Uganda's Ebola Victory: A Triumph Against Ebola virus disease Re-emergence ?

Uganda declared the end of the Ebola outbreak caused by the Sudan ebolavirus on 11 January 2023. This declaration came after 42 consecutive days without any reported cases following the release of the last patient from care. As of now, there have been no recent incidents of Ebola reported.

The Ebola virus is re-emerging, posing a significant threat due to its high fatality rate, which averages around 50% and can reach up to 90%. While it's endemic to African nations, its broad transmission methods mean it can quickly escalate from outbreaks to epidemics or even pandemics, especially in our interconnected world.

To tackle this threat effectively, are we prepared with effective antivirals, safe vaccines, and widespread public awareness about the virus?

Ebola virus causes rare but fatal lethal hemorrhagic fever. This viral infection is not limited to humans but also causes diseases in nonhuman primates (monkeys, chimpanzees).

The Ebola virus first emerged in 1976 during separate hemorrhagic fever outbreaks in Yambuku, Zaire (now Democratic Republic of Congo), and Nzara, Sudan, approximately 800km apart. The virus was isolated from a patient in Yambuku and named after the nearby Ebola River to prevent stigmatization of the town. Initially believed to be related, subsequent research confirmed they were caused by distinct strains: Ebola Zaire and Ebola Sudan, named after their respective countries of discovery.

Ebola has history of re-emergence. 

Since its discovery in 1976, Ebola has caused sporadic outbreaks primarily in Central and West Africa. The first outbreak occurred near the Ebola River, spanning what is now the Democratic Republic of Congo and South Sudan. Subsequent years saw smaller outbreaks in Central Africa, affecting countries like Sudan, DRC, Gabon, and Uganda. The largest outbreak in history occurred from 2013 to 2016 in West Africa, primarily in Guinea, Liberia, and Sierra Leone, resulting in over 28,000 cases and 11,000 deaths. Smaller outbreaks continued in subsequent years, including in the DRC in 2018 and 2018-2020 and in Guinea during 2021-2022. Efforts to contain Ebola have involved international organizations and national health agencies, facing challenges due to the virus's high mortality rate and difficulties in diagnosis and treatment.
The virus belongs to the Filoviridae family, Ebolavirus genus, which includes Zaire ebolavirus (EBOV), Reston ebolavirus (RESTV), Bundibugyo ebolavirus (BDBV), Taï Forest ebolavirus (TAFV), Sudan ebolavirus (SUDV), and Bombali ebolavirus (BOMV). EBOV, responsible for Ebola hemorrhagic fever (EHF), exhibits the highest human mortality rates, followed by SUDV and BDBV. TAFV has caused only two nonlethal human infections to date, while RESTV leads to asymptomatic human infections, primarily identified in the Philippines.
 
Fruit bats of the Pteropodidae family, including Hypsignathus monstrous, Epomops franqueti, and Myonycteris torquata, serve as natural hosts of the Ebola virus (EBOV) in Africa. Nonhuman primates can contract the virus by consuming partially eaten fruits and subsequently transmit it to humans. The virus is typically introduced into human populations in endemic African regions by handling infected animal carcasses, commonly referred to as bushmeat. Subsequent human-to-human transmission then becomes a prominent feature of any epidemic. Intimate physical contact with patients in acute disease stages and exposure to blood/fluids from deceased individuals are primary transmission modes. Traditional funeral practices in African countries involve the direct handling of bodies, significantly contributing to disease spread.

EBOV RNA can persist for up to a month in rectal, conjunctival, and vaginal discharges, and up to three months in semen, indicating the virus may persist in recovering patients.
A case of sexually transmitted EVD has been reported between a convalescent patient and a close family member.

Asymptomatic carriers of EBOV are not infectious and do not play a significant role in Ebola virus disease outbreaks. Patients can only spread the infection when they have symptoms; transmission does not occur during the incubation period.

