Eye on ID

The global yellow fever threat and how to deal with it

Donald Kaye

Before 2016, Angola was listed as a low-risk country for yellow fever — the last epidemic was 3 decades ago. But on Jan. 20, the health minister of Angola reported 23 cases of yellow fever, including seven deaths of foreign citizens, in Viana, a suburb of Luanda, capital of Angola.

The report was posted on ProMED-mail the same day with the comment, “Because [yellow fever] vaccine needs 10 days to take effect, vaccination should be carried out in the area while waiting for confirmation from Dakar.” WHO reported the outbreak 3 weeks later. The health agency apparently waited for clearance from Angola, possibly at the government’s request, remembering the harm caused by the announcement of the Ebola epidemic to the economies of West African countries, the whole of Africa and the global commodities market. However, WHO is authorized under the revised International Health Regulations to report outbreaks of international concern before official confirmation from the country involved.

Jack P. Woodall

In early February, WHO sent Angola the entire global stock of yellow fever vaccine — more than 6 million doses — and 4 months later, as of June 23, the country was still vaccinating Luanda province. Meanwhile, yellow fever has spread throughout the country, and vaccination is proceeding in other provinces, but there is a shortage of vaccine, and the manufacturers cannot easily increase production because the live-attenuated yellow fever vaccine must be made with virus-free eggs; it is not scalable like vaccines made in fermenters.

Thomas M. Yuill

Official figures from Angola indicate that the total number of notified cases has increased since early 2016. As of July 21, a total of 3,748 suspected cases have been reported, of which 879 are confirmed. The total number of reported deaths is 364, of which 119 were reported among confirmed cases. Suspected cases have been reported in all provinces, and confirmed cases have been reported in 16 of 18 provinces and in 80 of 125 reporting districts. However, as far back as March, a WHO yellow fever expert who had visited Angola reported that the true numbers were probably at least 10 times greater, putting deaths in the thousands. Diagnosis was complicated by a severe epidemic of malaria with similar symptoms and many deaths. It is not clear whether the small numbers of confirmations are due to a backlog in lab testing or the unavailability of specimens for testing. But as long as there are reports of thousands of cases of Zika spreading in the Americas, with more than 1,000 pregnant women in Brazil at risk for bearing microcephalic babies, the international media are understandably not very interested when the Angola Ministry of Health reports no more than 364 deaths since Dec. 5, 2015.

Luanda has an international airport from which direct flights reach Hawaii, the continental United States and Sydney within a day — well within the 3-6 day incubation period of yellow fever. A person who has yellow fever is infectious for mosquitoes the day before symptoms appear, so a passenger from Angola could arrive in another country with an undetected yellow fever infection and be bitten by local mosquitoes. If those mosquitoes should be the species that carry yellow fever, Aedes aegypti, an epidemic could result. A map of the at-risk areas in the U.S. as of 2016, showing the distribution of A. aegypti in the country, can be found on page 26 of this issue of Infectious Disease News.

As of June 15, three countries had confirmed yellow fever cases imported from Angola: Democratic Republic of the Congo, or DRC (n = 53 cases); Kenya (n = 2); and People’s Republic of China (n = 11). This highlights the risk for international spread through unimmunized travelers. On June 20, the DRC reported 67 confirmed cases, five fatal, and 1,000 suspected cases under monitoring.

Coincidentally, as of June 17, three African countries (Chad, Ghana and Uganda) and three South American countries (Brazil, Colombia and Peru) were reporting yellow fever outbreaks or sporadic cases not linked to the Angolan outbreak, increasing the demand for vaccine. These sporadic outbreaks of sylvan yellow fever do occur, and must be dealt with swiftly to prevent spread, placing further demands on limited vaccine stocks. With urgent need for vaccine to control the outbreaks in Angola and the DRC, establishing priorities for delivery of vaccine elsewhere has become difficult.

On March 22, the Ministry of Health of neighboring DRC confirmed cases of yellow fever in connection with Angola. The government officially declared the yellow fever outbreak on April 23 — again, long after cases had been laboratory-confirmed. Infected Angolans have arrived in Kenya, fortunately without further spread so far. A new autochthonous case was reported in Kinshasa, DRC, on June 8, signifying infection among its 8 million inhabitants. Ethiopia has reported 22 cases unconnected with Angola; one has been confirmed immunoglobulin M-positive, suggesting a recent infection. There is need for an adequate supply of vaccine as soon as possible.

According to WHO, the cumulative number of vaccine doses was projected to increase from 6 million at the end of June to only 17.1 million by the end of 2016. However, the demand can be expected to increase as the weeks go by and more at-risk countries request vaccine for prevention.

WHO’s International Coordinating Group on vaccine provision for yellow fever committed 2.3 million additional doses of yellow fever vaccine for Angola. A plan for pre-emptive vaccination in high-risk districts and borders was being finalized with the minister of health in Angola, based on recommendations from WHO, UNICEF and their scientific partners. It would also be advisable to vaccinate all health and essential services workers in the country to ensure the continued functioning of hospitals, clinics and the energy sector.

