22 Sep 2017

Pushing the boundaries of vaccine research

L-R: Dr Kirsty Wilson, Honours student Julie Tran and Professor Magdalena Plebanski
by Anne Crawford

In 2010 Professor Magdalena Plebanski observed something that didn’t make sense to her as an immunologist; a nanoparticle made of polystyrene exposed to the lungs of mice was rendering the animal resistant to developing asthma.

But why would it? she asked.

The inert polystyrene particle did not cause inflammation, was non-toxic, safe and protected the mouse against the disease in a similar way to a vaccine. Conventional immunology with its antigens, T cells and antigen-specific responses, didn’t explain it.

Those pioneering studies went on to develop new nanotechnology applications to prevent allergic airways disease.

Her observations and others like them made Professor Plebanski and her colleagues in the Department of Immunology and Pathology's Vaccine and Infectious Diseases Unit
wonder whether “real” vaccines had potentially beneficial effects beyond those against the specific disease they are designed for, and whether these could be of major significance.

It led them to becoming leaders in the emerging field of what are called non-specific effects (NSE) – that is, those that go beyond the intended protective effects gained by targeting a specific disease.

Professor Plebanski and Monash University collaborator Associate Professor Katie Flanagan are in the midst of having a series of papers published relating to the topic; with three just out and one more in the pipeline, also co-authored by Julie Tran, an Honours student they co-supervise with the Department’s Dr Kirsty Wilson and Associate Professor Menno van Zelm. Associate Professor Flanagan is Adjunct Associate Professor at Monash and an Infectious Diseases specialist at the Launceston General Hospital.

“It’s really exciting,” Professor Plebanski said. “The area’s really emerging and becoming stronger and stronger. It’s not a big field but we’re very much on the front wave of it at the moment,” she said.

The human body has evolved to recognise pathogens, even when they’re attenuated in vaccines, and reacts in different ways, not all of which are specific to the intended pathogen, she explained. For example, the body is able to recognise whole classes of bacteria using TLR receptors. TLRs are proteins that play a key role in the early innate immune system response to invading pathogens.

“What has been emerging is that our body remembers a general assault or attack on it so it has a general state of readiness to react in a particular way to subsequent danger-signals, which is not specific.

“The non-specific or heterologous effects of vaccines as they’re sometimes called, in recent times are being linked to concepts such as innate imprinting or trained immunity, which have become important and very popular. If I get the diphtheria vaccine that changes monocytes and the immune system, my body is then more or less geared to react later against any insult, such as a measles infection. A vaccine designed for pathogen A can have a big effect on pathogen B,” Professor Plebanski said.

This concept has increasing implications for treatments and improvements in them.

“Vaccines at the moment are starting to be considered as potential tools to manipulate, or help prevent, much more than the specific disease against which they were originally designed, to start modulating things like allergies or auto-immunity.”

The BCG vaccine, primarily used for tuberculosis for example, is now being used to treat other diseases such as prostate and some bladder cancers.

“Conversely and unfortunately – and this needs more exploration – not all vaccines have positive non-specific effects and the positive effects can be sex-differential,” she said.

The theory of non-specific effects of vaccines was pioneered by Danish investigator Professor Peter Aaby in the early 1990s although the idea was slow to become accepted and at times contentious. In early 2010 an international consortium, Optimmunize, was established to investigate NSE and sex-differential effects of vaccines – recognised as a key factor in the research – aiming at raising awareness of the matter among the wider scientific community. Professor Plebanski and Associate Professor Flanagan were early members.

It wasn’t until 2016 however that the World Health Organization recognised the value of researching the NSEs in vaccines. Its Strategic Advisory Group of Experts (SAGE) then recommended an “advance toward the implementation of NSE clinical trials”.

Professor Plebanski and Associate Professor Flanagan had been publishing papers on the topic well before this. Two of their recent papers provide a review of the area and further explore the sex differential effects of vaccines.

‘Sex-differential heterologous (non-specific) effects of vaccines: an emerging public health issue that needs to be understood and exploited’ in the journal Expert Review of Vaccines, reviews the evidence and public health implications of NSEs. It discusses the World Health Organization review of the evidence for sex-differential heterologous effects of vaccines, and other studies on NSEs concerning susceptibility to infectious diseases, allergy, autoimmunity and malignancy in animals and humans. It evaluates potential immunological mechanisms and describes how advances in systems biology might be applied to study such effects.

The Expert Commentary in the paper points out the need to understand immune mechanisms in order to exploit beneficial vaccine effects and diminish deleterious ones, suggests that further analysis of vaccine effects by sex is important, and discusses the future for personalised vaccines that take these effects into account.

‘Sex and Gender Differences in the Outcomes of Vaccination over the Life Course’ in the Annual Review of Cell and Developmental Biology reports that clinical data illustrate that among children, young adults and aged people, males and females differ in vaccine-induced immune responses, adverse events and protection. Although males are more likely to receive vaccines, females typically develop higher antibody responses following vaccination, and report more adverse effects than males, it said.

“It’s known that efficacy in certain vaccines differs in males and females across the lifespan and that these become more evident, counter-intuitively, in very young infants and the elderly,” Professor Plebanski said.

“It’s an area still being investigated, as well as trying to understand how to better apply conventional vaccines to get the adaptive response to work more equally in both sexes. The challenge is to understand normal innate imprinting and innate training mechanisms and how they may differ in males and females and how they can be manipulated to provide better outcomes.

“We need understand the mechanisms that underlie the sex-differential vaccine-induced positive effects and to be able to harness these non-specific positive effects,” she said.

Another paper on non-specific effects of a vaccine is due for publication in October. A collaboration with Monash bio-statistician Associate Professor John Reynolds, it studies the non-specific effects of BCG vaccination in infants in Africa.

Katie L. Flanagan, Ashley L. Fink, W. Harry Feinstone, Magdalena Plebanski. Sex and Gender Differences in the Outcomes of Vaccination over the Life Course. Annual Review of Cell and Developmental Biology Vol. 33:- (Volume publication date October 2017)

Flanagan KL, Plebanski M. Sex-differential heterologous (non-specific) effects of vaccines: an emerging public health issue that needs to be understood and exploited. Expert Rev Vaccines. 2017 Jan;16(1):5-13. Epub 2016 Jun 30.

Related research
Ndure J, Noho-Konteh F, Adetifa JU, Cox M, Barker F, Le MT, Sanyang LC, Drammeh A, Whittle HC, Clarke E, Plebanski M, Rowland-Jones SL, Flanagan KL. Negative Correlation between Circulating CD4+FOXP3+CD127- Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria-Tetanus-Pertussis Vaccine Implies a Regulatory Role. Front Immunol. 2017 Aug 14;8:921. doi: 10.3389/fimmu.2017.00921. eCollection 2017.

Fatoumatta Darboe, Jane U. Adetifa, John Reynolds, Safayet Hossin, Magdalena Plebanski, Mihai G. Netea, Sarah L. Rowland-Jones, Jayne S. Sutherland, Katie L. Flanagan. Minimal Sex-Differential Modulation of Reactivity to Pathogens and Toll-Like Receptor Ligands following Infant Bacillus Calmette–GuĂ©rin Russia Vaccination. Front. Immunol., 08 September 2017 | https://doi.org/10.3389/fimmu.2017.01092 Publication date October 2017


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