Pharmacology Consult

Yellow fever outbreak complicated by vaccine shortage

The news here in the United States has been consumed with information about Zika virus because it has been affecting Americans and causing devastating effects on infants. However, an outbreak of another mosquito-borne disease, yellow fever, has been going on outside the U.S. since December 2015. Yellow fever virus is a single-stranded RNA virus that belongs to the genus Flavivirus. It is transmitted via a bite from an infected Aedes or Haemagogus spp. mosquito. Yellow fever is endemic in approximately 47 countries in sub-Saharan Africa and tropical South America. Worldwide, there are an estimated 200,000 cases of yellow fever and up to 30,000 deaths each year, with 90% of the cases occurring in Africa.

Jeff Brock

The latest outbreak began in Angola, where it has infected thousands of people and killed hundreds thus far. The number of suspected cases there has been decreasing due to mass vaccination campaigns, but the outbreak in Angola is not under control yet. Infected travelers have spread the disease to other countries like the Democratic Republic of the Congo (DRC), Kenya and China. The cases in Angola and the DRC have been concentrated in cities, suggesting transmission through an urban cycle in which the virus is transmitted between humans via a mosquito bite. This increases the risks for further spread to other countries.

Symptoms of yellow fever virus infection usually begin abruptly 3 to 6 days after a bite from an infected mosquito. Some patients will not have any symptoms, but when they do occur, the most common are fever, muscle pain, headache, loss of appetite, and nausea or vomiting. Symptoms generally last 3 to 4 days. About 15% of infected patients enter a more toxic phase with return of high fever, multi-organ dysfunction, jaundice, abdominal pain with vomiting, and possibly bleeding from the mouth, nose, eyes or stomach. Approximately 50% who enter the toxic phase will die within 7 to 10 days.

Risk for travelers

The risk for a traveler contracting yellow fever is determined by several factors, including immunization status, season, location, activities and duration of travel. Reported cases of yellow fever in a location is the primary indicator of disease risk when traveling, but lack of case reports in a location with known yellow fever risks does not mean protective measures should not be taken. Vaccination is the only true way of limiting the risks. Only 23 vaccine failures have been identified after administration of more than 500 million doses of the yellow fever vaccine. Five of these cases occurred less than 10 days after vaccination because they did not have enough time to fully develop an antibody response.

Yellow fever vaccine and indications

A vaccine has been available for prevention of yellow fever since 1937. Yellow fever vaccines are live-attenuated viral vaccines from the 17D lineage. Currently, the minimum potency for human yellow fever vaccine is set at 3 log10 IU per dose, which is 0.5 mL given subcutaneously. However, there is not a limit on the maximum potency. All available yellow fever vaccines have proved to be efficacious, but the standard laboratory defined potency may vary by manufacturer.

The yellow fever vaccine is recommended for anyone aged 9 months and older who is living in or traveling to endemic areas. In outbreak situations, the vaccine may be given to those who are aged 6 months and older. It also is recommended for laboratory workers who might be exposed to either yellow fever virus or to concentrated preparations of yellow fever vaccine virus strains.

Many of the endemic countries require proof of vaccination for entry into the country. Providers should refer to the CDC Health Information for International Travel 2016 (the “Yellow Book”), in the section titled “Yellow Fever & Malarial Information, by Country,” for information regarding which countries require yellow fever vaccination for entry and for additional CDC recommendations. It is important to note that the country entry requirements can be different than the CDC’s recommendations. Yellow fever vaccine entry requirements are established by individual countries to prevent the importation of yellow fever, and travelers must comply unless they have been issued a medical waiver. These requirements are subject to change at any time, so it is important to check current requirements before departure.

Immune response

The vaccine produces a robust immune response and high levels of protection in those who receive it. Within 10 days after vaccination, 90% of patients will have protective immunity, and in nearly 100% after 3 to 4 weeks following immunization. Certain individuals such as infants, toddlers, pregnant females and those with immunosuppressive diseases may not respond as vigorously to the vaccine.

Yellow fever virus infection induces a rapid immune response with immunoglobulin M antibodies appearing during the first week after infection, peak during the second week, and slowly decline over 1 to 2 months. IgG antibodies start to appear at the end of the first week of infection and persist for at least 35 years or even for life, providing lifelong protection against subsequent infection.

