Influenza A virus is a major public health threat, killing more than

Note: A literature review has been compiled on the topic: Interferon Inhibition by the NS1 protein - Enhanced virulence/viral pathogenesis by enabling the virus to disarm the host cell type IFN defense system http://www.pathobiologics.org/ivphc/ref/ns1_ref121904.html

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Low Dose Interferon, Immune Modulation and Emergency Influenza Prophylaxis

Prepared by Joseph M. Cummins, DVM, PhD and Chad G. Thompson, BA

Amarillo Biosciences, Inc. 800 West 9 th Avenue, Amarillo, Texas 79101-3206 Telephone:806-376-1741, Fax: 806-376-9301 Email: jcummins@amarbio.com

Abstract: Warnings have been issued that the avian influenza virus presently killing animals and people in Asia may become the new strain of pandemic flu which could potentially kill millions of people.  These warnings have sparked renewed interest in ways to treat or prevent influenza. Clinical observations from thousands of influenza patients in Russia, Ukraine, Bulgaria, China, and Japan claim significant clinical benefits to patients intranasally given low-dose (a few hundred to 10,000 units) interferon during natural outbreaks of influenza. In contrast, in experimental influenza virus challenge studies with human volunteers, those volunteers given 800,000 to 70 million units of interferon by intranasal delivery did not experience a clinical benefit. Data generated using low dose interferon was rejected by Western scientists because of the impure nature of the interferon used in early studies and because the low dose interferon did not seem to make any sense. This review proposes that the subject of low dose interferon for influenza be revisited.  Intranasal and oral administration of low-dose interferon deliver interferon to the same receptors in the oral-pharyngeal cavity. Low-dose oral interferon may represent an inexpensive, safe way to modulate the immune system during, or before, influenza infection. 

History: Influenza virus is a major public health threat, killing more than 30,000 per year in the U.S. alone, and sickening millions.  Novel influenza virus strains emerge periodically to which humans have little immunity, resulting in devastating pandemics.  The 1918 pandemic killed nearly 700,000 Americans and 40 million people worldwide.  Pandemics in 1957 and 1968, while much less devastating than 1918, also caused tens of thousands of deaths. Influenza virus is capable of genetic variability, both by continuous, gradual mutation and by reassortment of gene segments between viruses.  Both the 1957 and 1968 pandemic strains are thought to have originated as reassortants, in which one or both human-adapted viral surface proteins were replaced by proteins from avian influenza virus strains (Reid & Taubenberger, J Gen Virol 84, 2285-2292, 2003).

Influenza has been called the last great plague. The pandemic of 1918-19 raced around the world in three waves, killing millions of people and causing enormous social and economic disruption.  Over the past 250 years, at least 10 and perhaps as many as 20 lesser influenza pandemics have swept the globe, interspersed with a much larger number of milder, more localized epidemics (Kaplan & Webster, Sci Am  237(6):88-106,1977).

According to Shope (U.S. Pub Health Rep 73: 165-168, 1958), pandemic influenza dates its initial recognition to the year 1173.  Since then it has recurred at irregular intervals under various names: febris catarrhalis epidemica, tussis epidemica and finally influenza. Kaplan and Webster assert that the highly contagious, acute respiratory illness now known as influenza appears to have afflicted humans since ancient times. The individual symptoms and epidemiological traits of the disease are sufficiently characteristic to enable one to identify a number of major epidemics in the distant past. One such epidemic was recorded by Hippocrates, in 412 B.C., and numerous episodes were described in the Middle Ages (Kaplan & Webster, 1977).  With history as our guide, it is certain that a new influenza pandemic will eventually occur with deadly consequences. It is only a question of when.

In terms of numbers of human victims the great pandemic of 1918-19 was unprecedented. Estimates run from 20-40 million killed throughout the world.  More than 500,000 deaths were recorded in the U.S., and other parts of the world were equally or more gravely struck.  One authority estimated 20 million deaths in India alone, and some parts of Alaska and the Pacific islands lost more than half their population (Kaplan & Webster, 1977).

