Why we do not use RNAi to control ebola?

Why we do not use RNAi to control ebola?

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As you know using RNAi we are able to prevent gene expression. so why we do not use it to stop viral genes expression?

Delivering siRNA in vivo is a difficult prospect, but has been overcome in research environments and several commercial in vivo solutions are on the market see examples from Life Technologies here.

The bigger problems come from potential off-target effects. siRNA tend to be double stranded and both the 'guide' and 'passenger' strand can occasionally target multiple sequences that you did not intend. Additionally, siRNA tend to activate the body's immune system in ways that would inhibit therapy or cause excess inflammation and cell death. See the detailed review here.

In short, it is a good idea, and the current research in the field is working to overcome technical challenges, but we are not there yet.

Battling Ebola: Working with a Deadly Virus

Ebola researcher Elke Mühlberger says humans have not adapted to Ebola virus and have no immunity. Photo by Kalman Zabarsky

An Ebola vaccine was more than two decades in the making. Here are some key people who made it happen

By 2014 Feldmann had long since given up hope that the vaccine — known in the myriad studies he and others published on it as rVSV-ZEBOV — would ever get made. But through an unlikely series of twists and turns, some fortuitous and not-so-fortuitous, the vaccine has finally been developed by Merck, approved by regulatory agencies in the United States and Europe late last year, and used in the field to save lives in Africa. It is known as Ervebo.

It is a feat that built on the work of scientists in multiple countries on three continents who toiled in obscurity for years. And it ensured that when future outbreaks strike, health workers have a crucial new tool at their disposal.

“This vaccine … from the beginning to the end — it should have never happened. On so many levels … against all odds, it made it,” said Kobinger, now director of the Infectious Disease Research Center at Laval University in Quebec.

T he story of the Ebola vaccine began, as scientific advances often do, with a good idea and a lucky break.

In the early 1990s, a Yale University scientist named John “Jack” Rose was trying to figure out a way to use a livestock virus called vesicular stomatitis virus, or VSV, as a vaccine delivery system. While it can infect people, VSV doesn’t sicken them. The immune system response to the virus is rapid and the levels of antibodies induced are surprisingly high.

Rose thought the virus could be an effective backbone for a vaccine — if it could be engineered to include genes of viral pathogens like influenza or HIV. The idea was that the harmless virus would teach the immune system to recognize harmful potential invaders.

But he and students in his lab had been trying for about six years to successfully manipulate VSV to add in the genes of other viruses. One very good student left his lab, he recalled, because she concluded the work was never going to pan out.

Then, in 1994, Rose heard that researchers in Germany had succeeded where he had struggled — with a rabies virus. Using their approach, he was able to recover modified VSV viruses in a few months.

“That opened up a whole new area of research on VSV for us and others,” Rose recalled.

To see if the system worked, his group added a protein from an influenza virus to VSV and injected it into mice. “The neutralizing antibody responses were fast and off the charts,” he said. “And of course the mice were completely protected after a single dose.”

Rose’s lab and others later used VSV as a backbone for experimental vaccines for bird flu, measles, SARS, Zika, and other pathogens. It always worked.

Without the high-security laboratories needed to handle the world’s most dangerous viruses, the researchers couldn’t work on Ebola. Rose, nonetheless, thought a VSV Ebola vaccine, in theory, would work as well.

Yale patented Rose’s VSV construct, and licensed it to Wyeth Pharmaceuticals.

B y his own estimate, Rose shared his VSV vector with at least 100 labs worldwide. One of them was located in a city in Germany with a rather auspicious name: Marburg.

It was there, in 1967, that laboratory workers and people related to them became sick with what was later named the Marburg virus. The source: primates imported for research purposes. (Nine years later, scientists would discover a related virus, Ebola.)

When a scientist named Hans-Dieter Klenk moved to the city in the 1980s to lead the Institute of Virology at the Philipps-University Marburg, there was no research being conducted there on Marburg or Ebola. Klenk decided that ought to change. He asked one of his students, Heinz Feldmann, if he wanted to continue to work on influenza, or move over to filoviruses like Marburg. “He did not think long,” Klenk said. “This is how it started.”

John “Jack” Rose in his lab at Yale. Courtesy

With Rose’s virus, Klenk’s team could study individual Ebola genes by putting them onto the VSV backbone. The beauty of the approach was that they could do the work at lower biocontainment levels than Ebola research is normally conducted, which made it safer, faster, and cheaper.

At first, the protein on the surface of the VSV virus — known as the glycoprotein or G protein — was swapped out and replaced with the Ebola glycoprotein. Later the group made a VSV virus with the G protein of the Marburg virus.

Klenk said that, even then, there was some discussion about whether the hybrid VSV virus could be made into Ebola or Marburg vaccines. But the group didn’t have high-containment labs in which to do animal studies, so it couldn’t test the theory.

Back across the Atlantic, though, Canada was building a new national microbiology laboratory — one that included biosafety level 4 facilities, the type needed to study Ebola. Feldmann was recruited to lead the special pathogens team there. And when he left Germany in 1999, he asked Klenk if he could take the VSV construct with him, so he could continue his work. Klenk agreed.

“This became ‘the Canadian vaccine’ — how it was known for many years. But certainly it has also roots in Marburg,” Klenk said.

A s Feldmann recalls it, he wasn’t even thinking about using Rose’s VSV construct as a vaccine when he was in Marburg. “We had no vaccine program. We had no interest in vaccines,” he said. “We used it basically as a model system to study the glycoprotein.”

After he’d moved to the Canadian lab, though, Feldmann and Tom Geisbert, a friend and frequent collaborator, heard Dr. Gary Nabel, then head of the National Institutes of Health’s Vaccine Research Center, deliver a lecture on Ebola. He argued the glycoprotein was the cause of the profound damage Ebola does when it infects animals and people.

Feldmann and Geisbert, an Ebola expert who was then at the U.S. Army Medical Research Institute of Infectious Diseases, thought Nabel was wrong and that they could use the VSV construct to prove it.

