Maternal antibodies transferred through the placenta can impact how infants respond to the malaria vaccine. This effect could clarify why the vaccine is less effective in babies younger than five months, according to new research. The study suggests that infants younger than the age currently recommended by the WHO could benefit from the RTS,S and R21 malaria vaccines if they reside in areas with low malaria transmission, where their mothers have lower antibody levels against the parasite.
Research led by the Barcelona Institute for Global Health (ISGlobal) in partnership with seven African centers (CISM-Mozambique, IHI-Tanzania, CRUN-Burkina Faso, KHRC-Ghana, NNIMR-Ghana, CERMEL-Gabon, KEMRI-Kenya) has found that maternal antibodies can hinder the response to the malaria vaccine in infants under five months. The study’s results published in Lancet Infectious Diseases indicate that infants younger than the WHO’s current recommendations may gain advantages from the RTS,S and R21 malaria vaccines, particularly in regions with low malaria transmission where maternal antibodies are less prevalent.
A significant achievement has been made globally with the introduction of the first two malaria vaccines – RTS,S/AS01E and the newer R21/Matrix-M – designed to protect African children against the malaria caused by Plasmodium falciparum. Both vaccines target a specific protein component of the parasite known as circumsporozoite (CSP) and are currently advised for use in children aged 5 months or older at the time of the first dose.
“We know that RTS,S/AS01E is less effective for infants below five months, but the reasons behind this discrepancy remain under discussion,” says Carlota Dobaño, the head of the Malaria Immunology group at ISGlobal, which is backed by “la Caixa” Foundation.
To explore this, Dobaño and her colleagues examined blood samples from over 600 children (aged 5-17 months) and infants (aged 6-12 weeks) who took part in the phase 3 clinical trial for RTS,S/AS01E. They utilized protein microarrays to assess antibodies against 1,000 P. falciparum antigens before vaccination, aiming to understand how malaria exposure and age influenced IgG antibody responses to the vaccine.
“This microarray method enabled us to accurately evaluate malaria exposure at an individual level, accounting for maternal exposure for infants and past infections in older children,” explains Didac Maciá, an ISGlobal researcher and the study’s lead author.
The role of maternal antibodies
The analysis of antibodies in children who received a control vaccine instead of RTS,S/AS01E showed a typical “exposure” pattern. This pattern featured high antibody levels in the initial three months of life due to maternal antibody transfer through the placenta, a decrease over the first year, followed by a gradual rise due to natural infections.
In children who were vaccinated with RTS,S/AS01E, naturally induced antibodies did not impede the vaccine response. However, in infants, higher levels of antibodies against P. falciparum, likely transferred during pregnancy, were associated with diminished vaccine responses. This effect was particularly pronounced for maternal anti-CSP antibodies focused on the protein’s central region. In contrast, infants with very low or undetectable maternal anti-CSP IgGs had vaccine responses similar to those of older children.
The exact molecular mechanisms by which maternal antibodies interfere are not completely understood, although this phenomenon has been noted in other vaccines, including measles.
Overall, the findings confirm a previously suspected but not clearly evidenced point: despite their protective role, maternal anti-CSP antibodies—declining within the first three to six months—may hinder vaccine effectiveness. Higher malaria transmission rates result in more maternal antibodies being passed to infants, leading to reduced vaccination effectiveness. The results further imply that infants under five months could gain benefits from RTS,S or R21 vaccination in low malaria transmission environments, during outbreaks in malaria-free areas, or among populations moving from low- to high-transmission regions.
“Our research emphasizes the importance of timing and maternal malaria antibody levels in enhancing vaccine efficacy for the youngest and most vulnerable infants,” states Gemma Moncunill, an ISGlobal researcher and co-senior author of the study, alongside Dobaño.
This study was funded by the National Institute of Allergy and Infectious Diseases, which is part of the National Institutes of Health, through grants R01AI095789 and U01AI165745.
