Search

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.

Cotton rats (Sigmodon hispidus) are susceptible to the recently discovered human metapneumovirus (hMPV), an agent closely related to human respiratory syncytial virus. Since certain respiratory syncytial virus vaccines can induce enhanced disease upon viral challenge, we have done similar experiments with hMPV in cotton rats. Young adult cotton rats were vaccinated with a formalin-inactivated preparation of hMPV strain C-85473, or with a mock preparation of the vaccine on day 0 and again on day 28. All animals were challenged intranasally on day 49 with 10(7) TCID50 of the same hMPV strain. Animals were sacrificed on days 4, 7, and 10 post-challenge and lungs were removed for viral quantitation, histopathology, and cytokine mRNA expression analysis (interferon-gamma (IFN-gamma) and interleukin-4 (IL-4)). Although the vaccinated animals showed almost complete protection from viral replication in the lungs (10(2.0) TCID50 per gram), there was a dramatic increase in the lung pathology, particularly the interstitial pneumonitis and alveolitis with elevated serum neutralizing antibody titer prior to challenge. Cytokine profiles were distinctive from those observed during primary infection and re-infection. The data raise safety concerns for hMPV vaccine preparations.

Epidemiologic evidence suggests that cross-protective immune responses to influenza A viruses that have different hemagglutinin and neuraminidase subtypes occur in humans. This study characterized this heterosubtypic immunity in cotton rats (Sigmodon hispidus). Animals were infected with influenza A/PR/8/34 (H1N1) or A/Wuhan/359/95 (H3N2), and then challenged with A/Wuhan/359/95(H3N2) virus 4 weeks later. Viral titers, respiratory rates, and pathology of the respiratory tract following primary and secondary infection were compared. Cross-protection from heterosubtypic influenza A challenge in cotton rats was characterized by enhanced viral clearance, protection from tachypnea, a vigorous early cellular recall response, and a reduction in bronchiolar epithelial cell damage. Cross-protection was retained in steroid treated animals, in which the inflammatory recall response was minimal. Identification of the mechanisms that contribute to cross-protection in cotton rats may lead to the development of influenza vaccine strategies that are broadly protective.

Formalin-inactivated respiratory syncytial virus vaccine (FI-RSV) induces a poorly understood immunopathological response that leads to disease enhancement upon RSV infection of vaccinees. In the cotton rat model, inclusion of monophosphoryl lipid A (MPL) in the FI-RSV formulation was found to mitigate the lung pathology associated with vaccine-enhanced disease. Here we report that the protective effect of MPL on FI-RSV vaccine-enhanced disease is associated with a dramatic reduction in levels of Th1- and Th2-type cytokines and chemokines normally elicited in response to RSV challenge. Our data illustrate the complexity of proinflammatory response elicited by FI-RSV vaccination and RSV infection and the potential importance of MPL in modifying this response.

The mechanisms by which administration of a formalin-inactivated respiratory syncytial virus vaccine resulted in enhanced disease among children after they later became naturally infected with the virus remains largely undefined. After immunization and live virus challenge, the cotton rat demonstrated the histopathologic marker of the enhanced disease, polymorphonuclear leukocyte infiltration of lung alveolar spaces. We now report that immunization with formalin-inactivated vaccine formulated with the adjuvant, 3-deacylated monophosphoryl lipid A, dramatically reduces or eliminates the polymorphonuclear leukocyte infiltration within the alveoli of cotton rats post-challenge. We suggest, that this or similar adjuvants may be beneficial components of candidate non-replicating respiratory syncytial virus vaccines, whose development has been hampered by safety concerns.

In its programme for accelerated development of vaccines for viral respiratory and enteric tract diseases the WHO has assigned a very high priority to respiratory syncytial virus (RSV), parainfluenza viruses and rotaviruses. There is also some interest in alternative approaches to immunization against influenza viruses because of the failure of inactivated vaccines to provide complete and reasonably durable immunity. Current attempts to develop satisfactorily attenuated viruses for use in prevention of disease caused by the above viral pathogens are described.