The Present: The H5N1 strain of Avian Influenza has presented widespread problems in Asia with a 70% mortality rate in humans. In an effort to contain widespread outbreaks, the Food and Agriculture Organization of the United Nations (FAO) has reported that more than 450 million birds have been killed in Asia, excluding China (approximately 0.7 percent of the region's total inventory). The following concerns have prompted a call for countries to develop an Influenza Pandemic Preparedness and Response Plan.

WHO warns flu threat could hit billions (Friday, November 26, 2004 - Web posted at 7:25:43 GMT)  BANGKOK - An influenza pandemic is likely to affect every country leaving millions dead and make more than a quarter of the world's population ill with no vaccines available until at least next March, the World Health Organization (WHO) said yesterday. An outbreak of bird flu that has killed 32 people in Thailand and Vietnam this year is the most likely cause of an inevitable pandemic but it was not clear if it would start in the "next week or the next years", said Dr. Klaus Stohr of the WHO global influenza program. He predicted more than a quarter of the world's estimated 6.4 billion population would fall ill from influenza.

"There are estimates that would put the number of deaths at the range between two to seven millions and the numbers of people affected will go beyond the billion because 25 to 30 percent will fall ill," he told reporters at a meeting in Bangkok of health ministers and officials from 13 Asian nations. "An influenza pandemic would spread globally and every country would be affected." The WHO has sounded similar warnings during two waves of bird flu outbreaks across Asia that have destroyed bird stocks and infected 44 people, killing 12 in Thailand and 20 in Vietnam.

"Every hundred years there has been three or four pandemics and there's no reason to believe we will be spared," Stohr said.  "There's no date. There's going to be another pandemic, whether it happens this year or next, we don't know." The Asian H5N1 strain of the virus was "certainly the most likely one that will cause the next pandemic", Stohr said. But he said there had been no sign of the virus mutating since April - health officials fear it would change to a form that could spread easily between humans and trigger the pandemic - and said a vaccination program could prove effective.

The meeting in Bangkok follows complaints that Asian nations have not done enough to tackle the crisis and the WHO warned the disease could now be permanent in the region. Dr. Bjorn Melgaard, of the WHO's Southeast Asia regional office, said officials had hoped the bird flu outbreak would be a one-off epidemic but now appeared to be a "long-term to permanent situation". He said it could prove to be a virus "that is able to maintain its life in bird populations continuously".

In virtually all cases in Asia this year, humans have contracted bird flu from close contact with birds although one Thai woman is suspected to have caught the disease while caring for her sick child in hospital. Similar "dead-end" cases of limited transmission have been detected in humans before and officials says it did not mark the start of a human pandemic. The WHO said international co-operation was essential and brought together the 10-member Association of Southeast Asian nations along with Japan, China and South Korea for the meeting.

Russian Expert Says Flu Epidemic May Kill Over One Billion This Year (Created: 28.10.2004 18:06 MSK (GMT +3), Updated: 18:15 MSK  MosNews)  The world is on the brink of a major flu epidemic — one that could claim more than a billion lives, the head of the Russian Virology Institute, Academician Dmitry Lvov said at a press conference organized by the RIA-Novosti news agency on Thursday.  “Up to one billion people could die around the whole world in six months,” Lvov said. The expert did not give a timeframe for the epidemic, but said that it is highly probable that it will start this year. “We are half a step away from a worldwide pandemic catastrophe,” the academic said.

The Russian expert said that U.S. researchers possessed data suggesting that if a pandemic hits, up to 700,000 people will fall ill in the United States. He said that the population of the United States can be roughly compared to that of Russia and thus the number of cases will be approximately the same. The academician said the pandemic was most likely to be caused by the so-called bird flu. “The death rate among those who contract this type of flu reaches 70 percent,” Lvov said. The expert called for the Russian authorities to prepare for the epidemic. The country will need a reserve of at least 300,000 hospital beds if an epidemic breaks out, he said.