EBOV has been detected in blood, saliva, semen, and breast milk. RNA has been isolated from sweat, tears, stool, and on skin, vaginal, and rectal swabs. Exposure to infected bodily fluids is the main mode of transmission. Eating undercooked meat from infected animals, hospital-acquired infections, and poor sanitation, have also been reported in EVD dissemination. Transmission can also occur through contaminated materials (fomites) carrying infected bodily secretions. It's not clear if the disease can spread through the air or droplets.
 
Ebola viruses entering the human body infect immune system cells (dendritic cells, monocytes, and macrophages), endothelial and epithelial cells, hepatocytes, and fibroblasts, where they replicate actively, leading to high levels of virus in the bloodstream. The virus spreads to regional lymph nodes causing swelling, then travels through the blood to the liver and spleen, triggering an intense inflammatory response. This response, driven by inflammatory chemicals (cytokines and chemokines), disrupts vascular function, leading to disseminated intravascular coagulation and multiple organ failure.

Ebola can only spread to others after symptoms appear, typically within 8 to 10 days after contact, occasionally up to 21 days. Early symptoms are nonspecific, which complicates diagnosis.

Initial Ebola Virus Disease (EVD) symptoms are nonspecific, resembling dengue, typhoid fever, malaria, and flu. They typically appear 8–11 days post-infection and include high fever, headaches, sore throat, cough, abdominal pain, nausea, vomiting, and diarrhoea. As the disease progresses, symptoms worsen with bleeding manifestations such as gum and nosebleeds, gastrointestinal bleeding, and hematuria. Severe cases can lead to dehydration, shock, multiorgan dysfunction, and death.

Reverse transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) are the primary diagnostic tests for confirming Ebola virus disease (EVD) in laboratories.

Two licensed vaccines are available for the Ebola virus (Orthoebolavirus zairense): ERVEBO (Merck), a single-dose rVSVΔG-ZEBOV-GP vaccine approved by the FDA in the United States, and Zabdeno/Mvabea (Johnson & Johnson), a two-dose regimen of Ad26.ZEBOV and MVA-BN-Filo were used in outbreaks but were not FDA-approved in the United States.

Ebola Virus Disease (EVD) is a life-threatening condition associated with a high global mortality rate and significant chronic sequelae. Survivors often experience chronic manifestations resembling autoimmune and auto-inflammatory conditions. 

Developing antiviral medications and establishing safe and effective vaccines are crucial for preparedness in managing EBOV disease under any circumstances. Antiviral drugs can provide immediate treatment options for those infected, potentially reducing severity and mortality rates. On the other hand, vaccines play a pivotal role in prevention by priming the immune system to recognize and combat the virus before infection occurs, thus curbing transmission and preventing outbreaks mainly in endemic regions. 

These approaches are essential components of a comprehensive strategy to combat EBOV disease effectively and ensure global health security.

 
 
 
 
 
 
 
 
 

Zika Virus: Emerging Threat to Human Civilization

Zika virus (ZIKV) is a mosquito-borne virus classified within the Flaviviridae family, alongside notable members such as Japanese encephalitis (JEV), West Nile (WNV), dengue (DENV), and yellow fever (YFV) viruses. The Zika virus was initially isolated in 1947 from a rhesus macaque monkey in the Zika Forest, located on the Entebbe Peninsula, Uganda. Subsequently, it was isolated from Aedes africanus mosquitoes. Mosquitoes are the primary mode of viral transmission across various geographical regions. Originating in the Ugandan forest, the virus has spread to the Pacific Islands, Latin America, North America, and now Southeast Asia.

Zika virus (ZIKV) primarily transmits to humans through the bite of infected mosquitoes. Additionally, it can cross the placental barrier, affecting the fetus during pregnancy, and spread through sexual contact, breastfeeding, or blood transfusion.

The Zika virus primarily circulates through two transmission cycles: the sylvatic cycle, occurring in forested areas where the virus is maintained between non-human primates and arboreal mosquitoes and the urban cycle, prevalent in urban settings where the virus circulates between humans and urban mosquitoes.

