by Adaikalavan Ramasamy
Malaria is a mosquito-borne disease that represents a major public health risk, affecting nearly half the world population and causes a significant economic burden. The World Health Organization (WHO) estimates approximately 214 million new malaria cases and 438,000 malaria deaths worldwide in 2015 alone . Children under the age of 5 living in sub-Saharan Africa accounted for 70% of these deaths. Other high-risk groups include pregnant women, immunosuppressed individuals (e.g. HIV infected patients), travellers and the elderly.
Malaria could be prevented either by eliminating the mosquitoes that act as the vector for the parasites, limiting the spread of the disease by rapid diagnosis and treatment of suspected cases or by using vaccines to enhance the human immune system to kill the pathogen rapidly. In reality, a combination of all these approaches will be required to eliminate malaria.
Malaria life cycle
Malaria is caused by the Plasmodium parasites transmitted by infected female Anopheles mosquitoes. A female mosquito requires blood to produce eggs and through the process of biting the parasite enters the host’s blood vessels, where it travels rapidly to the liver to mature and multiply. Then it breaks out of the liver to infect red blood cells to multiply again, causing red blood cells to burst, thus releasing the parasites back into the bloodstream. If another female mosquito bites the infected human at this stage, the mosquito also becomes infected, thus completing the life cycle of malaria transmission (Figure 1).
Different types of malaria
Six different species of Plasmodium are currently known to infect humans. Each species has a different geographical spread, life cycles, incubation periods, disease severity and treatment approaches. P. falciparum is the most common species worldwide (~75%) and the main cause of severe and complicated malaria. The second most common species worldwide is P. vivax (~20%) which is predominantly found in South America and Asia (Figure 2).
However, the most common species in Malaysia  are P. knowlesi (38%), P. vivax (31%) and P. falciparum (19%) . Note that P. knowlesi traditionally infected monkeys only but it has recently acquired the ability to infect humans as well and this is an emerging problem particularly in Malaysia (Figure 3).
Malaria symptoms, diagnosis and treatment
Symptoms usually begin between 10 – 30 days after being bitten. The symptoms include fever, chills, headache, fatigue and vomiting. Classic hallmarks of malaria is a repeated cycle of cold stage (intense cold and shivering lasting < 1 hour) followed by hot stage (intense heat, headache, dry skin lasting 2 – 6 hours) and sweating stage lasting 2 – 4 hours.
Early and accurate diagnosis is key to selecting the correct treatment, shortening illness duration and to prevent life-threatening complications (e.g. cerebral malaria, severe anaemia, respiratory distress). However, early diagnosis can be difficult as the initial symptoms of malaria are similar to flu. Malaria is confirmed either examining blood smear from finger prick under a microscope (Figure 4) or commercially available rapid diagnostic test kits.
WHO currently recommends five Artemisinin-based combination therapies for uncomplicated P. falciparum malaria. These drugs are considered to be the most effective antimalarial currently available and contribute hugely to malaria reduction. However, counterfeit or substandard drugs threaten to undermine this success. Further, parasites that are resistant to these antimalarial drugs have been reported in Cambodia, Laos, Myanmar, Thailand and Vietnam. This is worrying given that no new antimalarial drugs are anticipated in the near future.
Malaria control and elimination efforts in Malaysia
Malaria elimination programs focusing on mosquito control in Malaysia have been successful in reducing the number of cases from ~50,000 in the early 1990s to ~5,000 in 2012 with a corresponding reduction in deaths due to malaria per year from 43 to 16 .
Elimination strategies include indoor residual spraying, using insecticide treated bed nets and good and fast management of malarial outbreaks. However, these efforts require constant monitoring, funding and considerable foresight. Furthermore, majority of malaria cases arise from remote areas in Sabah and Sarawak where access remains difficult. A substantial portion of malaria cases (~30%) are “imported cases” – where migrant workers from Indonesia and Philippines who acquire malaria during home visit before returning to Malaysia where their access to medical doctors is more limited .
Vaccine development for malaria
Vaccines have been generally considered to be the cheapest and most effective public health measure for many infectious diseases and malaria is no exception. They could be integrated along with the routine vaccination schedule and could offer long lasting protection as well as herd immunity if sufficiently large proportion of the population is vaccinated. Therefore, the availability of affordable malaria vaccines will considerably enhance and complement the malaria elimination efforts. Numerous vaccines are in development but they mainly focus on P. falciparum and target the parasite before they burst out of the liver. In the following sections, we discuss the three most advanced and promising vaccines: RTS,S/AS01, ChAd-MVA with MeTRAP and PfSPZ.
RTS,S/AS01 vaccine (tradename Mosquirix)
RTS,S/AS01 is a recombinant vaccine which fuses the P. falciparum circumsporozoite protein with surface antigen from Hepatitis B and adjuvanted with AS01 (to increase immune response). The vaccine induces high levels of anti-circumsporozoite antibodies which can attack the parasite before it can invade the liver cells. It also provokes a strong CD4 T-cell response which can kill the parasite in the liver before it can break out of the liver.
