On Tuesday, highly-anticipated preliminary results from a phase 3 clinical trial of the RTS,S vaccine against malaria found that vaccinated young children had a 56% lower risk of developing the infection. The vaccine’s maker, London’s GlaxoSmithKline (GSK), has been involved with the vaccine since the early 1980s. But its history goes back further to mouse research conducted at New York University (NYU) in the 1960s. Yet, despite a half century of research into malaria vaccines and numerous clinical trials, laboratory models of the disease have changed little — a fact that experts say could be hindering the development of new vaccines.
“The mouse models have not been very predictive,” says Jean Langhorne, an immunopathologist at the MRC National Institute for Medical Research in London. “They’re very good at telling us what vaccines don’t work, but not very good at telling us what vaccines should work.”
When NYU immunologist Ruth Nussenzweig started her hunt for malaria vaccines in the 1960s, mouse models for the disease were brand new. The parasite that causes malaria in humans, Plasmodium falciparum, does not naturally infect mice, so researchers were at a loss for how to study even malaria’s basic immunology. In the 1950s, scientists traveled to the Congo to collect parasites related to malaria from tree-dwelling African thicket rats, and then adapted them to infect mice in the lab. And, thus, scientists developed the mouse model first used for RTS,S: a lab mouse artificially infected with Plasmodium berghei.
In 1967, Nussenzweig carefully dissected the salivary glands of mosquitoes, zapped the retrieved immature P. berghei parasites with radiation and injected them into lab mice. After challenging those mice two weeks later with live P. berghei, she found that the mice were immune to malaria. Over the following two decades, Nussenzweig and her colleagues identified the antigens associated with mouse immunity, selected the most promising — the circumsporozoite protein used in RTS,S — confirmed its analog on P. falciparum, and then GSK picked it up to develop a vaccine for people.
But, beyond Nussenzweig’s work, vaccines that protect mice against malaria have not been successfully translated into people. The mouse model’s utility has been mainly informative, uncovering the stages of malaria infection and the basics of immune reaction. “They can tell us what controls the immune response,” says Langhorne. “Where they probably are not so good is in predicting exactly what parts of an antigen might be important for inducing protective immunity.”
The best thing we have
The main roadblock to new vaccines in the mouse model is that the coevolution that naturally occurs between parasite and host — with the host adapting to evade attack and the parasite adapting, in turn, to evade host immune responses — is out of the picture entirely. The parasites have few mechanisms of tripping up the mouse’s immune system, and are just too easy for researchers to beat with vaccines or medicine. But these models are still used because there are no other options. “I don’t think that anyone would say the models are perfect, but they’re the best thing we have,” says Andrew Taylor-Robinson, a parasite immunologist at Leeds University in the UK.
To make a better model, some researchers are trying to build mice that P. falciparum can infect. For example, Lenny Shultz, a mouse modeler at the Jackson Laboratory in Bar Harbor, Maine, is engineering a mouse with the human components required for the malarial lifecycle and a more human-esque immune response. In 2010, he engrafted human red blood cells (where adult parasites lurk into a mouse) and injected human bone marrow to generate human immune cells. And more recently, in unpublished work he has implanted humanized liver tissue, in which malaria parasites mature. There are still some kinks to work out — few human immune cells actually persevere in the blood, and mouse liver cells quickly outcompete their human counterparts — but the mice are already being used by GlaxoSmithKline to test malaria drugs, he says.
Meanwhile, Patrick Duffy, head of the Laboratory of Malaria Immunology and Vaccinology at the US National Institute of Allergy and Infectious Diseases, is moving beyond the mouse altogether. This summer, he imported 15 African thicket rats from the Congo, and they’re already breeding in the rodent facilities in Bethesda, Maryland. Duffy hopes these rats, which have naturally coevolved with P. berghei, will better replicate the human-malaria system and will be better models for vaccine development.
“Other than RTS,S, other vaccine attempts have not been successful” based on mouse models, Duffy says. “Maybe we need a more vigorous screen that a natural host parasite could provide.”
Image 2: An African thicket rat from the NIH colony, courtesy of Patrick Duffy and taken by African thicket rat caretaker Lynn Lambert