WHY THE WORLD NEEDS AN EFFECTIVE MALARIA VACCINE

Malaria is one of the deadliest diseases that has ever existed. Every year, there are over 200 million new cases of malaria infection and nearly half a million people succumb to the disease. Tragically, most of those deaths are young children.

A dedicated malaria research team at the Institute for Glycomics is fighting to reverse these alarming statistics through the development of a world-first whole blood-stage parasite vaccine, which is currently in human clinical trials. Dr Danielle Stanisic and Ms Winter Okoth, part of this research team within the Institute’s Laboratory of Vaccines for the Developing World, talk to us about malaria, their unique vaccine candidate, and how they hope to achieve what no one else has yet been able to, and that is to end malaria… for good.

What causes malaria?

Malaria is a mosquito-transmitted disease caused by parasites of the genus Plasmodium. Today, there are eight different Plasmodium parasite species that have been identified that can infect humans, including P. falciparum which causes the majority of illness and death, especially in sub-Saharan Africa.  Two of the Plasmodium species that infect humans, P. knowlesi and P. simium are zoonotic parasites which means that they are transmitted from animal to human.

Some of the clinical symptoms of malaria infection include profuse sweating, nausea, muscle pains, body aches, headaches, chills, and periodic fevers. Severe malaria is life-threatening and is associated with certain complications including cerebral malaria, severe anaemia, acute respiratory distress syndrome, and multi-organ failure.

What is the global impact of malaria?

Malaria is a life-threatening disease and a major global public health problem. Some of the groups most vulnerable to this disease include: children under the age of 5 years who have not yet developed immunity, pregnant women (usually in their first or second pregnancies), immunocompromised individuals (someone whose immune system is weaker or low and cannot easily fight off infections) and travellers to malaria endemic areas, who lack immunity. 

Despite the prevention and control measures currently in use (e.g. bed nets, mosquito spraying programs), malaria is still one of the leading causes of illness and death, especially in sub-Saharan Africa. According to the World Health Organisation’s 2020 World Malaria Report, there were an estimated 229 million cases and 409,000 malaria deaths recorded globally in 2019 (see link).  The WHO’s African region accounted for 94% of these cases.

Malaria has major economic and social impacts in affected countries. Direct costs (for example, illness, treatment, premature death) have been estimated to be at least US$12 billion/year (see link). The cost in lost economic growth is much greater than that.

We understand that your research team is currently developing a malaria vaccine candidate. Can you tell us a bit about that journey?

We are currently developing a whole parasite vaccine that targets the stage of the malaria parasite that is found in the blood.  As the name suggests, the vaccine contains the whole blood-stage parasite.  In our pre-clinical studies, we demonstrated that this approach of using the whole blood-stage parasite in the vaccine could induce a broad protection against infection with different malaria parasites.  We have a number of different whole blood-stage parasite vaccine candidates that have been evaluated or we are currently evaluating in pre-clinical studies.

Following these observations, we then progressed our most advanced vaccine candidate, chemically attenuated whole blood-stage parasites, into clinical studies.  This vaccine contains blood-stage malaria parasites that have been treated with a chemical so that they are no longer infectious and cannot cause disease but can still simulate an immune response.

To evaluate this vaccine approach in humans, we had to first develop human malaria parasites that were safe to administer to humans.  These parasites are used to make the human vaccine and to test whether the vaccine can protect healthy, malaria-naïve humans from developing a malaria infection.  We also had to establish the capacity and capability to manufacture and evaluate the vaccine on site at Griffith University’s Gold Coast Campus.

We have conducted a number of clinical studies that have evaluated our chemically attenuated whole blood-stage parasite vaccine in malaria-naïve human volunteers.  They demonstrated that it is safe, well tolerated and can induce an immune response in humans that is similar to the protective immune responses we observed in our pre-clinical studies.  We are currently making some small changes to the vaccine formulation to make it more suitable for deployment in malaria endemic areas.  

Why did you run the first clinical trials for the vaccine in Australia?

