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Transcriptional Signatures May Identify Whether Malaria Vaccines Are Effective

NEW YORK – Gene expression signatures may be able to predict which individuals are more likely to be protected by a malaria vaccine before it is administered, a new study has found.

There are nearly 200 million cases and more than 400,000 deaths due to malaria, caused by the mosquito-borne Plasmodium falciparum, each year. While vaccines for malaria are under investigation, such work is hampered by the lack of immune markers denoting protection and the lack of understanding of the mechanisms behind protection. 

Using data from two vaccine trials — for the RTS,S (GlaxoSmithKline's Mosquirix) vaccine and the chemoprophylaxis and sporozoite (CPS) immunization regimen — an ISGlobal-led team searched for post-inoculation blood transcriptome changes that were associated with protection from malaria. The RTS,S vaccine, which is being tested in large-scale pilot studies in Africa, has had moderate efficacy in early trials, while the CPS approach has exhibited high efficacy in controlled infection studies, but has not been extensively studied in natural exposure situations, the researchers noted. 

As the researchers reported Wednesday in Science Translational Medicine, they uncovered gene expression signatures associated with vaccine efficacy in both cohorts, some of which implicated the same genes and mechanisms in vaccine efficacy. Additionally, they found a pre-immunization signature that predicted vaccine protection.

"This suggests that we could identify individuals who lack such baseline signatures and give them a higher CPS vaccine dose, or simply boost their immune system before vaccine administration to improve its efficacy," first author Gemma Moncunill, from ISGlobal in Barcelona, said in a statement.

For their analysis, the researchers drew on data from a subset of the phase 3 RTS,S trial in which 255 infants or children received three doses of the RTS,S vaccine or a comparator vaccine, such as the rabies or meningococcal C conjugate vaccine, and were followed to see if they developed malaria. 

Likewise, they amassed data from the CPS trial in which 24 malaria-naive adults were immunized with suboptimal doses of P. falciparum-infected mosquitoes during chloroquine prophylaxis and after five months were challenged with bites of infected mosquitos.

The Barcelona-led researchers examined the transcriptomic profiles of peripheral blood mononuclear cell samples collected from the children following RTS,S immunization and from the adults before and after CPS immunization.

While they did not uncover any differentially expressed genes in the RTS,S vaccine cohort, the researchers found 60 genes that were up-regulated and 18 that were down-regulated in the CPS cohort following immunization. Many of these genes, such as TIFNG and GZMB, are involved in immune response.

Additionally, in a gene set analysis, the researchers identified in both cohorts blood transcriptional modules associated with immunization. They also generated transcriptional signatures that predicted vaccine-conferred protection. Many of these, again, included genes linked to immune function and implicated the interferon, NF-κB, and Toll-like receptor pathways in generating an immunization response.

"These results, obtained with two different vaccines and groups of individuals, suggest there are common protective responses against malaria," senior author Carlota Dobaño from ISGlobal said in a statement.

These signatures, the researchers add, could be used to determine vaccine efficacy in clinical trials and potentially speed up the testing of candidate vaccines.

The researchers additionally uncovered a transcriptomic signature among the adults before they were immunized that predicted vaccine efficacy. 

This type of signature, the researchers noted, could be used to identify individuals who are likely to be low vaccine responders and who might then benefit from strategies to boost their immune systems prior to immunization.

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