Use of cotton rats for preclinical evaluation of measles vaccines
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.
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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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Measles Vaccines
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2012, Vaccines: Sixth EditionThe recombinant globular head domain of the measles virus hemagglutinin protein as a subunit vaccine against measles
2012, VaccineCitation Excerpt :Subunit vaccines are among those currently being considered as alternative measles vaccine candidates [4]. The ISCOM and Protollin formulations incorporating measles virus (MV) glycoproteins have been shown to induce both humoral and cell-mediated immune responses, as well as antiviral protection in rodents and macaques [5–10]. In addition, ISCOM formulations have been shown to be protective in the presence of passively acquired MV-specific antibodies [8].
Dry powder measles vaccine: Particle deposition, virus replication, and immune response in cotton rats following inhalation
2011, VaccineCitation Excerpt :Cotton rats (Sigmodon hispidus) are the only rodents that support the replication of measles virus following intranasal inoculation [11] and have proven useful in the preclinical evaluation of measles vaccine [12,13]. Primates are considered to be the best model for studying measles vaccines [12], but with our novel dry powder formulation and method of delivery we wanted to establish a proof of concept before moving forward with testing in monkeys. In the following report, we elaborate on the details of an effort to formulate traditional Edmonston-Zagreb (EZ) live attenuated measles virus vaccine [14] as a well-characterized, dry powder that has the ability to reconstitute at the mucosal surface after inhalation and allow replication of the vaccine virus to induce an immune response.
Mucosal adenovirus-vectored vaccine for measles
2010, VaccineCitation Excerpt :The cotton rat (Sigmodon hispidus) is a suitable small animal model for preliminary testing of MV vaccines because cotton rats are semi-permissive for MV. After intranasal challenge, MV replicates in the lungs of cotton rats for 10 days with peak titers at day 4 and 5, causing a mild interstitial pneumonia without overt clinical signs of disease [29,35]. In our study, a single intranasal vaccination of cotton rats with a combination of the recombinant adenoviruses induced high MV-specific serum neutralizing-antibody response and completely protected rats from MV replication in lungs.
Analysis of antibody response by temperature-sensitive measles vaccine strain in the cotton rat model
2009, Comparative Immunology, Microbiology and Infectious DiseasesCitation Excerpt :However, there is a need for a more convenient, technically less demanding and inexpensive small-animal model. The cotton rat is the only rodent that replicates MeV (including non-adaptive wild type MeV) in lung tissue, and is thus considered an alternative model to assess vaccine efficacy [11]. However, it is not clear whether ts MeV live vaccine strains can be evaluated in cotton rats, especially because the body temperature of rodents is higher than in humans [12,13] and a ts virus may not induce an immune response in the rodent model.