Recent concern has focused on managing urban mosquitoes, specifically two species: Aedes aegypti, identified by white bands on its legs, and Aedes albopictus, known for a single long dorsal stripe and white leg bands. These mosquitoes are active during daylight hours.

Zika virus can spread through sexual contact, blood transfusion, and breastfeeding. It can also be transmitted from a pregnant woman to her fetus. The virus has been found in urine, saliva, and nasopharyngeal swabs. Direct transmission through skin or mucous membranes is uncommon due to low viral levels in the blood.
Zika virus (ZIKV) symptoms range from mild to severe. Mild cases typically resolve within 4–10 days after an incubation period. Symptoms include flu-like syndromes such as low-grade fever, rash, arthritis, conjunctivitis, headache, myalgia, edema, and vomiting. Severe cases may lead to Guillain-Barre syndrome in adults, characterized by autoimmune attacks on the peripheral nervous system causing tingling, muscle weakness, and paralysis. In infants born to infected women, ZIKV can cause microcephaly, a condition where the brain does not develop properly, resulting in a smaller-than-normal head.

Currently, there are no specific medications available for preventing or treating Zika virus (ZIKV) infection. Developing a safe and effective vaccine is crucial to stop the spread of the virus. Progress in Zika vaccine development is ongoing, using various technologies such as DNA vaccines, subunit vaccines, live-attenuated vaccines, virus-vector-based vaccines, inactivated vaccines, virus-like particles (VLPs), and mRNA-based vaccines.
Before a safe and effective vaccine becomes available, the primary strategy to prevent Zika virus infection is vector control, which focuses on reducing mosquito populations, eliminating breeding sites, and avoiding mosquito bites. These measures are also effective in preventing Dengue and Chikungunya infections.

Reasons for the Increasing Frequency of Viral Diseases Emergence

Several global trends have significantly increased the risks associated with the emergence and spread of infectious diseases. Urbanization and population growth have transformed our cities into densely populated hubs where diseases can easily spread. Moreover, advancements in transportation have made global travel faster and more accessible than ever before, reducing the time it takes to circumnavigate the globe from months to just hours. This rapid movement of people means that viruses can potentially travel across continents within the incubation period of an infection before symptoms even manifest.

The SARS pandemic of 2002–2003 serves as a stark example of how quickly a new virus can spread globally. Originating in China, SARS-CoV spread to more than two dozen countries within a matter of months, highlighting the interconnectedness of our modern world and the challenges it poses for disease control and prevention.

In addition to human activities, environmental changes driven by agriculture and urban development play a crucial role in disease emergence. The conversion of natural habitats for agriculture or infrastructure projects creates new ecological niches that can harbour disease vectors and reservoirs. For instance, urban yellow fever likely originated when humans entered jungle areas where the virus was maintained in a cycle between monkeys and mosquitoes. The introduction of infected individuals back into urban centres facilitated the virus's adaptation to a new cycle involving mosquitoes like Aedes aegypti, which thrive in urban environments and preferentially feed on humans.

Furthermore, the intensification of agribusiness has led to the concentration of large numbers of livestock or crops in confined spaces. This practice increases the risk of rapid disease transmission among closely packed animals or plants, creating conditions ripe for the emergence of new pathogens or the spread of existing ones.

International trade in plants and animals has also contributed to the spread of diseases across borders. The 2003 outbreak of monkeypox in the United States, for example, was traced back to the importation of Gambian giant rats from Africa as exotic pets. The virus spread from these animals to domestic pets and then to humans, causing public health concerns due to its similarity to smallpox.

These interconnected factors underscore the urgent need for global cooperation and proactive measures to monitor, prevent, and respond to emerging infectious diseases. As our world becomes increasingly interconnected and urbanized, understanding and mitigating the risks posed by infectious diseases have become critical global health priorities.

