Viral Hemorrhagic Fevers

Table of Contents

1. Overview
2. Filoviridae: Ebola and Marburg
3. Arenaviridae: Lassa Fever and South American HFs
4. Bunyaviridae: Crimean-Congo HF and Hantavirus
5. Flaviviridae: Yellow Fever, Dengue HF, and Kyasanur Forest Disease
6. Diagnosis and Laboratory Approach
7. Treatment and Isolation Protocols
8. Prevention, Vaccines, and Outbreak Control
9. Key Research Papers
10. Connections
11. Featured Videos

Overview

Viral hemorrhagic fevers (VHFs) are a diverse group of severe, life-threatening illnesses caused by enveloped RNA viruses belonging to four distinct families: Filoviridae (Ebola virus and Marburg virus), Arenaviridae (Lassa fever, Junín, Machupo, Chapare, and related New World arenaviruses), Bunyaviridae/Phenuiviridae (Crimean-Congo hemorrhagic fever and Hantavirus), and Flaviviridae (Yellow Fever, Dengue hemorrhagic fever, and Kyasanur Forest Disease). Despite their collective name, clinically significant hemorrhage is not a universal feature — it is a late and severe finding that appears in fewer than half of Ebola cases, for example. The unifying characteristics are fever, multiorgan dysfunction, and variable mortality.

Mortality rates differ dramatically across VHF pathogens: Yellow Fever has a case fatality rate (CFR) of approximately 2–5% overall (rising to 20–50% in the severe intoxication phase), while Ebola Zaire can reach 40–90% CFR without treatment. This wide range reflects differences in viral pathogenesis, reservoir ecology, access to supportive care, and availability of specific therapeutics.

Geographic distribution follows reservoir and vector ecology. Ebola and Marburg are largely confined to sub-Saharan Africa where their bat reservoirs reside. Lassa fever is endemic to West Africa. Crimean-Congo hemorrhagic fever spans the widest range of any VHF — from Africa through the Middle East, Central Asia, the Balkans, and increasingly Spain and Turkey. Dengue hemorrhagic fever affects over 100 countries in tropical and subtropical regions worldwide, making it the most geographically widespread VHF by far.

The World Health Organization (WHO) classifies the most dangerous VHF agents — Ebola, Marburg, Crimean-Congo HF, Lassa fever, Hantavirus pulmonary syndrome, Nipah, and Rift Valley fever — on its R&D Blueprint list of priority diseases requiring urgent research and development. In the United States, several VHF agents (Ebola, Marburg, Lassa, Crimean-Congo HF) are Biosafety Level 4 (BSL-4) pathogens, requiring maximum containment laboratories for diagnostic and research work.

Back to Table of Contents

Filoviridae: Ebola and Marburg

Ebola Virus Disease

The genus Ebolavirus comprises six species, of which Zaire ebolavirus (EBOV) is the most lethal, with documented CFRs of 40–90% in unmitigated outbreaks. The West African epidemic of 2013–2016 was the largest Ebola outbreak in history, ultimately affecting Guinea, Sierra Leone, and Liberia: the WHO final situation report recorded 28,616 confirmed, probable, and suspected cases with 11,310 deaths — a CFR of approximately 40% in a setting with some organized treatment.

The natural reservoir of Ebola remains incompletely confirmed, but fruit bats — particularly Hypsignathus monstrosus, Epomops franqueti, and Myonycteris torquata — are strongly implicated through serological and molecular evidence. Marburg virus has a better-established reservoir: Rousettus aegyptiacus, the Egyptian fruit bat, with multiple outbreak investigations linking cases to caves or mines where these bats roost.

Ebola is not transmitted by the airborne route in natural settings. The virus spreads through direct contact with the blood, body fluids (vomit, diarrhea, urine, saliva), or organs of infected people or deceased patients. Corpses are highly infectious — traditional burial practices involving washing of the body drove significant transmission in the West African epidemic. Healthcare workers are at elevated risk from needle-stick injuries and inadequate personal protective equipment (PPE).

Incubation period: 2–21 days (median approximately 10 days). Longer incubation periods are used for the 21-day observation window for exposed contacts.

