Scientists are a step closer to better understanding the mechanisms underlying the efficacy of malaria vaccines in infants thanks to research led by investigators in the IU School of Medicine Department of Medicine’s Division of Infectious Diseases.
Malaria is a life-threatening, mosquitoes-borne disease found mostly in tropical climates, like those in Africa, Central America, and Southeast Asia. In 2022, the global malaria cases reached 249 million, according to the World Health Organization’s latest World Malaria Report. This data shows an increase of about five million cases compared to those in 2021, according to the WHO.
There were also 608,000 malaria deaths in 2022 in 85 countries.
The first malaria vaccine was approved for public use in 2021; but several additional vaccine candidates are currently in development, and one – called the PfSPZ Vaccine – was the focus of the IU School of Medicine study, which was published recently in JCI Insight.
Researchers with the Tran Lab in Indianapolis performed a comprehensive analysis of blood samples from infants in Kenya who were enrolled in a randomized, placebo-controlled clinical trial of the PfSPZ Vaccine. In this clinical trial, the infants who received the highest dose of the PfSPZ Vaccine regimen were significantly protected against malaria infections – but only up to three months.
Tuan Tran, MD, PhD, and his research team set out to understand why the vaccine did not provide more durable protection.
They examined gene expression signatures, immune cells – including those that specifically react to the parasite that causes malaria – and sporozoite-specific antibodies in blood samples collected before and two weeks after these infants had received the PfSPZ Vaccine.
By comparing these to blood samples from the infants who received only a saline solution placebo as part of the clinical trial, and by using computational methods, the researchers worked to determine which elements contributed to protection against malaria infection in the vaccinated patients. Mouse models and cell culture models of malaria infection were used to corroborate observations gleaned from the infant data, Tran said.
They found inflammatory gene signatures and a combination of monocytes and anti-malaria antibodies at the pre-vaccination baseline were associated with a lack of protection in the infants who received high-dose PfSPZ Vaccine, but protection in infants who received placebo. Both inflammatory signatures and monocytes were associated with higher sporozoite-specific antibody responses but undetectable CD8+ T cell responses after vaccination.
The data suggests that baseline inflammation may reduce the effectiveness of the PfSPZ Vaccine by limiting sporozoite-specific CD8+ T cell responses rather than affecting antibody responses, Tran said.
“Interestingly, baseline inflammation, while having an overall negative effect on the PfSPZ Vaccine, may confer some measure of short-term protection against natural malaria infection in the unvaccinated placebo group,” he said. “Understanding the elements that affect the effectiveness of this particular malaria vaccine may help us develop methods to identify children who may be less responsive to whole-sporozoite malaria vaccines that work in a similar manner.”
Malaria is just one part of the active research portfolio maintained by the Division of Infectious Diseases.
Supported by NIH, CDC, and various foundations and industry partners, the division dedicates time and resources to basic science research in bacterial pathogenesis, HPV, malaria, HIV and toxoplasmosis. Faculty investigators in the division also conduct clinical prevention and treatment trials in HIV, HPV and a variety of sexually transmitted infections (STIs); diagnostic trials for STIs; epidemiologic studies of STIs, HIV, HPV and malaria; and implementation science research in HIV.
This study was led by members of the Tran Lab – including lead authors Leetah Senkpeil, PhD, and Jyoti Bhardwaj, PhD – in close collaboration with the Schmidt Lab, led by Department of Pediatrics Associate Professor Nathan Schmidt, PhD. The IU Center for Medical Genomics provided all sequencing for the study.
Other essential collaborators included Robert Seder, MD, at the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center, and researchers at the Centers for Disease Control and Prevention, Sanaria, and Kenya Medical Research Institute (KEMRI).
This work was supported by a Doris Duke Foundation Clinical Scientist Development Award as well as grants from NIAID, the National Institute of Health (NIH), the NIH/NIAID Vaccine Research Center.
