Yellow Fever Disease

Yellow Fever: Understanding Advancements and Treatment Modalities and Diagnosis

As of February 25, 2024, thirteen countries within the WHO African Region—Burkina Faso, Cameroon, the Central African Republic, Chad, Republic of the Congo, Côte d'Ivoire, Guinea, Niger, Nigeria, South Sudan, Togo, and Uganda—had recorded probable and confirmed cases of yellow fever (YF). (World Health Organization, 2023). An 11% case fatality rate (CFR) is projected for 2023 based on preliminary data. Because of the competent vector's existence in nearby regions and the possibility of onward transmission through travel, active surveillance is necessary even though the overall risk at the regional level was reassessed as moderate and the global risk is still low.

Aedes spp. mosquitoes are daytime biters, and their urban growth can greatly increase the risk of transmission, especially in densely populated regions, potentially resulting in rapid outbreaks. Preventive and reactive measures were coordinated by the WHO-led global Eliminate Yellow Fever Epidemics (EYE) secretariat, which significantly increased vaccination coverage in 2023. Through proactive and reactive mass vaccination initiatives, some 62 million people in Africa have received vaccinations. Furthermore, about 4 million people in Sudan received YF vaccinations as part of catch-up campaigns.

Since the start of 2023 until February 25, 2024, a cumulative total of 13 countries within the WHO African Region have recorded probable and confirmed cases of yellow fever (YF). These countries include Burkina Faso, Cameroon, the Central African Republic, Chad, Republic of the Congo, Côte d’Ivoire, the Democratic Republic of the Congo (DRC), Guinea, Niger, Nigeria, South Sudan, Togo, and Uganda.

Preliminary data for 2023 suggests a case fatality rate (CFR) of 11% and a male-to-female sex ratio of 1.7 (M: F). The median age of cases is 25 years, with approximately 69% of cases being over the age of 15 years. Many affected countries face challenges in surveillance capacity, including data fragmentation, limited integration with routine surveillance and clinical systems, and a lack of standardized case definitions, which contribute to underreporting and higher mortality rates.

During the last quarter of 2023 and up to February 25, 2024, eight countries (Cameroon, Chad, Congo, DRC, Guinea, Niger, Nigeria, and South Sudan) have reported active transmission of YF with confirmed cases. These countries have initiated response planning activities.

Chad, Gabon, Niger, Nigeria, and Togo are currently awaiting the final classification of YF laboratory plaque reduction neutralization test (PRNT) positive samples.

In Cameroon, three YF cases were confirmed by polymerase chain reaction (PCR) testing, occurring between October and November 2023. Chad reported a yellow fever PCR-positive case with negative serology on January 18, 2024, from the Léré district of the Mayo-Kebbi Ouest region.

In the Republic of the Congo, cases are pending classification by national health authorities. In the Democratic Republic of the Congo, one YF PCR-positive case with unknown vaccination status was reported in December 2023, along with nine PRNT-positive cases, eight of which have unknown vaccination status.

In Guinea, three YF PCR-positive cases were confirmed at the Institute Pasteur Dakar, representing three out of the seven regions of the country. Niger reported a case in Tahoua city during the first week of January 2024, with ongoing investigations. Nigeria reported one YF PRNT-positive case in January 2024 in Lagos state, with investigations ongoing.

South Sudan reported a confirmed YF case on December 24, 2023, and two additional cases on February 2, 2024. As of February 12, 2024, South Sudan reported a total of 64 cases fulfilling the current outbreak case definition of YF, including suspected cases, and confirmed cases across six out of 10 counties in Western Equatoria state. Among the suspected cases, there were six suspected deaths currently under investigation.

Yellow fever is a disease prone to epidemics and preventable with vaccination. It is caused by an arbovirus transmitted to humans mainly through the bites of infected Aedes spp. and Haemagogus spp. mosquitoes. The incubation period typically lasts from 3 to 6 days. While many individuals may not exhibit symptoms, those who do often experience fever, muscle pain (particularly in the back), headache, loss of appetite, and nausea or vomiting. Symptoms usually resolve within 3 to 4 days. However, a small percentage of cases progress to a toxic phase characterized by systemic infection affecting the liver and kidneys. Individuals in this phase may experience severe symptoms such as high fever, abdominal pain accompanied by vomiting, jaundice, and dark urine due to acute liver and kidney failure. Bleeding may also occur from various parts of the body such as the mouth, nose, eyes, or stomach. In approximately half of cases with severe symptoms, death can occur within 7 to 10 days.