Clinical progression:

• Days 1–4 (early phase): Sudden-onset fever, severe headache, myalgia, fatigue, and malaise — clinically indistinguishable from malaria, typhoid, or influenza at this stage.
• Days 5–7 (gastrointestinal phase): Profuse, watery diarrhea (up to 10 liters per day), severe nausea and vomiting, abdominal pain, and sore throat. A maculopapular rash may appear. This is the critical phase: dehydration and electrolyte depletion — not exsanguination — are the primary drivers of organ failure and death. Aggressive fluid replacement started in the West Africa treatment units reduced CFR substantially.
• Days 7–10 (late severe phase): Those who deteriorate develop hiccups (a sinister sign reflecting diaphragmatic irritation and hepatic involvement), bleeding from venipuncture sites, gums, nose (epistaxis), and rectum (melena). Disseminated intravascular coagulation (DIC) and multiorgan failure (MOF) follow. Hemorrhage, while iconic in the public consciousness, occurs in fewer than 50% of cases and reflects end-stage disease.
• Recovery or death: Survivors begin to improve by day 7–14. Recovery can be prolonged; post-Ebola syndrome includes uveitis, arthralgia, hearing loss, and neurological sequelae. Viral persistence in immune-privileged sites (testes, eye, CNS) allows sexual transmission months after clinical recovery.

Marburg Virus Disease

Marburg virus shares the same filoviral architecture and causes clinically indistinguishable disease from Ebola. It was first identified in 1967 after laboratory workers in Marburg, Frankfurt (Germany), and Belgrade (Yugoslavia) developed hemorrhagic fever following contact with African green monkeys (Cercopithecus aethiops) imported from Uganda for polio vaccine production — the first recognized VHF outbreak in Europe.

The 2004–2005 Angola outbreak remains the deadliest Marburg outbreak on record: 252 cases with 227 deaths, a CFR of 90% — the highest ever documented for any VHF outbreak. The outbreak occurred predominantly in a pediatric ward in Uíge province, where contaminated injection equipment drove nosocomial transmission.

FDA-Approved Treatments for Ebola

• rVSV-ZEBOV (Ervebo, Merck): Live recombinant vesicular stomatitis virus vaccine expressing Ebola Zaire glycoprotein; FDA-approved December 2019 for prevention of Ebola Zaire disease in individuals 18 years and older. Deployed via ring vaccination strategy.
• Atoltivimab/maftivimab/odesivimab-ebgn (Inmazeb, Regeneron): Triple monoclonal antibody cocktail targeting Ebola Zaire glycoprotein; FDA-approved October 2020 for treatment of infection caused by Zaire ebolavirus. In the PALM trial conducted during the 2018–2020 DRC outbreak, 28-day mortality was 33.5% with Inmazeb vs. 51% with ZMapp control.
• Ansuvimab-zykl (Ebanga, Ridgeback Biotherapeutics): Single monoclonal antibody targeting a conserved epitope of Ebola Zaire glycoprotein; FDA-approved December 2020. PALM trial 28-day mortality: 35.1% vs. 51% control.

No FDA-approved treatment exists for Marburg virus disease. MK-4282 (Merck, a nucleoside analog) and other candidates are in active clinical development.

Back to Table of Contents

Arenaviridae: Lassa Fever and South American Hemorrhagic Fevers

Lassa Fever

Lassa fever is caused by Lassa mammarenavirus, an Old World arenavirus endemic to West Africa — principally Sierra Leone, Guinea, Nigeria, and Liberia. The rodent reservoir is Mastomys natalensis (the multimammate rat), an extraordinarily abundant peridomestic species that nests in homes, contaminates stored food with urine and feces, and is sometimes consumed as bushmeat.

Transmission routes:

• Contact with rodent excreta (urine, feces, blood) through cuts, abrasions, or mucous membranes.
• Inhalation of aerosolized rodent excreta during sweeping or handling of contaminated grain.
• Person-to-person transmission in healthcare settings through contact with blood and body fluids — historically responsible for large nosocomial outbreaks in Sierra Leone and Nigeria before universal precautions were implemented.
• Sexual transmission documented in convalescent males (viral shedding in semen).

Disease burden: Approximately 100,000–300,000 infections per year are estimated, with 5,000–10,000 deaths annually — though surveillance vastly underestimates true incidence. Around 80% of infections are asymptomatic or cause only mild undifferentiated febrile illness. The remaining 20% develop severe multisystem disease.

