The effects of post-exposure smallpox vaccination on clinical disease presentation: Addressing the data gaps between historical epidemiology and modern surrogate model data

Abstract

Decades after public health interventions – including pre- and post-exposure vaccination – were used to eradicate smallpox, zoonotic orthopoxvirus outbreaks and the potential threat of a release of variola virus remain public health concerns. Routine prophylactic smallpox vaccination of the public ceased worldwide in 1980, and the adverse event rate associated with the currently licensed live vaccinia virus vaccine makes reinstatement of policies recommending routine pre-exposure vaccination unlikely in the absence of an orthopoxvirus outbreak. Consequently, licensing of safer vaccines and therapeutics that can be used post-orthopoxvirus exposure is necessary to protect the global population from these threats. Variola virus is a solely human pathogen that does not naturally infect any other known animal species. Therefore, the use of surrogate viruses in animal models of orthopoxvirus infection is important for the development of novel vaccines and therapeutics. Major complications involved with the use of surrogate models include both the absence of a model that accurately mimics all aspects of human smallpox disease and a lack of reproducibility across model species. These complications limit our ability to model post-exposure vaccination with newer vaccines for application to human orthopoxvirus outbreaks. This review seeks to (1) summarize conclusions about the efficacy of post-exposure smallpox vaccination from historic epidemiological reports and modern animal studies; (2) identify data gaps in these studies; and (3) summarize the clinical features of orthopoxvirus-associated infections in various animal models to identify those models that are most useful for post-exposure vaccination studies. The ultimate purpose of this review is to provide observations and comments regarding available model systems and data gaps for use in improving post-exposure medical countermeasures against orthopoxviruses.

Co-administration of the broad-spectrum antiviral, brincidofovir (CMX001), with smallpox vaccine does not compromise vaccine protection in mice challenged with ectromelia virus

“…Therefore, one key advantage to any anti-OPV regimen is the ability to protect following exposure to the virus. Several antiviral drugs have been demonstrated to provide post-exposure protection in animal models (Nalca et al, 2008;Parker et al, 2008b,c;Quenelle et al, 2007a,c;Smith et al, 2011;Stabenow et al, 2010) and some studies have indicated that smallpox vaccines can also be given post-exposure and still provide protection (Keckler et al, 2013). Others have shown that vaccinating C57BL/6 or BALB/c mice with VACV-Lister (a first-generation smallpox vaccine similar to Dryvax) or ACAM3000 provides post-exposure protection up to 2-3 days post IN ECTV challenge (Paran et al, 2009).…”

Treatment with the Smallpox Antiviral Tecovirimat (ST-246) Alone or in Combination with ACAM2000 Vaccination Is Effective as a Postsymptomatic Therapy for Monkeypox Virus Infection

“…Limited epidemiological data from the smallpox eradication era suggest that vaccination 1 to 3 days following exposure to smallpox might be effective at reducing the rate of occurrence and/or severity of smallpox (1,2). Afterwards, vaccine efficacy appears to progressively decline throughout the incubation phase of the disease (ϳ12 days), and vaccination appears to be wholly ineffective following onset of clinical symptoms.…”

Postexposure Smallpox Vaccines - Can We Extend the Therapeutic Window?

“…Yet, the concomitant use of these drugs, during the 468 course of treatment, does not allow to determine their sole efficacy in those cases. 469 Although the above data strongly support the use of these drugs for treatment of The feasibility of postexposure vaccination against smallpox is based on historical 480 anecdotal data, and on recent publications using surrogate animal models 34,[87][88][142][143] .…”

“…The cumulative data, considering gaps arising from limited epidemiological data and 482 the ability to correlate data from surrogate animal models, suggest that active 483 vaccination up to 4 days postexposure is protective 54,87,[144][145][146] . However, as already 484 discussed, in a population scale, the unknown exposure rate and the limited supply, human, and the extremely short incubation period of about 2-3 days is much shorter 497 than in the human disease (7-14 days).…”

“…One attempt to improve and/or extend the efficacy of postexposure vaccination was to 502 co-administer the vaccine with an antiviral drug like VIG, CDV or in Table 1) 54,87,118,123,137,[142][143][147][148] . Indeed, the intendent use of these drugs is either 504 treatment of vaccine adverse reactions once they occur or given concomitantly to 505 prevent the adverse reaction in at risk populations 125,149 .…”