Fever is Rising

Fever is Rising

125 years after the discovery of the malaria parasite, an ideal drug or vaccine for malaria has been elusive so far. Efforts have not been successful so far because scientists don’t have knowledge about the components of the natural immune response to malaria that provide protection against the dreaded disease. Sapna Dogra takes stock of the current state of affairs

Malaria has staged an alarming comeback as a global threat and is estimated to infect over 100 million people annually. The emergence and spread of drug resistance in malaria has accounted for the re-emergence of the disease as a major global threat in the past 20 years. Over two million people in India are affected every year by the mosquito-borne disease, which claims hundreds of lives. But, there is hope that a vaccine could one day be developed.

According to Dr Krishna M Ella, Chairman and Managing Director, Bharat Biotech International, there are no vaccines licensed against malaria in the world. In fact, there are no vaccines licensed against any human parasite. Many scientists, however, are trying to develop vaccines around the world. There is tremendous progress being made and more malaria vaccines are being tested in people every year.

With sequencing of the genome of Plasmodium falciparum and Plasmodium vivax, along with the genome of Anopheles gambiae, the mosquito that transports the deadly disease from person to person, the path to identify potential proteins to target in a new vaccine is clear. The scientists have sequenced 5300 genes in P falciparum, which would help them to study the signals that allow P falciparum to constantly present different combinations of proteins. Over half of the parasite’s gene code for proteins has never been seen before. This may prove useful because these proteins are not found in humans and they may make good drug targets.

In a landmark development, by 2008, about 2,000 infants in Africa will be inoculated against malaria in the largest-ever trial undertaken of an experimental vaccine for malaria. As of now no malaria vaccine has ever progressed to manufacture and licensing as RTS,S has. Experts feel that if the vaccine, known as RTS,S, proves effective in reducing the rates of death and serious illness in children with malaria, it would undoubtedly be a public health triumph. It also holds high stakes for GSK Biologicals that is hoping to license the product.

The Indian scenario

At the International Centre for Genetic Engineering and Biotechnology, New Delhi, (ICGEB) a blood stage peptide vaccine is in the final stages of development, informs Dr V S Chauhan, Director. It is a totally independent project in collaboration with Bharat Biotech and funded by the DBT.

At ICGEB, scientists have selected two blood stage antigens, P falciparum merozoite surface protein-1 (PfMSP-1) and 175 kD erythrocyte binding antigen (EBA-175). Both of them play an important role in red cell invasion for development of a combination blood-stage vaccine for P falciparum malaria. “One must remember that these are experimental vaccines: they may or may not work,” says Chauhan and adds that the basic aim of this vaccine would be to help children develop immunity in malaria-endemic regions like Orissa, Madhya Pradesh, Jharkhand and Assam.

Already a study has been initiated to understand the epidemiology and immunology of malaria in Sundergarh in Orissa. The objective of the study is to develop a field site for vaccine trial. According to A P Dash, Director, National Institute of Malaria Research in India (NIMRI), more new sites for vaccine trials are being prepared in Rourkela in Orissa and Mandala in Madhya Pradesh. Another site in Madhya Pradesh is also being prepared for future trials of a DNA-based vaccine against malaria.

When asked, what would be an ideal vaccine for the Indian subcontinent, Chauhan replies, “Any vaccine that prevents death in children would be ideal because they suffer the most from malaria.” Keeping in mind the dynamic nature of the parasite, India needs a cocktail vaccine. Unfortunately, it would be a very complicated and expensive proposition, according to Dash.

Vaccines could be of various types and combinations. The liver-stage vaccines are designed to prevent malaria infection; however, they must be 100 percent effective to protect people with no natural immunity. They include, vaccines containing whole killed sporozoites and those based on antigenic portions of sporozoite proteins. The blood-stage vaccines seek to elicit antibodies to merozoites (the blood-cell-infecting stage of the parasite).

