Malaria vaccination has traditionally focused on those who need it most: children living in areas where transmission is high. But what happens when protection is needed later in life?

That was the question behind a new study by Miguel Prudêncio’s team at GIMM, which investigated how ageing affects the effectiveness of two different whole-sporozoite malaria vaccination strategies.

Today, two malaria vaccines (RTS,S/AS01 and R21/Matrix-M) are being used in children in areas of high transmission. But these are the so-called subunit vaccines, targeting a specific malaria protein. The study looked at a different approach: whole-sporozoite vaccines, which use weakened forms of the malaria parasite to expose the immune system to a broader range of parasite antigens.

Research led by Helena Nunes-Cabaço, and available online in npj Vaccines, found that age was a major factor in determining protection against malaria in mice by two whole-sporozoite vaccines.

The question is increasingly relevant beyond malaria-endemic populations. Travelers, healthcare workers, military personnel, NGO workers and migrants may all be exposed to the parasite when entering endemic regions. “We want to protect everyone. Children are of course the first people we are thinking about. But if one of us goes to an endemic country, we are going to be exposed”, Miguel Prudêncio notes.

The two vaccines in test were the radiation-attenuated sporozoites (RAS) and the late-arresting genetically attenuated parasites (LA-GAP). RAS is considered a benchmark whole-sporozoite approach in which the sporozoites are stopped relatively early during the parasite’s development in the liver. By contrast, LA-GAP are genetically modified so that they continue developing for longer in the liver before being arrested.

In this new study, the Prudêncio lab showed that ‘middle aged’ mice do not benefit from RAS vaccination in the same way that younger mice do and that the LA-GAP approach has the potential to protect a wider age range.

With RAS vaccination, protection declined with age. But the genetically attenuated, late-arresting parasites maintained their protective effect on older animals. As Helena Nunes-Cabaço, the first author of the paper puts it, “the experiment showed that aging is affecting the response to the vaccine. It also showed that it is possible to recover this protection by using a different vaccine strategy.”

The reason may lie in how long the parasite remains in the liver. Because LA-GAP parasites develop for longer, they expose the immune system to a broader and more prolonged set of parasite antigens. Thus LA-GAP provides some extra time for the ‘old and tired’ immune cells of the ‘middle aged’ mice to form a protective immunological response.

The researchers found that this was associated with a different quality of the immune response, including the accumulation of antigen-specific CD8+ T cells in the liver.

Importantly, the study does not show that the vaccine has been improved or modified specifically for older people. Instead, it compares two existing whole-sporozoite strategies and shows that they behave differently with age.

“We didn’t modify the vaccine to make it more effective,” Miguel Prudêncio stresses. “It’s about comparing two alternative rodent surrogates of existing candidates to vaccination against malaria and showing that one of them works better in younger than in older mice, whereas the other one works equally well in both groups.”

The findings add an important dimension to the development of malaria vaccines: age. Vaccines do not necessarily produce the same immune response throughout life, and ageing can affect the expansion and function of immune cells involved in protection.

Hence, vaccine design may help overcome some of those age-related limitations. In older mice, LA-GAP vaccination restored robust protection without simply producing more CD8+ T cells. Instead, the results point towards qualitative differences in the immune response, particularly in which parasite antigens the T cells recognize.

There is still a long way to go before these findings can be translated into recommendations for people. The experiments were performed in mice using Plasmodium berghei, a model that allows researchers to dissect liver-stage immunity but does not reproduce the full complexity of human P. falciparum infection or the immune history of people living in malaria-endemic regions.

Nevertheless, the results strengthen the case for late-arresting whole-sporozoite vaccines as a potential next-generation whole-sporozoite vaccine. If these vaccines ultimately prove effective and safe in humans, the question of age may become an important part of deciding not only whether someone should be vaccinated against malaria, but which type of vaccine might work best.