Prevention of yellow fever primarily involves the administration of an effective and affordable vaccine. A single dose of the yellow fever vaccine is adequate to provide sustained immunity and lifelong protection against the disease. There is no need for a booster dose. The vaccine typically confers effective immunity to 80-100% of vaccinated individuals within 10 days, and to over 99% within 30 days post-vaccination.

Diagnostic Testing –

A suspected diagnosis of yellow fever is typically based on the patient's clinical symptoms, travel history (particularly if the patient is from a non-endemic region), activities, and the epidemiological context of the area where the presumed infection occurred.

Laboratory confirmation of yellow fever often involves testing serum samples to detect virus-specific IgM antibodies and neutralizing antibodies. In some cases, the virus can be identified in blood samples obtained early in the illness.

In fatal instances, additional diagnostic methods such as nucleic acid amplification, histopathology combined with immunohistochemistry, and virus culture of biopsy or autopsy tissues may yield positive results. However, these specialized tests are only conducted in a few state or specialized laboratories, including those at CDC. Typically, test results become available within 4 to 14 days after the receipt of specimens. During periods of increased domestic arbovirus activity, such as in the summer months, reporting times for test results may be longer. Receipt of hard copy results usually occurs at least 2 weeks after testing is finalized. Initial serological testing involves IgM-capture ELISA, MIA (Microsphere-based Immunoassay), and IgG ELISA. If initial results are positive, further confirmatory testing may prolong the reporting of results.

Disease Landscape Insights helps in the product portfolio analysis, market assessment, and pricing analysis of the kits, devices, and laboratory equipment of market players working in diagnostic product manufacturing of Yellow Fever.

Below is a list of manufacturers operating in the diagnostic field of Yellow Fever-

Treatment / Management

Yellow fever is a notifiable infection, with symptoms typically manifesting 3 to 6 days after contracting the virus. Although no specific treatment exists, severe cases require intensive supportive care and hydration, often managed in the ICU. Close monitoring for complications such as disseminated intravascular coagulation (DIC), hemorrhage, and kidney, and liver dysfunction is essential. Management may involve fresh frozen plasma for coagulopathy and dialysis for renal failure. While person-to-person transmission is rare, isolation of the infected individual is recommended until diagnosis confirmation. Universal precautions should be observed when caring for patients, despite the low likelihood of person-to-person transmission. Infected individuals should also avoid mosquito bites to prevent further transmission to mosquitoes, which serve as vectors.

Prevention is paramount due to the lack of effective treatment or vaccine. Avoiding mosquito bites entirely is the most effective approach. Wearing appropriate protective clothing such as long sleeves, pants, socks, and closed-toe shoes, along with using EPA-registered insect repellents containing permethrin, DEET, or oil of lemon eucalyptus, can significantly reduce the risk. Treating clothing with permethrin provides long-lasting protection even after washing. Mosquitoes are most active during dawn and dusk, so outdoor activities during these times should be minimized. Additionally, Aedes Aegypti mosquitoes, which transmit the virus, feed during the daytime, necessitating constant vigilance and repellent use throughout the day. Sleeping in air-conditioned spaces or using mosquito nets further mitigates the risk. Eliminating standing water sources, such as flowerpots and buckets, helps disrupt mosquito breeding grounds.

A highly effective live-attenuated vaccine is available for yellow fever prevention. A single dose confers lifelong immunity and becomes effective within 30 days for most recipients. Patients with relative contraindications to live attenuated vaccines should review vaccination recommendations before traveling to endemic areas.

Yellow Fever Vaccine Information for Healthcare Providers

Yellow fever vaccine is a live-attenuated virus vaccine that has been available since the 1930s. No vaccine efficacy studies have been performed with yellow fever vaccine. However, the number of yellow fever disease cases was substantially reduced following the introduction of the vaccine supporting it being protective in humans.

Yellow Fever Vaccine Recommendations

Yellow fever vaccine is recommended for people who are aged 9 months or older who are traveling to or living in areas at risk for yellow fever virus transmission in South America and Africa. Yellow fever vaccine may be required for entry into certain countries. Yellow fever vaccination requirements and recommendations for specific countries are available on the CDC Travelers’ Health page.

Serious adverse events can occur following yellow fever vaccination. Therefore, persons should only be vaccinated if they are at risk of exposure to the yellow fever virus or require proof of vaccination for country entry.

