Gene in Plasmodium Opens Path to Next-Generation Malaria Vaccine: Study
Wed, April 21, 2021

Gene in Plasmodium Opens Path to Next-Generation Malaria Vaccine: Study


A new study developed the next-generation genetically attenuated parasite (GAP) vaccine model for malaria. This vaccine could arrest the late liver stage of the parasite in humans.

The new GAP vaccine design for malaria was developed by scientists at Seattle Children's, a children's hospital in the US. Their model involved live parasites but genetically altered to be less virulent. It could provide protection for people living in regions currently endemic with malaria. The primary feature of their vaccine is the Mei2 gene, which permitted arrest at the very late liver stage. It was found successful in the first safety phase of clinical trials. The results were published in the journal JCI Insight.

Distribution of Malaria Cases Worldwide

Malaria is a parasitic disease caused by Plasmodium parasites, which are spread by female Anopheles mosquitoes. There are five known Plasmodium species that can make people sick. Out of five species, two are recognized for being deadly to humans. Both P. falciparum and P. vivax dominate the global cases of malaria. Because the disease is deadly and can be transmitted easily by mosquitoes, malaria is a high-burden illness in endemic regions.

According to Statista, a German portal for statistics, Nigeria had the highest cases of malaria worldwide in 2018 at 25%. It was followed by the Democratic Republic of the Congo at 12%, Uganda at 5%, Mozambique, the Ivory Coast at 4%, and Niger at 4% each, Burkina Faso, Mali, Angola, United Republic of Tanzania, India, Ghana, Cameroon, and Rwanda at 3% each, Benin, Malawi, Kenya, and Guinea at 2% each, and Burundi at 1%. Other countries comprised 15% of all cases in that year.

In 2018, malaria was confirmed to be one of the global leading causes of deaths among children aged one to 59 months. Out of all pediatric deaths worldwide, 47% were among newborns and 53% were among children aged between one and 59 months. About 5% of deaths among children aged one to 59 months were associated with malaria. The highest specified leading cause of death among those children was pneumonia at 12%.



GAP Vaccines for Malaria

Since children are highly susceptible to malaria, there is a great need for better preventive measures and treatments to eradicate the disease. But the scientific community is hindered by challenges. The parasites are tricky once inside the human body. Plasmodium species have several unique ways to avoid and survive an immune response. These methods are what made it difficult for newer drugs to be developed.

At Seattle Children's, scientists revived the use of GAP vaccines in developing a preventive measure against malaria. Their GAP LIVER-print targeted the late liver stage of human malaria. But to provide such protection, their blueprint involved live and weakened Plasmodium parasites, similar to any other GAP designs before. If a person is compatible with the vaccine, they are unlikely to be infected by new malaria infection.

"Even the most promising experimental vaccine candidates, which can offer up to 52% protection in areas with intense malaria transmission, need to be improved upon to eliminate malaria. We must strive for 100% protection," said Dr. Debashree Goswami, the lead author of the study and researcher from the Center for Global Infectious Disease Research at Seattle.

GAP vaccines for malaria are slightly different when compared to other vaccines that contain weakened, yet live pathogens. The similarity between GAP and other vaccines is the ability to provide protection by triggering a correct immune response, without risking the person to develop severe symptoms, in case symptoms do appear. The difference is the way the pathogen has been weakened.

In most vaccines, such as for measles and influenza, the pathogens passed through cell cultures of animal cells multiple times. The most commonly used animal cell cultures are chick embryos. The pathogens are cultured to become better in replicating within animal cells and worse in replicating in human cells. This technique can render the pathogens either very weak at replicating or completely unable to do so within human cells. But the immune system can still recognize them because the pathogens never loso their antigens.



In GAP vaccines, the pathogens must be edited genetically to disable key processes associated with disease progression. For malaria, Plasmodium parasites are edited to remove critical genes. Once removed, the parasites are unable to complete the next stage of their cycle inside the human liver. Unable to complete that stage breaks the disease progression of malaria. Though, the concept of GAP vaccines is mostly established in mice models.

In this study, scientists upgraded the first-generation GAP vaccines. They specifically engineered a GAP that begins in the liver stage of malaria. The novel GAP would hold the liver stage for as long as possible before arresting the process. This was done after comparing the performance of arrests between early and late liver stages. Compared to early arrest, the late arrest was overall superior in triggering better immune responses.

What made their GAP model distinct was the inclusion of the Mei2 gene. They discovered that the gene in malaria strains in humans and mice played a crucial role in arrest development. When the gene was deleted, the parasite would normally develop in the liver. But it would be arrested at the very late stage to effectively call an immune response.

Scientists tested their Mei2 GAP vaccine model in human liver-chimeric mice, a model dedicated to human liver studies in lab settings. They observed that the Mei2 GAP variant performed similarly in letting the parasite develop in the liver. Roughly before the liver stage ends and the blood stage begins, the vaccine kicked in and arrested the parasite. This halted the liver stage and blocked the next stage of the disease.

Despite the promising findings in lab settings, scientists admit that they cannot exactly tell how the Mei2 GAP vaccine will behave in a real human liver. But the results they have gathered can provide sufficient evidence to initiate early phase clinical trials. So far, they only managed to complete the first safety phase.

GAP vaccines convey hope for an effective preventive measure for malaria. Endemic regions need a vaccine with a 100% protection level. If one is successfully created and determined safe for humans, it will help the global health response for malaria. The same anticipated vaccine may lead the path to malaria eradication.