surface antigen. Hence, potential surface epitope change and when these vaccine targets are lost or modified, older vaccines (in the case of malaria, which were never available to begin with) become obsolete.

Polymorphisms in surface antigens play important roles in determining strain specific immunity.

Malaria vaccines typically target a specific stage of the parasitic lifecycle and show effect only against that stage. However, even a single surviving parasite such as a sporozoite could multiply to produce thousands of merozoites in 48 hours and result in an infection.

THE STORY SO FAR ..

Vaccines against malaria that have been experimentally created fall under these main categories. Classification is based on the stage of protection, rather than the conventional classification of vaccine type.

> Pre Erythrocytic vaccines

>Blood stage vaccines

>Transmission blocking vaccines

>Whole organism vaccines

 (malariavaccine.org)

PRE ERYTHROCYTC VACCINES

RTS,S/ AS01 is an experimental subunit vaccine that targets the pre-erythrocytic circumsporozite protein CSP of Plasmodium falciparum. It consists of CSP (which has a central conserved region flanked by T cell epitopes) in Adjuvant System 01 (a proprietary adjuvant that contains monophosphoryl lipid A and QS21). This vaccine showed up to 60 % protection in field trials. It is currently in phase III trials in seven African countries.

To offer substantial protection, subunit vaccines have to be combined with strong adjutants. This in itself poses a risk of severe reactions against the adjuvant.

Other pre-erythrocytic vaccines that have passed preclinical and early clinical trials have not shown too much promise.

BLOOD STAGE VACCINES

These are usually based on antigens that coat the surface of the invasive merozoites or are involved in the hijacking of the erythrocyte. The merozoite surface protein 1 or MSP1 and the apical membrane antigen 1 or AMA 1 has both shown some promise as vaccine candidates.

Two AMA1 vaccines have passed the preclinical and clinical stages of development.

A vaccine directed against merozoites surface protein 3 has shown some efficacy against the clinical stage of malaria.

TRANSMISSION BLOCKING VACCINES

These vaccines target immunogenic epitopes on gametocytes and other mosquito stages that are important for the transmission of the parasite.

Although one such vaccine appeared to produce immunity by blocking transmission, the adjuvant that it was formulated with viz., Contained ISA 51 created safety issues by being extremely reactive.

MULTI STAGE MULTI ANTIGEN VACCINES

Plasmodium is a complex organism and so to be efficacious against different stages, a vaccine must target different antigens that are immunodominant at different stages of the organism.

SPf66 is one such vaccine. It is a synthetic vaccine that targets the CSP expressed in the pre-erythrocytic stage. SPf66 is derived from the MSP1 and hence is also protective in the erythrocytic stages.

WHOLE ORGANISM VACCINES

Although one would assume that this would be the direct approach to a vaccine against malaria, some of the early trials in which whole organisms were used were not interpreted as a direct path to a vaccine.

However, the report on CNN concerned a vaccine that was made from radiation attenuated, metabolically active, non-replicating cryopreserved sporozoites. This vaccine did not show protection when injected via the intradermal or subcutaneous routes. Intravenous route that mimicked the bite of a female mosquito showed the best effect. After delivery, the sporozoites were able to reach and replicate in the liver and induce protection.

A list of antigenic candidates that can be targeted and used in a vaccine  are listed here : http://www.hindawi.com/journals/bmri/2013/282913/tab2/

THE START OF A JOURNEY

Developing an efficient vaccine against malaria is not an end by itself. The vaccine is only a tool that will be useful in combating the deadly disease and will help in its eradication.


References : 

Thera MA, Plowe CV. Vaccines for malaria: how close are we? Annu Rev Med 2012;63:345-357.

Malaria vaccine initiative : http://www.malariavaccine.org/malvac-lifecycle.php