Trust for America’s Health Report on Public Health Preparedness (released December 14, 2004) Lowell Weicker, a former US Senator and Governor from Connecticut, is the Board President of the non-profit Trust that reported that 20 US states do not have a public response plan to deal with a flu pandemic.  According to the Trust report, Scientific models show that in the US, a major flu outbreak could result in 89,000 to 207,000 deaths and cost the economy $166.5 billion.

Proposed Intervention with Oral Interferon: Most of the world either can not afford, or does not have access to, influenza vaccines or antiviral drugs. Oral or nasal delivery of interferon has been reported to be safe and effective against influenza in humans(see literature review below). Interferon lozenges are inexpensive, non-toxic, easy-to-administer, stable at room temperature for 2 years, exert systemic beneficial effects and fit the medical needs of the developing nations.      

Brief Literature Review of Orally Administered Interferon: Interferon is a name first used in 1957 to describe a protein that was “interfering” with replication of influenza virus in chicken eggs (Issacs & Lindenmann, Proc R Soc London Ser B 147:258-267, 1957). Thirty years later in 1987, high-dose injectable interferon gained its first FDA approval (as a treatment for hairy cell leukemia). The use of low-dose oral interferon has been reported to be safe and beneficial in various diseases in animals and man (Cummins et al. Am J Vet Res, Jan 2005). It has been reported that low doses of intranasal or oral interferon exerts positive systemic effects.  Furthermore, it has been reported that increasing the oral dose of interferon does not improve the clinical effect but instead, the beneficial effect wanes (Cummins et al. Am J Vet Res, 66(1): 164-176, 2005).  In an animal model of asthma, interferon beta in the drinking water at 500 units/day had a suppressive effect on eosinophil cell counts, but 50,000 units did not (Satoh et al, J Int Cyto Res 19:887-894, 1999).  Significant (P<0.01) protection from a lethal challenge of Semliki Forest virus was observed when low levels (10-100 units/ml), but not higher levels, of interferon were added to drinking water (Stanton et al, J Int Res 10:S99, 1990).

In animal models of multiple sclerosis, (EAE or experimental allergic encephalomyelitis), low doses (10 units) of interferon given to mice were significantly (P<0.01) better than higher doses (1000 units) in suppressing the clinical EAE (Brod SA, Khan M. Cytokine 6:567, 1994).  Cats with feline leukemia responded better to oral delivery of 0.5 IU human interferon alpha than to 5.0 IU (Cummins et al, J Biol Resp Mod 7:513-523, 1988). Horses with inflammatory airway disease responded better to oral delivery of 50 IU human interferon than to 450 IU (Moore et al, Vet Immunol Immunopathol 49:347-358, 1996. Newborn piglets had significantly greater survival if they were treated with 1 IU human interferon alpha orally, compared to 20 IU (Cummins et al, Vet Immunol Immunopathol 45:355-360, 1995). Non-obese diabetic (NOD) mice given 100 IU of murine interferon alpha orally had greater survival than mice given 100,000 IU orally (Tanaka et al, J Int Cyto Res 19:877-879, 1999).

Besides examples in animals, there are also examples in human disease in which low dose oral interferon seems to be better than high dose oral interferon.  It is reported that low dose (150 IU) human interferon alpha given daily three times per day (t.i.d.) for 6 months was better than higher dose (450 IU) human interferon alpha given t.i.d. to patients with Sjögren’s syndrome (Ship et al, J Int Cyto Res 19:943-950, 1999).

Brod et al (Multiple Sclerosis: 3:1-7, 1997) studied subjects with relapsing-remitting multiple sclerosis (RRMS).  In subjects with RRMS, a significant decrease in surrogate markers for MS were observed at 10,000 and 30,000 units of human interferon-a (ingested by mouth) but not 100,000 units.  The authors reiterate that parenterally administered type 1 IFN use is limited by clinical and chemical toxicities.  They conclude “these results demonstrate that systemic immunobiological effects result from hrIFNa ingestion of comparatively low doses (10,000-30,000 units) compared to parenteral doses (6-9x10⁶) units used clinically in subjects with RRMS.”

