Elsevier

Vaccine

Volume 19, Issue 1, 15 August 2000, Pages 42-53
Vaccine

Use of cotton rats for preclinical evaluation of measles vaccines

https://doi.org/10.1016/S0264-410X(00)00151-1Get rights and content

Abstract

The continued prevalence and medical impact of measles worldwide has created interest in the development of new generations of measles vaccines. Monkeys can be used for preclinical testing of these vaccines. However, a more practical and less expensive animal model is highly desirable, particularly for initial vaccine development and evaluation. Cotton rats have been shown to support the replication of different strains of measles virus (MV), and thus may be useful for these purposes. To test this concept, the immunogenicity and protective efficacy of two standard (Moraten and trivalent measles, mumps, rubella) and four experimental (two recombinant ALVAC, one ISCOM subunit and live attenuated Edmonston–Zagreb) MV vaccines were evaluated in naı̈ve cotton rats, and cotton rats with passively acquired MV-specific neutralizing serum antibodies. All of the test vaccines were immunogenic and protected naı́ve animals from pulmonary infection and viral dissemination. However, under the conditions utilized, only the Edmonston–Zagreb vaccine provided such protection to animals with significant levels of passively acquired MV-specific neutralizing antibodies. The results of these tests and the potential of using cotton rats as an animal model for preliminary testing of MV vaccines are discussed.

Introduction

Forty million cases of measles and nearly one million deaths due to this disease still occur worldwide annually, despite the presence of efficacious live measles vaccines and a vigorous measles virus (MV) eradication effort [1], [2], [3]. This can, at least in part, be attributed to the inability of live attenuated measles vaccines to induce protective immunity in the presence of maternally derived MV-specific antibodies. The continuing impact of measles has lead to the development of new generation measles vaccine candidates that may be effective in the presence of pre-existing immunity. Monkeys, because they are susceptible to MV infection and develop a disease similar to measles in man [4], [5], [6], have been used to help develop and evaluate measles vaccines [4], [7], [8]. However, these primates can be difficult to obtain, expensive and exacting to work with, making even simple evaluation of the effects of vaccine composition, vaccine dose, inoculation schedule or ancillary adjuvants costly and problematic. Hispid cotton rats (Sigmodon hispidus) have recently been shown to support the replication of different strains of MV [9], [10], [11], including non-culture adapted wild-type isolates, and thus may be useful for initial preclinical testing of candidate measles vaccines. To evaluate this possibility, two licensed (Enders–Moraten [E–M] and trivalent measles, mumps, rubella [MMR]), and four experimental (two recombinant ALVAC, one ISCOM and one live attenuated [Edmonston–Zagreb; E–Z]) measles vaccines were compared for immunogenicity and protective efficacy in naı̈ve hispid cotton rats and in hispid cotton rats with passively acquired MV neutralizing serum antibodies. The results of these tests and the potential of using these animals as a model for initial testing of measles vaccines are discussed below.

Section snippets

Cell culture

B95-8 (Epstein–Barr virus-transformed marmoset leukocyte; cat. no. CRL 1612) and Vero (African green monkey kidney; cat. no. CCL 23) cells were obtained from the American Type Culture collection (ATCC; Rockville, MD). The latter cells were grown in minimum essential medium (MEM; Sigma Chemical Co., St. Louis, MO; cat. no. M4655) supplemented with 5% fetal calf serum (FCS), penicillin (100 units/ml), streptomycin (100 (g/ml), sodium bicarbonate (0.2%) and l-glutamine (2 mM/ml; 5% FCS-MEM). RPMI

Virus-specific neutralizing antibody responses and protective efficacy in cotton rats administered licensed measles vaccines

Cotton rats vaccinated with two doses of commercially available E–M or MMR measles vaccine produced significant levels of VN antibodies (Table 1, column 4). The mean VN titers seen in these groups were equivalent (i.e., 7.3–7.8 for the groups inoculated with E–M virus versus 7.2–7.8 log2/0.05 ml serum for the cotton rats vaccinated twice with MMR). These titers were about twice those measured in animals inoculated once with wild-type MO2 MV (i.e., 6.6 log2/0.05 ml serum). Following challenge, 1

Discussion

Six vaccines, representative of the major types of MV vaccines currently available (replicating recombinant [ALVAC-H,F and ALVAC-H,F,M,N], non replicating subunit vaccine [ISCOM-MV] and live attenuated [E–M, MMR, E–Z]), were used in these studies. The ALVAC-MV vaccines tested are just two of many recombinant avianpox virus vaccines that have been developed. These vaccines differ from many live recombinant virus vaccines in that although they are capable of good growth in avian host cells, their

Acknowledgements

This work was supported by contract NO1-AI-65292 from the Virology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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