In the mid-1800s, rabbits brought from Europe to Australia for sport quickly multiplied without natural predators, threatening grasslands and crops in southern Australia. To control their numbers, the myxomatosis virus was introduced in 1950, causing a devastating outbreak among the rabbit population due to its high lethality. Over time, the virus evolved, with less deadly strains becoming more common as rabbits developed genetic resistance. This natural selection favoured moderately harmful strains because milder ones struggled to spread, while highly lethal ones killed rabbits too quickly to transmit effectively.

This situation demonstrates the complexities of using viruses for population control and raises concerns about unintended consequences. Introducing viruses, even for beneficial purposes like managing wildlife, can disrupt ecosystems and pose biosecurity risks. Such considerations are crucial in both wildlife management and assessing the potential risks associated with intentional virus introductions, which could also serve as models for bioterrorism.

Significant progress has been made in the field of xenotransplantation, particularly in using genetically modified pigs as organ donors to address the shortage of human organs for transplantation. Research has focused on various areas such as pancreatic islets, neuronal cells, corneas, and vascularized organs like kidneys and hearts. However, a critical concern arises regarding the potential transmission of known or unknown latent or persistent viruses from donor organs to transplant recipients. This is especially pertinent because transplant recipients undergo immunosuppression to prevent rejection of the transplanted organ, which could make them more vulnerable to infections from viruses originating from the donor species.

In the worst-case scenario, this situation could facilitate the transmission of a foreign virus across the species barrier, allowing it to establish itself as a new human virus. Such a virus could potentially spread from the graft recipient to others, posing significant public health risks. Therefore, while xenotransplantation offers promising solutions to organ shortages, careful consideration and ongoing research are essential to mitigate the risks associated with viral transmission and ensure the safety of transplant recipients and the broader community.

Is it typical for Influenza Virus A to infect cattle?

The influenza virus, a single-stranded negative-sense RNA virus of the Orthomyxoviridae family, causes acute respiratory illness in animals, birds, and humans. It is classified into types based on genetic traits and their impact. The virus possesses surface glycoproteins hemagglutinin and neuraminidase, with 18 hemagglutinin (H1-H18) and 11 neuraminidase (N1-N11) subtypes. These glycoproteins facilitate attachment to host cell receptors.

Influenza A is the most prevalent type, causing seasonal flu outbreaks in humans and animals. Subtypes like H1N1 and H3N2 are defined by their surface proteins. Influenza B virus also infects humans, causing seasonal flu but with less variation than influenza A. Influenza C virus can infect humans but typically causes milder illness than A and B types. Influenza D virus primarily affects cattle and rarely infects humans. Understanding these distinctions aids researchers and healthcare providers in effectively monitoring and responding to influenza outbreaks.

Viruses employ host adaptation strategies to enter and cause diseases in various hosts, including birds, animals, and humans. Influenza virus can successfully cross species barriers by adapting through several key factors. These include receptor affinity, which determines its ability to bind to host cells (tropism); stability in various environments, allowing it to survive and spread effectively (environmental stability); and its capacity to evade the host immune system's defences (immune evasion). These adaptations enable the virus to infect and potentially establish new reservoirs in different species.
Domestic cattle are crucial in food and agriculture, maintaining significant importance in the modern world. However, pigs have served as mixing vessels for avian and human influenza A viruses. Human interaction with swine has facilitated the bidirectional influenza transmission at the pig-human interface. Cattle were domesticated by humans long before pigs were.
Cattle were largely unaffected by influenza A and were not considered susceptible hosts for the virus. Certain bovine host factors, including specific serum components and secretory proteins, possess anti-influenza properties. These factors may contribute to the resilience of bovines to influenza A virus (IAV). 

Swine (pigs) are the primary hosts where different subtypes of influenza viruses mix. When these subtypes replicate within the same host, antigenic shift and drift occur. Antigenic drift results from mutations in the hemagglutinin (HA) and neuraminidase (NA) genes, gradually altering the virus's surface proteins. This diminishes the effectiveness of previous immunity, requiring regular updates to influenza vaccines. Antigenic shift, meanwhile, happens when different influenza viruses exchange genetic material, creating new strains that can lead to global pandemics due to limited existing immunity in humans.

