There is strong evidence that oral or intranasal administration of interferon (IFN) protects mice, guinea pigs, ferrets and humans against influenza virus.

 

MICE 

 

Recombinant murine IFNαA was given orally to C57BL/6J mice once daily for 7 consecutive days before challenge with mouse-adapted human influenza virus A/PR/8/34(H1N1).  Oral administration with as little as 100 IU of IFN significantly (P<0.05) reduced viral replication in the lungs of mice (Beilharz et al., 2007).

 

In contrast, a single intranasal dose of 10,000 units of human IFNαB/D given 8 hours before challenge with 1000 LD50 influenza (A/Vietnam/1203/04) virus protected BALB.A2G-Mx1(Mx1+/+) mice.  Virus titers in the lungs of IFN-treated mice were 1000 times lower than control mice (Tumpey et al., 2007).

 

In agreement with Tumpey et al., Grimm et al., 2007 reported that a single intranasal dose of human IFNαB/D protected B6.A2G-Mx1 mice given 10 hours before challenge with 100 LD50 of influenza A/PR/8/34(H1N1) virus.  The protective effect of a single dose of IFN resulted in at least 10,000 fold reduced viral titers in the lungs.

 

FERRETS

 

Intranasal treatment with ferret IFNα several hours before infection with the H1N1 influenza A virus strain A/USSR/90/77 reduced viral titers in nasal washes at least 100-fold compared to mock-treated controls.  IFN-treated animals developed only mild and transient respiratory symptoms, and the characteristic fever peak seen in mock-treated ferrets 2 days after infection was not observed.

 

 Repeated application of IFNα substantially increased the protective effect of the cytokine treatment.  IFNα did not increase survival after infection with the highly pathogenic H5N1 avian influenza A virus strain A/Vietnam/1203/2004.  However, viral titers in nasal washes were significantly reduced at days 1 and 3 post infection (Kugel et al., 2009).

 

GUINEA PIGS

 

Human IFNαB/D treatment (500,000 IU/kg) initiated 1 day prior to challenge significantly reduced or prevented infection of guinea pigs by both 1918 pandemic H1N1 virus or a contemporary H5N1 virus as measured by virus titer determination and seroconversion.  A single dose of IFN resulted in 300 fold lower virus titers in nasal washes 1 day after virus inoculation.  Doses of IFN on days -1, 0, 1, 3, 5 and 7 post-infection, completely blocked virus infection or resulted in less virus replication and less severe lung lesions (VanHoeven et al., 2009).

 

 HUMANS

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. The interferon treatment was free of adverse events (Soloviev, 1967).

In 1969, Soloviev reported that approximately 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.

There was a significant (P<0.01) difference between placebo and interferon treatment for each age comparison. 

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 September 1971, a group of U.S. scientists visited the Soviet Union and reported that there was advanced clinical work on the use of exogenous interferon in Russia (Galasso et al., 1972). 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., 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, 600 units of interferon 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.

In 1976, Arnaoudova 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.

Imanishi et al., 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. 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., 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 addition to observations on influenza by Jia-Xiong, it was reported that 5 children with respiratory syncytial virus (RSV) had fewer days of clinical signs and more mild illness than 12 children with RSV not given IFN.

References supplied upon request.

SUMMARY

There is strong evidence that oral or intranasal administration of interferon protects mice, guinea pigs, ferrets and humans against influenza virus. When interferon is given orally or intranasally, the interferon reaches the mucosa of the back of the throat where the interferon attaches to receptors and activates hundreds of interferon sensitive genes that help the immune system respond to the viral infection. Summaries of our work and observations on the mechanism of action of oral interferon are available upon request.

Interferon lozenges are stable at room temperature for up to 2 years and are easy-to-administer orally. In contrast to high dose injectable interferon, low-dose oral interferon is less expensive and virtually non-toxic. Health officials facing an influenza pandemic need to recognize the safety and benefits of oral interferon and consider the use of oral interferon to help prevent and treat influenza.

 

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