Human Studies; Interferon and Influenza: There are numerous publications showing that specific influenza vaccines or antivirals protect animals or humans against influenza virus. For the purpose of this review, only those publications are reviewed which describe the safety and efficacy of interferon given to humans during or before natural or experimental influenza virus infections. Several influenza natural outbreaks or challenge studies have been conducted in man which demonstrate that low doses (but not high doses) of intranasal interferon may be safe and effective.

When leukocyte interferon was given in low doses intranasally for 3 consecutive days to 374 subjects "at the height" of an influenza outbreak, interferon-treated subjects had less severe illness than 382 subjects given placebo. When interferon was given to 320 subjects "before" the influenza outbreak, these subjects had less illness than the 317 subjects given placebo. Soloviev reported that the interferon treatment was free of adverse events and proposed that interferon "will be given proper place in the arsenal of means for fighting virus infections (Soloviev in The Interferons, Baron and Rita, eds., New York, Academic Press, p. 233-243, 1967).

In 1969, Soloviev reported (Bull. WHO 41:683-688) that about 14,000 people participated in controlled studies of placebo versus interferon treatment during a natural outbreak of Hong Kong influenza. Interferon (about 128 units) or placebo was dripped into the nose daily for 5 days starting about the time of the first reported influenza cases. Interferon treatment significantly (P<0.01) reduced the number of influenza cases.

Efficacy of human leukocyte interferon against Hong Kong influenza

Group	Treatment	Number of patients		% sick
		Enrolled	Sick
Adults	Interferon	2994	231	7.7
	Placebo	3129	551	17.6
Children 7-12 years	Interferon	1917	119	6.2
	Placebo	2055	413	20.1
Children 2-6 years	Interferon	463	22	4.8
	Placebo	454	53	11.7

In his discussion, Soloviev stated that "there are sufficient grounds to recommend human leukocyte-produced interferon as one of the means of influenza prophylaxis. The method is absolutely harmless, simple and convenient, and should be applied where there is an immediate threat of infection, that is, as a means of emergency prophylaxis."

In September 1971, group of U.S. scientists visited the Soviet Union and reported (Antiviral Research in the Soviet Union, J Infect Dis 125:455-456, 1972) that there was advanced clinical work on the use of exogenous interferon in Russia. Furthermore, the U.S. delegation reported that human leukocyte interferon was available through pharmacies in the Moscow area for use as a nasal spray against influenza.

Another group of U.S. scientists arrived in Moscow on January 20, 1973, during the waning days of an extensive influenza epidemic (Jordan et al, J Infect Dis 128:261-264, 1973). During the peak of the epidemic January 8, the number of influenza cases reported in Moscow reached 90,000 per day. The U.S. scientists reported that Russians were using two types of live vaccines to treat and prevent influenza. Although "one director of the institute indicated that neither live vaccine nor exogenous interferon was useful in the prevention of influenza," it was reported that for 3 years several Soviet medical centers observed that human leukocyte interferon was effective in the prophylaxis of influenza. When interferon treatment (500 units of leukocyte interferon given by nasal spray three times daily for 3 days and then once daily for two days) was started in a factory or school immediately after the first case of influenza, approximately a 60% decrease in influenza symptoms was reported in interferon-treated patients, without adverse events.

To achieve therapeutic effects, leukocyte interferon was given by aerosol and orally. At the first sign of influenza illness, 20 ml of interferon (300 units/ml) was given over 5 minutes duration by the oral and nasal aerosol routes. This was repeated in 2 hours if the patient's symptoms were severe and was always followed by intranasal administration of leukocyte interferon twice daily for three days at the dosage used for prophylaxis. Clinicians reported that the interferon treatment caused symptoms to disappear more quickly; fever and headache were thought to clear almost immediately.