In Winnipeg, Feldmann’s team infected mice with the VSV virus containing the Ebola glycoprotein. If Nabel’s theory was correct, exposure to the protein should have been toxic to the mice.

The rodents were unharmed.

As an afterthought, the group decided to expose the mice to Ebola to see what would happen. All the mice that had been infected with the VSV virus carrying the glycoprotein were fully protected from illness the mice that had not been exposed to the VSV virus all died.

“I guess that was basically the start of the vaccine project, even though I don’t think we really jumped on it with a lot of priority right away,” said Feldmann.

GMOs advance science of vaccines

One disease currently being addressed with the help of molecular biology is hepatitis B, which kills one person every minute worldwide – even though we do have an effective vaccine.

In the 1960s, virologists realized that the hepatitis B antigen – a protein from the virus’ outer shell that triggers an immune response in an infected person – showed up in the blood of hepatitis B patients. To their surprise, injecting a healthy person with the purified antigen protected against future infections. The first hepatitis B vaccine (HBV), approved in 1981, was made by harvesting the antigen from the blood of hepatitis B carriers, including intravenous drug users.

Administering the hepatitis B vaccine to a child at a rural health center in India. United Nations Development Programme, CC BY-NC-ND

Once recombinant DNA technology was developed, researchers could isolate the gene for the virus’ antigen protein, allowing for HBV to be manufactured in laboratories via those genetic instructions instead of from infected blood. Currently, both FDA-approved vaccines for hepatitis B include the recombinant version of the antigen.

And molecular biology can be used to accelerate the development of new vaccines. For example, in late June, a “DNA vaccine” was the first to be approved for human trials against the Zika virus. Rather than containing the Zika antigen itself, the vaccine contains a gene for the Zika antigen which the patient’s body then produces.

The announcement of this breakthrough came less than five months after the World Health Organization declared Zika a “public health emergency of international concern.” Without the tools to modify and isolate sections of DNA, Dr. Esparza of the Global Virus Network notes, “we would not be able to do this with the necessary speed and efficiency.”

Materials and Methods

Infection of Flies and Cells.

Information regarding the mutant strains used, the tissue culture conditions, and propagation and titration of viral stocks can be found in the SI Materials and Methods. Infection by intrathoracic injection was performed as described previously (3).

RNA Isolation and Immunoprecipitation of dsRNA.

For dsRNA detection, 1.5 × 10 7 S2 or Kc167 cells were infected with VSV (MOI 10), DCV (MOI 10), or FHV (MOI 0.1). Cells were collected in 15-mL reaction tubes and total RNA was extracted using TriReagent (Gibco-BRL) according to the manufacturer's instructions. RNA was quantified and immunoprecipitation was performed as previously described (45). In brief, 40 μg of total RNA was incubated overnight at 4 °C in polysomal lysis buffer with 10 μg J2 or K1 antibody (Scicons). Then, 50 μL of protein A-agarose solution (Invitrogen) was added, and incubation continued at 4 °C for 4 h. Complexes were washed eight times in polysomal lysis buffer and, after degradation of the protein complexes by proteinase K digestion (30 min at 50 °C), RNA was recovered by phenol-chloroform extraction and ethanol precipitation. The RNA pellet was resuspended in 10 μL RNase-free water.

Sequencing, Assembly, and Analysis of Small RNA Libraries.

The small RNA library of S2 cells and whole flies were constructed as described (46) and sequenced by the Illumina Genome Analyzer II. Reads were then aligned to a reference consisting of the VSV genome from National Center for Biotechnology Information (NCBI) (accession number NC_001560) using the Bowtie program with standard parameters in genome assembly. Reads aligning to the VSV genome with zero mismatches were retained and analyzed using in-house Perl scripts and Excel. Sequences were submitted to the NCBI Small Read Archive under the accession number SRP002753.

Silencing of a VSV Sensor RNA.

Construction of the sensor plasmids and monitoring of their activities were done using standard protocols as described in SI Materials and Methods.


The rVSV-ZEBOV vaccine uses a genetically engineered version of vesicular stomatitis virus (VSV), an animal virus that primarily affects cattle, to carry an Ebola virus gene insert. Experts at the Public Health Agency of Canada originally developed the vaccine, which is now licensed to Merck. NIAID and the Walter Reed Army Institute of Research (WRAIR) evaluated rVSV-ZEBOV in Phase 1 clinical trials which showed rVSV-ZEBOV is safe and able to induce a robust immune response in recipients.

NIAID, under a clinical research collaboration with the Liberian Ministry of Health known as PREVAIL, also conducted a Phase 2 randomized, placebo-controlled clinical trial of the vaccine in Liberia during the 2014-2016 outbreak of Ebola virus disease. The trial originally was designed to advance to Phase 3 and enroll 28,000 volunteers but was scaled back because the decline in new Ebola cases made it impossible to conduct the larger study. The trial ultimately enrolled 1500 participants and results indicated that the vaccine was well-tolerated and induced an immune response among participants.

Other partners in the research response to the Ebola outbreak in West Africa, including the U.S. Centers for Disease Control and Prevention (CDC), conducted additional studies of rVSV-ZEBOV. The WHO's trial involved vaccinating contacts of people with Ebola virus disease and contacts of those contacts on an immediate or delayed vaccination schedule.

NIAID also is part of an international consortium conducting an ongoing clinical trial of various vaccine regimens using rVSV-ZEBOV and another experimental prime-boost regimen known as Ad26.ZEBOV/MVA-BN-Filo. See PREVAIL 5 or PREVAC under Researching Ebola in Africa for more information.

Why Ebola isn’t contagious until symptoms appear

Fear of Ebola has put many on high alert and there is increasing anxiety about the possibility of individuals with minimal exposure and no symptoms introducing the virus into communities – people such as Craig Spencer, the doctor who contracted Ebola while working in Guinea who then went bowling and rode the subway in New York before exhibiting symptoms.