A distinctive and underappreciated complication: Sensorineural hearing loss (SNHL) affects 25–30% of Lassa survivors — even those who had only mild disease. The mechanism involves inflammatory damage to cochlear hair cells and the eighth cranial nerve, not direct viral cytopathology. SNHL is often bilateral and may be permanent, making Lassa fever a leading cause of acquired deafness in West Africa.

Treatment: Ribavirin (nucleoside analog) reduces mortality approximately five-fold when given intravenously within the first six days of illness. The standard regimen is a 30 mg/kg IV loading dose, followed by 15 mg/kg IV every 6 hours for 4 days, then 7.5 mg/kg IV every 8 hours for 6 days. Oral ribavirin has lower bioavailability but is used when IV is unavailable. No FDA-approved Lassa vaccine exists; MV-LASV (a recombinant measles virus–vectored candidate) and rVSV-LASV are in Phase 2 trials as of 2024.

Prognosis: Overall CFR 1–15%; 15–25% among hospitalized patients; 50% in pregnant women during the third trimester, with near-universal fetal loss. Fetal evacuation, though distressing, improves maternal survival.

South American Hemorrhagic Fevers

A clade of New World arenaviruses causes geographically distinct hemorrhagic fever syndromes, each named for its country of origin:

• Argentine HF (Junín virus): Endemic to the pampas agricultural belt; seasonal peaks coincide with the corn harvest when workers disturb rodent burrows. CFR 15–30% untreated. Immune plasma (convalescent plasma) is highly effective, reducing mortality from 15–30% to 1–3% — the most proven use of convalescent plasma for any VHF.
• Bolivian HF (Machupo virus): Calomys callosus rodent reservoir; occasional person-to-person transmission documented.
• Brazilian HF (Sabiá virus): Rare; two naturally acquired cases documented plus a laboratory-acquired infection.
• Venezuelan HF (Guanarito virus): Zygodontomys brevicauda rodent reservoir; rural farming communities in Portuguesa state.

A live-attenuated Junín vaccine (Candid#1) is deployed in Argentina and has dramatically reduced Argentine HF incidence, demonstrating that vaccination can control New World arenavirus outbreaks when implemented systematically.

Back to Table of Contents

Bunyaviridae: Crimean-Congo Hemorrhagic Fever and Hantavirus

Crimean-Congo Hemorrhagic Fever (CCHF)

Crimean-Congo hemorrhagic fever is caused by Nairovirus (family Nairoviridae, formerly Bunyaviridae) and has the widest geographic range of any tick-borne VHF — spanning sub-Saharan Africa, the Middle East, Central Asia (Kazakhstan, Uzbekistan, Tajikistan), the Balkans (Kosovo, Bulgaria, Turkey), and increasingly southwestern Europe (Spain recorded its first autochthonous cases in 2016).

Vector: Hyalomma ticks — specifically H. marginatum and related species. Hyalomma is a "two-host" tick that completes its life cycle by feeding on a large mammal host (cattle, sheep, hares) for both the nymph and adult stages, making livestock a critical amplifying reservoir. Tick bites or crushing infected ticks with bare hands are the primary transmission routes; direct contact with the blood, organs, or tissues of infected livestock at slaughter is also documented.

Person-to-person transmission: Well-documented in healthcare settings through contact with blood, body fluids, or contaminated sharps — CCHF has caused multiple fatal nosocomial outbreaks in Turkey, Pakistan, and South Africa. This distinguishes CCHF from most other tick-borne diseases.

Clinical course: Incubation 1–3 days (tick bite) to 5–6 days (contact with infected blood). Four phases: incubation → prehemorrhagic (fever, headache, myalgia, thrombocytopenia) → hemorrhagic (mucosal bleeding, petechiae, ecchymosis, DIC) → convalescence or death. CFR 5–40% depending on outbreak setting, viral clade, and healthcare access. Thrombocytopenia is the most consistent laboratory finding and a useful early diagnostic signal.

Treatment: Ribavirin is recommended by WHO based on observational data and in vitro activity, though randomized trial evidence is limited. Supportive care including blood product transfusion for severe hemorrhage is the mainstay. An investigational inactivated CCHF vaccine (developed in Bulgaria and former Soviet states) has been used in endemic regions but is not widely approved.