Merigan et al (Lancet i; 563-567, 1973) reported on the treatment of 11 human volunteers with placebo and 11 volunteers with human leukocyte interferon (800,000 units given by spray-gun with a nozzle yielding a fine mist).The interferon was given in divided doses 24, 5, 3 and 1 hour before challenge with 10,000 TCID₅₀ of influenza B/Hannover/1/70. Interferon therapy did not alter the subsequent frequency or severity of infection as judged by clinical signs, symptoms, sero-conversion and frequency or intensity of virus shedding on days 3 and 4 after infection. The dose and schedule used by Merigan were different that the dose and schedule used in the Soviet Union. The dose of interferon given to 11 volunteers in one day by Merigan was approximately 1,000 times higher than the dose given to thousands of subjects in the Soviet Union. The prestige of Merigan and his co-authors, the high quality of Merigan's study, and the prevailing belief that "more is better" cast doubt on the Soviet results.

In 1976, Arnaoudova (Rev Roum Med-Virol 27:83-88) reported from Bulgaria on the therapeutic and prophylactic benefit of “160 units” of interferon given 5 times a day for 3 days (therapeutic) or 160 units given 3 times a day for 3 days repeated twice at 10-day intervals (prophylactic). No allergic or adverse events were observed in any of 868 children, including newborns and premature babies given interferon during a natural outbreak of influenza A (Port Chalmers variant). The author reported that interferon therapy reduced the severity and duration of disease, especially if started on the first day of illness. The author also reported that interferon was effective in preventing influenza.

In their review of clinical trials with exogenous interferon, Dunnick and Galasso (J Infect Dis 139:109-123, 1979) reported on Soviet research by stating that "interferon is said to prevent or ameliorate influenza A when a relatively small amount is administered intranasally as a spray over a period of three to four days." The authors then pointed out that other studies needed much greater amounts of interferon (even 14 billion units) to show an antiviral effect against other respiratory viruses. Still others reported that rapid mucociliary clearance mechanisms would predict the need for much larger doses of interferon. The clinical observations from Russia and Bulgaria did not fit the "more is better" view of interferon therapy.

Imanishi et al (J. Interferon Res 1: 169-178, 1980) reported intranasal drops of human interferon alpha (5,000 units/daily) for 4 months reduced the frequency and severity of disease due to influenza A (H₃N₂ and H₁N₁) and parainfluenza virus. Data was collected on 83 volunteers in the study. Fever occurred in 6 of 40 volunteers given interferon and in 15 of 43 volunteers given placebo (P<0.01). Subjective symptoms such as headache, cough, fatigue, anorexia, myalgia, etc. occurred in 34% of volunteers given interferon and in 67% of volunteers given placebo (P<0.01).

In 1982, Isomura et al. (Biken Journal 25:131-137) reported that human leukocyte interferon (10,000 units/day) or placebo was dripped into the nostrils of 27 children daily for 60 days. The children lived in an orphanage where natural outbreaks of influenza A and influenza B occurred during the treatment period. Interferon did not prevent illness but significantly reduced the duration of fever and reduced the mean peak fever. Clinical manifestations of influenza were milder in children given interferon compared to placebo. Adverse events due to interferon therapy were not observed.

During influenza epidemics in 1983, 1984 and 1985, Jia-Xiong et al. (Chinese Medical Journal, 100(2): 161-162, 1987) treated 140 children with a spray of natural human interferon alpha into the nose and mouth twice daily for 3-4 days.  The total daily dose was reported to be 700-1600 units.  The 53 control children were given traditional Chinese herbs.  Children given interferon had a significantly (P<0.01) faster normalization of temperature at 24, 36 and 48 hours after the first treatment.  The clinicians reported that pharyngitis and lymphadenosis of the posterior pharynx improved when fever subsided.

