Author(s): Stephen R Walsh [[dagger]] 2 , Raphael Dolin 1
ACAM2000; clinical trials; Dryvax; IMVAMUNE; MVA; orthopoxviruses; smallpox; vaccine; vaccinia
Smallpox is a contagious and highly morbid disease with approximately 30% mortality  . It is notable for a striking and characteristic exanthem that scars survivors [2-5] . The causative agent, variola virus (VARV), is a member of the orthopoxvirus family  , of which the best characterized is the smallpox vaccine virus, vaccinia virus (VACV). Although VARV was eradicated in 1978 following an intensive worldwide vaccination effort [1,2,5] and is now maintained in only two secure laboratories  , recent events have renewed concerns that VARV from an undeclared stockpile might be used as a biological weapon [3,8,9] or could be inadvertently released from the two reference laboratories. Over 100 million Americans have been born since universal immunization ceased  , and immunity has waned in an estimated 150 million Americans who were vaccinated at earlier times. This means that a smallpox outbreak in the USA could lead to catastrophic consequences [10-14] , although rapid diagnosis of cases and aggressive public health interventions could help contain an epidemic [15,16] . The smallpox vaccine used in the USA until 2008 was live calf lymph-derived Dryvax® (Wyeth; derived from the New York City Board of Health [NYCBH] strain of VACV), and while highly effective in preventing smallpox [4,5,8] , it has a significant incidence of adverse effects, which have prompted efforts to develop safer smallpox vaccines [17,18] .
Historically, VACV vaccination was associated with a large number of side effects including encephalitis, encephalopathy, vaccinia conjunctivitis, fetal vaccinia, inadvertent spread of VACV and even death [19-25] . The recent limited civilian vaccination program for 'first-responders,'â as well as the larger military vaccination program, provide some insights into the frequency of adverse events (AEs) in highly selected populations. While the overall frequency of significant side effects appeared to be quite low [26-28] , there were rare AEs  , most notably myopericarditis [30,31] , which had been underappreciated in historical studies  . Dermatologic complications following smallpox vaccination via scarification have long been recognized and include potentially life-threatening reactions such as progressive vaccinia or vaccinia necrosum [33,34] , eczema vaccinatum [35,36] and disseminated vaccinia [37,38] . More commonly seen, however, are less serious reactions such as satellite lesions, viral cellulitis and a variety of exanthems, including vaccinia folliculitis [39,40] , which have been estimated to occur at an overall frequency of approximately one per 3700 vaccinees  . These numerous and significant AEs have led to an extensive list of contraindications to vaccination, and therefore a substantial fraction of the public cannot receive VACV. Indeed, some have estimated that up to 25% of the US population have contraindications to the current smallpox vaccine  . These contraindications include immunosuppression (i.e., organ transplantation or immunosuppressive medications), pregnancy, breast-feeding, HIV infection, atopic dermatitis or eczema, household contact with any person who cannot receive VACV and all persons under 18 years of age [42,43] .
As smallpox is both a cutaneous and systemic disease  , an important correlate of protection that has been examined in both preclinical studies and clinical trials of...