The Paper's reporter He Liping
In April 2016, China reported the last local primary case of malaria, and more than five years later, the World Health Organization (WHO) announced that China had been certified for malaria elimination. However, the malaria burden remains high globally, particularly in the hardest-hit region of Africa, where more than 90 per cent of global malaria cases occur each year.
Professor Patrick Duffy, director of the Malaria Immunization and Vaccines Laboratory at the National Institute of Allergy and Infectious Diseases, and others believe that the development of vaccines with lasting immunity is imminent when the global decline in the burden of malaria has stagnated.
On the evening of June 30, Beijing time, the top academic journal Nature published a paper by Duffy and colleagues online, entitled "Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity", reporting a malaria vaccine strategy: vaccination with weakened malaria parasites and then treated with preventive drugs. A high level of protection was demonstrated in a trial involving 56 participants.
Nature also published commentaries on the views of Nana K. Minkah et al. from the Center for Global Infectious Diseases Research at the Children's Institute in Seattle. Minkah et al. comment that Duffy et al. reported a vaccination strategy using live, intact Plasmodium falciparum that provides a high level of protection against infection, "and this work is a significant advance in finding an effective malaria vaccine." ”
Malaria is caused by the parasite Plasmodium falciparum, which is transmitted through the bite of infected mosquitoes. In humans, spore-like parasites are called sporozoites, which enter the liver and replicate in hepatocytes. Thousands of infective parasites are then released into the bloodstream, infecting red blood cells. The first stage of human infection occurs in the liver, where no symptoms of the disease appear, and the second stage occurs in the blood, but in the blood phase it triggers disease and even death.
Although scientists identified malaria parasites as malaria pathogens 140 years ago, there has not yet been a vaccine on the market that provides a high level of protection against malaria parasite infections. Malaria parasites have about 5300 genes, and the complexity of their genomes and the complex life cycle of the parasite have hampered the development of vaccines.
Spores and hepatic phases, known together as pee phases, have been targeted for malaria vaccine development since more than 50 years ago. In the paper, Duffy et al. briefly review the history of malaria vaccine development. In the 1980s, GlaxoSmithKline (GSK) began developing a malaria vaccine candidate, RTS.S.S.(trade name Moquirix), a major surface protein for Plasmodium falciparum sporidium, cyclosporidine protein CSP, which has been shown in previous clinical trials to protect against about 40% of malaria cases, including about 30% of life-threatening severe malaria.
However, given the limitations of the use of single-protein vaccine methods, vaccines using living PE parasites that infect the liver but do not cause malaria are gradually receiving greater attention. Immunization with replication-deficient Plasmodium falciparum radiation attenuated sporeworm (PfSPZ-RAS) is the most studied total parasite vaccine to date. Candidate vaccine Sanaria PfSPZ, i.e. chMI (controlled human malaria infection) scenarios of homologous (i.e., identical Plasmodium falciparum strains in the vaccine) and heterologous (different strains) and in naturally transmitted settings in Africa.
In this latest study, Duffy and colleagues optimized a chemopretination (CVac) regimen in which sterile, purified, cryopreservation, infectious Plasmodium falciparum spores (PfSPZ), pyrimethamine, and chloroquine kill hepatic and blood-stage parasites under the prophylaxis of pyrimethamine (PYR) or chloroquine (CQ).
The research team immunized 56 healthy adult volunteers and a dose of pyrimethamine or chloroquine a few days later. They evaluated the efficacy of the vaccine against homologous and heterologous controlled human malaria infection (CHMI) after 3 months of immunity.
Studies have found that higher doses of vaccines are associated with higher levels of vaccine efficacy. After a 4-fold increase in the dose of PfSPZ-CVac (PYR), the vaccine's protective efficacy against homologous CHMI increased from 22.2% to 87.5; at high doses, the vaccine's protective efficacy against heterologous CHMI was 77.8%.
The PfSPZ-CVac (CQ) regimen was preferable, with high doses of chloroquine and immunization with infectious spores, achieving 100% protection against the 7G8 strain found in Brazil for up to three months. This validates important nonspecific protective effects, as an effective vaccine must be protective against a wide variety of naturally circulating Plasmodium falciparum strains.
Minkah et al. similarly note that a major obstacle to the development of a successful malaria vaccine is the large diversity of Plasmodium falciparum strains worldwide.
Minkah et al. also commented that there are still several limitations of this reported vaccine that need attention. Of greatest concern is the need for this live parasite vaccine to strictly comply with the regulations on the administration of accompanying medicines in order to prevent malaria caused by vaccination. This is feasible in controlled clinical trials, but it is difficult to implement if billions of people are vaccinated.
Another issue to consider is that any current total parasite vaccine strategy requires the production of sporozoites in live mosquitoes, thus facing significant challenges in scaling up production.
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