Recent changes to vaccine recommendations

Historically, a booster dose of the yellow fever vaccine was recommended after 10 years. However, in 2013, the WHO Strategic Advisory Group of Experts in Immunization concluded that a single primary dose of yellow fever vaccine is sufficient to provide sustained immunity and lifelong protection. The recommendation was based on a systematic review of the available evidence on the duration of immunity following a single dose of yellow fever vaccine. The data suggest that vaccine failures are very rare, and the risk does not increase over time. In May 2014, the World Health Assembly adopted the recommendation to remove the booster dose requirements from the International Health Regulations by June. The Advisory Committee on Immunization Practices guidelines state that booster doses may be given to certain travelers who received the vaccination at least 10 years prior and who will be in a higher-risk setting, or plan to spend a prolonged period in endemic areas or traveling to highly endemic areas of West Africa during peak season or an ongoing outbreak.

Yellow fever vaccine shortage

Worldwide, there are six manufacturers of the vaccine that produce 50 million to 100 million doses each year. However, the manufacturers’ output has been falling short of the world’s needs, and the current outbreak in Angola has emptied the world’s strategic stockpile of the vaccine. The process to produce the vaccine is slow and hard to scale up in times of need, as is the case during an outbreak. The only manufacturer of the vaccine in the U.S., Sanofi Pasteur, informed the CDC that vaccine supply is limited, so ordering restrictions have been implemented. The vaccine will be prioritized for patients who are traveling in the next 30 days to an area where yellow fever vaccine is required or recommended. Health care providers must call Sanofi Pasteur and a customer service representative will work with them to determine their vaccine needs for their patients.

WHO is currently considering ways to stretch the existing yellow fever vaccine supply. One such way is to recommend using one-fifth the normal dose for vaccinations. This proposal would reduce the dose, but also recommend revaccinating people who received the lower dose at some time in the future when the vaccine supply has recovered. Studies mostly done in Brazil have suggested that smaller doses can be used to protect against the disease. However, these studies were conducted only in adults, so it is currently unknown if this strategy would be sufficient to protect children who may require higher doses of vaccine to be fully protected. At the time of writing this article, the adoption of this strategy has not been recommended.

Anyone traveling outside the U.S. can visit the CDC website at http://wwwnc.cdc.gov/travel/destinations/list/ to review important health information related to their travel destination. If yellow fever vaccine is required, they should visit a travel clinic that is authorized to administer the yellow fever vaccination at least 10 days prior to travel to assure proper antibody response before departure.

Disclosure: Brock reports no relevant financial disclosures.

The news here in the United States has been consumed with information about Zika virus because it has been affecting Americans and causing devastating effects on infants. However, an outbreak of another mosquito-borne disease, yellow fever, has been going on outside the U.S. since December 2015. Yellow fever virus is a single-stranded RNA virus that belongs to the genus Flavivirus. It is transmitted via a bite from an infected Aedes or Haemagogus spp. mosquito. Yellow fever is endemic in approximately 47 countries in sub-Saharan Africa and tropical South America. Worldwide, there are an estimated 200,000 cases of yellow fever and up to 30,000 deaths each year, with 90% of the cases occurring in Africa.

Jeff Brock

The latest outbreak began in Angola, where it has infected thousands of people and killed hundreds thus far. The number of suspected cases there has been decreasing due to mass vaccination campaigns, but the outbreak in Angola is not under control yet. Infected travelers have spread the disease to other countries like the Democratic Republic of the Congo (DRC), Kenya and China. The cases in Angola and the DRC have been concentrated in cities, suggesting transmission through an urban cycle in which the virus is transmitted between humans via a mosquito bite. This increases the risks for further spread to other countries.

Symptoms of yellow fever virus infection usually begin abruptly 3 to 6 days after a bite from an infected mosquito. Some patients will not have any symptoms, but when they do occur, the most common are fever, muscle pain, headache, loss of appetite, and nausea or vomiting. Symptoms generally last 3 to 4 days. About 15% of infected patients enter a more toxic phase with return of high fever, multi-organ dysfunction, jaundice, abdominal pain with vomiting, and possibly bleeding from the mouth, nose, eyes or stomach. Approximately 50% who enter the toxic phase will die within 7 to 10 days.

Risk for travelers

The risk for a traveler contracting yellow fever is determined by several factors, including immunization status, season, location, activities and duration of travel. Reported cases of yellow fever in a location is the primary indicator of disease risk when traveling, but lack of case reports in a location with known yellow fever risks does not mean protective measures should not be taken. Vaccination is the only true way of limiting the risks. Only 23 vaccine failures have been identified after administration of more than 500 million doses of the yellow fever vaccine. Five of these cases occurred less than 10 days after vaccination because they did not have enough time to fully develop an antibody response.

