Data from about a decade back indeed suggested a promising role for Type I interferon (IFN) as anti-Ebola Rx and then nothing much afterwards. The 2013-14 West African Ebola epidemic changed this, and it’s back on the table now.
The following quotes are from reference 1.
‘Dr. Michael Kurilla, director of the Office of Biodefense Research Affairs at the US National Institutes of Health (NIH), reviewed what he terms “a fair amount of existing data on interferon,” and concluded, “It’s certainly not a cure for the disease, that’s clear.” But he, too, thinks it has a role.
“If you can get interferon in early on, in the nonhuman primate [monkey] model, what you see is a delay to death and a reduction in the level of viremia, both of which would seem to be good.”
The NIH is discussing a combination therapy ─ adding interferon to another available antiviral drug, ribavirin ─ and “working out the details” for studying the combination in monkeys. “If it shows efficacy in a nonhuman primate study, that might be something easily implementable in patients,” Kurilla says.
WHO Assistant Director-General Dr. Marie-Paule Kieny gave the WHO assessment at the close of the consultation: interferon could be tried in patients “with early disease.” ‘.
This is what the WHO recommended in 2014 pertaining to IFN Rx for Ebola
Not sure if IFN works for Ebola prophylaxis but a few non-human primate studies suggest it could help with Ebola Rx.
Ebola Cynomolgus monkey IFN-alpha studies (3, 4)
Cynomolgus monkeys study 1 with anti-Ebola monoclonal antibodies (mAbs) (3). No IFN Rx in this study.
- Cynomolgus monkeys intravenously (iv) injected with human-derived Ebola.
- Treated iv with anti-Ebola mAbs ZMAb, 3 Ebola-GP protein–specific neutralizing mAbs (1H3, 2G4, and 4G7).
- 100% protection (4/4) when 1st mAb (25mg/kg per dose) given 24-hour post-exposure plus 2 more every 3 days.
- 50% protection (2/4) when 1st mAb dose given 48-hour post-infection.
Cynomolgus monkeys study 2 with anti-Ebola mAbs (4). IFN Rx added to same ZMAb Rx.
- 75% protection (3/4) when 1st mAb dose given 72-hour post-exposure.
- 50% protection (2/4) when adenovirus vector-derived human-IFN-alpha given intramuscularly 24-hour post-exposure then anti-Ebola mAbs 96-hour post-exposure.
Far from perfect study design.
Comparison of 1st mAb dose 48-hour post-infection with/without adenovirus vector-derived human-IFN-alpha would have been much more convincing. Small numbers of subjects so data very much preliminary.
Ebola Rhesus monkey IFN-beta study (5)
- Subcutaneous Type I IFN alone delayed time to death.
- Reduced plasma and tissue viral burden.
- Reduced pro-inflammatory cytokine production, i.e. reduced ‘ ‘, a key effect since Ebola mortality is not so much from the virus as from uncontrolled, i.e. ‘cytokine storm’, immune response. By preventing such deadly unrestrained immunity, IFN could help a more restrained and regulated anti-Ebola immunity to develop and also gain time for targeted anti-Ebola Rx such as anti-Ebola mAbs to kill the virus.
A 1999 study (6) of 4 patients (lab personnel involved in experimental Ebola studies) suspected exposed to Ebola.
- Treated with goat anti-Ebola antibodies intramuscularly.
- Plus IFN-alpha twice daily for 12 days (authors don’t mention route).
All 4 patients recovered.
Limitations of IFN for Ebola Rx
- Ebola targets and shuts down Type I IFN (7, 8).
- IFN is unlikely to be effective as a stand-alone anti-Ebola Rx, with the caveat that oromucosal Type I IFN has never been tested for this purpose.
- IFN works best when given early following Ebola infection. Ensuring early IFN Rx in the field then becomes a logistical challenge. Salient questions:
– How quickly following earliest symptoms do people seek treatment from a health care facility?
– How quickly do such facilities diagnose Ebola?
Advantages of IFN Rx for Ebola
- Pegylation (attaching PEG, polyethylene glycol) increases its bioavailability.
- Already approved, as subcutaneous, not as oromucosal, for variety of diseases such as Hepatitis C, MS (Multiple Sclerosis) so regulatory approval path easier and faster than for new drugs.
- Long history of human (subcutaneous) use so plenty of safety data available.
IFNs induce IFITM (Interferon-induced transmembrane proteins) (9, 10). Such proteins have broad (HIV, HCV, SARS, Corona, and also Ebola) anti-viral activity (11).
- IFITM inhibit viral entry by preventing viral fusion and viral content release into the cell cytosol.
- When restricted by IFITM proteins, viruses fuse with host cell membranes, a process that induces type I IFN, i.e. a positive feedback loop.
- In turn, IFN-beta induce IFITM to restrict Ebola entry (12).