To minimize the risk of serious adverse events, healthcare providers should carefully observe the contraindications and consider the precautions about vaccination before vaccine administration (see below). A medical waiver can be given for persons with a precaution about or contraindication to vaccination. More information about medical waivers is available on the CDC Travelers’ Health website.

For more information about the use of yellow fever vaccine in travelers or laboratory workers, see the Advisory Committee on Immunization Practice (ACIP) recommendations.

This vaccine is administered only at designated vaccination centers. For healthcare professionals who want to learn more about yellow fever disease and vaccines, a continuing education module is available.

Booster doses of the vaccine

In February 2015, the CDC Advisory Committee on Immunization Practices (ACIP) approved a new recommendation that a single dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers. The updated recommendations also identify specific groups of travelers who should receive additional doses and others for whom additional doses may be considered including:

• Woman who was pregnant when first vaccinated
• Persons who received a hematopoietic stem cell transplant following their last dose of yellow fever vaccine
• HIV-infected persons
• Travelers who received the yellow fever vaccine at least 10 years previously and who will be in a higher-risk setting based on season, location, activities, and duration of their travel.
• Laboratory workers who routinely handle wild-type yellow fever virus

The official ACIP recommendations were published on June 19, 2015 (see Advisory Committee on Immunization Practice (ACIP) recommendations. All current ACIP yellow fever vaccine recommendations can be found on the ACIP website.

Although ACIP no longer recommends booster doses of yellow fever vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations (IHR) have not yet been fully implemented. In 2014, the World Health Organization adopted the recommendation to remove the 10-year booster dose requirement from the IHR as of June 2016. Once this change is instituted, a completed International Certificate of Vaccination or Prophylaxis will be valid for the lifetime of the vaccine. Some countries have already adopted this change, which is noted under the yellow fever vaccine requirements on each country’s destination page. However, it is uncertain when and if all countries with yellow fever vaccination requirements will adopt this change.

Contraindications

• Allergy to a vaccine component
• Aged younger than 6 months
• Symptomatic HIV infection or CD4+ T-lymphocytes <200/mm3 (<15% of total in children aged <6 years)
• Thymus disorder is associated with abnormal immune function.
• Primary immunodeficiencies
• Malignant neoplasms
• Transplantation
• Immunosuppressive and immunomodulatory therapies

Precautions

• Age 6 to 8 months
• Age 60 years or older
• Asymptomatic HIV infection and CD4+ T-lymphocytes 200 to 499/mm3 (15-24% of total in children younger than 6 years old)
• Pregnancy

A recent review was conducted to evaluate the necessity of booster vaccinations based on the long-term effectiveness of primary yellow fever vaccination.

The researchers concluded that most individuals who received the primary vaccine maintain sufficient levels of neutralizing antibodies for protection for at least ten years or more.

Among healthy adults in non-endemic regions, particularly travelers, the review found a high rate of seroprotection ranging from 10 to 60 years post-vaccination, with an overall rate of 94%.

These findings align with the International Health Regulations, which assert that a single dose of yellow fever vaccine offers lifelong protection to travelers.

However, individuals with HIV and young children may still require booster doses due to lower levels of protection observed in these populations.

Residents of endemic areas in Brazil also exhibited lower rates of protection.

Additionally, since the yellow fever vaccine is not recommended for individuals using immunosuppressive medications, guidelines do not provide advice regarding booster vaccinations in such cases.

Clinical Trials –

Disease Landscape Insights provides detailed insights and analysis regarding the ongoing clinical trials and the outcomes of the clinical trials. The below table enlists the ongoing clinical trials.

In conclusion, yellow fever remains a significant global health concern, particularly in endemic regions. While strides have been made in vaccination efforts and understanding the long-term effectiveness of primary immunization, challenges persist, especially for vulnerable populations such as those living with HIV and young children. Continued research, surveillance, and public health interventions are essential to mitigate the spread of this mosquito-borne disease and protect communities worldwide. By raising awareness, promoting vaccination, and implementing effective prevention strategies, we can work towards reducing the burden of yellow fever and ensuring the health and well-being of individuals everywhere.

Conclusion -

DiseaseLandscape Insights (DLI) plays a pivotal role in assisting companies in crafting and implementing effective strategies aimed at preventing and controlling ACC epidemics. With the rise in awareness and the anticipation of epidemics, there is an increasing demand for diagnostic tools, clinical evaluations, and innovative therapeutics.

The expertise provided by DLI is invaluable to major players in the production of medicinal products. It aids in the development of patient recruitment strategies, ensuring regulatory compliance, and planning and executing clinical trials for novel medications and pharmaceuticals.

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