Fear has kept people away from school and work, despite reassurances from the World Health Organisation (WHO) and the American Centers for Disease Control and Prevention (CDC) that someone with Ebola becomes contagious only once they develop symptoms.

In light of this, it is worthwhile explaining the data behind these assurances, which the WHO and CDC haven’t done, to make clear why we are so confident that people without symptoms can’t give you Ebola.

The Kikwit outbreak

There are five different known types of ebolavirus (the genus), including Zaire ebolavirus, which is behind the 2014 outbreakin West Africa. The best epidemiological data on Ebola virus (the disease) transmission comes from the 1995 outbreak in Kikwit, in the Democratic Republic of the Congo, which was caused by the same species as the current epidemic.

The Kikwit outbreak marked the first appearance of EBOV since its initial discovery in 1976, and a team from the CDC and WHO extensively studied what interactions, and when, led to EBOV transmission. The team followed 173 household members of 27 active cases until the end of the outbreak. They were able to identify who became sick and which interactions between sick people and their family members during the incubation period, early illness, and late illness were associated with transmission.

The biggest risk factors for becoming infected with Ebola virus, identified in the 1995 outbreak, and outbreaks in 1979 and a different species in 2000-2001, are direct physical contact with a sick person, primarily with bodily fluids such as blood, vomit, diarrhoea, and later in the disease, sweat and saliva. Ebola virus can survive outside the body for anywhere from hours to days, depending on the environmental conditions such as dampness and exposure to sunlight. Therefore, infection by contact with objects contaminated with bodily fluids is also theoretically possible, but is likely to be rare in practice.

During the Kikwit outbreak, 95 family members of the 27 cases had direct physical contact with someone who was actually sick, and 28 of these individuals became sick with Ebola themselves. Of the 78 family members who did not have direct physical contact with a sick person, none got Ebola. Among these 78 were family members who had extensive contact with infected individuals during the incubation period, including such close interactions such as touching and sharing a bed.

Virus levels in the blood

We also have data on virus levels in the blood that suggests people aren’t contagious before they are symptomatic. As the most infectious fluids are blood and vomit, the amount of virus in these fluids is a critical factor in whether an infected person can transmit the virus.

During the 2000-2001 outbreak the virus was often just barely detectable at the first sign of symptoms and in other cases wasn’t detectable until two or three days later.

We understand this to be true in West Africa today as well. Our tests are extremely sensitive, and it’s clear that little virus is present in the blood when symptoms appear and even less during the incubation period, explaining why we aren’t able to diagnose people during this time.

Without these high levels of virus in the blood and other fluids, it is exceedingly unlikely that someone would be contagious.

To be fair, however, we never say never in biology and we can’t prove a negative, so no experiment could tell us that transmission during the incubation period is truly impossible. But what we do know is that it doesn’t seem to happen in past or current outbreaks and is biologically implausible. Rather than panic about getting Ebola from a seemingly uninfected neighbour, we should focus on isolating people at the first sign of symptoms so that when they do get sicker and become highly contagious, they aren’t in a position to infect anyone else.

Flying nurses

In light of Dallas nurse Amber Vinson’s recent travel on a commercial airline with a mild fever before she was diagnosed (now Ebola-free), many people want to know whether individuals in the early stage of the disease – say with just a fever – are contagious. School districts and employers have been treating Pham’s fellow airline passengers as being at risk of disease and as potential transmitters, but should they be?

The answer is almost certainly no. Levels of virus in the blood increase rapidly following the onset of symptoms, but at this early stage people aren’t vomiting or bleeding, which would expose those around them to potentially infectious fluids, and onward transmission.

While it’s true that virus can be found in fluids such as saliva and sweat, this mostly occurs later in disease, when the individual would be hospitalised. During the 1995 outbreak having a conversation, sharing a meal and sharing a bed with people in the early stage of disease were not associated with becoming infected oneself.

Later in the disease this changes, but it seems clear that slightly sick people aren’t much of a risk to those around them. Anecdotally, we also now know that the family of Thomas Eric Duncan, the man who contracted Ebola in Liberia and was later cared for by Vinson and Nina Pham, remained healthy despite being in an apartment with him for the first several days of his illness.

Knowing this, we shouldn’t be barring people with no direct exposure from school, or work. It’s not “an abundance of caution” to do this, it’s harmful. Unless you sat next to the sick nurse on that plane, your exposure was almost zero. If you did, you’re still almost certainly fine. If you had contact with her before she was sick, you definitely are. Still, it’s natural to worry, which is why we need to stop the epidemic in West Africa, mostly for them, but also so we can stop worrying about Ebola virus here at home.

Published in collaboration with The Conversation

Author: Stephen Goldstein is a graduate student at the University of Pennsylvania pursuing a PhD in Cell and Molecular Biology, with a specialization in virology.

Image: A health inspection and quarantine researcher demonstrates to customs policemen the symptoms of Ebola, at a laboratory at an airport in Qingdao, Shandong province August 11, 2014. REUTERS/China Daily

Why we do not use RNAi to control ebola? - Biology

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NEW BRUNSWICK, N.J., 1 July 2020 – Johnson & Johnson today announced that the European Commission (EC) has granted Marketing Authorisation for its Janssen Pharmaceutical Companies’ Ebola vaccine regimen for the prevention of Ebola Virus Disease. Enabled by this approval, Janssen is now collaborating with the World Health Organization (WHO) on vaccine pre-qualification, which should help accelerate registration of its preventive Ebola vaccine regimen in African countries and facilitate broader access to those most in need.

Two Marketing Authorisation Applications (MAAs) were submitted to the European Medicines Agency (EMA) for the vaccines composing the two-dose regimen, Zabdeno ® (Ad26.ZEBOV) and Mvabea ® (MVA-BN-Filo). Marketing Authorisation under exceptional circumstances has been granted following Accelerated Assessment of the MAAs and a positive opinion by the EMA’s Committee for Medicinal Products for Human Use (CHMP). Janssen’s Ebola vaccine regimen is indicated for active immunization for the prevention of Ebola Virus Disease caused by the Zaire ebolavirus species in individuals aged one year and above.