Other Drugs that could drive type I IFNs during Ebola infection
An older pair of mouse Ebola infection studies from 2000 and 2002 found massive IFN-a production when they subcutaneouslyinjected SAH (S-adenosyl-L-homocysteine) hydrolase inhibitors such as 3-deazaneplanocin A (c3-NpcA) and carbocyclic 3-dezaadenosine (C-c3Ado) (13, 14) following intraperitoneal Ebola infection.
- Is this IFN-a causal or casual? Not clear yet but SAH inhibitor plus anti-mouse IFN-α/βantibodies eliminated this protective effect (15).
- Perhaps SAH inhibitor blocks methylation of (+)RNA transcribed from the (-)RNA filovirus genome.
- This would prevent mRNA release from the (-)RNA(+)RNA duplex.
- Accumulation of such double-stranded (ds) RNA molecules would be powerful IFN inducers.
Such data suggest SAH inhibitors should be studied in non-human primates for Ebola Rx, specifically to induce Type I IFN.
Plausible theory for how anti-Ebola Type I IFN Rx could work
How Ebola does what it does
- Ebola deliberately evades type I IFNs by suppressing them (7, 8).
- In absence of type I IFNs, Ebola replicates much more rapidly.
- In turn, host immunity responds disproportionally (‘cytokine storm’) to such rapid and exponential viremia.
Using Type I IFN to counter Ebola’s tactic
- Give patients type I IFN early after infection to keep viremia down.
- Lower viremia in turn would stave off uncontrolled anti-Ebola immunity, i.e. prevent ‘cytokine storm’.
- Targeted anti-Ebola Rx such as anti-Ebola mAbs and/or antivirals would then control and eliminate the virus.
Using Type I IFN early on to deliberately tamp down ‘cytokine storm’-like immunity would thus allow a protective anti-Ebola adaptive immunity to develop. Since subcutaneous Type I IFN is already approved for human use, probably this usage could be fast-tracked for Ebola Rx. Oromucosal Type I IFN is a different story, first needing studies in non-human primates, then safety studies in humans, though I agree that oromucosal Type I IFN may be more effective, even at lower doses. Path to regulatory approval for oromucosal Type I IFN is rather steep though.
- Shuchman, Miriam. “Could interferon help treat Ebola?.” Canadian Medical Association Journal (2014): cmaj-109.
- World Health Organization. “potential Ebola therapies and vaccines.” (2014).
- Qiu, Xiangguo, et al. “Successful treatment of Ebola virus–infected cynomolgus macaques with monoclonal antibodies.” Science translational medicine 4.138 (2012): 138ra81-138ra81.
- Qiu, Xiangguo, et al. “mAbs and Ad-vectored IFN-α therapy rescue Ebola-infected nonhuman primates when administered after the detection of viremia and symptoms.” Science translational medicine 5.207 (2013): 207ra143-207ra143.
- Smith, Lauren M., et al. “Interferon-β therapy prolongs survival in rhesus macaque models of Ebola and Marburg hemorrhagic fever.” Journal of Infectious Diseases 208.2 (2013): 310-318.
- Kudoyarova-Zubavichene, Natalya M., et al. “Preparation and use of hyperimmune serum for prophylaxis and therapy of Ebola virus infections.” Journal of Infectious Diseases 179.Supplement 1 (1999): S218-S223.
- Kühl, Annika, and Stefan Pöhlmann. “How Ebola virus counters the interferon system.” Zoonoses and public health 59.s2 (2012): 116-131.
- VanHook, Annalisa M. “How Ebola Shuts Down Antiviral Signaling.” Science Signaling 7.339 (2014): ec216-ec216.
- Chutiwitoonchai, Nopporn, et al. “Characteristics of IFITM, the newly identified IFN-inducible anti-HIV-1 family proteins.” Microbes and Infection 15.4 (2013): 280-290.
- Perreira, Jill M., et al. “IFITMs restrict the replication of multiple pathogenic viruses.” Journal of molecular biology 425.24 (2013): 4937-4955.
- Lai, Kang Yiu, Wing Yiu George Ng, and Fan Fanny Cheng. “Human Ebola virus infection in West Africa: a review of available therapeutic agents that target different steps of the life cycle of Ebola virus.” Infectious Diseases of Poverty 3.1 (2014): 43.
- Huang, I-Chueh, et al. “Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus.” PLoS pathogens 7.1 (2011): e1001258.
- Bray, Mike, John Driscoll, and John W. Huggins. “Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor.” Antiviral research 45.2 (2000): 135-147.
- Bray, Mike, et al. “3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice.” Antiviral research 55.1 (2002): 151-159.
- Bray, Mike. “The role of the Type I interferon response in the resistance of mice to filovirus infection.” Journal of General Virology 82.6 (2001): 1365-1373.