Biodefense and special pathogen vaccines in development 2

We will now walk through three case studies of biodefense vaccines. The first one will take us through over 300 years of medical history with the advent of variolation to prevent smallpox. The second study deals with the use of the FDA animal rule to expand the indication of BioThrax, the anthrax vaccine, from pre-exposure to post-exposure prophylaxis. And lastly, we will cover a more recent event that has mobilized the biomedical community in ways that we've never witnessed before, the Ebola outbreak.

Let's begin with smallpox. Smallpox is believed to have killed more people than all wars combined. It has devastated mankind for centuries. We are, indeed, fortunate for the work of Edward Jenner and the many scientists and clinicians that worked towards the ultimate eradication of this scourge from humanity. Along with rinderpest, a disease of ruminants, smallpox is the only other disease eradicated from this planet.

But long before Edward Jenner discovered the protective effects of cowpox by observing that milk maids rarely developed smallpox, people had been using variolation to protect against smallpox infection. However, the observation that cowpox could also protect against smallpox and that it was much safer to use renders Jenner's observation one of the most important medical discoveries of all time. Shown here is Dr. Jenner vaccinating eight-year-old James Phipps on May 14, 1796 with the material he obtained from cowpox lesions on the hands of the young dairy maid, Sarah Nelmes. Two months after the boy was vaccinated with cowpox, Jenner challenged him with matter from a fresh smallpox lesion. Mind you, this was well before the days of informed consent and INDs. Fortunately, the boy did not develop smallpox, and Jenner rightly concluded that cowpox protected against smallpox infection. But smallpox continued to be a scourge on humanity for centuries thereafter, until a hemisphere-wide effort began in the 1950s by the Pan American Health Organization. Most of the smallpox vaccine that was produced during this period was derived from vaccine grown on the skin of live calves. During the eradication period, the World Health Organization called upon Wyeth, the company that had been manufacturing smallpox vaccine since the late 19th century, to not only continue to manufacture this vaccine but also develop a better injection system. This led to the discovery and the implementation of the bifurcated needle and the eventual eradication of smallpox. Dryvax, the Wyeth vaccine, is a live virus preparation of vaccinia virus prepared from calf lymphs. It was a highly-effective vaccine, but with serious adverse events in 1% to 2% of all vaccinees. After the WHO declared smallpox eradicated, Wyeth discontinued manufacturing Dryvax. It wasn't until 2001, after the attacks on the World Trade Center and Pentagon and the subsequent anthrax letters, that a smallpox vaccine was deemed necessary. At the time, it was believed that after the collapse of the Soviet Union smallpox may have become available to other countries or terrorist groups. Moreover, since vaccinations had been halted in the US in the late 1960s, over half of the population was susceptible to smallpox. A major effort was taken to resuscitate the smallpox vaccine. ACAM2000 was derived by a small biotech company by the name of Acambis. It was eventually bought by Sanofi Pasteur. ACAM2000 is a clonal isolate from Dryvax. Dryvax is a vaccine composed of many different variants of vaccinia virus. ACAM2000 is a clonal isolate, grown in defined vero cell culture. ACAM2000 was approved by the FDA in 2007 and has been stockpiled by the US government ever since. It is routinely used to vaccinate laboratory workers and military personnel who may be at high risk for exposure. It is administered by scarification using bifurcated needles, just like Dryvax. But like Dryvax, it also adds to the potential for transmission to close contacts of vaccinees. Several cases of contact vaccinia have been documented in adults and infants living in households of vaccinated military personnel. And unexpectedly, a high incidence of miopericarditis also was reported in clinical trials and in military personnel during ACAM2000's implementation. As a result, the FDA placed what is known as a black box warning on the label of ACAM2000, indicating that the product carries with it a significant risk for adverse effects. One of the phase IV commitments for this product is to continue monitoring cardiac events in all vaccinees. The time the US government realized that although ACAM2000 can be an effective vaccine to protect the general population, there could be risks during a mass vaccination campaign, especially in immunocompromised and HIV-infected individuals.