“The European approval of Janssen’s Ebola vaccine regimen is a landmark moment – both for our Company and in the world’s battle against the deadly Ebola virus. Building on our history, we are committed to bringing forward vaccines to help overcome the threat of some of the world’s most life-threatening infectious diseases,” said Paul Stoffels, M.D., Vice Chairman of the Executive Committee and Chief Scientific Officer of Johnson & Johnson.

The worst Ebola outbreak to date was the West African epidemic, which caused nearly 30,000 cases and more than 11,000 deaths in 2014-2016. [1] There are two outbreaks currently ongoing in the Democratic Republic of the Congo (DRC), the first of which began in 2018 and is the world’s second worst Ebola outbreak on record. It has since caused more than 3,000 cases and over 2,000 deaths – a mortality rate of 65 percent. [2]

“The approval of our Ebola vaccine symbolizes the progress Janssen has made towards achieving our vision of delivering potentially transformational vaccines to communities most at risk of deadly infectious diseases. Not only is it the first vaccine to emerge from our vaccines pipeline, it is also the first approved vaccine to be developed using Janssen’s AdVac ® technology. The same technology is being used to develop vaccines candidates to protect against SARS-CoV-2, as well as Zika, RSV and HIV,” said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, LLC.

Janssen’s Ebola vaccine regimen is specifically designed to induce long-term immunity against the Ebola virus [3],[4] in adults and children aged one year and above. As such, it will be used to support preventive vaccination in countries most at risk of outbreaks, as well as for other at-risk groups such as healthcare workers, biosafety level 4 (BSL4) laboratory workers, military personnel deployed in the affected regions, airport staff and visitors to high-risk countries.

The regimen includes Ad26.ZEBOV as the first dose, based on Janssen’s AdVac ® viral vector technology, [5] and MVA-BN-Filo as the second dose, based on Bavarian Nordic’s MVA-BN ® technology, administered approximately eight weeks later. [6]

“I am enormously grateful for the dedication from everyone who has been a part of this development, including our many global strategic partners for their extraordinary commitment to helping make this regimen a reality,” said Johan Van Hoof, M.D., Managing Director, Janssen Vaccines and Prevention B.V. “The devastating 2014 outbreak of Ebola in West Africa grew exponentially, overwhelming healthcare systems. In less than six years, with the strength of global public-private collaborations, we have an approved Ebola vaccine which could help those most in need, with the ultimate goal of preventing outbreaks before they start.”

Janssen supported vaccination initiatives in the DRC and neighboring Rwanda, with the goal of preventing Ebola’s geographic spread beyond the outbreak zone. When considering both clinical studies and vaccination initiatives, approximately 60,000 people have been vaccinated with Janssen’s preventive Ebola vaccine regimen to date. [7] Janssen-sponsored Phase 1 studies have been reported in peer-reviewed journals including JAMA 3,[8] and the Journal of Infectious Diseases, [9],[10] and Phase 1, 2 and 3 data were presented at the 2019 European Congress of Clinical Microbiology & Infectious Disease (ECCMID). 4,6,[11] These studies indicate that the vaccine regimen is well tolerated, inducing robust and durable immune responses to the Zaire ebolavirus species. The evaluation of the protective effect of the vaccine regimen was demonstrated through the bridging of clinical immunogenicity results to efficacy and immunogenicity data obtained in non-human primates (NHP). [12]

In May 2019, the WHO’s Strategic Advisory Group of Experts (SAGE) on immunization recommended the use of the Janssen Ebola vaccine regimen as part of efforts to contain the DRC outbreak [13] and more than 50,000 people in the DRC [14] and Rwanda [15] have been vaccinated to date through this initiative alone. 7

Johnson & Johnson has made a significant investment in the Ebola vaccine regimen since its decision to accelerate the development program in 2014 in response to the Ebola crisis in West Africa. The Company is grateful to its global strategic partners who have helped to support and co-fund these efforts, including Bavarian Nordic A/S, the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services (HHS), the Innovative Medicines Initiative (IMI) funded through the EU Horizon 2020 program, and the National Institutes of Health (NIH) at the U.S. Department of Health and Human Services (HHS).

Regulatory Submissions & Status
Today’s European Commission Marketing Authorisation decision follows the positive opinion in May 2020 from the CHMP of the EMA[16] and the granting of an Accelerated Assessment for Janssen’s investigational preventive Ebola vaccine regimen MAAs by the CHMP in September 2019. [17] The MAAs are supported by data from eleven Phase 1, 2 and 3 clinical studies [18] evaluating the safety and immunogenicity (ability to induce an immune response) of the vaccine regimen in more than 6,500 adults and children aged one year and above across the U.S., Europe and Africa 17 preclinical studies, and immunobridging analyses comparing the results of clinical and preclinical efficacy studies.

Discussions with the U.S. Food and Drug Administration (FDA) have taken place to define the required data set for filing US licensure.

About Janssen’s Ebola Vaccine Regimen
The Janssen preventive Ebola vaccine regimen, Ad26.ZEBOV and MVA-BN-Filo, utilizes a non-replicating viral vector strategy in which viruses – in this case adenovirus serotype 26 (Ad26) and Modified Vaccinia Virus Ankara (MVA) – are genetically modified so that they cannot replicate in human cells. In addition, these vectors carry the genetic code of several Ebola virus proteins in order to trigger an immune response.

Janssen’s vaccine regimen originates from a collaborative research program with the NIH and received direct funding and preclinical services from the National Institute of Allergy and Infectious Diseases, part of NIH, under Contract Number HHSN272200800056C. Further funding for the Ebola vaccine regimen has been provided in part with federal funds from the Office of the Assistant Secretary for Preparedness and Response, BARDA under Contract Numbers HHSO100201700013C and HHSO100201500008C.