Hantavirus

Hantaviruses (family Hantaviridae) are carried by rodents that shed virus in urine, feces, and saliva without themselves becoming ill. The disease syndromes differ by geography:

Old World hantaviruses (Hantaan virus, Seoul virus — Asia and Europe) cause Hemorrhagic Fever with Renal Syndrome (HFRS), characterized by fever, hemorrhage, and acute kidney injury. CFR 1–15% depending on the specific virus (Hantaan = 5–15%; Seoul = <1%).

New World hantaviruses (Sin Nombre virus in North America; Andes virus in South America) cause Hantavirus Pulmonary Syndrome (HPS) — a cardiopulmonary syndrome with abrupt onset of severe noncardiogenic pulmonary edema, respiratory failure, and cardiovascular shock. CFR for HPS is 35–40%. The 1993 Four Corners outbreak in the US Southwest that first identified Sin Nombre virus had a CFR exceeding 50% before the clinical syndrome was recognized and supportive care optimized.

Key clinical distinction: Virtually all hantaviruses are NOT transmitted person-to-person — with one critical exception: Andes virus (South America) has documented person-to-person transmission in household and hospital contacts, making it unique among hantaviruses. This was first described in an Argentinian outbreak and has been confirmed in subsequent Chilean outbreaks.

Transmission: Inhalation of aerosolized rodent excreta during cleaning of rodent-infested spaces (cabins, barns, grain storage). Incubation 1–5 weeks. No proven specific antiviral for HPS (ribavirin failed in a US HPS trial); treatment is aggressive supportive care with ECMO used for severe cardiac failure.

Back to Table of Contents

Flaviviridae: Yellow Fever, Dengue Hemorrhagic Fever, and Kyasanur Forest Disease

Yellow Fever

Yellow fever, caused by Yellow fever virus (YFV, Flavivirus), remains a serious public health threat in tropical Africa and South America despite the existence of one of medicine's most effective vaccines. The WHO estimates 200,000 cases and 30,000 deaths annually, with 90% of cases occurring in Africa.

Transmission cycles: Two epidemiologically distinct transmission cycles coexist:

• Urban cycle: Aedes aegypti mosquitoes transmit between humans in densely populated areas; causes large explosive urban epidemics.
• Sylvatic (jungle) cycle: Haemagogus and Sabethes mosquitoes transmit among non-human primates (monkeys serve as the reservoir); humans are incidental hosts infected at the forest edge.

Clinical phases:

• Infection phase (days 1–4): Sudden fever, headache, myalgia, flushing, and malaise. Most patients recover at this stage.
• Remission (24–48 hours): Brief period of apparent improvement — clinically deceptive.
• Intoxication phase (15% of patients): Return of fever with jaundice (reflecting massive hepatocyte destruction — hence "yellow" fever), renal failure (albuminuria, oliguria), and hemorrhage. The classic "black vomit" — vómito negro — is hematemesis from GI hemorrhage. Faget's sign (relative bradycardia despite high fever) is a historically noted but non-specific finding. CFR in the intoxication phase is 20–50%.

Treatment: No specific antiviral. Aggressive supportive care, management of renal failure (dialysis if needed), blood products for hemorrhage. Liver transplantation has been attempted but outcomes are poor.

Prevention: The 17D live-attenuated yellow fever vaccine is one of the most successful vaccines ever developed — a single dose provides lifelong protection in over 95% of recipients and is recognized internationally as a travel requirement for entry into endemic countries. Vaccination campaigns in West Africa following the 2016 outbreak (Angola, Democratic Republic of Congo) involved mass immunization of millions of people.

Dengue Hemorrhagic Fever

Dengue virus (DENV, 4 serotypes: DENV-1 through DENV-4) causes approximately 390 million infections per year worldwide — making dengue the most prevalent VHF by an enormous margin — with 96 million manifesting clinically (Bhatt et al., Nature 2013). Endemic in over 100 countries in tropical and subtropical regions.

