The Immune System’s Baseline Status Strongly Determines the Response to the Malaria Vaccine

A new study shows that a certain gene expression profile in innate immune system cells at the time of vaccination is associated with an increased risk of contracting malaria later on. The study, an international collaboration co-led by the Institute for Global Health (ISGlobal), a center supported by the ”la Caixa” Foundation, was conducted in the framework of the Phase 3 clinical trial for RTS,S in several African countries.

The recent approval of RTS,S (or Mosquirix), the first malaria vaccine for general use in children living in malaria-endemic regions, is a historic milestone. Its use, combined with other available tools, will help advance malaria control and elimination. However, its efficacy in children aged 5 to 17 months is only 50% at one year post-vaccination. The team of ISGlobal researchers Carlota Dobaño and Gemma Moncunill has devoted much effort to understanding the type of immune response associated with protection against malaria, and how to improve the vaccine.

In this study, conducted as part of the RTS,S phase 3 clinical trial, the research team analysed gene expression by cells of the immune system at baseline (i.e. at the time of receiving the first dose) and one month after the third and final dose. To do this, they took blood samples from more than 350 vaccinated children (in Bagamoyo in Tanzania and Manhiça in Mozambique) and analysed the RNA in these cells (i.e. the transcriptome).

The results show that, one month after the third dose, there is an activation of genes related to a T lymphocyte response and an inhibition of genes related to B lymphocytes and monocytes, but the only association found was between the monocyte profile and an increased risk of malaria. An association was also observed between the activation status of monocytes and dendritic cells (innate immune cells that constitute our first line of defense) at baseline, and the risk of subsequent malaria in vaccinated children. These results were confirmed with samples from RTS,S-vaccinated adults who participated in two other independent studies.

"Our results are in line with a growing number of studies indicating that the basal state of the immune system can influence the response to different vaccines," says Gemma Moncunill, first author of the study. "In addition, two previous studies have shown an association between a higher proportion of monocytes and an increased risk or severity of malaria," she adds. Although the mechanisms behind this association are not yet clear, one hypothesis is that increased expression of certain genes (such as the STAB1 gene) by monocytes could inhibit T-cell activation.

"The strength of our study is that it was conducted in infants and young children, who may have different immune responses than adults. In addition, it was conducted in malaria-endemic areas, where immunity from natural exposure to the parasite could interact with vaccine-conferred immunity," adds Carlota Dobaño, senior co-author of the study. The authors conclude that this study indicates that innate immune cells may influence the response to vaccination, and sheds light on how to improve vaccine-mediated protection.

Reference:

Gemma Moncunill, Jason Carnes, William Chad Young, et al. Transcriptional correlates of malaria in RTS,S/AS01-vaccinated African children: A matched case-control study. eLife 2022;11:e70393. DOI: https://doi.org/10.7554/eLife.70393