The IMI provided funding through the IMI Ebola+ Programme to support a number of consortia that initiated multiple clinical trials and other vaccine development activities. The consortia funded by the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking are EBOVAC1 (grant nr. 115854), EBOVAC2 (grant nr. 115861), EBOVAC3 (grant nr. 800176), EBOMAN (grant nr. 115850) and EBODAC (grant nr. 115847). This Joint Undertaking receives support from the EU’s Horizon 2020 Framework Programme for Research and Innovation and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

Johnson & Johnson also acknowledges its many strategic partners in the ongoing global clinical program for the vaccine regimen, including Bavarian Nordic A/S, Centre Muraz, College of Medicine and Allied Health Sciences (COMAHS, University of Sierra Leone), Grameen Foundation, Inserm, Inserm Transfert, London School of Hygiene & Tropical Medicine (LSHTM), Wellcome Trust, Coalition for Epidemic Preparedness Innovations (CEPI), Uganda Virus Research Institute (UVRI), University of Antwerp, University of Oxford, Université de Kinshasa (UNIKIN), Vibalogics GmbH, Walter Reed Army Institute of Research (WRAIR), World Vision Ireland, The Ministry of Health and Sanitation Sierra Leone, Republic of Rwanda Ministry of Health and the Democratic Republic of the Congo Ministry of Public Health and all the people who participated in clinical trials during the Ebola epidemic in West Africa and the DRC.

About the Janssen Pharmaceutical Companies
At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Biology 171

By the end of this section, you will be able to do the following:

  • Identify major viral illnesses that affect humans
  • Compare vaccinations and anti-viral drugs as medical approaches to viruses

Viruses cause a variety of diseases in animals, including humans, ranging from the common cold to potentially fatal illnesses like meningitis ((Figure)). These diseases can be treated by antiviral drugs or by vaccines however, some viruses, such as HIV, are capable both of avoiding the immune response and of mutating within the host organism to become resistant to antiviral drugs.

Vaccines for Prevention

The primary method of controlling viral disease is by vaccination , which is intended to prevent outbreaks by building immunity to a virus or virus family ((Figure)). Vaccines may be prepared using live viruses, killed viruses, or molecular subunits of the virus. Note that the killed viral vaccines and subunit viruses are both incapable of causing disease, nor is there any valid evidence that vaccinations contribute to autism.

Live viral vaccines are designed in the laboratory to cause few symptoms in recipients while giving them protective immunity against future infections. Polio was one disease that represented a milestone in the use of vaccines. Mass immunization campaigns in the 1950s (killed vaccine) and 1960s (live vaccine) significantly reduced the incidence of the disease, which caused muscle paralysis in children and generated a great amount of fear in the general population when regional epidemics occurred. The success of the polio vaccine paved the way for the routine dispensation of childhood vaccines against measles, mumps, rubella, chickenpox, and other diseases.

The issue with using live vaccines (which are usually more effective than killed vaccines), is the low but significant danger that these viruses will revert to their disease-causing form by back mutations . Live vaccines are usually made by attenuating (weakening) the “wild-type” (disease-causing) virus by growing it in the laboratory in tissues or at temperatures different from what the virus is accustomed to in the host. Adaptations to these new cells or temperatures induce mutations in the genomes of the virus, allowing it to grow better in the laboratory while inhibiting its ability to cause disease when reintroduced into conditions found in the host. These attenuated viruses thus still cause infection, but they do not grow very well, allowing the immune response to develop in time to prevent major disease. Back mutations occur when the vaccine undergoes mutations in the host such that it readapts to the host and can again cause disease, which can then be spread to other humans in an epidemic. This type of scenario happened as recently as 2007 in Nigeria where mutations in a polio vaccine led to an epidemic of polio in that country.

Some vaccines are in continuous development because certain viruses, such as influenza and HIV, have a high mutation rate compared to that of other viruses and normal host cells. With influenza, mutations in the surface molecules of the virus help the organism evade the protective immunity that may have been obtained in a previous influenza season, making it necessary for individuals to get vaccinated every year. Other viruses, such as those that cause the childhood diseases measles, mumps, and rubella, mutate so infrequently that the same vaccine is used year after year.

Watch this NOVA video to learn how microbiologists are attempting to replicate the deadly 1918 Spanish influenza virus so they can understand more about virology.

Vaccines and Antiviral Drugs for Treatment

In some cases, vaccines can be used to treat an active viral infection. The concept behind this is that by giving the vaccine, immunity is boosted without adding more disease-causing virus. In the case of rabies, a fatal neurological disease transmitted via the saliva of rabies virus-infected animals, the progression of the disease from the time of the animal bite to the time it enters the central nervous system may be two weeks or longer. This is enough time to vaccinate individuals who suspect that they have been bitten by a rabid animal, and their boosted immune response is sufficient to prevent the virus from entering nervous tissue. Thus, the potentially fatal neurological consequences of the disease are averted, and the individual only has to recover from the infected bite. This approach is also being used for the treatment of Ebola, one of the fastest and most deadly viruses on Earth. Transmitted by bats and great apes, this disease can cause death in 70 to 90 percent of infected humans within two weeks. Using newly developed vaccines that boost the immune response in this way, there is hope that affected individuals will be better able to control the virus, potentially saving a greater percentage of infected persons from a rapid and very painful death.

Another way of treating viral infections is the use of antiviral drugs. Because viruses use the resources of the host cell for replication and the production of new virus proteins, it is difficult to block their activities without damaging the host. However, we do have some effective antiviral drugs, such as those used to treat HIV and influenza. Some antiviral drugs are specific for a particular virus and others have been used to control and reduce symptoms for a wide variety of viral diseases. For most viruses, these drugs can inhibit the virus by blocking the actions of one or more of its proteins. It is important to note that the targeted proteins be encoded by viral genes and that these molecules are not present in a healthy host cell. In this way, viral growth is inhibited without damaging the host.

