Kiwi Vax was developed by Vaccine Alliance Aotearoa New Zealand—Ohu Kaupare Huaketo (VAANZ) as part of the Government’s Covid-19 vaccine strategy. VAANZ comprises Te Herenga Waka—Victoria University of Wellington. the Malaghan Institute of Medical Research, the University of Otago,  and a number of local and international collaborators.

Published in iScience, the study findings show that Kiwi Vax is highly immunogenic, robustly expressed, and has a strong stability profile. The vaccine was independently tested at the National Institutes of Health in the United States and at the University of Melbourne.

Dr Lisa Connor from the University's School of Biological Sciences is head of VAANZ's vaccine evaluation team, and says the vaccine's development would never have been possible were it not a combined effort.

"VAANZ brings together scientists across multiple institutes and disciplines, everything from immunology and protein engineering to virology and chemistry. It's always incredible to see so many people working towards a common goal."

Kiwi Vax is a protein-based vaccine which works in a similar way to many traditional vaccines, using genetic information from the virus’s distinct spikes.

Dr Connor, says their subunit vaccine combines two different parts of the spike protein: the receptor binding domain and the N-terminal domain. These specific regions have been identified to contain ‘hot-spots’ that trigger potent immune responses against critical areas of the SARS-CoV-2 virus required for infection.

"Kiwi Vax has a unique set of attributes—its clean design does not attract extraneous immune responses, and it is designed to be specific to the virus. It elicits a broad antibody and T-cell response to all variants of concern, including Omicron, providing complete protection against disease and preventing the virus from replicating in mice exposed to it.

"The immune response generated by the vaccine is also very durable and long-lasting and results to date indicate that Kiwi Vax is stable at refrigerator temperature for several months and at room temperature for at least one month. These are important advantages over current vaccines."

VAANZ Executive Director Dr Kjesten Wiig says the findings not only show that they have developed a promising booster vaccine candidate, but that New Zealand has the expertise, capability, and experience to make our own vaccines.

"Covid will be with us for many more years to come, so having safe and effective booster options, particularly for vulnerable populations, will help keep more people safe from the virus."

With philanthropic funding, the Malaghan Institute is planning to take Kiwi Vax through to a local phase I safety clinical trial later in 2023 using internationally-recognised GMP accredited New Zealand vaccine manufacturer, South Pacific Sera.

Dr Wiig says preclinically, Kiwi Vax is looking promising as a new potential COVID-19 vaccine booster vaccine, but human clinical trials are required to confirm efficacy.

“We’d need a significant industry, philanthropic or government partner to progress to later-stage clinical trials and regulatory approval. But wherever this lands, what we’ve set out to achieve here has been achieved. We’ve proven that New Zealand has the expertise and skills to develop a novel and effective vaccine against a pandemic virus and have built the capability, knowledge and connections to lay the foundations for New Zealand’s response to future pandemics.”

It sounds like a plot for a Cold War thriller—training a gene to infiltrate a cell and reside there, unnoticed, until an external self-destruct signal induces it to destroy its new home.

However, this is not a Le Carré spy novel, but a piece of cutting-edge biomedical science undertaken by researchers from Te Herenga Waka—Victoria University of Wellington, and their Johns Hopkins University collaborators in the United States, that could have important applications in the treatment of cancer and other conditions.

Their paper has just been published in the journal Nature Methods.

David Ackerley, professor of biotechnology in the University’s Te Kura Mātauranga Koiora—School of Biological Sciences and leader of the New Zealand part of the study, says the agent in question is an “unassuming” bacterial enzyme called nitroreductase.

“While medical researchers usually want to focus more on ways to keep our cells alive, rather than killing them, being able to activate a genetic ‘kill switch’ that will target a precisely-defined set of cells actually has a wide range of uses.

“It can allow researchers to understand how certain cells function, by observing the effect of removing them from a model system, or screening for drugs that favour the regeneration and regrowth of those cells.

“A reliable ‘kill switch’ also enables doctors to trial otherwise risky new therapies, like engineering bone marrow or blood cells to protect vulnerable patients against a wide range of diseases.”

The need for this was illustrated by a gene therapy-trial in the early 2000s, which showed much promise for curing “bubble-baby disease”, where babies with immunodeficiency disorders must otherwise be raised in entirely sterile conditions, Professor Ackerley says.

“While some patients were completely cured by the gene therapy, unfortunately it caused leukaemia in others.

“Had the delivered genes included a safe and reliable ‘kill switch’, doctors would have been able to immediately eliminate any cancerous cells that had arisen. However, ensuring both safety and reliability is a scientific challenge.”

Co-leader of the study Professor Jeff Mumm, from the Wilmer Eye Institute at Johns Hopkins University, envisaged an elegant solution—a gene that encodes an enzyme able to activate an artificial drug from a non-toxic to a toxic form.