Of great concern is the estimated 100,000 Chinese working in Angola, many of whom are unvaccinated. Some of these workers, who became ill with yellow fever in Angola, have returned to China early in their illness for treatment, furthering the risk that they were still viremic on arrival and capable of infecting local A. aegypti — again, without spread so far. However, China has the yellow fever mosquito in its southern provinces, where it spreads dengue. The mosquito season in southern China began in June, so there is currently a risk from returning Chinese. If yellow fever breaks out there, there is a high risk for spread across the border to Southeast Asia. There will never be enough vaccine to protect the millions in megacities like New Delhi.

Now imported cases have been reported from Angola’s neighbors Namibia and Zambia, where the population, travelers and foreign workers are not vaccinated against yellow fever, and they are requesting vaccine for prevention. WHO is having to ration the scarce stocks of vaccine. A yellow fever vaccination campaign for 11.6 million people in three Congolese provinces was scheduled to start in late July, but only 1.3 million doses of the vaccine were available.

There is one way to alleviate the vaccine shortage, which is to use a lower-than-standard dose. A study published in 2013 showed that the Brazilian vaccine is sufficiently potent that a one-fifth dose protects adults. This strategy has been under consideration by WHO for some time, but there are a number of unresolved questions about protection in children, the potency of vaccine from other producers, duration of protection by a lower dose, and whether the response of Africans to the vaccines will be the same as for Brazilians. Unfortunately, studies to resolve those questions would take months, and there is no time for them to be carried out if stocks of the vaccine, which are rapidly being depleted, are to be conserved.

WHO is able to authorize the use of a lower dose of yellow fever vaccine as a temporary emergency measure. It is hoped that this will have been done by the time this editorial appears in print. The matter is urgent — every day that passes without action on this means more standard vaccine is irrevocably consumed when it could have been stretched to protect five times as many people.

A final thought: if the worst case scenario were to come to pass and yellow fever spreads in Asia, serious consideration should be given to using a 1/10th dose. First, a 1/10th dose is perfectly safe, no worries there. Second, although it would only partially protect any age group for no more than a few months, a 1/10th dose should mitigate the severity of a yellow fever infection, preventing some deaths. Third, in spite of the poor quality of the cold chain in some developing countries, the 25- to 50-fold over-strength of at least one of the WHO-approved vaccines should compensate for that. It would be advantageous to have an advance plan in place before the next scheduled meeting of the WHO Strategic Advisory Group of Experts on Immunization in October.

Disclosures: Kaye, Woodall and Yuill report no relevant financial disclosures.

Donald Kaye

Before 2016, Angola was listed as a low-risk country for yellow fever — the last epidemic was 3 decades ago. But on Jan. 20, the health minister of Angola reported 23 cases of yellow fever, including seven deaths of foreign citizens, in Viana, a suburb of Luanda, capital of Angola.

The report was posted on ProMED-mail the same day with the comment, “Because [yellow fever] vaccine needs 10 days to take effect, vaccination should be carried out in the area while waiting for confirmation from Dakar.” WHO reported the outbreak 3 weeks later. The health agency apparently waited for clearance from Angola, possibly at the government’s request, remembering the harm caused by the announcement of the Ebola epidemic to the economies of West African countries, the whole of Africa and the global commodities market. However, WHO is authorized under the revised International Health Regulations to report outbreaks of international concern before official confirmation from the country involved.

Jack P. Woodall

In early February, WHO sent Angola the entire global stock of yellow fever vaccine — more than 6 million doses — and 4 months later, as of June 23, the country was still vaccinating Luanda province. Meanwhile, yellow fever has spread throughout the country, and vaccination is proceeding in other provinces, but there is a shortage of vaccine, and the manufacturers cannot easily increase production because the live-attenuated yellow fever vaccine must be made with virus-free eggs; it is not scalable like vaccines made in fermenters.

Thomas M. Yuill

Official figures from Angola indicate that the total number of notified cases has increased since early 2016. As of July 21, a total of 3,748 suspected cases have been reported, of which 879 are confirmed. The total number of reported deaths is 364, of which 119 were reported among confirmed cases. Suspected cases have been reported in all provinces, and confirmed cases have been reported in 16 of 18 provinces and in 80 of 125 reporting districts. However, as far back as March, a WHO yellow fever expert who had visited Angola reported that the true numbers were probably at least 10 times greater, putting deaths in the thousands. Diagnosis was complicated by a severe epidemic of malaria with similar symptoms and many deaths. It is not clear whether the small numbers of confirmations are due to a backlog in lab testing or the unavailability of specimens for testing. But as long as there are reports of thousands of cases of Zika spreading in the Americas, with more than 1,000 pregnant women in Brazil at risk for bearing microcephalic babies, the international media are understandably not very interested when the Angola Ministry of Health reports no more than 364 deaths since Dec. 5, 2015.

