HRV-Xn - Universal Flu Vaccine
Human rhinovirus species (A, B, C)
99 serotypes of human rhinoviruses affecting humans have been sequenced out of 160
The rhinovirus (from the Greek ῥίς rhis "nose", gen ῥινός rhinos "of the nose", and the Latin vīrus) is the most common viral infectious agent in humans and is the predominant cause of the common cold. Rhinovirus infection proliferates in temperatures of 33–35 °C (91–95 °F), the temperatures found in the nose. Rhinoviruses belong to the genus Enterovirus in the family Picornaviridae.
Isosurface of a human rhinovirus, showing protein spikes
• Rhinovirus A
• Rhinovirus B
• Rhinovirus C
Cladistically included but traditionally excluded taxa
• Enterovirus A
• Enterovirus B
• Enterovirus C
• Enterovirus D
• Enterovirus E
• Enterovirus F
• Enterovirus G
• Enterovirus H
• Enterovirus I
• Enterovirus J
• Enterovirus K
• Enterovirus L
The three species of rhinovirus (A, B, and C) include around 160 recognized types of human rhinoviruses that differ according to their surface proteins (serotypes). They are lytic in nature and are among the smallest viruses, with diameters of about 30 nanometers. By comparison, other viruses, such as smallpox and vaccinia, are around ten times larger at about 300 nanometers; while flu viruses are around 80–120 nm.
Transmission and epidemiology
Main article: Common cold
There are two modes of transmission: via aerosols of respiratory droplets and from fomites (contaminated surfaces), including direct person-to-person contact.
Rhinoviruses are spread worldwide and are the primary cause of the common cold. Symptoms include sore throat, runny nose, nasal congestion, sneezing and cough; sometimes accompanied by muscle aches, fatigue, malaise, headache, muscle weakness, or loss of appetite. Most sinus findings are reversible consistent with a self-limited viral process typical of rhinovirus colds. Fever and extreme exhaustion are more usual in influenza. Children may have six to twelve colds a year. In the United States, the incidence of colds is higher in the autumn and winter, with most infections occurring between September to April. The seasonality may be due to the start of the school year and to people spending more time indoors (thus in proximity with each other), thereby increasing the chance of transmission of the virus. Lower ambient, especially outdoor, temperatures may also be factor given that rhinoviruses preferentially replicate at 32 °C (89 °F) as opposed to 37 °C (98 °F) – see following section. Variant pollens, grasses, hays and agricultural practices may be factors in the seasonality as well as the use of chemical controls of lawn, paddock and sportsfields in schools and communities. The changes in temperature, humidity and wind patterns seem to be factors. It is also postulated that poor housing, overcrowding and unsanitary conditions related to poverty are relevant factors in the transmission of 'common cold'.
Those most affected by rhinoviruses are infants, the elderly, and immunocompromised people.
The primary route of entry for human rhinoviruses is the upper respiratory tract (mouth and nose). Rhinovirus A and B use "major" ICAM-1 (Inter-Cellular Adhesion Molecule 1), also known as CD54 (Cluster of Differentiation 54), on respiratory epithelial cells, as receptors to bind to. Some subgroups under A and B uses the "minor" LDL receptor instead. Rhinovirus C uses cadherin-related family member 3 (CDHR3) to mediate cellular entry. As the virus replicates and spreads, infected cells release distress signals known as chemokines and cytokines (which in turn activate inflammatory mediators). Cell lysis occurs at the upper respiratory epithelium.
Infection occurs rapidly, with the virus adhering to surface receptors within 15 minutes of entering the respiratory tract. Just over 50% of individuals will experience symptoms within 2 days of infection. Only about 5% of cases will have an incubation period of less than 20 hours, and, at the other extreme, it is expected that 5% of cases would have an incubation period of greater than four and a half days.
Human rhinoviruses preferentially grow at 32 °C (89 °F), notably colder than the average human body temperature of 37 °C (98 °F); hence the virus's tendency to infect the upper respiratory tract, where respiratory airflow is in continual contact with the (colder) extrasomatic environment.
Rhinovirus C, unlike the A and B species, may be able to cause severe infections. This association disappears after controlling for confounders. Duly, amongst infants infected with symtomatic respiratory illness in low-resource areas, there appears to be no association between rhinovirus species and disease severity.
Rhinovirus was formerly a genus from the family Picornaviridae. The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals. In April 2008, the International Committee on Taxonomy of Viruses voted and ratified the following changes:
• 2005.264V.04 To remove the following species from the existing genus Rhinovirus in the family Picornaviridae:
◦ Human rhinovirus A
◦ Human rhinovirus B
• 2005.265V.04 To assign the following species to the genus Enterovirus in the family Picornaviridae:
◦ Human rhinovirus A
◦ Human rhinovirus B
• 2005.266V.04 To remove the existing genus Rhinovirus from the family Picornaviridae. Note: The genus Rhinovirus hereby disappears.
In July 2009, the ICTV voted and ratified a proposal to add a third species, Human rhinovirus C to the genus Enterovirus.
• 2008.084V.A.HRV-C-Sp 2008.084V To create a new species named Human rhinovirus C in the genus Enterovirus, family Picornaviridae.
There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005.