In 1985, Saito et al. (Rhinology 21:291-295) reported that human leukocyte interferon (50,000 units/day) was sprayed into the nasal passages of 37 human volunteers twice daily for 8 consecutive weeks. Placebo was given to 36 volunteers in this double-blinded, controlled study. Dosage compliance was a problem such that only 11 out of 73 volunteers administered over 90% of their medication. After excluding volunteers who took less than 50% of their medication, and excluding those volunteers who developed the common cold, and those who had a rise in antibody titers before the study, it was concluded the rise in complement fixation antibody titers against influenza A was not significantly different between treatments.

In 1984, Phillpots et al. (J Interferon Res 4:535-541) reported that 13 human volunteers self administered lymphoblastoid interferon (2.7 million units/dose) three times/day for 4 1/3 days starting one day before a challenge with influenza virus A/Eng/40/83. Illness occurred in 4 of 13 volunteers given interferon and in 10 of 17 volunteers given placebo (not significant). Serological responses and/or virus recovery were obtained in 11 of 13 volunteers given interferon and in 14 of 17 volunteers given placebo (not significant). Mean daily nasal secretion weight and mean clinical score were lower in the interferon group but were significantly different from placebo group only on post challenge day 2.

In 1987, Treanor et al (J Infect Dis 156:379-383) reported on intranasal delivery of interferon to 16 volunteers experimentally challenged with influenza A/California/78. The dose of interferon was 5 million international units (IU) twice daily delivered to each nostril by a hand-held metered pump spray. The spray was self-administered starting 48 hours before virus challenge and continued for 7 days. A total of 70 million IU was given to each volunteer treated with interferon. Nine volunteers were given placebo.

Treanor et al reported that illness developed in 5 of 9 placebo recipients and in 3 of 16 interferon recipients (P=0.087). There was no significant difference in median total score between treatment groups although scores in interferon recipients were consistently lower. None of the volunteers developed a fever. Eight of 9 placebo recipients excreted influenza virus compared to 13 of 16 interferon recipients. Placebo recipients excreted virus on 64% of test days compared to excretion of virus on 41% of test days by interferon recipients. Treanor et al concluded that intranasally administered interferon had a "definite antiviral effect" and a "possible clinical effect" in the prophylaxis of experimentally induced influenza A virus infection.

Hayden et al (J. Infect Dis 148:914-921, 1983) reported that a daily intranasal spray of 8.4 million IU for 28 days, and a total study dose of 235 million IU was too toxic and "not feasible for prophylaxis of respiratory virus infection." Hayden’s study enrolled 26 volunteers to receive interferon and 24 volunteers to receive placebo.

Phillpots et al reported that 11 volunteers were given 13 equal doses of 2.7 million IU of interferon (3 times daily for 4 1/3 days) but not challenged with virus. Mild "nasal symptoms" developed in 5 of 11 interferon treated volunteers compared to 1 of 11 volunteers given placebo.

Greenberg and Harman (In: Handbook of experimental pharmacology, P.E. Came and W.A. Carter, eds. Springer-Verlag, Vol 71, p. 433, 1984.) presented three possible explanations for the large in vivo dose requirements of intranasally applied interferon. First, the mucus overlying the nasal epithelial cells could contain a substance or substances that inactivate or inhibits the applied interferon before it could render the cells resistant to virus challenge. Second, the mucus barrier or rapid clearance mechanisms could prevent the interferon from reaching the nasal epithelial cells. Third, the nasal epithelial cells lining the nasal cavity could be insensitive to interferon compared with tissue culture cells. A series of experiments which addressed each of these possibilities was published and made the use of low dose interferon theoretically unacceptable.

The skepticism about the Soviet clinical research with interferon in influenza is summarized by Cantell in his 1998 book "The Story of Interferon" (World Scientific Publishing Co, Singapore, New Jersey, London, Hong Kong). On page 220, Cantell writes, "My attitude towards these results, like that of probably all other interferon workers in the western world, was extremely skeptical from the very beginning. Over the course of years, many visitors brought me interferon which they had purchased in the Soviet Union: we found that this was not only very impure but also contained only a few hundred units of interferon per milliliter. Our crude interferon preparations contained at least a hundred times more, and our concentrated interferon at least a hundred thousand times more interferon than those in the Soviet pharmacies. When glasnost and perestroika finally led to the break up of the Soviet Union, these interferon preparations silently vanished from the shelves of Russian pharmacies. I do not know whether they had ever done any actual harm to the recipients, but they certainly did not enhance the reputation of interferon, or the status of Soviet biomedical science.”

