'Universal key' approach to malaria points to new generation of vaccines

PhD student Kirsty Wilson is a co-author on both
papers on liver-stage infection by malaria parasites,
seen here presenting at a 2015 CCS symposium.

by Anne Crawford

Liver-stage infection by malaria parasites offers a key target for vaccines that aim to eradicate the disease. But the shape-shifting parasite has for decades defied concerted attempts by scientists to create a vaccine that will kill it in all its forms.

Monash researchers decided to review the field, hoping that insight and a fresh approach might point to a new solution. An unexpected finding they made in the research that followed could well be a pivotal first step in rationally designing a new generation of vaccines.



Professor Magdalena Plebanski, who heads the Vaccine and Infectious Diseases Laboratory in the Department of Immunology and Pathology, said the review showed that many of the vaccine candidates being clinically trialled have only one variant of the target protein and therefore don’t protect against all forms of the parasite. The malaria parasite uses polymorphism – occurring in different forms – to interfere with host immunity.

Another of its strategies is to disrupt the T cells so important in immunity from targeting liver-stage infections.

“The vaccines don’t protect against all the parasites in the population – the results of clinical trials for vaccines have been disappointing,” Professor Plebanski said.

“We decided to do original research into the adjuvants – or agents – used in the vaccines to make them more powerful. We thought if we changed the adjuvant we could broaden the spectrum of variants that a vaccine could recognise,” she said.

The team tested and developed a number of these agents using nanotechnology: disappointingly, none had the desired effect.

“We thought then that maybe the parasite has evolved and is actually fixing in the population variants that don’t induce cross-reactivity,” Professor Plebanski said.

“So we thought, what if we changed the actual antigen, if we change the sequence of what we immunise with artificially, could we broaden the immune response?”

The unusual approach, which also used nano particles, yielded remarkable results.

The team found that if they artificially changed one amino acid at the position at which it contacted the T cell receptor, that they could make responses that recognised not only the artificial variant they ‘immunised’ with but also a number of other variants, including the original one.

“This was an animal model but if it was a real human vaccine we could say that yes, we could target the prevalent parasite in the population as well as a number of other parasites that are bearing other variants in the population,” Professor Plebanski said.

“We believe this is a really key first step to point in a new direction to develop malaria vaccines, to start modelling malarial antigens to rationally design new generations of vaccines.”

Professor Plebanski said she wasn’t aware of the approach being used elsewhere in infectious diseases although it had been enlisted in research into tolerance. The approach could be broadened for use with other antigens.

The first author for the original research was Central Clinical School PhD student Kirsty Wilson, who presented the well-received paper at a couple of conferences including the International Congress of Immunology 2016 held in Melbourne. Dr Katie Flanagan was the first author for the review paper.

References:

Flanagan KL, Wilson KL, Plebanski M. Polymorphism in liver-stage malaria vaccine candidate proteins: immune evasion and implications for vaccine design. Expert Rev Vaccines. 2016;15(3):389-99. doi: 10.1586/14760584.2016.1125785. Epub 2015 Dec 23.

Wilson KL, Xiang SD, Plebanski M. A Model to Study the Impact of Polymorphism Driven Liver-Stage Immune Evasion by Malaria Parasites, to Help Design Effective Cross-Reactive Vaccines. Front Microbiol. 2016 Mar 11;7:303. doi: 10.3389/fmicb.2016.00303. eCollection 2016.