“That way, the gene would be completely inert in any natural context, and a scientist or doctor could have total control over silencing cells containing that gene, by choosing when to administer the drug.”

Professor Mumm’s preferred drug was metronidazole—a common antibiotic known to be safe in patients, but able to be converted by certain enzymes to a toxic form that is 100 percent-contained by the activating cell, Professor Ackerley says.

“That property enables very clean elimination of target cells, without harm to neighbouring non-target cells. But Jeff’s problem was that because metronidazole is a very artificial drug, nature has never evolved specific enzymes to be good at activating it.

“Our microbial biotechnology team has a lot of experience engineering enzymes to activate drugs like metronidazole and so we stepped in to help.”

Lead researcher and Te Herenga Waka postdoctoral fellow Dr Abby Sharrock, and key team member and University research fellow Dr Elsie Williams studied a family of related enzymes that were promising but inefficient with metronidazole, and proposed two changes they might be able to make to substantially boost this activity.

Professor Ackerley says the result is an enzyme able to kill cells at 100-fold lower doses of metronidazole, “opening the way to many different research and medical applications not previously possible”.

“Although our paper has only just been published, dozens of research teams from around the world have already requested the gene encoding the team’s engineered enzyme.

“We are optimistic that our enhanced enzyme will spur breakthroughs in treatment of a wide-range of disorders, including various cancers and degenerative conditions.”

Lead author Associate Professor Janet Pitman from Te Herenga Waka—Victoria University of Wellington said the University of Illinois test had a 99.1 percent accuracy rate in the study reported in the paper.

“It is the first New Zealand study to diagnostically validate a saliva test for COVID-19,” Associate Professor Pitman said.

The covidSHIELD test is licensed by Rako Science for use in New Zealand.

Associate Professor Pitman said it performed at least as well as nasopharyngeal swab tests, which have been widely used for COVID-19 surveillance testing in the community.

“With the emergence of new COVID-19 variants, it’s more important than ever that we have options for community testing that are acceptable to people getting tested and deliver reliable results. The covidSHIELD saliva test meets these criteria.”

The covidSHIELD test was developed by a multi-disciplinary team of 150 scientists led by Professor Martin Burke at the University of Illinois in Urbana-Champaign, United States.

Associate Professor Pitman and her team began working with the University of Illinois in September 2020 to validate covidSHIELD for use in Aoteoroa. The validation study used 147 saliva samples, each paired with a nasal swab taken at the same time, to measure the reliability of the covidSHIELD test method.

Testing was done at Te Herenga Waka—Wellington University and IGENZ Ltd, a medical test lab in Auckland. Samples were “blind” tested.

The New Zealand research team included Dr Amanda Dixon-McIver, laboratory director at IGENZ, Dr Arthur Morris, a microbiologist and pathologist, and Dr Stephen Grice, director at Rako Science.

“The University of Illinois’ covidSHIELD team was excited to support the New Zealand science team led by Associate Professor Janet Pitman and contribute to the New Zealand Medical Journal paper published today,” University of Illinois executive Discovery Partners Institute director Bill Jackson said.

“Around the globe, the response to the COVID-19 pandemic has driven a well-head of innovation and new global connections. Our collaboration with Associate Professor Pitman and her team is another example of that.

“The University of Illinois is proud to see its innovation being leveraged at scale in New Zealand to keep Kiwis safe, The covidSHIELD test is helping to save lives in the United States and we are pleased it is helping save lives downunder,” Mr Jackson said.

Te Herenga Waka—Wellington University’s Vice Chancellor Dr Grant Guilford said the validation study was “an important contribution to Aotearoa’s public health response to COVID-19. The test provides a practical way to broaden current testing regimens”.

“Global research connections have been crucial during the pandemic and the University of Illinois research relationship with Te Herenga Waka is an excellent demonstration of this,” Dr Guilford said.

It’s World Antibiotic Awareness Week, with scientists and the World Health Organization this year focusing on the theme of “Spread Awareness, Stop Resistance” to raise global understanding of antibiotic and antimicrobial resistance.

The fear is that continuing overuse and abuse of antibiotics will render them much less effective, because it is driving exponentially-increasing levels of bacterial resistance.

For a newly-emerging resistance function to survive, there needs to be some selection pressure for it - that is, bacteria with that function gain something by keeping it around. If there is no selection pressure, it will just fizzle out.

By using antibiotics inappropriately, we maintain a selection pressure for the bacteria to evolve resistance, effectively setting up a scenario in which the resistant ones will have an advantage over the non-resistant ones, and start to dominate the population.

