Elsevier

Vaccine

Volume 30, Issue 7, 8 February 2012, Pages 1291-1296
Vaccine

Efficacy of trivalent inactivated influenza vaccines in the cotton rat Sigmodon hispidus model

https://doi.org/10.1016/j.vaccine.2011.12.084Get rights and content

Abstract

Annually adjusted inactivated influenza vaccines can prevent infection and limit the spread of seasonal influenza when vaccine strain closely matches circulating strain. For the years when the match is difficult to achieve, a rapid screening of a larger repertoire of vaccines may be required but is difficult to accomplish due to the lack of a convenient small animal model of seasonal influenza vaccines. The goal of this work was to determine whether the cotton rat Sigmodon hispidus, a small laboratory animal susceptible to infection with unadapted influenza viruses, may become such a model. Cotton rats were immunized with a trivalent inactivated vaccine (TIV) FluLaval (2006/2007) and vaccine immunogenicity and antiviral efficacy was evaluated against the homologous H1N1 and a heterologous H3N2 challenge. FluLaval induced a strong virus-specific IgG and neutralizing antibody response against homologous virus, elicited sterilizing immunity in the lungs and significantly reduced viral replication in the nose of infected animals. FluLaval was efficacious in cotton rats as either a single-time or a double immunization, although higher level of protection of the upper respiratory tract was achieved following two doses of vaccine. Antibodies against a heterologous influenza strain were induced in FluLaval-vaccinated animals, but vaccine lacked antiviral efficacy and did not reduce replication of a heterologous virus. Similarity of these findings to human TIV data suggests that the cotton rat may prove to be a reliable small animal model of human influenza vaccines.

Highlights

► Cotton rats are susceptible to infection with unadapted seasonal influenza viruses. ► We use cotton rats to model efficacy of human trivalent inactivated vaccines (TIV). ► TIV induces a strong humoral response and protects cotton rats against replication of a vaccine-matched strain. ► TIV does not protect cotton rats against replication of a heterologous influenza strain, in spite of eliciting heterologous antibodies. ► Similarity to human TIV data suggests a high potential for the cotton rat model of human influenza vaccines.

Introduction

Influenza infection results in 200,000 cases of hospitalizations and over 36,000 deaths in the United States alone [22]. Vaccination is the most effective method of preventing influenza infection and its potentially severe complications. Of the two different types of influenza vaccines approved for human use: inactivated and live attenuated, inactivated influenza vaccine is targeted to a wider demographic cohort. Inactivated influenza vaccines include antigens from at least three different influenza strains and are prepared annually in an effort to match vaccine composition with the global epidemiological surveillance data for that particular year [1]. In the years when a close match between the vaccine and the circulating seasonal strain is achieved, approximately 73% protection is seen [2]. During the seasons of low vaccine match, however, low- to no vaccine effectiveness is reported [3], [4]. Vaccine manufactures examine multiple candidate strains to increase the chances for a better match to circulating strain. As inactivated vaccine composition is adjusted yearly to match seasonal influenza strain assortment, and selection of the best vaccine candidates should be rapidly achieved, a convenient small animal model that allows for a fast assessment of vaccine efficacy would be instrumental in ensuring public health during influenza season. Moreover, the constant threat of emergence of a novel highly pathogenic influenza strain increases the need for a reliable animal model for screening available vaccine formulations to identify potentially cross-protective vaccine.

At present the most widely used small animal model for influenza research is mice. However, common laboratory mice are not susceptible to seasonal human H1N1 and H3N2 viruses and to model seasonal influenza in these animals, mouse adapted strains are needed. Infection with unadapted seasonal influenza can be achieved in ferrets and guinea pigs, but the use of these animals is limited due to their size, cost, and husbandry requirements [5]. The cotton rat Sigmodon hispidus is a small animal model easily amenable to laboratory manipulation. The cotton rat was shown to be susceptible to infection with unadapted human influenza viruses, including A/Wuhan/359/1995 (H3N2), A/Malaya/302/54 (H1N1), B/Sichuan/379/99, B/HK/330/01, and B/HK/73 [6]. The list has recently been expanded to include additional seasonal and pandemic influenza H1N1, H5N1 and H9N2 strains that infect cotton rats without the need for adaptation (manuscript in preparation). Replication of seasonal influenza in the cotton rat is rapid, resembling dynamics reported for humans [7].

The value of a small animal model relies on its ability to accurately predict efficacy of human vaccines and therapeutics in a setting best mimicking natural human infection. To achieve that goal, a pathogen of interest that has not been adapted in the laboratory setting is required. To ascertain the relevance of cotton rats as the model of human influenza vaccines, we selected an inactivated trivalent influenza vaccine known to be effective in humans (FluLaval, 2006–2007 season) and tested its efficacy against a natural, unadapted virus that was included in the vaccine formulation, namely Influenza A/New Caledonia/20/1999 (H1N1) (New Caledonia). Although the New Caledonia strain has never been tested in the cotton rat before, infection of animals with this virus was easily achieved, similar to infection with other unadapted human influenza viruses tested in the cotton rat up to date. Experiments described in this work evaluated immunogenicity and antiviral efficacy of FluLaval against homologous and heterologous influenza challenge in cotton rats. Our results indicate that human influenza vaccines are highly efficacious in cotton rats when vaccine strain matches the challenge virus strain. They also show that heterologous protection is not efficiently induced by trivalent inactivated influenza vaccines in cotton rats, pointing to an important similarity with humans [8].

Section snippets

Animals

Inbred S. hispidus cotton rats were obtained from a colony maintained at Sigmovir Biosystems, Inc. Animals were housed in large polycarbonate cages and were fed a standard diet of rodent chow and water. The colony was monitored for antibodies to adventitious respiratory viruses and other common rodent pathogens and no such antibodies were found. All studies were conducted under applicable laws and guidelines and after approval from the Institutional Animal Care and Use Committee (IACUC).

Viruses

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Infection of cotton rats with influenza A/New Caledonia/20/99 (H1N1)

The seasonal 2006/2007 FluLaval vaccine chosen for this study included antigens from three different influenza strains: A/New Caledonia/20/99 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. None of these three strains have been tried in the cotton rat before. We have selected influenza A/New Caledonia/20/99 (H1N1) (New Caledonia) to test FluLaval efficacy. To establish dynamics of cotton rat infection with this particular strain, animals were inoculated with 106 TCID50 New

Discussion

Annually adjusted inactivated influenza vaccines are efficacious in preventing infection and limiting the spread of disease when vaccine strain closely matches circulating strain. For the years when the match is difficult to achieve, a fast selection from the larger repertoire of vaccines may be required but is difficult to accomplish due to the lack of a convenient small animal model of seasonal influenza vaccines. The goal of this work was to determine whether the cotton rat S. hispidus, an

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