There are highlights from research
Anopheles coluzzii malaria: A Collapse in the Populations of amphibians is Driving an Increase in Central America Malaria Incidence
The team from the United States provided evidence that more than a fifth of the Anopheles coluzzii mosquitoes in western Africa survive the dry season by entering a state of aestivation. Scientists have been puzzling over how mosquito populations rebound so quickly in the event of rain for decades.
The sexual phase of the development of Malaria parasites occurs inside the mosquito. The parasites that affect people in the mosquito population combine to form the sporozoites that cause infections in people. Scientists typically feed a sterile mosquito with gametocytes, which is the same kind ofocytes that are utilized in vaccines, to allow the chloramphenicol to develop and then purify it from the mosquito’s salivary glands. This could cause an issue for the widespread use of vaccines based on sporozoites, because it is costly and time-Consuming.
An international team led by Michael Springborn at the University of California, Davis, suggests that a collapse in the populations of amphibians such as frogs and salamanders drove an increase in malaria incidence in Central America. This is the first evidence that an amphibian species loss is affecting human health in a natural setting.
The warming climate is supporting the idea that the distribution of these types of infectious diseases will be changed by it. The authors warn that more work is needed to understand the extent to which climate change can explain the observations.
Source: https://www.nature.com/articles/d41586-023-02050-5
Vaccination of parasites with whole, live sporozoites, based on a gametocyte-containing vaccine from Drosophila melanogaster
The researchers exposed the P. falciparum parasites to the drugs in an attempt to generate resistance. They discovered that the new resistant parasites had evolved changes in agene believed to be involved in the assembly of virulence factors for the parasites.
There are other compounds that can be used to target a certain class of enzyme, but their use is limited partly due to drug toxicity. The team investigated the compounds and found low toxicity against human cell lines. The compounds also block cIRS activity by binding to a different region of the enzyme. The researchers think that the multistage effects of these compounds, and the nature of the resistance-conferring mutations encountered during testing, means that there is little risk that substantial resistance will emerge.
At Sanaria, scientists are taking another tack. They are delivering whole, live sporozoites instead of singling out a single one. The key advantage of a whole-parasite vaccine, says Kappe, is that it provides a multipronged immune response against “dozens, if not hundreds of proteins”. As the parasites evolve, that could allow the vaccine to hold up better. He says that the parasites cannot change 500 genes at the same time.
To solve this problem, a team led by Stephen L. Hoffman at biotechnology firm Sanaria in Rockville, Maryland, processed gametocyte-containing blood in wells containing cells from the fruit fly, Drosophila melanogaster. These feeder cells aided the development of oocytes, from which millions of sporozoites emerged.
In 1967, Austrian–Brazilian immunologist Ruth Nussenzweig made a momentous discovery. She was able to weaken the parasites by using radiation. When injected into mice, these feeble parasites were unable to replicate and cause disease. But they could prompt an immune response.
It took a long time to develop a malaria vaccine, but the discovery of it was the beginning. In the 1990s, there was pessimism that there would ever be a Malaria vaccine, according to Patrick Duffy, who is head of the Laboratory of Malaria Immunology and Vacciant at the National Institute of Allergy and Infectious Diseases.
The Malaria eradication is likely to require a combination of vaccines that hit multiple parasites at the same time. We are seeing how they can work together, as we are moving to an era that combines these different activities. The two are working together on a test with a small group of kids. “We’re excited about that,” Hill says. If R21 is able to get 75% efficacy then adding an rhythym 5 will bring it up to 90 percent. Birkett says that PATH is also interested in this approach. The opportunity is most likely to be the one that I think is most positive in the near term.
The parasite begins its journey in a mosquito’s gut, and then migrates to the insect’s salivary glands. When an infected insect bites a person, the parasites are injected into the bloodstream in the form of worm-shaped sporozoites. These work their way through a process where they mature and replicate into larger, merozoites before returning to the bloodstream. The merozoites cause red blood cells to stop working and cause a outbreak of a high temperature. Some merozoites transform once again into a sexual form that the mosquito will take up during its next blood meal, ready to repeat the cycle.