Yellow fever vaccine and indications

A vaccine has been available for prevention of yellow fever since 1937. Yellow fever vaccines are live-attenuated viral vaccines from the 17D lineage. Currently, the minimum potency for human yellow fever vaccine is set at 3 log10 IU per dose, which is 0.5 mL given subcutaneously. However, there is not a limit on the maximum potency. All available yellow fever vaccines have proved to be efficacious, but the standard laboratory defined potency may vary by manufacturer.

The yellow fever vaccine is recommended for anyone aged 9 months and older who is living in or traveling to endemic areas. In outbreak situations, the vaccine may be given to those who are aged 6 months and older. It also is recommended for laboratory workers who might be exposed to either yellow fever virus or to concentrated preparations of yellow fever vaccine virus strains.

Many of the endemic countries require proof of vaccination for entry into the country. Providers should refer to the CDC Health Information for International Travel 2016 (the “Yellow Book”), in the section titled “Yellow Fever & Malarial Information, by Country,” for information regarding which countries require yellow fever vaccination for entry and for additional CDC recommendations. It is important to note that the country entry requirements can be different than the CDC’s recommendations. Yellow fever vaccine entry requirements are established by individual countries to prevent the importation of yellow fever, and travelers must comply unless they have been issued a medical waiver. These requirements are subject to change at any time, so it is important to check current requirements before departure.

PAGE BREAK

Immune response

The vaccine produces a robust immune response and high levels of protection in those who receive it. Within 10 days after vaccination, 90% of patients will have protective immunity, and in nearly 100% after 3 to 4 weeks following immunization. Certain individuals such as infants, toddlers, pregnant females and those with immunosuppressive diseases may not respond as vigorously to the vaccine.

Yellow fever virus infection induces a rapid immune response with immunoglobulin M antibodies appearing during the first week after infection, peak during the second week, and slowly decline over 1 to 2 months. IgG antibodies start to appear at the end of the first week of infection and persist for at least 35 years or even for life, providing lifelong protection against subsequent infection.

Recent changes to vaccine recommendations

Historically, a booster dose of the yellow fever vaccine was recommended after 10 years. However, in 2013, the WHO Strategic Advisory Group of Experts in Immunization concluded that a single primary dose of yellow fever vaccine is sufficient to provide sustained immunity and lifelong protection. The recommendation was based on a systematic review of the available evidence on the duration of immunity following a single dose of yellow fever vaccine. The data suggest that vaccine failures are very rare, and the risk does not increase over time. In May 2014, the World Health Assembly adopted the recommendation to remove the booster dose requirements from the International Health Regulations by June. The Advisory Committee on Immunization Practices guidelines state that booster doses may be given to certain travelers who received the vaccination at least 10 years prior and who will be in a higher-risk setting, or plan to spend a prolonged period in endemic areas or traveling to highly endemic areas of West Africa during peak season or an ongoing outbreak.

Yellow fever vaccine shortage

Worldwide, there are six manufacturers of the vaccine that produce 50 million to 100 million doses each year. However, the manufacturers’ output has been falling short of the world’s needs, and the current outbreak in Angola has emptied the world’s strategic stockpile of the vaccine. The process to produce the vaccine is slow and hard to scale up in times of need, as is the case during an outbreak. The only manufacturer of the vaccine in the U.S., Sanofi Pasteur, informed the CDC that vaccine supply is limited, so ordering restrictions have been implemented. The vaccine will be prioritized for patients who are traveling in the next 30 days to an area where yellow fever vaccine is required or recommended. Health care providers must call Sanofi Pasteur and a customer service representative will work with them to determine their vaccine needs for their patients.

WHO is currently considering ways to stretch the existing yellow fever vaccine supply. One such way is to recommend using one-fifth the normal dose for vaccinations. This proposal would reduce the dose, but also recommend revaccinating people who received the lower dose at some time in the future when the vaccine supply has recovered. Studies mostly done in Brazil have suggested that smaller doses can be used to protect against the disease. However, these studies were conducted only in adults, so it is currently unknown if this strategy would be sufficient to protect children who may require higher doses of vaccine to be fully protected. At the time of writing this article, the adoption of this strategy has not been recommended.

Anyone traveling outside the U.S. can visit the CDC website at http://wwwnc.cdc.gov/travel/destinations/list/ to review important health information related to their travel destination. If yellow fever vaccine is required, they should visit a travel clinic that is authorized to administer the yellow fever vaccination at least 10 days prior to travel to assure proper antibody response before departure.

Disclosure: Brock reports no relevant financial disclosures.