Issue #57: Interventional trials - preclinical to phase I

Written by Nobel Laureate Professor Peter Doherty

Last week’s discussion (#56) addressed the basic ground rules for designing an acceptable (to ethics and regulatory committees) double-blind, randomised, interventional clinical trial, the gold standard for drug or vaccine evaluation and eventual approval for community use. Prior to that, (#54) we also looked a little at the complementary observational trial strategy, along with relating some personal experience of enrolling as a clinical trial participant. That included the need to sign an informed consent form that clearly lays out any known risks, what will be required of you with regard to providing samples of blood and other body fluids or solids, and the information that you will receive at the end of the trial.

When it comes to clinical trials that are being done in Australia, you would most likely be signing-up to either an observational trial or a Phase 1 interventional trial. The Australian Phase 1 trial capacity has been developing for some years and reflects that we have a comprehensive and high-quality public health system.

When it comes to, say, the initial phase of testing a vaccine to prevent SARS-CoV-2 infection, Australia has the further advantage that there has been minimal ‘background’ infection across the community, so results are unlikely to be confounded by prior exposure and pre-existing immunity.

The primary role of a Phase 1 trial is to check that the product is safe and, beyond that, to determine what is likely to be an optimal dose to prevent infection (a vaccine trial) or to treat an ongoing disease (a drug trial). Prior to injecting any product into humans, it will first have been assessed for any inherent toxicity – generally by toxicologists (chemists) and certified veterinary pathologists who work for companies specialised in this area – then by preclinical studies in animals. When it comes to COVID-19 and SARS-CoV-2, the animal species of choice will initially be mice, followed by (though not invariably) further virus challenge studies in non-human primates.

The AstraZeneca (AZ) vaccine (#43, #44) was first evaluated in ferrets at the CSIRO Australian Centre for Disease Preparedness (formerly the Australian Animal Health Laboratory) in Geelong, then in six rhesus macaques at the NIAIID laboratory in Hamilton, Montana. These SARS-CoV-2 infection studies in animals showed that, when challenged intranasally (IN) with live virus at 28 days after priming with a single (or prime and boost 28 days apart) intramuscular (IM) dose (#17, #53) of the AZ vaccine, both virus production in the nose and upper airways and the extent of any pathology lower down in the lung was massively diminished. The earlier ferret studies were also used to probe the possibility that the vaccine might be given IN rather than IM, with IM being found to work better.

In animal studies, the investigators were watching particularly for any evidence of ‘enhancing antibodies’, a concern suggested from much earlier studies in monkeys directed at making a vaccine (especially inactivated whole virus products) against the SARS-CoV-1 virus that caused the 2002/3 outbreak in East Asia and Toronto. Enhancing antibodies have been discussed mainly with regard to the haemorrhagic dengue syndrome (#20) but, fortunately, they have not been reported as an issue in any of the SARS-CoV-2 vaccine trials.

The Phase 1 clinical study of the AZ vaccine was done as part of a combined Phase I/II trial in the UK, so we may discuss that next week. Though it has taken longer to emerge from the human trials process, the Australian Government has also signed-up for 50 million doses of the Novovax (NVX) vaccine that was evaluated in Phase 1 clinical trial sites in Brisbane and Melbourne. The NVX protein component could potentially be made in the Broadmeadows CSL facility that is currently manufacturing the AZ vaccine. The NVX vaccine is comprised of trimers of the full-length SARS-CoV-2 spike protein mixed in with their proprietary Matrix M1 adjuvant. The NVX M1 adjuvant consists of two types of tiny (40 nm) saponin particles - separated from the inner bark of the Chilean soapbark tree Quillaja saponaria - plus a bit of cholesterol and lipid. Look up ‘saponins’ on Google and you’ll find yourself reading accounts of fancy soaps!

This was a typical double blind, randomised Phase 1 interventional vaccine trial. A total of 83 healthy men or non-pregnant women aged 19-59 were primed IM with either 5mg or 25mg of the NVX spike protein + 50 mg of the M1 adjuvant, then boosted in the same way three weeks later. Another 25 were primed and boosted IM with the NVX spike but no MI and a further 25 were given a placebo (#53). As a precaution, 48 hours before the main trial started, six (3+3) participants were injected IM with these two spikes + M1 doses to check for possible reactogenicity (#45), particularly redness, swelling and soreness at the injection site, or severe headaches that could result from the blood-borne distribution of cytokines, induced particularly by the M1 adjuvant. All went well. Measuring the serum antibody responses later showed that the adjuvant – which is designed to stimulate the innate immunity that functions to enhance the virus-specific response – has an ‘antigen sparing’ effect, meaning that less protein is required for the vaccine. At this stage, the NVX vaccine looks to be both safe and very effective. More next week as we go on to discuss Phase II and Phase III trials.