Chemoprophylaxis and Virus Infections of the Respiratory Tract

Volume 2

J.S. Oxford

• Publisher: CRC Press
• Year: 2018
• ISBN:
  9781351087520
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Microbiology
• Index: Biological Sciences

Originally, it was our intention to produce a single-volume book covering all aspects and approaches to the problem of specific inhibitors of respiratory viruses. However, as the work progressed it became obvious that certain chapters, because of the research interests of the authors, concentrated particularly on influenza viruses. It seemed logical therefore, to divide the book into two volumes, the first emphasizing influenza and the second concentrating on other viruses as well as discussing important general aspects of drug screening and clinical testing, although the second volume does have some chapters which deal mainly with influenza.

Chapter 1

ANIMAL MODELS OF INFLUENZA VIRUS INFECTION AS APPLIED TO THE INVESTIGATION OF ANTIVIRAL COMPOUNDS

C. W. Potter and J. S. Oxford

TABLE OF CONTENTS

I.	Introduction
II.	The Ferret Model
	A.	The Response of Ferrets to Influenza Virus Infection
		1.	Temperature
		2.	Virus Multiplication
		3.	Local Symptoms
		4.	Nasal Wash Antibody
		5.	Serum Antibody Response
		6.	Interferon Response
		7.	Delayed Hypersensitivity Response
	B.	The Study of Antiviral Compounds in Ferrets
		1.	Studies of Amantadine
		2.	Studies with Ribavirin
		3.	Studies with Cyclooctylamine
		4.	Studies with Aspirin
		5.	Comparative Studies
III.	The Mouse Model
	A.	Infection and Adaptation of Influenza A Viruses to Mice
	B.	Pathology of Influenza in the Mouse
	C.	Response to Infection
		1.	Death
		2.	Lung Consolidation
		3.	Virus Hemagglutinin in Mouse Lungs
		4.	Food and Water Intake and Body Weight
		5.	Changes in Lung Weight
		6.	Contact Infection
	D.	Studies of Antiviral Compounds in Mice
		1.	Amantadine
		2.	Ribavirin
IV.	Conclusions
References

I. INTRODUCTION

The initial screening of compounds for antiviral activity has usually been carried out in tissue cultures. In some cases the in vitro antiviral activity shown by these techniques has been subsequently demonstrated in both animal and clinical studies; thus, the antiviral activity of the compound N-methylisatin-β-thiosemicarbazone against vaccinia virus infection has been demonstrated in tissue culture systems,¹ experimental animals,² and clinical studies.³ However, studies with other compounds have not shown this agreement; isoprinosine was reported to be active against influenza virus infection in tissue cultures and mice,^4,5 but tests in human volunteers failed to show significant antiviral activity.⁶ Although in clinical studies these results fail to demonstrate the results obtained in laboratory experiments, it is possible that the reverse may occur, and compounds potentially active in clinical tests are discarded because of a lack of in vitro activity. For these reasons, in vitro and in vivo studies should both be conducted to ensure that useful compounds are not overlooked. Since it is not ethically possible to simultaneously carry out in vitro and clinical studies, there is a need for studies in suitable animal model(s); the choice of animals depends principally on the virus infection for which compounds are to be evaluated.

The evaluation of antiviral compounds against influenza could be carried out in a number of animal models, since mice,⁷ hamsters,^8,9 dogs,¹⁰ guinea pigs,¹¹ ferrets,^12,13 monkeys,¹⁴ and pigs¹⁵ are all susceptible to infection by human influenza viruses. Monkeys are too expensive to maintain for initial studies of antiviral compounds, and the same is true of dogs and pigs. Ferrets are highly susceptible to infection with unadapted influenza virus; infection produces a clinical response similar to that observed in man, with symptoms including a febrile reaction,^12,13,16,17 nasal obstruction,^18,19 and an increase in nasal wash protein.²⁰ However, ferrets are relatively large laboratory animals that are difficult and expensive to maintain; they are an outbred species that show individual variation of susceptibility to influenza virus infection. In addition, ferrets do not produce local 11S secretory IgA antibody,²¹ and in this respect the ferret is not an exact model for influenza in man.

Mice are small and relatively easy to maintain; they are available as inbred strains that would be expected to give a reproducible response to influenza virus infection. A considerable body of experience and information on antiviral compounds has been accumulated by experimentation in mice which allows the relative values of many different compounds to be assessed. On the other hand, there are disadvantages in using mice. These animals are difficult to infect with many strains of influenza virus; although these viruses can be adapted to produce lung lesions and death in mice, this can be criticized as an artificial model system quite distinct from influenza in man. Furthermore, influenza virus infection of mice does not produce the febrile response seen in man and ferrets, while infection does induce a heterotypic immunity^22,23 which has not been reported in other species.⁹ Both of these reactions suggest that the mouse is not an ideal model for the study of influenza virus infection.

Studies of influenza virus infection in guinea pigs has shown these animals to be susceptible to infection with unadapted influenza viruses; however, guinea pigs do not produce a clinical response to infection, and the sera of these animals contain high titers of inhibitors.¹¹

Hamsters are very sensitive to infection with human influenza viruses, and this species may provide a valuable model system.^9,24 Hamsters breed easily and are relatively inexpensive to maintain. They are closely related, since all the hamsters in England originate from a single litter; this would suggest that results obtained in this species would be reproducible. Influenza virus infection in hamsters is principally an upper respiratory tract infection, and relatively high titers of virus can be recovered from nasal washings.⁹

It is likely that no single animal species will prove to be a completely adequate model for human influenza; the extremes of convenience supplied by mice and the similarity to influenza infection of man which is shown by ferrets may be two models that should be used in parallel. However, results obtained for chemotherapeutic compounds against influenza virus infection in mice and/or ferrets cannot be translated to man without qualification; although animal studies are necessary and can be of considerable value, the effect of antiviral compounds on influenza in man can only be accurately assessed by clinical studies.

However, the rapid antigenic changes detected in influenza A virus (Chapter 4, Volume I) raise the important question of whether clinical trials have to be repeated each year with any new influenza variant and an antiviral compound licensed for use against influenza H3N2 strains. In particular, amantadine has been shown to be an active inhibitor of influenza A (H2N2) and (H3N2) subtypes in the laboratory, in animal models, and in man. We consider that an in vitro or in vivo demonstration of efficacy against any new influenza A variant would provide sufficient data to decide its potential usefulness without the delaying requirement of new clinical trials. This is particularly pertinent at present as regards the possible emergence of A/New Jersey/76 (H_swine1 N1) as a possible epidemic virus. Chemoprophylaxis in influenza could be used as a stopgap measure until sufficient vaccine ha...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Chapter 1 Animal Models of Influenza Virus Infection as Applied to the Investigation of Antiviral Compounds
• Chapter 2 The Study of Antiviral Compounds in Volunteers
• Chapter 3 Clinical Testing of Antiviral Compounds on a Large Scale in General Practice
• Chapter 4 The Strategy of the Picornavirus Genome: Some Implications for Chemotherapy
• Chapter 5 The Coronaviruses
• Chapter 6 The Discovery and Development of Antiviral Drugs – The Commercial Approach
• Chapter 7 The Potential of Interferon and Interferon Inducers
• Chapter 8 Some New Approaches to Antiviral Chemotherapy, Metalloenzyme Inhibition, and Transport by Liposomes
• Index