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Immunology and Cell Biology (2010), 1–7 & 2010 Australasian Society for Immunology Inc. All rights reserved 0818-9641/10 $32.00
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ORIGINAL ARTICLE

Antiviral protection following immunization correlates with humoral but not cell-mediated immunity
Vijay Panchanathan, Geeta Chaudhri and Gunasegaran Karupiah
Smallpox was a deadly disease when it was rife yet despite its eradication more than 30 years ago, the possibility of accidental or intentional release has driven research in search of better definitions of correlates of protective immunity. Mousepox, a disease caused by ectromelia virus (ECTV), is arguably one of the best surrogate small animal models for smallpox. Correlates of protection in mousepox are well defined during primary infection, whereas those in a secondary infection, which have definite relevance to vaccination strategies, are less well understood. We previously established that neutralizing antibody (Ab), which is generated far more rapidly during a secondary infection compared with a primary infection, has a key role during a secondary virus challenge. In this study, we show that the route of immunization or the use of homologous or heterologous virus vaccines for immunization does not influence the ability of mice to control high-dose virulent ECTV challenge or to mount a substantial secondary neutralizing Ab response. In contrast, the recall cytotoxic T lymphocyte (CTL) responses generated under these regimes of immunization were varied and did not correlate with virus control. Furthermore, unlike the recall Ab response that was generated rapidly, the kinetics of the secondary antiviral CTL response was no different to a primary infection and peaked only at day 8 post-challenge. This finding further underscores the importance of Ab in conferring protection during secondary poxvirus infection. This information could potentially prove useful in the design of safer and more efficacious vaccines against poxviruses or other diseases using poxvirus vectors. Immunology and Cell Biology advance online publication, 12 January 2010; doi:10.1038/icb.2009.110 Keywords: antibody; cytotoxic T lympohocyte; memory; poxvirus infection protective immunity; vaccination

Smallpox was an ancient scourge, causing mortality rates as high as 30–40% in the past.1 Fortunately, this deadly disease was eradicated through the highly successful smallpox eradication campaign involving vaccination.1 Fears of an intentional or accidental release of variola virus, the causative agent of smallpox, have sparked interest in understanding the correlates of protection in smallpox. Very little is known regarding protective immunity to smallpox as the currently available tools of molecular biology, immunology and virology were not available at the time the disease was rife. Furthermore, the fact that the currently licensed vaccine for smallpox has unacceptable rates of adverse effects emphasizes not only the need to understand immunity to smallpox but also to develop effective and safer vaccination strategies.2 In the absence of clinical cases of smallpox, surrogate animal models such as variola virus and monkeypox virus (MPXV) infection in macaques and vaccinia (VACV) and ectromelia virus (ECTV) infection in mice have been used to infer requirements for recovery and protection from smallpox. Both ECTV and variola virus are highly virulent, cause disease with high mortality rates in their respective natural hosts and share many similarities in virus biology, pathogenesis and disease. Thus, the mousepox model makes for an excellent

surrogate animal model to understand the requirements for recovery and protection from smallpox. In contrast, experiments with VACV in mice and MPXV in macaques use very high doses of virus in an attempt to mimic the situation in smallpox infection. In contrast, in experiments with VACV in mice and MPXV in macaques, very high doses of virus are injected directly into the bloodstream, bypassing