key: cord-0038853-gu7yoolp
authors: Scott, Geoffrey M.
title: Interferons: what future?
date: 2004-08-26
journal: Trends Biotechnol
DOI: 10.1016/0167-7799(86)90197-6
sha: 5fd05f7deb080516bb23cea6b89ad22008514db1
doc_id: 38853
cord_uid: gu7yoolp

nan

public at large is kept uninformed, no basis for understanding and trust can be established. Over the next few months it will become extremely important for governments and regulatory authorities to initiate open public debates on deliberate release in order to provide balanced information. Without open debate a polarized, unworkable entrenchment will develop between the biotechnology industry and its opponents. In Europe the BioTa2000 multi-media programme, partly financed by the European Commission, has started to provide the public with information.

Many of the positive contributions that the new genetic technologies could make, like crops with disease and insect resistance or with higher nutritional value, are at stake. It is a mistake, born of concern for share prices or scientific prestige, to try to sell the public the wonders of biotechnology without properly addressing, the risks. Public suspicion delays development as the 'ice-minus' case has clearly demonstrated. 

It is hard for us to imagine how revolutionary were the discovery and first description of the substance that Alec Isaacs called 'interferon' in the late 1950s 1. To many it was a figment of a vivid scientific imagination, yet the original observations were carefully repeated in many laboratories and the production by cells of a soluble substance to explain viral interference was more or less accepted by the 1970s. When interferon was discovered, it was realized that it was possible to interfere with viral replication without necessarily endangering cellular metabolism and many thought that interferon might prove to be a useful antiviral agent. However, a major problem was in material supply and this remained so until the cloning of interferon genes inE. coliin the late 1970s, and the concomitant successful development of large-scale lymphoblastoid interferon production. To give examples of the early supply problems, a two-year collaboration between Glaxo and Wellcome laboratories produced sufficient monkey kidney cell interferon for a single small dose to be inoculated intradermally in 36 volunteers to prevent vaccinia. This was an expensive business and even though the trial was very successful (vaccinia appearing to be highly susceptible in rive), it was considered of very dubious commercial merit.

In the mid-1960s Kari Cantell started to make leucocyte interferon from buffy coats from blood destined for transfusion, and managed to make sufficient to supply nearly all the important trials reported through the 1970s. The successful trial reported in 1973 (Ref. 2) of repeated intransal sprays of interferon against experimental common colds in volunteers given rhinovirus type 2, used about one year's manufacturing supply from this process. Thus although it was a success, there was insufficient interferon to pursue further studies, let alone sell interferon for common colds.

Greenberg and coworkers 3 established the minimum dose of interferon which could protect volunteers against rhinovirus and devised ways of enhancing the effects (for example, by putting a cotton wool pledget saturated with interferon into the nose or by using concomit- It was partly because of the exciting results in viral studies, but perhaps more because of the unreasonable prediction that interferon would have powerful effects against human tumours, that DNA chemists addressed the problems of cloning and expressing human interferon genes. This was done remarkably successfully and several pharmaceutical companies have collaborated with gene technology firms to develop the products of this work. It should be understood that even though successful trials had been done with buffy coat interferon, each product of gene cloning needed to be thoroughly evaluated for quality assurance, activity and toxicity, much in the same way as a new pharmaceutical product. There are many a-interferon genes but so far there is no evidence that one interferon will be better than another. Those that have been developed are a-2 and a-l, which are predominant in natural leucocyte and lymphoblastoid preparations. Cloned y-interferon is also under trial but the results are slow to emerge. It is not surprising that progress has seemed to be slow and much of the artificial enthusiasm for these 'cure-all' products has waned since 1980. The hopes and predictions made public at that time were quite unrealistic and were not generally felt by those working in the interferon field. Nevertheless, interferons do appear to have some important clinical applications.

The common cold has been pursued diligently by several groups. The findings of many trials, summarized recently by Phillpotts and Tyrrell 4, show first, that interferon has to be given before the virus to prevent colds. This is not surprising when we consider that the maximal endogenous interferon response coincides with peak virus replication, which in turn coincides with symptoms. Secondly, the minimum dose needed to inhibit a virus given at any time of the day or night is about 2 × 106U intranasally, taken 8-hourly.

This sort of dose schedule offers protection against experimental coronavirus 5 and influenza 6 virus infections, although several studies have shown excellent protection against rhinovirus when interferon is given just once a day. If intranasal interferon is continued for more than a few days, some volunteers begin to develop local nasal symptoms, which reflect nasal mucosal ulceration and intense mucosal lymphocytic infiltrates. These side-effects seem to be consistent for each interferon tested but are dose dependent and may be made worse by preservatives in the nasal solutions. By the end of two weeks, as many as 50% of volunteers taking the minimum dose needed to protect against wild colds may have symptoms.

Two recent papers published by groups in the USA 7 and Australia 8 have attempted to prevent natural colds in family contacts using short, well-tolerated courses of intranasal ~-2 interferon (INTRON A, Schering Corporation). Similar protocols were used and the results were almost identical. These studies were possible because of the way in which common cold viruses appear to be transmitted. The reservoir of circulating viruses is mainly in nonimmune children at school who play in close contact with each other and observe no simple hygienic precautions. These children contract colds and bring home large quantities of virus in their nasal secretions to infect susceptible adults, principally by mucosa-to-hand-to-mucosa contact and even via fomites contaminated with nasal mucus, where many respiratory viruses can survive for hours.

In these trials, when one family member developed symptoms of a cold, treatment with intranasal interferon or placebo was started by all the other family members except children. Compared with placebo recipients, the interferon recipients had significantly fewer rhinovirus colds but not fewer infections caused by corona, influenza or pareinfluenza viruses. However, colds in the interferon recipients were less severe.

Here is a clear beneficial effect of intranasal interferon against naturally acquired colds. Perhaps better effects against other viruses could be achieved by increasing the frequency of doses, but each trial of a new dose schedule will be difficult and expensive. If interferon is to be used in this way, it will have to be available cheaply over the counter so that it can be taken soon enough to be effective. Perhaps initially it could be used by those for whom a cold is more than an inconvenient nuisance and may, for example, herald worsening bronchitis, asthma or diabetes.

So when you clone a new protein into E. coil or a yeast and generate a new magic immune modulator or vaccine which is 'bound to' alter the course of this or that human disease think, just for a moment, of the time, financial and intellectual investment which will be required to bring your wonder drug profitably to the market. Look hard at the long development and present results with interferons, confusing to the clinician by their heterogeneity and toxic properties but with an enormous potential spectrum of activity!

Whittington Hospital