The more we misuse antibiotics, the faster this will happen. Moreover, bacteria are really good at trading genes to each other - so, by using antibiotics when the disease-causing bacterium is not there, we still massively increase the chance that a different species will become resistant and then pass the resistance gene to the dangerous bacterium.

In addition to not using antibiotics when not needed, we can minimise the risk of that happening by using compatible combinations of antibiotics, because it is far less likely that a bacterium will serendipitously evolve two new functions at once.

For example, even if one cell in a billion gains a chance mutation that improves resistance to an antibiotic, if a pair of antibiotics is used it will still be killed by the second antibiotic. To avoid that, it would need to gain two chance mutations at once, and the odds of that happening are one in a billion multiplied by a billion - an unfathomably unlikely one-in-a-quintillion.

DNA is the information store in cells that acts as the genetic blueprint for life. The information encoded by individual genes in our DNA is used to build individual proteins - a vast number of them, which play diverse roles in cells.

Many of the most essential proteins are enzymes, which are tiny nanomachines that perform virtually all of the chemistry of life, including replicating the DNA and helping to build other proteins.

While it has traditionally been thought that each enzyme was contributing a very specific function to our cells, evolutionary history is considerably less straightforward and simple than that. It’s a noisy and tumultuous affair, and a function that is critically important for a cell today may have been virtually irrelevant millennia ago.

What has become clear is that enzymes with some capacity to “moonlight”, i.e. perform additional jobs beyond their current primary role, can buffer cells against new stresses that arise. If the new stress persists, the enzyme can adapt, honing their new skills and turning the moonlighting job into a fixed full-time role.

This type of enzymatic career change can be particularly important for bacteria, which cannot run away from new stresses but must either evolve to meet the challenge or risk extinction.

A classic example of this is the development of antibiotic resistance. In complex environments such as soil, which can harbour more than 10,000 different bacterial species per gram, microbes collectively produce a bristling array of antibiotics as weapons. These enable them to battle with other species competing for the same limited resources.

Bacteria that can withstand the onslaught of a new antibiotic have a competitive advantage in this life-or-death struggle. A moonlighting enzyme which happens to be able to detoxify a particular antibiotic may provide that critical edge.

In natural environments, bacteria are confronted with an ever-changing host of enemies that all make different antibiotics, so there is seldom the sustained pressure required to adapt an amateur moonlighting enzyme into an antibiotic-resistance specialist.

But humans have changed the game by repurposing nature-derived antibiotics to treat clinical infections. Suddenly, antibiotics are being produced and used on a scale the world has never seen before. If used inappropriately, say by patients who fail to complete a course, then bacteria containing a partially-effective moonlighting enzyme may survive and move one step closer to developing full immunity to that antibiotic.

Our team in the Microbial Biotechnology Lab at Te Herenga Waka–Victoria University of Wellington is being supported by the Royal Society Te Apārangi’s Marsden Fund to investigate how entirely new forms of antibiotic resistance can develop from moonlighting enzymes.

While studies like this are usually performed by choosing a single disease-causing bacterium and growing it over many weeks in the presence of incrementally-escalating doses of an antibiotic, we are focusing on soil as a rich model environment and purifying all of the DNA from the thousands of bacterial species that reside there.

This gives us access to the collective set of genetically-encoded enzymes, and we have developed a unique way of breaking this DNA up into small gene-sized fragments and maximising the amount of protein they will produce when transferred into E. coli, a tame laboratory bacterium.

From this we are able to detect very weak moonlighting activities that help defend their new E. coli home against an antibiotic challenge. We can then use artificial evolution techniques to evaluate whether these have the propensity to adapt into dangerous levels of antibiotic resistance.

Of course, we have to be very careful in doing so, as we want to understand the spread of antibiotic resistance but not contribute to it! All our work is conducted under the same physical-containment conditions as used to study disease-causing bacteria that are already antibiotic resistant.

Our work also provides insights into how readily resistance to new antibiotic drugs might arise in the clinic, and the most likely way or ways for this to happen. This can in turn inform possible counter-measures.

For example, we have tested a promising new antibiotic candidate called niclosamide, which several research teams have shown bacteria struggle to become resistant to. Concerningly, we have found a type of enzyme that is common in soil bacteria and can readily be evolved to confer high-level niclosamide resistance.

The good news is, as this enzyme evolves to make bacteria more resistant to niclosamide, it makes them more sensitive to another common antibiotic, metronidazole. So, by administering metronidazole with niclosamide, doctors should be able to prevent this form of resistance arising.

This would be an encouraging step in our crackdown on the moonlighters.

Professor David Ackerley is a microbiologist and enzyme engineer in Te Kura Mātauranga Koiora–School of Biological Sciences at Te Herenga Waka–Victoria University of Wellington.

Read the original article at Newsroom.