Inaugural Post

A gracious good morning, afternoon, evening, and welcome to the Inaugural Post of yet another health-related blog by another overly educated individual. To knock off 2007 and ring in 2008, the last 10 days of the year will be used to count down what have been decided solely and exclusively by me to be the top 10 medical/pharma stories of 2007. If you have absolutely nothing to do for the holidays and consequently stick around for all 10 stories, you’ll discover a really unsettling pattern.

For those who have stumbled across this site hoping to satisfy some unbelievably disturbing fetish and are compelled to leave feedback, just clean it up.

And here we go:

No. 10: Emerging Deadly Adenoviral Infection

From February to June, hospitalization was required for 53 of 140 US adults who were infected with a newly emerging pathogen, adenovirus serotype 14 (Ad14). Nine patients died of the infection; 7 were reportedly immunocompetent adults. Typically accounting for fewer than 2% of respiratory illnesses in civilian adults, adenovirus infection has been a historically benign illness outside of infancy and old age.

Persons hospitalized in 2007 for Ad14 pneumonia included 22 community-dwelling individuals in Oregon, 4 adults from a residential-care facility in Washington State, and 27 military trainees at Lackland Air Force Base, according to the MMWR. Twenty-four, or 45%, of these patients required ICU admission. The 2007 cases were preceded by the Ad14-associated death of a 12-day-old, otherwise healthy, full-term girl in New York in May 2006. The viral isolate from this case was genetically identical to isolates from the cases observed in 2007.*

Adenovirus outbreaks are certainly not unknown to US military bases, but infection in this setting infrequently necessitated hospitalization and rarely, ICU care. In addition to the cases described, the MMWR article retrospectively identifies 220 cases of Ad14-associated illness from March to September on three other Texas military bases, which received Lackland trainees. How these cases are related, if at all, has not been determined.

Adenovirus can be transmitted by more than one method: by inhalation, through the conjunctiva (think poorly chlorinated swimming pools), and probably by fecal-oral spread. Ad14 PCR testing at Lackland suggests that healthcare workers in contact with infected individuals are at risk for infection and for propagating transmission, but no staff or other residents at the Washington facility tested positively.

Why this Ad14 isolate appears more pathogenic than other serotypes is currently unknown. The 2007 serotype is distinct from the Ad14 isolate of 1955 (a serotype recovered from military recruits in The Netherlands), according to the MMWR, thereby indicating that the 2007 pathogen is new.

Tuve et al (J Virol. 2006;80:12109-12120.) confirm that some serotypes of group B adenovirus, to which Ad14 belongs, use the ubiquitous and often microbially exploited CD46 receptor for host entry. However, they allege that Ad14—or at least the 1955 serotype—uses an as-yet-unidentified, highly expressed glycoprotein “receptor X.” Knowledge of how adenovirus serotypes infect host cells not only has implications for understanding the pathogenesis of (and subsequent immunity to) adenovirus infection, but informs the success of gene therapies (eg, for cystic fibrosis) and vaccinations (eg, for HIV) that use modified adenovirus as a delivery vector.

Adenoviral infections are treated with supportive care, and prevention requires the typical infection-control measures. Adherence to infection control is important, because adenovirus can persist for weeks on fomites. The efficacy of the antiviral agents ribavirin, vidarabine, and cidofovir has not been definitively demonstrated.

Adenoviral Vaccination

Adenoviral vaccination has its own interesting history. Live, oral pill vaccines against serotypes 4 and 7—which were determined to be the most important disease-causing serotypes among military trainees during the mid-20th century—were developed and then implemented at US recruitment camps, beginning in 1971 (Russell KL et al. Vaccine. 2006;24:2835-2842.). According to the US Army Medical Materiel Development Activity (USAMMDA), the original vaccines were manufactured by Wyeth Laboratories, and clinical development was cosponsored by the US Army and the NIAID. The 2-pill vaccine was approved by the FDA in 1980 but was available earlier through an IND exemption. With the institution of the vaccine among military recruits, the rate of adenoviral infection dropped dramatically, by up to 96%.

In 1984, Wyeth asked the DoD to underwrite a $5-million renovation of its Pennsylvania vaccine manufacturing facility, to comply with FDA safety standards. According to an unclassified 2001 report by US Army Colonel Niranjan Balliram, Wyeth’s vaccine-production equipment was woefully outdated and in severe disrepair, with at least one machine worthy of donation to the Smithsonian Institute. Moreover, live adenovirus was being transported by gurney without appropriate infection precautions. The Defense Personnel Service Center in Philadelphia, which was responsible for the Wyeth contract, requested money from the Pentagon to fund the facility update, but the request was rejected. The search for other adenovirus vaccine manufacturers was fruitless.

The reasons for the Pentagon’s reluctance to support Wyeth’s facility upgrade are unclear; however, according to a DoD press release, the decision may have been based partly on data indicating that the vaccine was no longer necessary. In 1994, Wyeth declared that it would no longer produce the vaccine, and manufacture ceased in 1996. Viable stocks, with seasonal rationing, were exhausted by 1999 (Russell KL et al. Vaccine. 2006;24:2835-2842.).

After vaccination against adenovirus was terminated, a 5-year DoD surveillance identified a greater-than-3-fold increase in culture-positive adenoviral infections among recruits, with an average of 14,750 cases per year among 8 military training sites (Russell KL et al. Vaccine. 2006;24:2835-2842.). Adenoviral infection was the suspected cause of death of 2 naval trainees in July and September, respectively, during 2000 (MMWR. 2001:50;553-555.).

In 2001, William Winkenwerder, Jr., then Assistant Secretary of Defense for Health Affairs, urged the redevelopment and manufacture of the Ad4 and Ad7 vaccines, and a $35.4-million contract was awarded to Barr Laboratories for the effort. According to the USAMMDA, the Barr vaccine would be a redeveloped, updated version of the Wyeth products.

Barr’s 2006 annual report indicates that phase 1 study of its adenovirus vaccine (DR-5001) was completed at the end of 2006. A phase 3 study at the Great Lakes, IL, and Fort Jackson, SC, training centers is not yet recruiting subjects. According to the MMWR, “work is ongoing” to determine if the Barr vaccine will protect against infection caused by the Ad14 serotype.

* At the most recent meeting of the Infectious Diseases Society of America, Lewis et al retrospectively identified 31 cases of Ad14 infection in Oregon from November 2006 through April 2007; according to specimens logged at the state public health lab, PCR-confirmed Ad14 emerged in this state as early as 2005.