Blood stage vaccines could be designed to reduce or interfere with parasite growth but they could also be designed to prevent adhesion of infected cells to endothelium, thus preventing what appears to be the key step in pathogenesis leading to organ failure. Such blood-stage vaccines would not produce sterile immunity (a potentially dangerous situation for the time when immunity fades), but could mimic the development of immunity that occurs with natural exposure, by converting the immune status of a baby to that of a clinically immuned ten-year-old. Transmission-blocking vaccines would not protect the recipient but could help the spread of malaria. Sexual-stage parasite antigens are complex and have been difficult to produce. Multistage vaccines target antigens from multiple stages of the parasite’s life cycle.

Manufacturing the vaccine

Any vaccine is still many years away from complition, says Ella and informs that the final components of PvRII (or, the ICGEB-Bharat vaccine) have not been selected and tested. “Depending on the specific components that will be required, different manufacturers will be involved,” he adds.

Talking about the financial viability Chauhan says that it would not be a problem once the vaccine is ready, but it is far-fetched because we are still in the development stage. Ella agrees, “For any vaccine to have the maximum impact, it will have to be accessible to all segments of the population. As is the case with current childhood vaccines it is anticipated that a combination of private, government and international agencies will co-operate to make malaria vaccine accessible.”

Genetically modifying the mosquito: European researchers have developed a technology to introduce more useful changes that prevent mosquitoes from spreading malaria. These include, altering the insects’ own immune system so that they cannot carry the parasite that causes malaria; modifying the insects’ sense of smell, so that, they seek out and bite animals rather than humans; altering the insects in a way that would allow large-scale breeding of sterile males. These could then be released into dangerous populations to keep numbers down.

However, according to Ella, it is not clear whether using genetically modified mosquitoes will solve the problem of malaria. Certainly having an effective malaria vaccine will be very helpful.

RBx 11160: Ranbaxy Laboratories and Medicines for Malaria Venture, Geneva (MMV) collaborated for a new antimalarial drug, designated RBx 11160. Successful Proof of Concept studies in humans were recently completed for this drug. The findings indicate that the drug is safe and effective in reducing the malaria parasite count. The company, together with MMV, will soon initiate Phase-IIb clinical studies on this molecule in India, Thailand and Africa.

CDRI (Central Drug Research Institute, Lucknow): CDRI has significantly contributed in Nation’s malaria control programme by launching a new antimalarial drug E-Mal. Marketed by Themis Medicare, this drug is currently available in India and several African countries for the management of drug resistant malaria. This drug belongs to the group of first generation derivatives of artemisinine which is the active principal in a shrub Artemisia annua. Owing to the rising costs and scarce a vailability of this naturally derived chemical agent, CDRI is working towards developing second generation fully-synthetic derivatives as an economical substitute for natural resource based derivatives.

Challenges in developing a vaccine

Efforts have not been successful so far because scientists don’t have knowledge about the components of the natural immune response to malaria that provide protection against the dreaded disease. There are scientific challenges in developing the malaria vaccine, which are proving to be the stumbling blocks, suggests Chauhan.

“This is a devious pathogen, which can change proteins on the surfaces of its cells to evade detection by the human immune system,” he adds. The parasite has evolved a series of strategies that allow it to confuse, hide, and misdirect the human immune system, thus confusing the scientists.

“The size and genetic complexity of the parasite suggests that each infection presents thousands of antigens to the human immune system. Getting to know which of these would be a useful target for vaccine development, has been complicated, and to date, dozen promising antigens have been identified,” comments Ella.

Moreover, the parasite passes through several life stages even while in the human host, presenting a different subset of molecules for the immune system to combat at each stage, adds Ella. The problem is complicated because it is possible to have multiple malaria infections of not only different species but also of different strains at the same time. “For instance,” informs Dash, “Indian anopheline fauna comprises 58 species, of which nine act as vectors of malaria and of these, eight have a number of morphologically indistinguishable biological species, commonly known as sibling, cryptic or isomorphic species.”

“So far, in various pilot studies, the vaccines’ efficacy in protection against malaria infection has been about 30-50 percent and malaria vaccines, to date, have not been entirely effective, but only able to temporarily suppress the disease,” rues Dash. He adds, “The truly effective vaccine would have at least 80 percent efficacy, consisting of several components, each only partially successful at fighting malaria on its own.”