Human rhinovirus serotype names are of the form HRV-Xn where X is the rhinovirus species (A, B, or C) and n is an index number. Species A and B have used the same index, while Species C has a separate index. Valid index numbers are as follows:
• Rhinovirus A: 1, 2, 7–13, 15, 16, 18–25, 28–34, 36, 38–41, 43–47, 49–51, 53–68, 71, 73–78, 80–82, 85, 88–90, 94–96, 98, 100–103
• Rhinovirus B: 3–6, 14, 17, 26, 27, 35, 37, 42, 48, 52, 69, 70, 72, 79, 83, 84, 86, 91–93, 97, 99
• Rhinovirus C: 1–51
A new approach
The scientists were initially looking for a compound that would target a protein in malariaparasites. They found two likely molecules and discovered that they were most effective when they were combined.
Using advanced techniques, they combined the two molecules and produced a new compound that blocks an enzyme found in human cells, called N-myristoyltransferase (NMT).
Viruses normally steal NMT from human cells and use it to create a protective shell around their genetic information, known as the capsid. NMT is vital for the survival of cold viruses; without it, they cannot replicate and spread.
All strains of the common cold virus use this technique, so inhibiting NMT would scupper all strains of common cold virus. In fact, it should also work against the related viruses that cause foot-and-mouth disease and polio.
Also, because the molecule targets human cells rather than the virus, resistance would not be an issue. The team’s findings were recently published in the journal Nature Chemistry.
The researchers have high hopes for the drug, which currently goes under the codename of IMP-1088
IMP-1088 is an enzyme inhibitor of the human N-myristoyltransferases NMT1 and NMT2 capable of preventing rhinoviral replication, an area of research relating to potential treatment of the common cold. IMP-1088 works to keep cells from generating infectious virus by targeting the cell instead of the rhinovirus itself. It does this by blocking the NMT protein of the host cell which prevents the virus from assembling its capsid, since viral capsid myristoylation by host NMT is essential for assembly. It is thought unlikely that viruses will evolve resistance to such an approach since IMP-1088 works against the human cell and not the virus.
3D model (JSmol)
Though other drugs that target human cells in this way have been trialed before, IMP-1088 is “more than 100 times more potent” than its predecessors.
Universal Flu Vaccine
MONDAY, March 9, 2020 -- Work is proceeding apace on a "universal" flu vaccine capable of protecting humans from all forms of influenza, researchers report.
A single dose of a synthetic universal flu vaccine called FLU-v appears capable of providing safe long-term protection across a broad spectrum of influenza viruses, a new clinical trial has shown.
FLU-v outperformed a placebo in elevating people's immune response, as measured by a number of different biomarkers related to the immune system, researchers found.
The experimental vaccine now awaits a phase 3 trial that will test how well it actually protects against the seasonal flu, said lead researcher Olga Pleguezuelos, chief scientific officer at SEEKacure, a London-based pharmaceutical development firm.
FLU-v works by targeting parts of the influenza virus that have been shown to evolve the least over time, Pleguezuelos said.
Influenza has sickened as many as 49 million Americans this season and caused up to 620,000 hospitalizations and 52,000 deaths, according to the U.S. Centers for Disease Control and Prevention.
Current annual vaccines trigger the production of antibodies that target proteins found on the surface of the flu virus, Pleguezuelos said.
Unfortunately, the virus regions targeted by those vaccine-produced antibodies tend to mutate frequently, requiring the development of new vaccines to keep up with the ever-changing flu bug.
FLU-v targets proteins that don't vary widely between different strains, reducing the ability of influenza to mask itself from the immune system by evolving into a different form, Pleguezuelos explained.
Researchers used computer algorithms to detect which protein regions in flu were likely to induce a strong immune response, and then analyzed how frequently those regions mutate.
To strengthen that protection, FLU-v also trains the immune system to target multiple flu proteins that typically aren't under evolutionary pressure to mutate, researchers added.
"FLU-v contains four different components against four different regions of the flu virus, so if one changed, three will still provide efficacy," Pleguezuelos said.
In the latest clinical trial, the researchers found the vaccine promoted antibody responses and immune system changes in 175 healthy adults assigned to receive either the flu shot or a placebo.
Side effects were limited mainly to injection site reactions, the researchers reported in the March 9 issue of the journal Annals of Internal Medicine.
"In order for the vaccine to reach the market, a phase 3 trial must be carried out to test efficacy and safety in large number of people," Pleguezuelos said. "This type of study is complex and very costly and we are currently in discussions with regulatory bodies to determine the requirements of such study, and searching for investment and funding."
The results from the latest clinical trial are "very encouraging," said Dr. Amesh Adalja, a senior scholar with the Johns Hopkins Center for Health Security in Baltimore.
"It illustrates that a candidate universal flu vaccine may be possible and sufficiently immunogenic. It will be important to follow this study up with a phase 3 study that looks at efficacy of preventing influenza versus just looking at immunogenicity," said Adalja, who was not part of the study.
"A universal flu vaccine would be a major advance and would change the dynamics between humans and the influenza virus in a very positive way," Adalja concluded.
The methods used to develop FLU-v also are being utilized to develop potential vaccines against HIV, mosquito-borne pathogens, hepatitis B and C, and rotavirus, Pleguezuelos said.
The same sort of platform also could be used to develop a coronavirus vaccine, she added.