Humoral Immunity to Smallpox Vaccines and Monkeypox Virus Challenge: Proteomic Assessment and Clinical Correlations

Abstract

c Despite the eradication of smallpox, orthopoxviruses (OPV) remain public health concerns. Efforts to develop new therapeutics and vaccines for smallpox continue through their evaluation in animal models despite limited understanding of the specific correlates of protective immunity. Recent monkeypox virus challenge studies have established the black-tailed prairie dog (Cynomys ludovicianus) as a model of human systemic OPV infections. In this study, we assess the induction of humoral immunity in humans and prairie dogs receiving Dryvax, Acam2000, or Imvamune vaccine and characterize the proteomic profile of immune recognition using enzyme-linked immunosorbent assays (ELISA), neutralization assays, and protein microarrays. We confirm anticipated similarities of antigenic protein targets of smallpox vaccine-induced responses in humans and prairie dogs and identify several differences. Subsequent monkeypox virus intranasal infection of vaccinated prairie dogs resulted in a significant boost in humoral immunity characterized by a shift in reactivity of increased intensity to a broader range of OPV proteins. This work provides evidence of similarities between the vaccine responses in prairie dogs and humans that enhance the value of the prairie dog model system as an OPV vaccination model and offers novel findings that form a framework for examining the humoral immune response induced by systemic orthopoxvirus infection.

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

“…The time it takes a virus to spread to the point where post-exposure vaccination is not beneficial will depend in part on the incubation period of the virus and the kinetics of the immune response. For example, primary exposure requires 7–13 days to produce neutralizing antibodies against vaccinia in human studies [87–89], and smallpox in humans has a combined incubation and prodromal period that lasts 7–17 days with a mean of 12.5 days [90]. Based on these data, smallpox contacts who have been exposed and have a shorter incubation period (<12.5 days) may not have time to mount a neutralizing antibody response to the VARV exposure and thus supplementing this response with a post-exposure vaccination may gain no protective benefit.…”

Development of Eczema Vaccinatum in Atopic Mouse Models and Efficacy of MVA Vaccination against Lethal Poxviral Infection

“…Original stocks of VACV strain Dryvax as well as second generation tissue culture-grown stocks (ACAM2000) have been used [2] . New, highly attenuated vaccine based on non-replicating Modified vaccinia virus Ankara (MVA; IMVAMUNE) is under clinical development and seems to induce good immune responses in blood tests and in animal models [3] , [4] , [5] , [6] , [7] . It is impossible, though, to test its efficacy in vivo in human.…”

Vaccinia Virus LC16m8∆ as a Vaccine Vector for Clinical Applications

“…Although several studies report that the B5 protein is the major target of EEV-neutralizing antibodies, which are significant for protection against smallpox infection, immunization with B5-deficient vaccine viruses protects animals against lethal challenge by pathogenic orthopoxviruses [ 58 , 64 , 65 , 66 , 67 ]. In addition, some reports show that smallpox vaccines do not always induce anti-B5 antibodies, and antibody response profiles against each viral protein are highly heterologous in humans [ 68 , 69 , 70 ]. They also concluded that the key to inducing a strong neutralizing antibody response is to elicit antibodies that recognize multiple viral proteins; these antibodies then act synergistically to provide better protection.…”