Discussion:  In other words, Cantell and others dismissed the observations made on thousands of influenza cases because they could not believe such trivial doses of impure interferon could have an effect.  After all, Merigan et al showed that 11 volunteers given 800,000 units of interferon were not protected against a challenge of influenza B. Didn’t Phillpots et al fail to demonstrate a benefit in 13 volunteers given 35 million units challenged with influenza A? Treanor et al could barely demonstrate a benefit from 70 million units given each of 16 volunteers before they were challenged with influenza A. The Soviet observations made no sense when compared to studies in which high doses failed to provide a benefit.

Did anyone in the West test interferon administered intranasally by low dose? No, testing was not conducted using low doses because "theoretically" it could not work and it did not fit the generally accepted "more interferon is better" philosophy.

When Japanese scientists tested low doses of interferon, benefits were reported. Imanishi et al reported a benefit from 5,000 units daily. Isomura et al reported clinical benefits from 10,000 IU daily. However, Saito gave volunteers 50,000 IU daily and did not report significant benefits. Perhaps the Soviet and Bulgarian claims of a benefit from a few hundred units, Jia-Xiang’s claim of a benefit from 700-1600 units, Imanishi’s claim of a benefit from 5,000 units, and Isomura’s claim of a benefit from 10,000 units should be reexamined. Low-dose oral or intranasal interferon should be tested rigorously using the pure interferon formulations available today.

The main point of the review (Cummins et al. Am J Vet Res, Jan 2005) is that low doses of interferon are sometimes safe and effective. Horses weighing 1,000 pounds responded to a daily oral dose of 50 IU, but not 450 IU, of human interferon alpha. Cattle, swine, dogs, cats, mice, rats, and other animals can be given low doses of interferon orally or intranasally and beneficial systemic effects are observed. Low doses of interferon are not having a direct antiviral effect but instead are exerting an immune modulatory effect through interferon stimulated genes (Tovey et al, abstract 137, Ann Mtg ISICR, 2003.  Dron et al, Genomics 79:315-325, 2002).

Clinical testing of low-dose oral interferon in blinded controlled studies of 370 human volunteers challenged with Rhinovirus failed to demonstrate a benefit (Gwaltney et al. ABI unpublished data, 1993-1997). Indeed, there are numerous examples in which oral or intranasal was not useful (Am J Vet Res 2005) but the observations from thousands of flu patients should not be dismissed.  Rhinovirus does not share the same classification with influenza virus and the pathobiology and response to interferon may be quite different.

Tovey and Maury (J Int Cyto Res 19: 145-155, 1999) introduced 10 ul of radiolabeled recombinant interferon alpha with a micropipette into the nostrils of normal adult mice which resulted in an almost immediate distribution of the dye or radiolabeled interferon over the whole surface of the oropharyngeal cavity. This so-called oromucosal route of administration delivers interferon to the same location as interferon given orally.  In our opinion, interferon given orally or intranasally to animals or humans is delivered to essentially the same anatomic sites.

Conclusion: In view of the serious consequences of an influenza pandemic and because of our modern understanding of the ability of small doses of interferon to modulate immune functions, it is time to revisit the subject of low dose oral or intranasal interferon for influenza therapy and/or prophylaxis. Perhaps the Soviets were correct in their observations. Perhaps our embrace of a "more interferon is better" philosophy has led to rejection of valid clinical observations made by Soviet, Bulgarian and Japanese investigators. It is time to put these old observations to the test, not by using high-doses of intranasal interferon but by using low-doses of high purity interferon.