The immunopathological mechanism of severe dengue: A secondary infection with a different DENV serotype (i.e., heterotypic reinfection) triggers antibody-dependent enhancement (ADE). Pre-existing, non-neutralizing antibodies from the first infection bind to the new serotype, facilitating enhanced uptake into Fc-receptor-bearing monocytes and macrophages, dramatically increasing viral replication and triggering an exaggerated cytokine response. This cascade leads to vascular endothelial leak — not direct blood vessel destruction — causing plasma extravasation, ascites, pleural effusions, and hemoconcentration.

WHO warning signs for severe dengue (require urgent medical attention):

• Abdominal pain or tenderness
• Persistent vomiting
• Clinical fluid accumulation (ascites, pleural effusion)
• Mucosal bleeding
• Lethargy or restlessness
• Liver enlargement greater than 2 cm
• Rising hematocrit concurrent with rapid decline in platelet count (the "critical phase" transition)

Dengue Shock Syndrome (DSS): Progression of plasma leakage to hemodynamic compromise — narrow pulse pressure (<20 mmHg), tachycardia, cold extremities, and altered consciousness. CFR with DSS in properly managed settings is 1–5%; in overwhelmed or under-resourced settings, up to 20%.

Treatment: No specific antiviral approved. IV fluid replacement is the cornerstone — isotonic crystalloids during the febrile phase; careful titration during the critical phase to avoid both inadequate resuscitation and fluid overload (which worsens pleural effusions). Aspirin and NSAIDs are contraindicated (platelet dysfunction, GI bleeding risk). Blood products for severe hemorrhage.

Kyasanur Forest Disease (KFD)

Kyasanur Forest Disease is a tick-borne flaviviral hemorrhagic fever endemic to Karnataka state, India, first identified in 1957 following mass die-offs of bonnet macaques (Macaca radiata) and langurs. The vector is Haemaphysalis spinigera and related Haemaphysalis ticks. Monkey die-offs precede human cases by weeks and serve as a sentinel surveillance signal. CFR approximately 3–5%. A formalin-inactivated KFD vaccine is available in Karnataka and deployed in at-risk communities.

Back to Table of Contents

Diagnosis and Laboratory Approach

All high-consequence VHF pathogens (Ebola, Marburg, Lassa, Crimean-Congo HF, and related agents) require BSL-4 laboratory conditions for confirmatory diagnostic work. In the United States, this means USAMRIID (Fort Detrick, Maryland) and the CDC Viral Special Pathogens Branch (Atlanta). Specimen transport requires triple-packaging per IATA Dangerous Goods Regulations P650 (UN2814 — infectious substance affecting humans), with prior notification to receiving laboratories and public health authorities.

Diagnostic tests by stage of illness:

Early diagnosis (days 1–3 of symptomatic illness — before antibody is detectable):

• Reverse transcriptase PCR (RT-PCR): Gold standard; detects viral RNA from day 1 of illness; high sensitivity and specificity; results available within hours at reference laboratories. This is the test that enables early case confirmation and isolation decisions.
• Antigen-capture ELISA: Detects viral proteins; positive from approximately day 3; less sensitive than RT-PCR in the very early phase but usable in field settings where PCR equipment is unavailable.

Later diagnosis (days 5–7 onward, or in convalescent patients):

• IgM ELISA: Appears days 5–7 of illness; indicates acute or recent infection.
• IgG ELISA: Rises later; used to confirm prior exposure in convalescent samples or for seroprevalence surveys.
• Virus isolation in cell culture: Definitive confirmation but requires BSL-4; used for reference and research.

Common laboratory abnormalities across VHFs (characteristic constellation):

• Thrombocytopenia: Near-universal; often profound (<50,000/μL); results from bone marrow suppression, consumptive coagulopathy, and splenic sequestration.
• Elevated AST/ALT: Hepatocellular injury; AST typically exceeds ALT (reflecting muscle involvement as well as liver); extremely elevated in Ebola and Yellow Fever.
• Elevated creatinine/BUN: Renal involvement; particularly prominent in Hantavirus HFRS and Lassa fever.
• Prolonged PT and aPTT: Coagulopathy; progresses to frank DIC in severe cases.
• Elevated D-dimer and fibrin degradation products: Markers of DIC activation.
• Hypoalbuminemia: Reflects capillary leak, impaired hepatic synthesis, and nutritional depletion.
• CBC: Leukopenia in early disease (lymphopenia particularly prominent); leukocytosis may emerge later with bacterial superinfection.
• Anemia: From direct hemorrhage, bone marrow suppression, and hemolysis.

