Malaria is one of the life-threatening diseases caused by a parasite that spreads to humans through bites of female infected mosquito known as ‘Anopheles’, which acts as a vector (carrier) for this parasite. Each year more than 400,000 people die of malaria-. According to World Health Organization (WHO), in 2019, there were approximately 229,000 million cases worldwide and about 409,000 deaths. Among the estimated death cases, 67% (274,000) were children under five years of age. Five species of Plasmodium infect humans, and 2 of them are the most significant threat- Plasmodium falciparum and Plasmodium vivax. Most of the African, Southern-East Asian region, Eastern Mediterranean, and Western Pacific cases are caused by P. falciparum, while P. Vivax is the prevalent one in America. Nearly half of the world’s population is at risk, and some groups are at higher risk, such as infants, children, pregnant women, etc.
The transmission intensity depends on many factors, such as a parasite, vector, the human host, and the environment. The transmission also depends on climatic conditions like rainfall, temperature, and humidity, which allowed mosquitoes to thrive. There is a higher prevalence of transmission in areas where partial immunity develops over time due to repetitive exposure that might cause less severe effects of the disease but never provides complete protection. Measures have been taken to prevent the occurrence by using insecticide-treated mosquito nets, anti-malarial drugs, and vaccination.
Vaccination plays a vital role in reducing the number of cases and death rates in the population. Due to vaccination only, we have successfully eradicated the diseases such as smallpox, Polio, etc. But, malaria, which highly affects young children, has escaped effective vaccination. Researchers have developed a single effective vaccine to date, RTS,S/AS01 (RTS,S), that showed a significant decrease in malaria. This vaccine has prevented around 39% of malaria cases (4 in 10) over four years of follow-up. But still, the efficiency rate is less than the recommended guidelines of WHO. Scientists are trying to develop a more efficient vaccine, and recently an RNA vaccine has shown promising results to be the candidate for the malarial vaccine. The study was carried out in a mouse model in Professor Dr. Richard Bucala’s lab, co-inventor of the new vaccine, and a physician from Yale School of Medicine. This has now been approved for clinical trials.
The development of a malaria vaccine is challenging because it is caused by a parasite rather than a virus or bacteria. The life-cycle of this parasite is complex as it requires both the vector and human host. There are various strategies that this parasite uses to escape the immune system. One of the tricks used by the parasite is to live inside the erythrocytes, which prevent direct contact with the antibodies. Another strategy used is the antigen-switching capability, as the surface proteins in the parasite change with the stages of the life cycle. In P.falciprium, the surface proteins of erythrocytes adhere to each other and coagulate the blood cells in the person infected.
One of the parasite’s offensive strategies is to encode for a similar human inflammatory cytokine molecule (cytokine) known as macrophage migration inhibitory factor (MIF). This molecule has been known to play an important role in evading the immune response. Researchers have found Plasmodium macrophage migration inhibitory factor (PMIF) binds to the host MIF receptor and releases inflammatory cytokines such as IL-12 and TNF-α by antigen-presenting cells. Additionally, in the presence of PMIF protein, CD4 T cells produce higher levels of interferon-gamma (IFN-γ) and express markers for terminally differentiated CD4T cells. Hence, the inflammatory cytokines IL-12 and IFN-γ severely affect the survival of CD4 T cells and hamper the establishment of immunological memory. Therefore, Bucala and Andrew Geall have discovered a novel RNA replicon-based vaccine, which prevents the impact of PMIF protein, reduces the expression of inflammatory molecules, and enhances the differentiation of memory CD4 T cells, and provides complete protection from re-infection.
Due to the COVID-19 pandemic, people are aware of the vaccine generated by Pfizer and Moderna, which is an mRNA-based vaccine and has been widely accepted due to its high efficiency, targeted design, flexibility, and rapid manufacturing. Next, for malaria, scientists are using a new platform, known as self-amplifying RNA (saRNA) platform, in which the RNA quickly produces its copies itself inside the cell, and hence the lower dose will be effective. This will be beneficial as it will allow the robust production of memory T-cells and thus to be completely immunized. This self-amplifying vaccine consists of code for your antigen of choice and the machinery to produce RNA polymerase, which generates more protein copies, hence called self-amplifying. This saRNA idea seems fascinating but comes with its challenges as they try to use a huge RNA construct to generate this vaccine. The mRNA or saRNA that has to be delivered inside the cell must be first encapsulated in an inactive viral particle or lipid nanoparticle. If the size of the RNA construct is big, this might decrease the efficiency of encapsulation, and hence the effective particle will be lesser in number. Another disadvantage of the big RNA construct will be the uptake by the cell because the bigger the size, the difficult is the uptake. But a lot of preclinical work has been done on this type of RNA vaccine, and hence the hope is that it will act as a potential candidate against the PIMF protein. This is a new way scientists are trying, and we hope that by the end of this year, the first human dose trial will start.
This is a new ray of hope towards preventing malaria as this vaccine can act as a total game-changer, but also, we should not forget that this is just the beginning, and we have to go a long way. Also, we hope more streamlined strategies will be discovered to tackle these life-threatening diseases. During this challenging time of the COVID-19 pandemic, the government and scientists came together to deal with this situation and tried to handle the situation in the best way possible. In the future, the unity among the scientist worldwide and cooperation with the people will help achieve this Herculean task of eradicating and preventing malaria.