Luanda has an international airport from which direct flights reach Hawaii, the continental United States and Sydney within a day — well within the 3-6 day incubation period of yellow fever. A person who has yellow fever is infectious for mosquitoes the day before symptoms appear, so a passenger from Angola could arrive in another country with an undetected yellow fever infection and be bitten by local mosquitoes. If those mosquitoes should be the species that carry yellow fever, Aedes aegypti, an epidemic could result. A map of the at-risk areas in the U.S. as of 2016, showing the distribution of A. aegypti in the country, can be found on page 26 of this issue of Infectious Disease News.

As of June 15, three countries had confirmed yellow fever cases imported from Angola: Democratic Republic of the Congo, or DRC (n = 53 cases); Kenya (n = 2); and People’s Republic of China (n = 11). This highlights the risk for international spread through unimmunized travelers. On June 20, the DRC reported 67 confirmed cases, five fatal, and 1,000 suspected cases under monitoring.

PAGE BREAK

Coincidentally, as of June 17, three African countries (Chad, Ghana and Uganda) and three South American countries (Brazil, Colombia and Peru) were reporting yellow fever outbreaks or sporadic cases not linked to the Angolan outbreak, increasing the demand for vaccine. These sporadic outbreaks of sylvan yellow fever do occur, and must be dealt with swiftly to prevent spread, placing further demands on limited vaccine stocks. With urgent need for vaccine to control the outbreaks in Angola and the DRC, establishing priorities for delivery of vaccine elsewhere has become difficult.

On March 22, the Ministry of Health of neighboring DRC confirmed cases of yellow fever in connection with Angola. The government officially declared the yellow fever outbreak on April 23 — again, long after cases had been laboratory-confirmed. Infected Angolans have arrived in Kenya, fortunately without further spread so far. A new autochthonous case was reported in Kinshasa, DRC, on June 8, signifying infection among its 8 million inhabitants. Ethiopia has reported 22 cases unconnected with Angola; one has been confirmed immunoglobulin M-positive, suggesting a recent infection. There is need for an adequate supply of vaccine as soon as possible.

According to WHO, the cumulative number of vaccine doses was projected to increase from 6 million at the end of June to only 17.1 million by the end of 2016. However, the demand can be expected to increase as the weeks go by and more at-risk countries request vaccine for prevention.

WHO’s International Coordinating Group on vaccine provision for yellow fever committed 2.3 million additional doses of yellow fever vaccine for Angola. A plan for pre-emptive vaccination in high-risk districts and borders was being finalized with the minister of health in Angola, based on recommendations from WHO, UNICEF and their scientific partners. It would also be advisable to vaccinate all health and essential services workers in the country to ensure the continued functioning of hospitals, clinics and the energy sector.

Of great concern is the estimated 100,000 Chinese working in Angola, many of whom are unvaccinated. Some of these workers, who became ill with yellow fever in Angola, have returned to China early in their illness for treatment, furthering the risk that they were still viremic on arrival and capable of infecting local A. aegypti — again, without spread so far. However, China has the yellow fever mosquito in its southern provinces, where it spreads dengue. The mosquito season in southern China began in June, so there is currently a risk from returning Chinese. If yellow fever breaks out there, there is a high risk for spread across the border to Southeast Asia. There will never be enough vaccine to protect the millions in megacities like New Delhi.

Now imported cases have been reported from Angola’s neighbors Namibia and Zambia, where the population, travelers and foreign workers are not vaccinated against yellow fever, and they are requesting vaccine for prevention. WHO is having to ration the scarce stocks of vaccine. A yellow fever vaccination campaign for 11.6 million people in three Congolese provinces was scheduled to start in late July, but only 1.3 million doses of the vaccine were available.

There is one way to alleviate the vaccine shortage, which is to use a lower-than-standard dose. A study published in 2013 showed that the Brazilian vaccine is sufficiently potent that a one-fifth dose protects adults. This strategy has been under consideration by WHO for some time, but there are a number of unresolved questions about protection in children, the potency of vaccine from other producers, duration of protection by a lower dose, and whether the response of Africans to the vaccines will be the same as for Brazilians. Unfortunately, studies to resolve those questions would take months, and there is no time for them to be carried out if stocks of the vaccine, which are rapidly being depleted, are to be conserved.

PAGE BREAK

WHO is able to authorize the use of a lower dose of yellow fever vaccine as a temporary emergency measure. It is hoped that this will have been done by the time this editorial appears in print. The matter is urgent — every day that passes without action on this means more standard vaccine is irrevocably consumed when it could have been stretched to protect five times as many people.

A final thought: if the worst case scenario were to come to pass and yellow fever spreads in Asia, serious consideration should be given to using a 1/10th dose. First, a 1/10th dose is perfectly safe, no worries there. Second, although it would only partially protect any age group for no more than a few months, a 1/10th dose should mitigate the severity of a yellow fever infection, preventing some deaths. Third, in spite of the poor quality of the cold chain in some developing countries, the 25- to 50-fold over-strength of at least one of the WHO-approved vaccines should compensate for that. It would be advantageous to have an advance plan in place before the next scheduled meeting of the WHO Strategic Advisory Group of Experts on Immunization in October.

Disclosures: Kaye, Woodall and Yuill report no relevant financial disclosures.