Malaria vaccine: An elusive dream?

Recently, in a rather unfortunate development, Malaria vaccine stumbled along its PATH (pun intended!). RTS,S/AS01E aka Mosquirix-the most advanced and the first ever malarial vaccine in a phase II clinical trial, waned over time. The results were published in the March 21weekly issue of the New England Journal of medicine. This study was supported by […]

Recently, in a rather unfortunate development, Malaria vaccine stumbled along its PATH (pun intended!). RTS,S/AS01E aka Mosquirix-the most advanced and the first ever malarial vaccine in a phase II clinical trial, waned over time. The results were published in the March 21weekly issue of the New England Journal of medicine. This study was supported by the Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative and the Wellcome Trust. GlaxoSmithKline Biologicals has been developing the product.

RTS,S/AS01E is one of several potential vaccines under development that target the pre-erythrocytic stage of the disease engineered using genes from the outer protein of Plasmodium falciparum malaria parasite and a portion of a hepatitis B virus with a liposomal chemical adjuvant to boost the immune system response.

Malaria

Malaria: A dreaded disease

Malaria is caused by a parasite carried in the saliva of mosquitoes and is endemic in more than 100 countries worldwide. As per the 2012 WHO fact sheet, malaria is a preventable and treatable mosquito-borne disease, whose main victims are children under five years of age in Africa. According to the latest WHO estimates, there were about 219 million cases of malaria in 2010 and an estimated 660,000 deaths. Africa is the most affected continent with about 90% of all malaria deaths. Pregnant women and their unborn children are particularly vulnerable to the disease.

 

Why vaccine?

The current war against malaria is fought with a variety of weapons, including the distribution of bednets, the promotion of indoor spraying, and the development of new medicines and insecticides. Deployment of these lethal weapons has been plagued with a variety of challenges ranging from lower manufacturing capacities for bednets, inefficient distribution channels, and parasites/mosquito’s resistance to drugs and insecticides. A vaccine is been developed to bridge these gaps. Even a modestly efficacious malaria vaccine would be very handy.

So far, vaccines have been developed by three main approaches: a) those targeting pre-erythrocytic stage of the parasite. b) those targeting the blood stage of the parasite and c) those interrupting the life cycle of the parasite by inducing antibodies that prevent the parasite from maturing in the mosquito. Elaborate spreadsheet is available in what is known as the ‘Rainbow table’ put together by WHO.

Vaccine story so far:

RTS,S was developed in the late 1980s by researchers at GlaxoSmithKline Biologicals in Rixensart, Belgium, and later in partnership with the PATH Malaria Vaccine Initiative. Work on the RTS,S vaccine began a quarter of a century ago within the US military, with development since 2001 being carried out by a public–private venture between the PATH Malaria Vaccine Initiative (MVI) – supported by the Bill & Melinda Gates Foundation and the pharma giant GlaxoSmithKline. Early results from larger, ongoing phase III trials have shown that the vaccine cut malaria cases to half during the first year of follow up in young children, and by about a third in babies. In November 2012, results from phase III tests on 6,500 infants showed that the RTS,S vaccine only protected about a third of infants, compared to success rates of between 47 percent and 55 percent in children between the ages of five and 17 months. This is also a matter of concern as the youngest age groups are most prone to the disease!

Recent Phase II results: A damp squib?

The latest setback is reported from a phase II follow-up study on 320 children in Kilifi, Kenya which found that in the first year after vaccination, protection against malaria was 43.6 percent, which dropped to zero by the fourth year. It was also found that the more often a child was exposed to malaria, the less effective the vaccine appeared to be. Briefly, the study showed that the vaccine’s efficacy was 45.1 percent in children with below-average exposure to malaria, and just 15.9 percent in children with above-average exposure. Interestingly, it was also found that for every 100 vaccinated children, 65 cases of clinical malaria were averted.

This study that began in 2009, with an objective to assess safety and efficacy ahead of the large-scale phase III trials involved 447 children, out of which 320 were able to be followed up for four years.

What’s in store?

Reportedly, Mary Anne Rhyne, the US spokesperson from GlaxoSmithKline, was of the opinion that the Kenya study is small and uses data from just one of many trial sites, while larger studies are still under way. According to her, the ongoing phase III pivotal study, involving 15,460 children should provide meaningful insights into the vaccine candidate’s efficacy in different malaria parasite transmission settings, longer-term efficacy (2.5 years after primary vaccination) and the impact of a booster dose. The results for these studies are expected by the end of 2014.

As per the reports, the researchers of the study, although disappointed, have not lost hope and believe that a booster dose could help pep up the response to the disease. This phenomenon is not unheard of in vaccine clinical use.

A glimmer of hope after all:

While researchers in Africa and elsewhere were grappling to come to terms with these results, path breaking progress was being made elsewhere. A prolific group of researchers from parts of US, Australia, Europe and Asia reported in their article published in Science Translational Medicine, discovery of a new compound ELQ-300 (chemical class: The 4(1H)-quinolone-3-diarylethers). ELQ-300 works by interrupting the lifecycle of Plasmodium, whereby it disables the power house aka mitochondria of Plasmodium cells. The parasite is thus destroyed, and a person does not experience symptoms. The researchers claim that ELQ-300 also prevents transmission since a person who has taken ELQ-300 no longer has active Plasmodium in their bloodstream. As per some of the reports that I went through, this drug is been tipped as the next big thing in the war against malaria. As per my analysis, most antimalarial drugs are high dosed and need frequent administration due to their poor bioavailability. Here’s a catch-22, food improves the bioavailability of these drugs but one of the side effects of these drugs is nausea and vomiting, thereby hindering food intake in patients. In their pre-clinical studies in mice, ELQ-300 has shown good bioavailability, metabolic stability and efficacy. Still early days for ELQ-300, but definitely promising!

Meanwhile, reportedly around the same time, another group based out of New Delhi, India took a great leap forward in their exciting search for an elusive malarial vaccine. The results published in The American Society for Microbiology-Infection and Immunity, pointed towards identification of three key parasite antigens that elicited potent inhibition against Plasmodium Falciparum strains. Going by the preclinical results, this could very well be a potent weapon in the arsenal against malaria!

With today being world Malaria day what could possibly be of more importance!?

-Shankar Swaminathan

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