Critical first step in any febrile returning traveler from an endemic region: Rule out malaria immediately with a rapid diagnostic test and thick blood film — malaria is far more common, treatable, and mimics early VHF. Other diagnoses to exclude: typhoid fever, meningococcal sepsis, leptospirosis, and rickettsial disease.

Back to Table of Contents

Treatment and Isolation Protocols

Supportive Care — The Foundation of VHF Management

For the majority of VHFs, supportive care remains the primary and most impactful intervention. The single most important early action is aggressive intravenous fluid and electrolyte replacement to counteract the profound dehydration caused by diarrhea, vomiting, and insensible losses. This insight — operationalized in the West Africa Ebola treatment units — substantially reduced Ebola CFR compared to historical outbreaks where supportive care was minimal.

Key supportive care components:

• IV fluid resuscitation: Lactated Ringer's or normal saline; guided by clinical response and urine output. Fluid overload must be carefully avoided, particularly in dengue (worsens plasma leak into third spaces) and in patients with cardiac compromise (Hantavirus cardiopulmonary syndrome).
• Vasopressors: Norepinephrine for refractory hypotension; inotropes for cardiogenic component in Hantavirus HPS.
• Blood products: Fresh frozen plasma (FFP) for coagulopathy/DIC; platelet transfusions for severe thrombocytopenia with active hemorrhage; packed red cells for severe anemia.
• Renal replacement therapy: Hemodialysis or continuous veno-venous hemofiltration (CVVHF) for acute kidney injury (particularly important in Hantavirus HFRS and Lassa fever).
• Extracorporeal membrane oxygenation (ECMO): Used for severe Hantavirus HPS with refractory cardiopulmonary failure; improves survival in specialized centers.
• Pain management and comfort care: Acetaminophen for fever (NOT aspirin or NSAIDs — platelet dysfunction risk); morphine for pain and dyspnea.
• Nutritional support: Enteral nutrition when feasible; parenteral when not.

Specific Antiviral Agents

• Ribavirin: Nucleoside analog that inhibits viral RNA-dependent RNA polymerase through lethal mutagenesis and competitive inhibition. Effective for Lassa fever (standard of care; reduces mortality ~5-fold when given early) and recommended for Crimean-Congo HF (evidence largely observational). IV regimen: loading dose 30 mg/kg (max 2g), then 15 mg/kg (max 1g) q6h × 4 days, then 7.5 mg/kg (max 500 mg) q8h × 6 days. NOT effective for Ebola, Marburg, Dengue, or Yellow Fever.
• Favipiravir: RNA-dependent RNA polymerase inhibitor; trials ongoing for Lassa fever. Used in a small Guinea Ebola trial with inconclusive results.
• Inmazeb (atoltivimab/maftivimab/odesivimab-ebgn): Triple mAb combination targeting Ebola Zaire glycoprotein; FDA-approved 2020 for Ebola Zaire disease. Reduces 28-day mortality vs. ZMapp control.
• Ebanga (ansuvimab-zykl): Single mAb targeting a conserved Ebola Zaire glycoprotein epitope; FDA-approved 2020.

Isolation Protocols for High-Consequence Pathogens

Patients with suspected filoviral hemorrhagic fever (Ebola, Marburg) require the highest level of containment isolation:

• Single room with negative pressure ventilation (if available) and dedicated bathroom.
• Contact and droplet precautions at minimum; airborne precautions (N95 respirator or powered air-purifying respirator, PAPR) are used in practice given the severity of disease despite no confirmed airborne natural transmission.
• Full PPE: Double gloves, fluid-impermeable gown, eye protection (goggles plus face shield), N95 respirator minimum; PAPR preferred for aerosol-generating procedures (intubation, bronchoscopy, blood draws).
• Dedicated medical equipment: Disposable where possible; disinfect reusable items with EPA-registered disinfectants effective against Ebola (10% bleach or quaternary ammonium compounds).
• Deceased patients: Bodies are highly infectious; strict no-touch burial, remains sealed in body bags after 10% bleach application, rapid burial recommended.
• Contact tracing: All individuals who had unprotected contact with the patient's blood or body fluids are placed under 21-day observation (Ebola) or appropriate monitoring per pathogen incubation period.
• Waste disposal: All materials (PPE, waste, linen) treated as Category A infectious waste, autoclaved or incinerated.

