It’s worth re-engineering the clamp

The Australian COVID-19 vaccine developed by the University of Queensland was abandoned last December after participants in human trials returned false-positive HIV tests.

The news was as devastating for the research group as it was for the many Australians who were hoping the vaccine would help life return to some kind of normality post-COVID-19.

Although the trials were halted, the UQ research group has not stopped its assiduous work. Back in the lab, the team is trying to re-engineer the clamp that holds the SARS-CoV-2 spike together to avoid the HIV-test cross-reactivity.

“We had to go back to the drawing board at the end of last year,” says Associate Professor Keith Chappell, one of the UQ researchers who helped develop the molecular clam technology. “But we have a pathway forward, and we think we can completely resolve the HIV issue.”

A spike protein sits on the cell surface of SARS-CoV-2 virions. When the virus enters our body, the spike attaches to the ACE2 receptors in our cells to insert its genetic material into the cell and to replicate.

Many COVID-19 vaccines target the spike rather than the whole virus to elicit an immune system response. But they have to deal with the instability of the spike.

The spike protein is anchored to the virus surface, held in place by the viral membrane. When researchers isolate the spike, it’s naturally unstable, and rearranges into a more stable shape that differs from what’s on the virus surface. This is what causes the immune system to produce antibodies designed for the wrong enemy.

The molecular clamp designed by the UQ researchers is a scaffold that holds the spike protein in the right shape for the immune system to make antibodies, leading to a highly effective vaccine.

“The whole theory behind our work is that stabilising [the spike] is going to give you a more efficient immune response at recognising the virus and getting rid of it,” says Chappell.

But one portion of the clamp is made of a protein found in HIV, which turns out to also elicits an immune response. Some participants developed antibodies against the clamp as well as the spike protein – and so returned a false-positive HIV test.

It is crucial to note that these test participants did not contract HIV: in fact, they developed antibodies against one protein found in the human immunodeficiency virus.

Preclinical trials published today in Clinical and Translational Immunology show not only that the vaccine is protective against COVID-19, but that it’s also stable at domestic refrigerator temperatures.

Despite the HIV test cross-reactivity issue, “this candidate vaccine has significant advantages that demonstrate the suitability of the underlying platform technology to meet the global response to the ongoing COVID-19 pandemic as well as novel viruses that may emerge in the future”, write the authors. 

“It’s definitely early days, but the first indications are looking good,” says Chappell. “We’re confident that we’ll be able to resolve the HIV issue completely. We will have a vaccine that works as well as the results we’ve just shown, without the diagnostic interference.” 

Chappell says he’d encourage everyone to get vaccinated with the vaccines currently available in Australia. In the meantime, the UQ research group is carefully monitoring the emergence of new variants to develop a vaccine that can fill the gaps other vaccines might leave. 

“We’ve tried to be completely upfront about the HIV issue,” Chappell adds. “We’ve published all the tests that react with the vaccine and those that don’t react. We think that being completely upfront and open, showing the integrity of science, should be a boost for public confidence in vaccines overall.”