Manufacturing issues have led to a shortage of the only yellow fever vaccine licensed in the United States; now, that shortage is expected to lead to a complete depletion of available vaccine by mid-2017.
The Centers for Disease Control and Prevention (CDC) announced in their latest Morbidity and Mortality Weekly Report (MMWR) that because of recent manufacturing issues, the supply of the only yellow fever vaccine licensed in the United States, YF-VAX, is expected to be completely depleted by mid-2017.
However, a powerful collaborative effort between the CDC, the US Food and Drug Administration (FDA), and Sanofi Pasteur—the developer of the vaccine—is set on assuring a “continuous yellow fever vaccine supply in the United States after the anticipated complete depletion.” How? Through the implementation of an expanded access investigational new drug (eIND) protocol that will allow for the importation and distribution of “an alternative yellow fever vaccine” manufactured by Sanofi Pasteur France.
Endemic to sub-Saharan Africa and South America, humans typically get yellow fever through the bite of a mosquito infected with yellow fever virus. Although most infected individuals are asymptomatic, 15% will go on to develop severe disease; of those individuals, the case-fatality ratio can range from 20% to 50%. With outbreaks occurring in Angola, the Democratic Republic of the Congo, and more recently, Brazil, the idea of a vaccine shortage is especially troublesome.
Currently, the live-attenuated virus vaccine, YF-VAX “produces neutralizing antibodies in 80% to 100%” of those who receive it as quickly as 10 days after reception. The CDC recommends that anyone over 9 months of age who are traveling to areas where yellow fever is endemic as they are at increased risk of infection and bringing the virus back home with them—that is how outbreaks happen. To this end, proof-of-vaccination is now required when entering specific countries.
According to the MMWR, in 2015, a staggering 8 million individuals living in the United States traveled to 42 countries that were endemic with yellow fever. Unless these individuals received vaccination against infection, they had the potential to unknowingly, “export” the virus to non-endemic countries. In fact, between 1970 and 2013, yellow fever was reported in “at least 10” US and European travelers who were not vaccinated. Furthermore, the report states that “yellow fever virus was exported from Angola during the 2016 outbreak to three countries, with resulting local transmission in the Democratic Republic of Congo.” This fact alone emphasizes the need for travelers to be vaccinated.
Currently, in the United States, YF-VAX is the only licensed vaccine available against yellow fever. According to the report, about 500,000 doses are administered to military and civilian travelers on a yearly basis; two-thirds of these doses are given at around 4,000 civilian clinical sites.
So, what went wrong? In November 2015, as Sanofi Pasteur was in the process of transitioning “production” from their old facility to a new one that is estimated to open in 2018, “a manufacturing complication resulted in the loss of a large number of doses.” Sanofi Pasteur responded to this by ordering restrictions to temporarily prolong the supply. By spring 2016, the vaccine developers “notified CDC of a probable complete depletion of YF-VAX later in the year.” At the end of 2016, Sanofi Pasteur was able to produce more doses of the vaccine, but only enough to delay the anticipated complete depletion of the vaccine until mid-2017.
Sanofi Pasteur proceeded to submit an eIND application to import Stamaril, an alternative yellow fever vaccine that is not yet licensed in the United States. Much like YF-VAX, Stamaril uses the same vaccine substrain 17D-204 and offers “comparable safety and efficacy.” In fact, around 70 countries have already licensed and distributed the vaccine dating to 1986. Not only is it available in both single- or multi-dose vials, but Sanofi Pasteur “projects that importing Stamaril single-dose vials into the United States under the eIND application will not substantially affect the Stamaril supply intended for global use.”
After the FDA accepted the eIND application in October 2016, the CDC and Sanofi Pasteur got to work on developing a process to select sites where Stamaril would be available for distribution in the United States. They developed a “two-tiered scheme” for selecting clinical sites; Tier 1 would include “large-volume sites with adequate geographic range,” “additional smaller-volume sites…to ensure access to Stamaril in all 50 states, the District of Columbia, and the 3 US territories (Guam, Puerto Rico, and the US Virgin Islands),” and sites that would provide access for civilian US government employees who are traveling for work; Tier 2 would include “multistate clinical organizations.” As of April 2017, 250 clinics were identified for inclusion.
Although the site selection took into account site volume and geographic reach, some international travelers might face accessibility difficulties because of the significant decrease in the number of clinics that will provide the vaccine—from 4,000 to 250. The CDC and Sanofi Pasteur will work together to keep an eye out on any “critical gaps in vaccine access” and will work to address any issues they might find.
The CDC say that they will provide updates to the public as new information becomes available.