"The plague" refers to an acute virulent disease, usually one reaching or threatening to reach epidemic proportions, and historically one caused by a bacterium. The medieval Black Death set much of the tone and metaphorical conventions still operating in many modern-era descriptions of plagues. The Last Man was written during one such early-nineteenth century outbreak, a cholera epidemic begun in India ca. 1817 and seen by the 1820s as posing a threat to Europe.
The history of nineteenth-century epidemics, and their construction as "the plague," reveals telling narrative and figurative patterns, all of them relevant to reading this novel (with its fabric of interwoven political, military, social, sexual, and medical narratives). As the histories are explained by Ranger and Slack (pp. 3-4),Flight from an infected place was usual, and had to be defended (or attacked) since it took people away from charitable, neighbourly or political duties. Carriers of disease were identified and scapegoats stigmatised: foreigners most often, as in Renaissance Italy and modern Hawaii, since epidemic disease came from outside, but also inferiors, carriers of pollution of several kinds, among whom disease had its local roots--untouchables in India and ex-slaves in Africa, for example, or Jews at the time of the Black Death (though less commonly in Europe in later outbreaks of plague). For their part, the inferiors themselves thought epidemics the consequence of plots by external enemies, or governors and elites, to 'poison' the poor. (p. 4)
In our own moment at the end of the twentieth century, as Susan Sontag has suggested, the very idea of "virus" itself (rather than any actual bacterial infection) has become the metaphorical equivalent of "plague." Today a "virus" can infect computers and cultures (where it takes the form of a "meme") as well as individuals (p. 157). The very real plague of our time is AIDS, a syndrome that has most often been figured (at least until very recently) as a potential pandemic threatening a mass population.
The comparison of Mary Shelley's fictional depiction of a world-wide apocalyptic plague to the actual plague of AIDS has been the subject of works by critics such as Audrey Fisch, Mary Jacobus, Anne K. Mellor, and Barbara Johnson.