Back to Table of Contents

Prevention, Vaccines, and Outbreak Control

Licensed and Emergency-Use Vaccines

• Yellow fever 17D vaccine: Live-attenuated vaccine; single dose produces protective immunity (>95% seroconversion) within 10 days; protection is lifelong after a single dose per 2016 WHO revised guidance. Required for entry into endemic countries and many neighboring states (international health regulations). One of the most successful vaccines in history, with over 600 million doses administered since the 1930s.
• rVSV-ZEBOV (Ervebo): FDA-approved 2019 for Ebola Zaire prevention. Deployed via ring vaccination — vaccinating the contacts and contacts-of-contacts of confirmed cases rather than universal population immunization. Ring vaccination was key to ending the 2018–2020 DRC Kivu epidemic. Provides protection within 10 days of vaccination.
• Dengvaxia (CYD-TDV, Sanofi Pasteur): Tetravalent dengue vaccine approved in multiple endemic countries. Critical caveat: vaccination of dengue-seronegative individuals (those with no prior dengue infection) worsens the risk of severe dengue upon subsequent natural infection — the vaccine acts like a first infection, priming ADE. WHO now recommends Dengvaxia only for seropositive individuals confirmed by serological testing. This restriction fundamentally limits its public health utility.

Vaccines in Development

• Lassa fever: MV-LASV (recombinant measles virus vectored, Themis Bioscience/Merck) and rVSV-LASV in Phase 2 trials; no approved vaccine.
• Marburg: MK-4282 (Merck) and cAd3-Marburg (University of Oxford/GSK) in Phase 1–2 trials. Accelerated development following 2021–2022 Guinea and Ghana outbreaks.
• Hantavirus: Inactivated vaccines used in South Korea and China (Hantaan and Seoul viruses) for HFRS prevention; not approved in Western countries. No HPS (Sin Nombre, Andes) vaccine available.
• Crimean-Congo HF: Inactivated vaccine used historically in Eastern Europe; efficacy data limited; no widely approved modern vaccine.

Vector Control and Environmental Prevention

• Mosquito control (Yellow Fever, Dengue): Source reduction (eliminate standing water for Aedes breeding), insecticide-treated bed nets, personal repellents (DEET, picaridin), larviciding, and adult mosquito control with pyrethroid sprays during outbreaks. Urban elimination of Aedes aegypti has historically prevented Yellow Fever urban epidemics.
• Tick prevention (CCHF, KFD): Long-sleeved clothing and trousers tucked into socks in tick-infested areas; permethrin-treated clothing; daily tick inspection and prompt removal; acaricides on livestock in CCHF-endemic areas.
• Rodent control (Lassa, Hantavirus, CCHF via animal reservoir): Food storage in sealed rodent-proof containers; structural rodent exclusion of homes; wet-mopping of rodent-contaminated surfaces (not dry sweeping, which aerosolizes excreta); protective equipment when cleaning rodent-infested spaces.

Outbreak Response Protocols

• WHO Global Outbreak Alert and Response Network (GOARN): Coordinates international outbreak response, deploying rapid response teams and laboratory support.
• WHO Integrated Outbreak Analytics: Real-time epidemiological analysis during outbreaks to guide resource allocation and intervention targeting.
• Safe and dignified burials: Trained burial teams in Ebola-affected communities prevent transmission from traditional burial practices while respecting cultural and religious needs — critical to achieving community acceptance and outbreak control.
• Community engagement: Experience from West Africa and DRC Ebola outbreaks demonstrates that technical interventions fail without community trust; involving local community health workers, religious leaders, and survivor networks is essential.
• Healthcare worker protection: Systematic PPE training, mentorship programs, and psychological support for frontline workers; healthcare workers infected during outbreaks drive amplified transmission if not identified early.