Antivirals have been developed to treat genital herpes (herpes simplex II) and influenza. For genital herpes, drugs such as acyclovir can reduce the number and duration of episodes of active viral disease, during which patients develop viral lesions in their skin cells. As the virus remains latent in nervous tissue of the body for life, this drug is not curative but can make the symptoms of the disease more manageable. For influenza, drugs like Tamiflu (oseltamivir) ((Figure)) can reduce the duration of “flu” symptoms by one or two days, but the drug does not prevent symptoms entirely. Tamiflu works by inhibiting an enzyme (viral neuraminidase) that allows new virions to leave their infected cells. Thus, Tamiflu inhibits the spread of virus from infected to uninfected cells. Other antiviral drugs, such as Ribavirin, have been used to treat a variety of viral infections, although its mechanism of action against certain viruses remains unclear.

By far, the most successful use of antivirals has been in the treatment of the retrovirus HIV, which causes a disease that, if untreated, is usually fatal within 10 to 12 years after infection. Anti-HIV drugs have been able to control viral replication to the point that individuals receiving these drugs survive for a significantly longer time than the untreated.

Anti-HIV drugs inhibit viral replication at many different phases of the HIV replicative cycle ((Figure)). Drugs have been developed that inhibit the fusion of the HIV viral envelope with the plasma membrane of the host cell (fusion inhibitors), the conversion of its RNA genome into double-stranded DNA (reverse transcriptase inhibitors, like AZT), the integration of the viral DNA into the host genome (integrase inhibitors), and the processing of viral proteins (protease inhibitors).

Unfortunately, when any of these drugs are used individually, the high mutation rate of the virus allows it to easily and rapidly develop resistance to the drug, limiting the drug’s effectiveness. The breakthrough in the treatment of HIV was the development of HAART, highly active anti-retroviral therapy, which involves a mixture of different drugs, sometimes called a drug “cocktail.” By attacking the virus at different stages of its replicative cycle, it is much more difficult for the virus to develop resistance to multiple drugs at the same time. Still, even with the use of combination HAART therapy, there is concern that, over time, the virus will develop resistance to this therapy. Thus, new anti-HIV drugs are constantly being developed with the hope of continuing the battle against this highly fatal virus.

The study of viruses has led to the development of a variety of new ways to treat non-viral diseases. Viruses have been used in gene therapy . Gene therapy is used to treat genetic diseases such as severe combined immunodeficiency (SCID), a heritable, recessive disease in which children are born with severely compromised immune systems. One common type of SCID is due to the lack of an enzyme, adenosine deaminase (ADA), which breaks down purine bases. To treat this disease by gene therapy, bone marrow cells are taken from a SCID patient and the ADA gene is inserted. This is where viruses come in, and their use relies on their ability to penetrate living cells and bring genes in with them. Viruses such as adenovirus, an upper-respiratory human virus, are modified by the addition of the ADA gene, and the virus then transports this gene into the cell. The modified cells, now capable of making ADA, are then given back to the patients in the hope of curing them. Gene therapy using viruses as carriers of genes (viral vectors), although still experimental, holds promise for the treatment of many genetic diseases. Still, many technological problems need to be solved for this approach to be a viable method for treating genetic disease.

Another medical use for viruses relies on their specificity and ability to kill the cells they infect. Oncolytic viruses are engineered in the laboratory specifically to attack and kill cancer cells. A genetically modified adenovirus known as H101 has been used since 2005 in clinical trials in China to treat head and neck cancers. The results have been promising, with a greater short-term response rate to the combination of chemotherapy and viral therapy than to chemotherapy treatment alone. This ongoing research may herald the beginning of a new age of cancer therapy, where viruses are engineered to find and specifically kill cancer cells, regardless of where in the body they may have spread.

A third use of viruses in medicine relies on their specificity and involves using bacteriophages in the treatment of bacterial infections. Bacterial diseases have been treated with antibiotics since the 1940s. However, over time, many bacteria have evolved resistance to antibiotics. A good example is methicillin-resistant Staphylococcus aureus (MRSA, pronounced “mersa”), an infection commonly acquired in hospitals. This bacterium is resistant to a variety of antibiotics, making it difficult to treat. The use of bacteriophages specific for such bacteria would bypass their resistance to antibiotics and specifically kill them. Although phage therapy is in use in the Republic of Georgia to treat antibiotic-resistant bacteria, its use to treat human diseases has not been approved in most countries. However, the safety of the treatment was confirmed in the United States when the U.S. Food and Drug Administration approved spraying meats with bacteriophages to destroy the food pathogen Listeria. As more and more antibiotic-resistant strains of bacteria evolve, the use of bacteriophages might be a potential solution to the problem, and the development of phage therapy is of much interest to researchers worldwide.

Section Summary

Viruses cause a variety of diseases in humans. Many of these diseases can be prevented by the use of viral vaccines, which stimulate protective immunity against the virus without causing major disease. Viral vaccines may also be used in active viral infections, boosting the ability of the immune system to control or destroy the virus. A series of antiviral drugs that target enzymes and other protein products of viral genes have been developed and used with mixed success. Combinations of anti-HIV drugs have been used to effectively control the virus, extending the lifespans of infected individuals. Viruses have many uses in medicines, such as in the treatment of genetic disorders, cancer, and bacterial infections.

Free Response

Why is immunization after being bitten by a rabid animal so effective and why aren’t people vaccinated for rabies like dogs and cats are?

Rabies vaccine works after a bite because it takes a week for the virus to travel from the site of the bite to the central nervous system, where the most severe symptoms of the disease occur. Adults are not routinely vaccinated for rabies for two reasons: first, because the routine vaccination of domestic animals makes it unlikely that humans will contract rabies from an animal bite second, if one is bitten by a wild animal or a domestic animal that one cannot confirm has been immunized, there is still time to give the vaccine and avoid the often fatal consequences of the disease.