The Spanish flu in 1918 was very deadly, causing about 50 million deaths. The Asian flu in 1957-1958 started in Asia and killed 1-2 million people globally. Then, the Hong Kong flu in 1968 started in Hong Kong and caused 1-4 million deaths worldwide. In 2009, the swine flu spread from pigs to people and caused millions of illnesses worldwide, though fewer deaths compared to earlier outbreaks. These outbreaks show how flu viruses can spread worldwide and influence how we get ready for future outbreaks.

Bovine milk can interfere with the hemagglutinating property of the influenza virus. Bovine IgG present in the milk binds with viruses, aiding in phagocytosis. In milk, oligosaccharides can block the influenza virus from binding to cells' sialylated glycans by acting as dummy receptors. 

Bovine lactoferrin (bLf) is a crucial 76 kDa glycoprotein composed of a single polypeptide chain containing 689 amino acid residues. It is found in biological fluids and specific granules of polymorphonuclear leukocytes. This protein plays key roles in immunomodulation, iron absorption, and inhibiting pathogens, including enveloped viruses like influenza.

In bovine serum, there are inhibitors similar to conglutinin. These inhibitors can help by acting as opsonins, which means they assist in phagocytosis (the engulfing and digestion) of influenza A viruses. 

Aprotinin, a natural protease inhibitor derived from bovine lung, is currently used in humans for treating pancreatitis and haemorrhage. It also shows promise in suppressing the cleavage of the pandemic H1N1 influenza virus.

The global agriculture and food systems are facing a serious challenge due to an outbreak of H5N1 avian influenza, or bird flu, centred in the United States. Although it rarely spreads to mammals, authorities are working hard to control it. 

So far, there hasn't been much impact on our food and nutrition, but experts warn that this situation shows potential problems for farming and serious health risks for animals and possibly humans. It's important to closely watch and take action to protect public health and ensure our food supply stays safe and reliable despite these challenges.

Immune Amnesia Associated with Measles

 The immune responses triggered by measles virus (MV) infection can unexpectedly suppress the body's ability to respond to other unrelated antigens, a condition that may persist for weeks to years after the acute illness subsides. This immune suppression significantly increases vulnerability to secondary bacterial and viral infections such as pneumonia and diarrhea, which are major causes of illness and death following measles.

Measles infection disrupts delayed-type hypersensitivity (DTH) responses to known antigens like tuberculin, and impairs both cellular and humoral responses to new antigens. This immune dysregulation also contributes to the reactivation of tuberculosis and the worsening of autoimmune diseases post-measles.

In essence, measles-induced immune suppression not only weakens immediate defenses against pathogens but also compromises the immune system's ability to mount effective responses to a range of antigens over an extended period.

Measles-induced immune suppression can occur due to changes in antigen-presenting cells or effector lymphocytes, or through the depletion of CD150+ memory lymphocytes. Measles virus (MV) infects CD150+ immune cells, including memory T- and B-lymphocytes. Studies comparing blood samples collected from unvaccinated children before and after measles reveal incomplete reformation of B-lymphocyte pools post-infection. Additionally, measles leads to a significant reduction in circulating antibodies against various viruses and bacteria, impairing immunological memory and causing what is termed 'immune amnesia'.

This mechanism contributes to increased childhood morbidity and mortality for more than two years after measles infection. Abnormalities in both innate and adaptive immune responses are evident following MV infection. Children commonly experience transient lymphopenia, characterized by decreased T and B lymphocytes in the blood. Furthermore, immune cells such as dendritic cells, crucial for presenting antigens to lymphocytes, show impaired maturation and reduced ability to stimulate lymphocyte proliferation.

In summary, measles disrupts immune function by compromising both cellular and antibody-mediated immunity, leading to prolonged susceptibility to infections and contributing to the severity of measles-related complications in children.