Back to Table of Contents

Key Research Papers

1. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849–862. PMID: 22460894 | DOI: 10.1016/S0140-6736(10)60549-1 — Comprehensive review of Ebola virology, epidemiology, pathogenesis, and clinical management; standard reference for the field.
2. WHO Ebola Response Team. After Ebola in West Africa — unpredictable risks, preventable epidemics. N Engl J Med. 2016;375:587–596. PMID: 26159768 | DOI: 10.1056/NEJMsr1513109 — Analysis of the 2013–2016 West Africa epidemic; lessons learned and policy implications for future outbreak prevention.
3. Bah EI et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med. 2015;372(1):40–47. PMID: 24572574 | DOI: 10.1056/NEJMoa1411249 — Clinical series characterizing the presenting features, laboratory findings, and outcomes of Ebola patients in a West African outbreak setting.
4. Henao-Restrepo AM et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial. Lancet. 2017;389(10068):505–518. PMID: 29788880 | DOI: 10.1016/S0140-6736(16)32621-6 — Pivotal ring vaccination trial demonstrating 100% protective efficacy for rVSV-ZEBOV (Ervebo) in Guinea; basis for FDA approval.
5. McCormick JB et al. Lassa fever. Effective therapy with ribavirin. N Engl J Med. 1986;314(1):20–26. PMID: 11555793 | DOI: 10.1056/NEJM198602273140903 — Landmark clinical study establishing ribavirin as the standard of care for Lassa fever, demonstrating ~5-fold mortality reduction with early IV treatment.
6. Siddle KJ et al. Genomic analysis of a Lassa virus epidemic in Nigeria. N Engl J Med. 2018;379:1745–1753. PMID: 32705833 | DOI: 10.1056/NEJMoa1804498 — Genomic epidemiology of the 2018 Nigerian Lassa surge; multiple independent zoonotic introduction events rather than person-to-person amplification.
7. Ergonul O. Crimean-Congo haemorrhagic fever. Lancet Infect Dis. 2006;6(4):203–214. PMID: 17406714 | DOI: 10.1016/S1473-3099(06)70435-2 — Comprehensive review of CCHF virology, tick vectors, geographic distribution, clinical features, and ribavirin treatment evidence.
8. Bhatt S et al. The global distribution and burden of dengue. Nature. 2013;496:504–507. PMID: 23563266 | DOI: 10.1038/nature12060 — Landmark modelling study estimating 390 million dengue infections per year globally; redefined understanding of the true worldwide burden of dengue.
9. Peters CJ, Khan AS. Hantavirus pulmonary syndrome: the new American hemorrhagic fever. Clin Infect Dis. 2002;34(9):1224–1231. PMID: 7603001 — Review of the discovery and characterization of Hantavirus Pulmonary Syndrome following the 1993 Four Corners outbreak; pathogenesis, diagnosis, and treatment.
10. Johnson KM et al. Isolation and partial characterisation of a new virus causing acute haemorrhagic fever in Zaire. Lancet. 1977;1(8011):569–571. Historical reference: first isolation and description of Ebola virus from the 1976 Zaire outbreak. Search PubMed: Ebola virus isolation 1976 Zaire
11. Markham A. REGN-EB3: First Approval. Drugs. 2021;81(2):175–178. PMID: 31706925 | DOI: 10.1007/s40265-021-01601-5 — First approval summary for Inmazeb (atoltivimab/maftivimab/odesivimab-ebgn); mechanism, clinical trial data, and approval rationale.
12. Wilkinson A et al. Principles of supportive care during viral hemorrhagic fever outbreaks. Lancet Infect Dis. 2020. PMID: 31756398 — Systematic review and practical guidance on fluid management, electrolyte replacement, and organ support in VHF outbreaks; challenges of delivering critical care in resource-limited settings.

PubMed Topic Searches

1. Ebola virus disease treatment clinical trials
2. Lassa fever ribavirin treatment outcomes
3. Crimean-Congo hemorrhagic fever epidemiology
4. Dengue hemorrhagic fever pathogenesis antibody-dependent enhancement
5. Hantavirus pulmonary syndrome treatment ECMO outcomes

Back to Table of Contents

Connections

• Bubonic Plague
• Dengue Fever
• Sepsis
• Malaria
• Cholera
• Typhoid Fever
• West Nile Virus
• Rabies

Back to Table of Contents

Featured Videos