The vaccine Gardasil that targets human papilloma virus (HPV), the etiological agent of genital warts, was developed after the anti-HPV medication podofilox. Why would doctors still want a vaccine created after anti-viral medications were available?

Anti-viral medications treat HPV after the skin of the genitals has been infected. Conversely, Gardasil stimulates the immune system to prevent infection of the tissue, even if a person is exposed to HPV. Since HPV is often asymptomatic, particularly in men, the vaccine also controls the spread of disease (patients will not seek treatment for a disease if they do not realize they are infected).


Results and discussion


Chickenpox is a febrile, vesicular rash illness caused by varicella zoster virus (VZV), a lipid-enveloped, double-stranded DNA virus, and a member of the Herpesviridae family.

For chickenpox, the evidence appears to be mainly epidemiological and clinical, though this has appeared to be sufficient to classify varicella zoster virus (VZV) as an airborne agent. Studies on VZV have shown that the virus is clearly able to travel long distances (i.e. up to tens of meters away from the index case, to spread between isolation rooms and other ward areas connected by corridors, or within a household) to cause secondary infections and/or settle elsewhere in the environment [22,23,24]. In addition, Tang et al. [25] showed that airborne VZV could leak out of isolation rooms transported by induced environmental airflows to infect a susceptible HCW, most likely via the direct inhalation route.


Measles (also known as rubeola) is a febrile, rash illness caused by the measles virus, a lipid-enveloped, single-stranded, negative-sense RNA virus, and a member of the Paramyxoviridae family.

For measles several studies examined a more mechanistic airflow dynamical explanation (i.e. based upon the fundamental physics and behaviour of airborne particles) for the main transmission route involved in several measles outbreaks [26], including that of Riley and colleagues who used the concept of ‘quanta’ of infection [27]. Later, two other outbreaks in outpatient clinics included retrospective airflow dynamics analysis, providing more evidence for the transmissibility of measles via the airborne route [28, 29].


Tuberculosis is a localized or systemic, but most often respiratory bacterial illness caused by mycobacteria belonging to the Mycobacterium tuberculosis complex.

For tuberculosis (TB), definitive experimental evidence of airborne transmission being necessary and sufficient to cause disease was provided in a series of guinea-pig experiments [30, 31], which has been repeated more recently in a slightly different clinical context [32]. Numerous other outbreak reports have confirmed the transmissibility of TB via the airborne route [33,34,35], and interventions specifically targeting the airborne transmission route have proven effective in reducing TB transmission [36].


Smallpox is a now eradicated, febrile, vesicular rash and disseminated illness, caused by a complex, double-stranded DNA orthopoxvirus (Poxviridae family), which can present clinically in two forms, as variola major or variola minor.

For smallpox, a recent comprehensive, retrospective analysis of the literature by Milton has suggested an important contribution of the airborne transmission route for this infection [37]. Although various air-sampling and animal transmission studies were also reviewed, Milton also emphasized clinical epidemiological studies where non-airborne transmission routes alone could not account for all the observed smallpox cases.

At least one well-documented hospital outbreak, involving 17 cases of smallpox, could only be explained by assuming the aerosol spread of the virus from the index case, over several floors. Retrospective smoke tracer experiments further demonstrated that airborne virus could easily spread to patients on different floors via open windows and connecting corridors and stairwells in a pattern roughly replicating the location of cases [38].

Emerging coronaviruses: Severe acute respiratory syndrome (SARS), middle-east respiratory syndrome (MERS)

Coronaviruses are lipid-enveloped, single-stranded positive sense RNA viruses, belong to the genus Coronavirus and include several relatively benign, seasonal, common cold viruses (229E, OC43, NL63, HKU-1). They also include two new more virulent coronaviruses: severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged in the human population in 2003 and Middle-East Respiratory Syndrome coronavirus (MERS-CoV), which emerged in humans during 2012.

For SARS-CoV, several thorough epidemiological studies that include retrospective airflow tracer investigations are consistent with the hypothesis of an airborne transmission route [39,40,41]. Air-sampling studies have also demonstrated the presence of SARS-CoV nucleic acid (RNA) in air, though they did not test viability using viral culture [42].

Although several studies compared and contrasted SARS and MERS from clinical and epidemiological angles [43,44,45], the predominant transmission mode was not discussed in detail, if at all. Several other studies do mention the potential for airborne transmission, when comparing potential routes of infection, but mainly in relation to super-spreading events or “aerosolizing procedures”such as broncho-alveolar lavage, and/or a potential route to take into consideration for precautionary infection control measures [46,47,48]. However, from the various published studies, for both MERS and SARS, it is arguable that a proportion of transmission occurs through the airborne route, although this may vary in different situations (e.g. depending on host, and environmental factors). The contribution from asymptomatic cases is also uncertain [49].

For both SARS and MERS, LRT samples offer the best diagnostic yield, often in the absence of any detectable virus in upper respiratory tract (URT) samples [50,51,52]. Furthermore, infected, symptomatic patients tend to develop severe LRT infections rather than URT disease. Both of these aspects indicate that this is an airborne agent that has to penetrate directly into the LRT to preferentially replicate there before causing disease.

For MERS-CoV specifically, a recent study demonstrated the absence of expression of dipeptidyl peptidase 4 (DPP4), the identified receptor used by the virus, in the cells of the human URT. The search for an alternate receptor was negative [53]. Thus, the human URT would seem little or non-permissive for MERS-CoV replication, indicating that successful infection can only result from the penetration into the LRT via direct inhalation of appropriately sized ‘droplet nuclei’-like’ particles. This makes any MERS-CoV transmission leading to MERS disease conditional on the presence of virus-containing droplets small enough to be inhaled into the LRT where the virus can replicate.


Influenza is a seasonal, often febrile respiratory illness, caused by several species of influenza viruses. These are lipid-enveloped, single-stranded, negative-sense, segmented RNA viruses belonging to the Orthomyxoviridae family. Currently, influenza is the only common seasonal respiratory virus for which licensed antiviral drugs and vaccines are available.

