A New Generation of Challenges for the Traditional Yellow Fever Vaccine

Anticipated shortages of the 17D vaccine for yellow fever (YF) have become a significant cause for concern in the wake of the re-emergence of a disease that was once well-controlled via vaccination.^1,2 Outbreaks in Sudan, Angola, and Brazil have resulted in spread of the disease to nearby countries and internationally by infected travelers.^3-5

The YF virus targets the liver, causing high fever that breaks on its own in 85% of cases. For the remaining 15%, additional symptoms of jaundice, bleeding, and renal damage may follow, resulting in death in half of these cases.¹ In tropical Latin American and Caribbean countries, and Africa, where mosquitos carrying the YF virus are most prevalent, an estimated 29,000 to 60,000 deaths are attributed to YF annually, despite routine infant immunization programs in 35 of the 44 at-risk countries.²

Yellow Fever Vaccination

The 17D YF vaccine is one of the most stable and effective vaccines in use, with an estimated 540 to 600 million doses distributed worldwide.^1,2 The attenuated live virus vaccine, developed in 1937, is still cultured in pathogen-free eggs and  has been shown to be 99% effective and safe in people age 9 months to 60 years who are immune-competent and do not have allergies to eggs.^2,6 The 2016 recommendations by the World Health Organization (WHO) reported that a single dose conferred sufficient lifetime immunity from YF, and that the 10-year booster schedule was no longer necessary.⁶

Eradication is not possible for a number of reasons, and so the potential for breakthrough epidemics will continue to exist. “The only diseases that can be eradicated are those that only infect humans. Any pathogen that has an animal reservoir cannot,” explained Alan DT Barrett, PhD, director, Sealy Center for Vaccine Development at the University of Texas Medical Branch in Galveston, to Infectious Disease Advisor.

Despite the high efficacy, whole populations are not considered for YF vaccination unless there is a prevailing risk for the disease due to the occurrence, although rare, of serious and sometimes fatal adverse effects, including vaccine-associated neurotropic disease (YEL-AND) and viscerotropic disease (YEL-VTD).

Challenges to Meeting the Demand

In a pair of opinion articles appearing in the Annals of Internal Medicine¹ and JAMA,⁷ Daniel Lucey, MD, MPH, adjunct professor, division of infectious diseases, Georgetown University Medical Center, Washington, DC,  draws attention to critical global vaccine shortages necessary to contain the spread of YF predicted for the immediate future (2017 to 2018). The egg-culturing method limits the quantity of vaccine that can be produced, forcing the need for new vaccine development technologies to prevent epidemic surges in worldwide YF infections. If the YF virus is introduced into the large populations of India and China, where 2 billion people are immunologically naïve to YF, the possible spread could be “catastrophic,” according to Drs Lucey and Donaldson.

A longer-term challenge also exists, as the initial production seeds used to make all 17D vaccines today were generated more than 50 years ago and are now aging past their peak. While continued use of these seeds insures stability of the vaccines, there will be a time when new production seeds will need to be created. “There is a comprehensive seed-lot (batch) system involving primary seeds that produce secondary seeds that are used to produce vaccine lots given to people,” said Dr. Barrett. “Eventually the primary seed lots will need to be replaced, but not yet. The quality of vaccine batches produced today is maintained by regulations and so there is no negative impact on current vaccine batches,” he noted.

When asked if the new vaccine schedules recommended by the 2016 WHO updates that do not require boosters have decreased the challenges to preventing the spread of YF, Dr Barrett responded, “I cannot answer that question directly as it is a complicated situation. However, GAVI (the Vaccine Alliance) has paid for extensive vaccine implementation in West Africa for the last 10 years. This program has been excellent and has resulted in the elimination (meaning no human disease) of yellow fever from all countries where the vaccine was utilized.”

But, he explained, risks of new outbreaks always exist. “The problem is that yellow fever is being seen in countries where the virus is not endemic (such as Angola last year), where outbreaks occur infrequently, and vaccination programs have not been implemented because priority has been on countries in West Africa where the virus is endemic.” The solution is to introduce vaccination programs in the areas in which outbreaks are infrequent, he said.

As currently, there is no cure — or even effective antiviral therapy for YF — vaccination remains the sole route to preventing mortality from the disease, and WHO projections have already pointed to a significant global shortage.

Various methods to meet the short- and long-term challenges need to be utilized, including the development of a faster, high volume production alternative to egg culturing; generation of newer seeds; and stockpiling of vaccines in time to meet sudden surges in need. 

References

1. Lucey DA, Donaldson HD. Yellow fever vaccine shortages in the United States and abroad: a critical issue. Ann Int Med. 2017;167:664-665.
2. Beck AS, Barrett ADT. Current status and future prospects of yellow fever vaccines. Expert Rev Vaccines 2015;14:1479-1492.
3. Buliva E, Elhakim M, Tran Minh NN, et al. Emerging and reemerging diseases in the World Health Organization (WHO) Eastern Mediterranean Region-progress, challenges, and WHO Initiatives. Front Public Health. 2017;5:276.
4. Freya M Shearer, Catherine L Moyes, David M Pigott, et al. Global yellow fever vaccination coverage from 1970 to 2016: an adjusted retrospective analysis. Lancet Infect Dis. 2017;17: 1109-1117.
5. Garske T, Van Kerkhove MD, Yactayo S, et al; Yellow Fever Expert Committee. Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data. PLoS Med. 2014;11:e1001638.
6. World Health Organization, International travel and health update for Yellow Fever Vaccine. 2016. www.who.int/ith/updates/20160727/en/
7. Lucey D, Gostin LO. A yellow fever epidemic: a new global health emergency? JAMA. 2016;315:2661-2662.