Smallpox was unique among infectious ills of the 1800's for having a specific preventive measure in vaccination, making it therefore, an avoidable disease. The advent of the publication of the William Jenner's 'Inquiry' in 1798 (full title: An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western countries of England, particularly Gloucestershire, and known by the name of the cow pox) resulted in vaccination being widely undertaken to protect people from smallpox. Despite the difficulties of transporting vaccine to the Colony, the first local vaccinations had been undertaken within six years of the Jenner discovery, by Principal Surgeon of the Colony, Thomas Jamison, Surgeon John Harris and assistant-surgeon John Savage.

The long and unsuccessful campaign for compulsory vaccination in New South Wales originated around this time with the first medical writings published in the Sydney Gazette of October 1804, and for the next few decades a cycle of panic and indifference seemed to dominate the public uptake of vaccination, dependent on the proximity and severity of outbreaks. By 1860, all colonies except New South Wales and Queensland had enacted compulsory vaccination legislation. New South Wales continued to resist based, perhaps on the lack of smallpox outbreaks experienced there. Despite several pushes to have vaccination made compulsory, the medical profession was largely frustrated by the government of the day. An 1856 report written by the non-medical Registrar General Charles Rolleston had a bet each way:

Although, as l have said, I cannot advocate a general system of compulsory vaccination I yet think that something should be done to encourage its voluntary adoption. There is much apathy and indifference to be overcome, originating, doubtless, in a sense of security, but I am not aware that prejudice and superstition rule here to the extent they are found to exist, to this day in the Mother Country.

By the late 1870's however, New South Wales' luck had run out and the first half of the next decade saw multiple outbreaks of smallpox. Once again the medical profession in New South Wales urged compulsory vaccination to be introduced. In 1881 the NSW Cabinet met as a Committee of Inquiry which heard evidence upon the value of vaccination from several medical practitioners and, although overwhelmingly in favour, compulsory vaccination was once again rejected due to ongoing concerns with implementation and enforcement. Smallpox was present in several colonies for much of this decade but despite the proximity of the disease, the anti-vaccination sentiment strengthened at the same time.

According to Edward Ford, as the medical profession became increasingly aware of anti-vaccination sentiment, the need to counter this with their own pro-vaccination material became vital. Hence the reprinting of the 'Inquiry' with an added preface which read in part:

This book will no doubt be found of great benefit to the Medical Profession and the general public by placing before them, without extraneous matter, the evidence upon which Vaccination was adopted by every civilized Government of the world.

In a letter to Edward Ford, John Cumpston, first Director-General of the Australian Department of Health (who also wrote the History of Smallpox in Australia), wrote that the anti-vaccination writings of Charles Creighton also had influence in the Colonies.

How many copies were made or how widely it was distributed is unknown, however the effort came to naught as compulsory vaccination was never legislated in the Colony of New South Wales. Medical men of New South Wales had to continue to push the message well into the nineteenth century. The last case of smallpox in Australia occurred in 1938. In 1980 the World Health Assembly endorsed the declaration that smallpox was eradicated worldwide making it the first disease the eliminated by vaccination.