Antiviral Drug Resistance: A Global Problem

 RNA viruses, renowned for their high mutation rates, undergo rapid evolution. Consequently, genotypes harbouring mutations conferring drug resistance can emerge swiftly. A virus strain is deemed 'resistant' to a drug if it can replicate in the body despite the presence of the drug at concentrations that inhibit replication of 'sensitive' strains. Drug-resistant virus isolates typically exhibit gene mutations encoding the proteins the drug targets. Most mutations leading to drug resistance in HIV-1 involve changes in amino acids. However, some mutations can also involve deletions or insertions of genetic material. In the HIV-1 virus, mutations in the reverse transcriptase gene that make it resistant to nucleoside analogues (such as AZT) occur in different specific codons compared to mutations that confer resistance to non-nucleoside inhibitors (like nevirapine). This difference is because these two classes of drugs target distinct regions within the reverse transcriptase enzyme. This specificity in mutation locations highlights how different drugs can influence HIV-1's genetic makeup differently, affecting its ability to resist treatment.

Clinical challenges arise when drug-resistant virus strains develop in patients undergoing treatment and when these resistant strains are transmitted to others. When drug-resistant HIV strains emerge during treatment, patients may switch to alternative medications. Initially, AZT was widely used for HIV treatment but resistance quickly developed. Similar challenges arose with other single-drug therapies. The current standard for treating HIV infection involves highly active antiretroviral therapy (HAART), which combines different classes of drugs like reverse transcriptase inhibitors and protease inhibitors.

Monitoring the effectiveness of HIV treatment involves measuring HIV RNA levels in the blood. HAART typically leads to a rapid reduction in HIV RNA within the first 10 days, followed by a slower decline over weeks. In some patients, HIV RNA stabilizes at low levels (5-50 copies/ml), while in others, it drops to less than 5 copies/ml over time.

HAART also reduces HIV levels in the seminal fluid of men and the genital secretions of women. While it doesn't eradicate HIV from the body, the virus persists in latent forms in macrophages, memory CD4 T cells, and possibly in immune-privileged sites like the brain and testes. Despite this persistence, HAART has significantly lowered AIDS-related mortality in developed countries. Additionally, treating HIV-positive women has substantially decreased mother-to-child transmission risks.

Overall, HAART represents a pivotal advancement in managing HIV infection, offering optimism through effective suppression of the virus and improved quality of life for patients.

Can all types of vaccines be given on the same date?

Administration of different vaccines at the same visit both live and inactivated vaccines does not result in decreased antibody responses or increased rates of adverse reaction. Simultaneous administration of all vaccines for which a child is eligible is very important in childhood vaccination programs because it increases the probability that a child will be fully immunized at the appropriate age.

For some vaccines, administration should not be done at different time intervals. The live parenteral (injected) vaccines (MMR, MMRV, varicella, zoster, and yellow fever) and live intranasal influenza vaccine (LAIV should be separated by at least 4 weeks. This interval is intended to reduce or eliminate interference from the vaccine. The yellow fever vaccine Should be administered less than 4 weeks after the single-antigen measles vaccine. A 1999 study demonstrated that the yellow fever vaccine is not affected by the measles vaccine given 1–27 days earlier. Live vaccines administered by the oral route (oral polio vaccine [OPV] oral typhoid, and rotavirus) are not believed to interfere with each other if not given simultaneously. These vaccines may be given at any time before or after each other. The Rotavirus vaccine is not approved for children older than 32 weeks, and oral typhoid is not approved for children younger than 6 years of age.

Parenteral live vaccines (MMR, MMRV, varicella, zoster, and yellow fever) and LAIV are not believed to have an effect on live vaccines given by the oral route (OPV, oral typhoid, and rotavirus). Live oral vaccines may be given at any time before or after live parenteral vaccines or LAIV. All other combinations of two inactivated vaccines, or live and inactivated vaccines, may be given at any time before or after each other.