For human influenza viruses, the question of airborne versus large droplet transmission is perhaps most controversial [54,55,56,57]. In experimental inoculation experiments on human volunteers, aerosolized influenza viruses are infectious at a dose much lower than by nasal instillation [58]. The likely answer is that both routes are possible and that the importance and significance of each route will vary in different situations [16, 20, 21].

For example, tighter control of the environment may reduce or prevent airborne transmission by: 1) isolating infectious patients in a single-bed, negative pressure isolation room [25] 2) controlling environmental relative humidity to reduce airborne influenza survival [59] 3) reducing exposure from aerosols produced by patients through coughing, sneezing or breathing with the use of personal protective equipment (wearing a mask) on the patient (to reduce source emission) and/or the healthcare worker (to reduce recipient exposure) [60] 4) carefully controlling the use and exposure to any respiratory assist devices (high-flow oxygen masks, nebulizers) by only allowing their use in designated, containment areas or rooms [61]. The airflows being expelled from the side vents of oxygen masks and nebulisers will contain a mixture of patient exhaled air (which could be carrying airborne pathogens) and incoming high flow oxygen or air carrying nebulized drugs. These vented airflows could then act as potential sources of airborne pathogens.

Numerous studies have shown the emission of influenza RNA from the exhaled breath of naturally influenza-infected human subjects [62,63,64,65,66] and have detected influenza RNA in environmental air [67,68,69]. More recently, some of these studies have shown the absence of [70], or significantly reduced numbers of viable viruses in air-samples with high influenza RNA levels (as tested by PCR) [66, 71, 72]. The low number of infectious particles detected is currently difficult to interpret as culture methods are inherently less sensitive than molecular methods such as PCR, and the actual operation of air-sampling itself, through shear-stress related damage to the virions, also causes a drop in infectivity in the collected samples. This may lead to underestimates of the amount of live virus in these environmental aerosols.

An additional variable to consider is that some animal studies have reported that different strains of influenza virus may vary widely in their capacity for aerosol transmission [73].

In some earlier articles that discuss the predominant mode of influenza virus transmission [74,75,76,77,78], these same questions are addressed with mixed conclusions. Most of the evidence described to support their views was more clinical and epidemiological, and included some animal and human volunteer studies, rather than physical and mechanistic. Yet, this mixed picture of transmission in different circumstances is probably the most realistic.

It is noteworthy that several infections currently accepted as airborne-transmitted, such as measles, chickenpox or TB present, in their classical form, an unmistakable and pathognomonic clinical picture. In contrast the clinical picture of influenza virus infection has a large overlap with that of other respiratory viruses, and mixed outbreaks have been documented [79]. Thus, a prevalent misconception in the field has been to study ‘respiratory viruses’ as a group. However, given that these viruses belong to different genera and families, have different chemical and physical properties and differing viral characteristics, it is unwise and inaccurate to assume that any conclusions about one virus can be applied to another, e.g. in a Cochrane review of 59 published studies on interventions to reduce the spread of respiratory viruses, there were actually only two studies specifically about influenza viruses [80]. As the authors themselves pointed out, no conclusion specific to influenza viruses was possible.

While many airborne infections are highly contagious, this is not, strictly speaking, part of the definition. Even so, the lower contagiousness of influenza compared to, say, measles has been invoked as an argument against a significant contribution of airborne transmission. Yet, it should be noted that a feature of influenza virus infections is that the incubation time (typically 1–2 days) is much shorter than its duration of shedding. This allows for the possibility that a susceptible person will be exposed during an outbreak to several different infectious cases belonging to more than one generation in the outbreak. This multiple exposure and telescoping of generations may result in an underestimate of influenza virus transmissibility, as fewer secondary cases will be assigned to a known index case, when in fact the number of secondary cases per index could be much higher. For example, it is known that in some settings a single index case can infect a large number of people, e.g. 38 in an outbreak on an Alaska Airlines flight [11].


Ebola is a viral hemorrhagic fever associated with a very high mortality, caused by the Ebola viruses these are enveloped single-strand, negative-sense RNA viruses comprising five species within the family Filoviridae. Four Ebola species have been implicated in human diseases the most widespread outbreak, also the most recent, was caused by Ebola Zaire in West Africa in 2013–2016. The transmission of Ebola viruses has been reviewed in depth by Osterholm et al. (4). These authors noted the broad tissue tropism, as well as the high viral load reached during illness and the low infectious dose, from which it appears inescapable that more than one mode of transmission is possible.

Regarding aerosol transmission, concerns are raised by several documented instances of transmission of Ebola Zaire in laboratory settings between animals without direct contact [81, 82] (also reviewed in [4]). Experimental infections of Rhesus monkeys by Ebola Zaire using aerosol infection has been shown to be highly effective [83, 84] and this experimental procedure has in fact been used as infectious challenge in Ebola vaccine studies [85, 86]. Rhesus monkeys infected by aerosol exposure reliably developed disseminated, fatal infection essentially similar to that caused by parenteral infection with the addition of involvement of the respiratory tract. Autopsies showed pathological findings in the respiratory tract and respiratory lymphoid system in animals infected by the aerosol route that are not found in animals infected parenterally [83, 84].

Such respiratory pathological lesions have not been reported in human autopsies of Ebola cases, but as noted by Osterholm et al. [4], there have been few human autopsies of Ebola cases, arguably too few to confidently rule out any possibility of disease acquired by the aerosol route. The precautionary principle would therefore dictate that aerosol precautions be used for the care of infected patients, and especially considering that infection of the respiratory tract in such patients is not necessary to create an aerosol hazard: Ebola viruses reach a very high titer in blood or other bodily fluids during the illness [87, 88] and aerosolization of blood or other fluids would create a significant airborne transmission hazard.

Watch the video: How Ebola Virus Infects a Cell (October 2022).