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

Abstract

Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40–50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism.

The Virulence of Different Vaccinia Virus Strains Is Directly Proportional to Their Ability To Downmodulate Specific Cell-Mediated Immune Compartments In Vivo

“…MVA administered transdermally yielded nondetectable or very small amounts of IgG, while MVA administered intramuscularly (i.m.) resulted in higher levels of specific IgG (42). Likewise, MVA administered in mice through percutaneous inoculation elicited specific antibody responses, and animals were protected from a consecutive VACV lethal challenge, at levels comparable to or higher than those with subcutaneous or i.m.…”

Vaccinia Virus Expressing Interferon Regulatory Factor 3 Induces Higher Protective Immune Responses against Lethal Poxvirus Challenge in Atopic Organism

“…Twenty-four days later, they were infected i.n. with a lethal dose of wt-WR, the surrogate of smallpox (10 5 PFU/mouse; volume of inoculum, 30 µL) [ 4 ]. The mice in the experiments were monitored daily for weight, body temperature, fur and behavioral changes.…”

“…Vaccination with the original crude VACV vaccines, as well as that with replicating vaccines of newer generations, reveals a risk of serious, even life-threatening complications. One of them is the development of eczema vaccinatum occurring in individuals suffering atopic dermatitis, excluding them from all preventive vaccination schemes based on replicating VACV [ 3 , 4 ].…”

“…We have previously developed a mouse model of eczema vaccinatum in the spontaneously atopic Nc/Nga mice that reveal many characteristics similar to atopic dermatitis in humans [ 12 , 13 ] and compared it with Balb/c and C57Bl/6 mice, using the wild-type VACV strain WR (wt-WR). We have shown that, after inoculation with wt-WR, Nc/Nga mice developed the largest primary skin lesions and the highest number of satellite lesions, the characteristics of eczema vaccinatum, even without any specific sensitization [ 4 ].…”

Modified Vaccinia Virus Ankara

“…Moreover, recent fears that monkeypox virus (MPXV) or VARV could be used as biological weapons have renewed the interest in safe vaccines against VARV or other zoonotic orthopoxviruses (Moss, 2011). MVA holds great promise for worldwide use as third-generation smallpox vaccine due to its well-established characteristics concerning safety and immunogenicity Jones et al, 2016;Knitlova et al, 2014;Meseda et al, 2016;Tree et al, 2016;Wyatt et al, 2004). In 2013, an MVA vaccine has been licensed in Europe for active immunization against smallpox in adults and for use in situations where it is considered necessary to protect against smallpox in accordance with official recommendations (European Medicines Agency, 2013).…”