When vaccines are first evaluated in humans, this is usually undertaken in healthy human adults in the general population, so it is suitable to do this in Australia. It was also necessary for practical reasons as our initial studies involved manufacturing and administering a “fresh vaccine” that needed to be prepared on the day of administration. This manufacturing process has to be undertaken in a cleanroom facility with a closely controlled environment. An appropriate cleanroom facility is at Griffith University.

Are there other malaria vaccines currently available, and if so, are they effective?

Researchers have been working on a malaria vaccine for nearly a century. Worldwide, there are many malaria vaccine candidates that are currently at different stages of development. The majority of these vaccines tend to target the parasite at a single point in the life-cycle (e.g. the sporozoite stage injected by the mosquito, the liver-stage, the blood-stage or the developmental stages in the mosquito) and each of these different life-cycle stages requires a different sort of immune response to eliminate the parasite.  This complexity of the malaria parasite is one of many challenges faced by researchers developing a malaria vaccine.

Only one vaccine candidate, Mosquirix™ (also known as RTS,S/AS01) has progressed through all of the different phases of clinical trial evaluation (Phase I, II and III) and is currently being further evaluated in pilot implementation programs in three African countries.  Mosquirix™ has only moderate efficacy and the protection offered by this vaccine fades quite rapidly following completion of the final vaccine dose.  Therefore, a more effective vaccine capable of inducing long-lived protection is still required.

How is your vaccine candidate different? What makes it a world-first?

Many of the malaria vaccine candidates currently in development contain only a small component of the malaria parasite in the vaccine.  These components or “antigens” (a substance/part of the pathogen that induces an immune response in the body) are often highly variable between the many different malaria parasite strains circulating in the field.

Thus, the efficacy of this sort of vaccine can be limited as it is generally only effective against parasite strains whose antigen matches the one in the vaccine. 

In contrast, we are focused on developing a vaccine against the blood-stage of the human P. falciparum parasite that contains all of the antigens.  By including the whole blood-stage parasite in the vaccine, a broad range of parasite antigens are presented to the immune system, including antigens that are conserved (i.e. the same) between different parasite strains.  This means that the whole parasite vaccine approach should induce a broad protective immune response against the multitude of parasite strains circulating in the field.

Other research groups have been working on whole parasite vaccines containing the sporozoite-stage (the parasite-stage injected by the mosquito) of the parasite.  However, our research group was the first to administer and evaluate in human volunteers a whole parasite vaccine containing the blood-stages of the parasite. This chemically attenuated P. falciparum whole blood-stage parasite vaccine was shown to be safe, well tolerated and it induced an immune response that recognised different strains of the malaria parasite. 

What stage of the development process is your malaria vaccine candidate currently at now?

We have now completed clinical studies to evaluate the safety, immunogenicity (development of an immune response) and efficacy of our chemically attenuated P. falciparum whole blood-stage parasite vaccine in malaria-naïve human volunteers.  As this vaccine will be challenging to preserve for field deployment in malaria endemic areas, we are making a few changes to the formulation to improve its field deployability.  This involves treating the vaccine to make it suitable for freeze-drying.  The vaccine can then be stored in powder form until required for administration.

What are the next steps?

We are now completing our pre-clinical studies with our whole blood-stage parasite field-deployable vaccine formulation.  We plan to evaluate this new vaccine formulation in malaria-naïve volunteers in 2022 to confirm it is safe and can induce a similar immune response to that seen with our chemically attenuated vaccine.  It will then be ready to evaluate overseas in malaria endemic areas.

What do you need in order to take this vaccine candidate from its current stage to completion?

To progress our vaccine, we first have to demonstrate that our improved field deployable vaccine formulation is safe and effective in malaria-naïve human volunteers.  We then need to evaluate and confirm the safety and efficacy of the vaccine in different age groups in malaria endemic countries. 

If proven effective, what impact could this vaccine have on global health?

Historically, vaccination has made a significant contribution to global health.  An effective malaria vaccine will save lives by reducing the morbidity and mortality associated with malaria infection. It will have substantial socio-economic benefits in malaria endemic countries including increased life expectancy, increased productivity, and empowerment of affected populations, freeing up and strengthening of health infrastructures and systems for future outbreaks or epidemics.  If proven effective, our vaccine will have an overall positive impact on global health by contributing to the control and eventual eradication of the malaria parasite.

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