At each stage, the parasite changes radically. The difference between the two is that the parasites pass through the blood stages and the parasites go through the bile duct. That isn’t the same as the parasites that pass through the mosquito. The vaccine developers want to target which form to use.
R21 is a vaccine currently being worked on at the University of Oxford, UK and targets the same drug as the one used for RTS,S. The main difference between R21 and RTS is that in R21, most of the hepatitis B fragments are not fused to circumsporozoite.
A small dose of R21 may give it a little more muscle than a larger one, says Kappe. However, differences in the amount of each vaccine given in one dose — 5 micrograms for R21 and 25 micrograms for RTS,S — mean that they probably deliver roughly the same amount of the protein in total, Duffy says.
Vaccine for merozoites by stimulating the immune system to generate antibodies against a protein that mimics the Achilles heel of the parasite
The WHO began reviewing the R21 data in March to determine whether or not the vaccine should be given the go-ahead. It’s too soon to give a time line. Nigeria and Ghana have approved the vaccine but it is not known when it will be available.
In the field, the results have been less impressive. A vaccine composed of irradiated sporozoites, called PfSPZ, showed little lasting efficacy in a study of around 300 infants in Kenya4. That could be because of the young age of the study participants and their immature immune systems. Another possible explanation is that malaria infection at the time of vaccination blunted the vaccine’s effect. Four of the six field trials in which participants were treated for Malaria before being given the vaccine showed efficacy when presented at the American Society of Tropical Medicine and Hygiene. Half of the 300 women who were in the trial got pregnant after being given the vaccine. Participants received antimalarial drugs and then either a high or low dose of PfSPZ. The vaccine showed substantial efficacy over the first two years. “It can be durable in a way that the other vaccines have not been so far,” Duffy says.
The vaccine developed by Draper and his colleagues is currently called Matrix-M. When these volunteers were intentionally exposed, the best regimen slowed the growth of the parasites. In field trials in Tanzania, the vaccine induced high antibody levels in children aged 6–11 months7. The levels of the immune system in infants are much higher than those seen in adults. That has been a good news story. A phase II efficacy trial in Burkina Faso launched in April.
But about a decade ago, researchers discovered PfRH5 — a protein that Draper thinks could be the merozoite’s Achilles’ heel5. PfRH5 binds to a receptor on the surface of red blood cells and helps the parasite to gain entry. “We have a highly conserved target, and an essential one,” he says. “There’s no spare key to the lock.”
The idea behind Duffy’s vaccine is to take out the gametes by stimulating the human immune system to generate antibodies against a protein called Pfs230 that gametes display on their surface. A feeding mosquito will then take up not just the gametocytes, but also those antibodies. When gametes emerge from red blood cells in the mosquito’s gut, the theory goes, the antibodies will be there to destroy them before they can complete their development (see ‘A vaccine for all occasions’).
We are grateful for the financial support of Ehime University, Medicines for Malaria Venture and Nagasaki University. No More Japan with funding from the Bill & Melinda Gates Foundation, Sumitomo Chemical, GHIT Fund and Eiken Chemical, in producing this Outlook. Nature is always responsible for all editorial content.
Some of the obstacles to progress are long-standing, such as a lack of money. Funding for malaria control in 2021 was estimated at US$3.5 billion, less than half of the $7.3 billion that was recommended to hit the 2030 target. It is difficult to imagine that this funding gap will be filled soon because of the economic shocks of the COVID-19Pandemic and the war in Ukraine. Other challenges are just emerging. Drugs based on artemisinin are some of the best weapons against the disease. But these drugs are showing signs of losing their efficacy in Africa, which is home to 95% of cases. Climate change could cause the spread of Malaria to new places.
