PLoS One. 2014 Dec 8;9(12):e114374.

Development of eczema vaccinatum in atopic mouse models and efficacy of MVA vaccination against lethal poxviral infection.

Knitlova J1, Hajkova V1, Voska L2, Elsterova J1, Obrova B1, Melkova Z1.
  • 1Department of Immunology and Microbiology, 1st Medical Faculty, Charles University, Studnickova 7, 128 00, Prague 2, Czech Republic.
  • 2Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Videnska 9, 140 21, Prague 4, Czech Republic.

 

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.

PMID: 25486419

 

Supplementary

The threat of smallpox has been largely eliminated by a successful vaccination campaign leading to eradication of the smallpox causative agent, variola. Consequently, vaccination of the common population was stopped, namely because of serious side effects (1). Thus today, most of the world population is largely non-immune and therefore sensitive not just to smallpox that is considered as a potential bioweapon as well as a risk arising from melting permafrost in Siberia (2), but also to other poxviruses such as monkey, camel or buffalo poxviruses and namely to the smallpox vaccine itself, vaccinia (3). Ironically, the reintroduction of vaccination with a life, wild-type vaccinia virus after 9/11 led to a significant number of cases of contact vaccinia, some of them being very serious and life-threatening (4, 5, 6).

There are several serious complications of the exposure to a replicating poxvirus among adults as well as children. Most of them occur in individuals with some kind of immune deficit, both inborn or attracted and therapeutically induced. Importantly, the number of immune compromised individuals is constantly rising (different kinds of atopy and allergy, HIV/AIDS, transplantations of bone marrow or other organs, treatment of different cancers or autoimmune disorders), thus representing a significantly large portion of the general population that is excluded from all preventive vaccination schemes involving a replicating vaccinia virus. Consequently, several attenuated vaccinia viruses have been tested as safer vaccines; among them, non-replicating MVA. Nevertheless, a drawback of all currently developed smallpox vaccines consists in the impossibility to test their efficacy in vivo in human; only blood tests characterizing certain immune responses in vitro can be performed. Animal models in which the efficacy of the newly developed vaccines can be tested are therefore valuable and useful.

In our work, we have decided to compare different mouse models of atopic dermatitis in their response to vaccinia virus and suitability to serve as model of eczema vaccinatum, with spontaneously atopic Nc/Nga mice found to represent the most suitable model. Further, we have chosen these mice to test efficacy of MVA to induce protective immunity against a lethal poxvirus challenge in an atopic organism. In addition to the results proving a good protective capacity of MVA (described above), we have observed a slightly higher mortality in vaccinated male mice, suggesting gender-dependent lower or delayed immune responses. When exploring the gender differences in a closer detail, we have found an age-dependent higher replication of wild-type vaccinia virus strain WR in skin of male mice (Fig. 1). It seems to be interesting and important to find if similar gender-dependent differences might be found also in human atopics.

 

zm fig1-2

Figure 1. WR titers (PFU/ml) in the site of WR inoculation at 2 days post infection in male and female Nc/Nga mice.

 

 

References

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