The Lancet Infectious Diseases: First clinical trial of antibody to neutralize henipaviruses finds it is safe and well tolerated in healthy volunteers

February 03, 2020

The first ever treatment for preventing a group of viruses from causing potentially lethal infections has been tested in a phase I clinical trial, and was found to be safe and able to neutralise the viruses, according to results from 40 patients published in The Lancet Infectious Diseases journal. The trial was conducted in healthy participants and further trials will be needed to demonstrate its efficacy in infected patients.

Hendra virus and Nipah virus are two closely related RNA henipaviruses that emerged in 1994 and 1998 respectively. Flying foxes, a type of fruit bat, appear to be the major natural reservoir hosts for henipaviruses. A mortality rate of 57% has been observed from seven known cases of Hendra virus in Australia, while 373 fatalities from Nipah virus have been reported in south and southeast Asia between 1998 and 2018.

Although the number of outbreaks has been small so far, Henipavirus diseases have been placed on the WHO list of diseases with epidemic potential that are a priority for research because there are no, or insufficient, countermeasures. Nipah virus has the potential to mutate rapidly, and human-to-human transmission is possible, raising concerns of pandemic potential.

"Given the high death rate from infection by henipaviruses, their ability to cause infection in multiple organs including the brain, and their unique ability to spread to humans from bats via a wide range of animal species including horses and dogs, doctors need a safe way to neutralise them," says Dr Elliott Geoffrey Playford from Princess Alexandra Hospital, Australia. "Our results are the first to confirm that administering an antibody that binds to the virus is safe, making it the most promising therapeutic option to date for addressing this unmet medical need." [1]

The monoclonal antibody m102.4 has successfully neutralised henipaviruses in previous experiments with non-human primates. It binds to proteins on the surface of virus cells that would normally allow the virus to gain access to host cells and cause infection. The antibody has been available since 2010 for compassionate emergency use in Australia for people exposed to Hendra virus, but the current study is the world's first clinical trial to assess its safety in humans and to determine its fate as it travels through the body. Laboratory experiments were also used to test the ability of the antibody to neutralise the viruses after it had been circulating in the body.

The study was randomised, double blinded and placebo-controlled. Forty eligible adults aged 18 to 50 were randomly assigned to five different groups: four groups receiving the antibody in single doses that escalated from 1mg/kg in the first group to 20mg/kg for the fourth group, and the fifth group receiving two doses of 20mg/kg. In each group, six participants received the antibody and two received a saline placebo.

The safety and tolerability of m102.4 was assessed using a combination of tests including physical examinations, clinical laboratory tests, electrocardiogram (ECG), and records of adverse events. Blood samples were taken from volunteers to test for any immune reactions and for the ability of the body to eliminate the antibody. The samples were also used to test the circulating antibody's ability to neutralise the viruses 12 hours, 24 hours, four days, and eight days after injection.

Overall, the doses of m102.4 used in the study were found to be safe and well tolerated. The researchers recorded no serious adverse events related to treatment. The most common treatment-related adverse events were headaches, which were reported by 12 out of 30 volunteers in those receiving the antibody and three out of 10 volunteers who received the placebo. Volunteers who received the double dose did not report an increase in headaches.

In tests on the blood samples, the body's ability to eliminate the antibody was found to be similar between participants receiving the single or repeated dose. At no time point during the study did the antibody generate an immune reaction against the antibody itself. Tests on the circulating antibody's ability to neutralise the viruses found neutralisation activity against both Hendra and Nipah viruses in all samples and at all the time points tested. The authors conclude that the antibody remained active for at least eight days after intravenous injection.

"When there's a possible case of henipavirus infection, or people suspect they might have been exposed to one of the viruses, there often isn't time to confirm a diagnosis before it could be become too late to do anything about it," says Dr Heidi Carroll from Queensland Health, Australia. "Based on the results of our trial, we suggest offering a single dose of 20mg/kg of m102.4 to people likely to have been exposed to one of the viruses, or two doses separated by 48 hours to patients with clinical signs of infection." [1]

The authors note that the main limitation of the study is the small number of participants, which is common in phase I studies. They also note that at the moment there is no evidence of viral mutants able to escape m102.4, and that escape is unlikely, but the potential for this with RNA viruses cannot be ruled out. Future studies will be needed to demonstrate the efficacy of the antibody against different strains of Nipah and Hendra viruses and it might be necessary to consider a cocktail of monoclonal antibodies to reduce the chances of m102.4 decreasing in efficacy.

Writing in a linked Comment, Dr Hossain Sazzad from the University of New South Wales, Australia, says: "The safety profile of both single and repeated dosing of m102.4 and the standard pharmacokinetic profile presented by Playford and colleagues make m102.4 a potential candidate for post-exposure prophylaxis against henipavirus infection. m102.4 prophylaxis will be crucial for accidental laboratory exposure or healthcare workers working in a high-risk setting. However, in real-world outbreak settings, such as Bangladesh, the situation might be different." He continues: "Further evaluation of efficacy of m102.4 in established clinical infection-- which was beyond the scope of the small-scale phase 1 trial done by Playford and colleagues--will be crucial."
-end-
NOTES TO EDITORS

This study was funded by Queensland Department of Health, the National Health and Medical Research Council, and the National Hendra Virus Research Program. It was conducted by researchers from Princess Alexandra Hospital, the University of Queensland Brisbane, Clive Berghofer Cancer Research Centre, QIMR Berghofer Medical Research Institute, Queensland Health, CSIRO Australian Animal Health Laboratory, Henry M Jackson Foundation for the Advancement of Military Medicine, Duke-National University Medical School, University of Pittsburgh Medical School and Uniformed Services University.

The labels have been added to this press release as part of a project run by the Academy of Medical Sciences seeking to improve the communication of evidence. For more information, please see: http://www.sciencemediacentre.org/wp-content/uploads/2018/01/AMS-press-release-labelling-system-GUIDANCE.pdf if you have any questions or feedback, please contact The Lancet press office pressoffice@lancet.com

[1] Quote direct from author and cannot be found in the text of the Article.

Peer-reviewed / Randomised Controlled Trial / People

The Lancet

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