This vaccine was developed by GlaxoSmithKline (GSK) over three decades with funding support from the PATH Malaria Vaccine Initiative (MVI) and Bill & Melinda Gates Foundation. This is the first malaria vaccine to have completed the critical Phase 3 clinical trial enrolling over 15,000 volunteers from 11 trial sites in seven African countries. Two age groups were included: infants aged 6 – 12 weeks and children aged 5 – 17 months with a median participant follow-up of 48 months .
The best protection was seen in the children recruited at ages 5 – 17 months who received four doses (vaccination at 0, 1, 2, and 20 months after recruitment) with an overall efficacy of 39% and significant protection (31.5%) against severe malaria, severe anaemia, malaria hospitalization, etc, compared to the control group. The efficacy was dropped to 27% in infants who received four doses (same schedule but starting at 6 weeks of life). Infants and young children who did not receive the fourth dose had an even lower overall efficacy. There was an excess of febrile seizures within 7 days of vaccination in the children in older groups compared to the control group.
The European Medical Agency evaluated the scientific merits of this vaccine and found that the quality of the vaccine and risk/benefit profile is favourable from a regulatory perspective. In October 2015, the WHO reviewed the evidence and recommended large-scale implementation pilots to replicate the protection reported in the children aged 5 – 17 months who received the 4-dose schedule . GSK is now in the process of planning Phase 4 study to further characterise the safety and effectiveness of RTS,S/AS01 vaccine. These studies are expected to eventually recruit 800,000 children aged 5 – 9 months in 3 – 5 sites located in sub-Saharan with moderate high malaria transmission settings.
ChAd63/MVA ME-TRAP vaccine
Viral vector vaccines use harmless and replication-defective viruses to carry and deliver pathogen sequences to train the human immune systems. The viruses are chosen from non-human species so they are not neutralised too quickly and designed to be harmless and replication-deficient. Viral vector vaccines have been shown to induce potent T-cell response  which is required to destroy liver cells that have been infected with the parasites.
Researchers from Jenner Institute, University of Oxford and the Malaria Viral Vectored Consortium reported their findings from a Phase 2 trial . They used a chimpanzee adenovirus (ChAd63), which is similar to human common cold virus, synthetically constructed to express the highly conserved regions of malaria antigens called ME-TRAP to prime 61 healthy adult males in Kenya. Eight weeks later, the volunteers were boosted with an attenuated poxvirus Modified Vaccinia Ankara (MVA), which is a type of smallpox vaccine, expressing ME-TRAP. This heterologous prime-boost strategy provokes strong immune response with a good safety profile and used as the backbone for many candidate vaccines including dengue, flu, RSV and more recently with Ebola. The control group consisted of 60 adult males who received rabies vaccine as placebo. All volunteers were given antimalarial drugs after vaccinations to clear parasites and then monitored for 8 weeks post MVA vaccination for infections.
They found that vaccinations reduced the risk of infection by 67%. While these results are very promising, the findings would need to be replicated in a much larger trial with longer follow-up and participants from multiple sites with different malaria transmission rates. Furthermore, the results need to be replicated in infants and young children who are at higher risk of malaria infection.
PfSPZ vaccine was developed by Sanaria and made up of non-replicating irradiated whole sporozoites. Sporozoite is the plasmodium form that leaves the mosquito during the feeding process and infects the liver cells. Sanaria currently collect sporozoites manually from dissecting salivary glands of mosquitoes and then irradiate and freeze them for vaccination. In an earlier study , they identified that administrating this vaccine intravenously in non-human primates and mice was far more immunogenic than subcutaneous or intradermal vaccinations.
Next, they recruited and vaccinated 40 adults with different dosages and number of vaccines and then deliberately challenged with the pathogen to assess efficacy . Among individuals who received the highest dose of the vaccine, they observed protection in 6 out of 9 volunteers who received four doses and 6 out of 6 volunteers who received five doses. Inspired by the success of this trial, the PfSPZ Vaccine Clinical consortium has set-up seven different clinical trials in USA, Africa and Germany which will recruit at least 450 volunteers.
While the reported efficacy of this vaccine is very high, there are several criticisms. Collection of large amounts of sporozoite manually will be challenging for large-scale implementation and Sanaria is working on a robot to automate this process. The second criticism is that the vaccine requires super-cold liquid nitrogen which would be logistically challenging in Africa. Finally, the practicality of intravenous injection five times in young children needs to be considered further.
About the Author:
Dr Adaikalavan Ramasamy is currently the Senior Leadership Fellow in Bioinformatics and heads the Transcriptomics Core Facility at the Jenner Institute, University of Oxford. His team uses gene expression as a tool to understand how the immune system responds to vaccination and why this response differs among individuals. Understanding the mechanisms of protection can help inform vaccine development for infectious diseases and cancer immunology. Adai and his team work on a broad range of novel and licensed vaccines in adults, children and livestock for many infectious diseases including malaria, TB, RSV, influenza and Ebola. Find out more about Adai by visiting his profile at http://www.scientificmalaysian.com/members/adairama/
This article first appeared in the Scientific Malaysian Magazine Issue 12. Check out other articles in Issue 12 by downloading the PDF version for free here: Scientific Malaysian Magazine Issue 12 (PDF version)
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