Yellow Fever Remains a Potential Threat to Public Health

Despite the identification of yellow fever virus (YFV) mosquito vector by Walter Reed in 1900 (Reed et al. 1901), and the use of an excellent vaccine since 1930s (Theiler and Smith 1937), yellow fever (YF) remains a potential threat to public health in the tropical and subtropical world. This lethal viral hemorrhagic fever caused fear due to urban epidemics spread by Aedes aegypti mosquitoes, has re-emerged in the present century, and is of greater concern because urbanization and air travel put more than 130 countries infested with A. aegypti and more than 4 billion people at risk of introduction and spread of the disease. Presently 44 countries are endemic/enzootic for YFV, 10 in South America and 34 in Africa; ∼80–90% of all annually reported cases occur in Africa, and the disease is consistently underreported. Areas of Asia, Oceania, southern Europe, and North America are at risk of introduction and local transmission of YF (Monath and Vasconcelos 2015, WHO 2016a).

The current YF epidemic in Angola shows the fragility of the international authorities to avoid the spread of YFV and potentially other arboviruses that can spillover from their original transmission area to other regions previously free of them. In 2013–2014, a closely related mosquito-borne virus with an identical transmission cycle—Zika virus—made its way to the New World by air travelers and has rapidly wreaked havoc in a widespread epidemic in the Americas (Faria et al. 2016). The potential for the Angolan YF epidemic to recapitulate this event, but with even more dire consequences because of the high lethality of YFV, is clear. In fact, as a result of air travel of infected persons from Angola, 11 YF cases were imported into China, the most populated country in the world with around 1.4 billion people, and situated in Asia a continent historically free of the YFV but infested by A. aegypti, and where annual outbreaks of dengue and chikungunya occur, transmitted by A. aegypti mosquitoes. So far, a total of 42 YF cases were also reported among persons traveling from Angola to Kinshasa, the capital city of 12 million people in neighboring Democratic Republic of Congo (DRC), and resulting in a local cycle of transmission. More than 700 suspected cases were reported (WHO 2016c). Two YF cases were also reported in Kenya, showing the dangerous and potential risk for spread of YFV to urban areas, in a moment with shortage of YF vaccine (WHO 2016b, 2016c).

Because of the threat of international spread, YF remains the only quarantinable disease in the International Health Regulations. The export of YF from Angola can be largely blamed on the failure of classic control measures, such as the vaccination of travelers and enforcement of requirements for a valid international certificate of vaccination to enter in endemic countries, such as Angola and the DRC (WHO 2016b, 2016c, 2016d). Similarly many countries free of YF but infested with A. aegypti mosquito vectors have regulations requiring proof of vaccination for entry, which are not enforced. These simple mistakes and lax regulations surrounding travel could result in a major health emergency if YFV were established in a local transmission cycle in Asia, in a critical moment when the shortage of YFV vaccine is of serious concern. People traveling from endemic areas to countries free of YF and vice versa should be vaccinated at least 10 days before travel, the necessary time for the development of specific YF antibodies (WHO 2013).

The WHO used its entire YF vaccine emergency stockpile (7 million doses) in an attempt to block YFV transmission in Luanda, Angola, but no effective transmission control was observed, because the disease had spread to other provinces inside the country. Immunization of the entire population of the country, estimated at around 24 million people, is required, but the approach being taken is salutatory and is constrained by vaccine supply. The overall situation illustrates the failure to anticipate this disease and provide a long-term policy of immunization in a country that is endemic for YFV and has sustained previous devastating outbreaks, and reveals the weaknesses of a fire-fighting campaign once the cat is out of the bag. The epidemic in Angola (WHO 2016b, 2016d) and an unrelated outbreak in South Sudan are the largest YF epidemics in the world in the present century. They show the need of a sustained policy of preventative vaccination to reduce the risk of epidemics and to prevent spillover to areas free of YFV circulation.

The Angolan epidemic has resulted in impressive numbers: a total of 2143 suspected cases with 277 deaths have been reported, of which 661 (70% from Luanda province) were laboratory confirmed cases (as of April 28, 2016). Sixty-seven districts in 13 out of Angola's 18 provinces now have confirmed cases (WHO 2016b). Approximately 70% of all cases occurred in Luanda, the capital of the country, a city of 8 million inhabitants, but the report in different and distant cities in the interior of the country recently documented is of concern, especially because many people of these areas have not been immunized with 17D vaccine.

Recently, a meeting of advisors to WHO concluded that the current situation with YF did not reach the level constituting “A Public Health Emergency of International Concern,” but nevertheless constituted a situation worth increased efforts in surveillance and control (WHO 2016d). WHO should convene more detailed meetings to develop strategies that adequately address the risk represented by YF on a global basis. The problems to be evaluated in a comprehensive strategy include the chronic shortage of YFV vaccine, increased density, and insecticide resistance of urban mosquito vectors in a globalized and changing world, where climate change is enhancing circulation and the spread of arthropod-borne viruses worldwide. Specific measures should be examined that would:

1. Stimulate the YFV vaccine producers to improve their capacity.

2. Look for donation of funds from state members and the private sector to cover the costs of the additional production of the vaccine.

3. Implement dose-sparing practices, including administration of a reduced (1/5th) dose, which would stretch supplies (Monath et al. 2016).

4. Lead a campaign to obligate the request of the international YFV vaccine certificate during international travels from and to the endemic countries, to protect the areas free of the YFV circulation.

Finally, new approaches are needed to combat A. aegypti mosquitoes, particularly in urban environments. Some novel biological control measures are beginning to be investigated at the demonstration level, but we see no clear strategy for integrated control. Surprisingly, there has been no attempt to study the mosquitoes responsible for the spread of YF and the complex interactions between humans and vectors during the course of a YF epidemic since the late 1970s, and that was in a different part of Africa with different species playing a role. If we better understand the vector distribution and density, breeding sites, and biting habits, and reproductive number of the YF epidemic, we may be able to design improved approaches to control the disease.