Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol.
Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead Read more
Flu viruses are constantly mutating and every year the seasonal flu shot is updated to keep up with the viruses that are making people sick. Readers interested in the prospect of a â€œuniversal flu vaccineâ€ may have noticed some experimental progress on that theme this week.
Some background: the head region of the flu virusâ€™s mushroom-like hemagglutinin protein is more variable, and more exposed to the immune system, while the stem/stalk region is less variable.
The underlying idea is: if someoneâ€™s immune system is exposed to flu viruses different enough than what it has seen before (like in the 2009 H1N1 outbreak and the H5N1 study), the antibodies to the stem region become more important and more prominent.
The NIAID team fused the flu hemagglutinin to ferritin, a platform for further protein engineering.
This week, what the researchers from NIAID (Nature Medicine) and Scripps/J&J (Science) showed is that experimental vaccines made from the stem region only can be broadly protective in several animal models. This required some protein engineering and reconstruction because chopping off the head of the hemagglutinin protein makes it fall apart.
Vaccine researchers have developed a strategy aimed at generating broadly cross-reactive antibodies against the influenza virus: embrace the unfamiliar.
In recent years, researchers interested in a “universal flu vaccine” identified a region of the viral hemagglutinin protein called the stem or stalk, which doesn’t mutate and change as much as other regions and could be the basis for a vaccine that is protective against a variety of flu strains.
In an Emory Vaccine Center study, human volunteers immunized against the avian flu virus H5N1 readily developed antibodies against the stem region of the viral hemagglutinin protein. In contrast, those immunized with standard seasonal trivalent vaccines did not, instead developing most of their antibodies against the more variable head region. H5N1, regarded as a potential pandemic strain, is not currently circulating in the United States and the volunteers had not been exposed to it before.
The results were published Monday, August 25 inÂ PNAS.
The key to having volunteers’ bodies produce antibodies against the stem region seemed to be their immune systems’ unfamiliarity with the H5N1 type of virus, says lead author Ali Ellebedy, PhD, postdoctoral fellow in the laboratory of Rafi Ahmed, PhD, director of Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.
Note: for a counterpoint, check out this 2013 Science Translational Medicine paper on how vaccination that induces anti-stem antibodies contributes toÂ enhanced respiratory disease in pigs.
Francis Collins, director of the National Institutes of Health, made a splash last week predicting the arrival of a universal flu vaccine in the next five years.
Francis Collins told USA Today he is "guardedly optimistic" about the possibility of long-term vaccination that could replace seasonal flu shots.
His prediction came at the same time as a report in Science identifying an antibody that can protect against several strains of the flu virus.Â Taking a look at the Science paper, how the scientists found the “super antibody” seems remarkably similar to how Emory’s Jens Wrammert, Rafi Ahmed and colleagues found a similar broadly protective antibody.Â Their results were published in the Journal of Experimental Medicine in January.
In both cases, the researchers started with someone who had been infected with the 2009 H1N1 swine origin flu virus, sifted through the antibodies that person produced and found some that reacted against several varieties of the flu virus. There must be something special about that 2009 pandemic strain!
Scientists at Emory and the University of Chicago have discovered that the 2009 H1N1 flu virus provides excellent antibody protection. This may be a milestone discovery in the search for a universal flu vaccine.
Researchers took blood samples from patients infected with the 2009 H1N1 strain and developed antibodies in cell culture. Some of the antibodies were broadly protective and could provide protection from the H1N1 viruses that circulated over the past 10 years in addition to the 1918 pandemic flu virus and even avian influenza or bird flu (H5N1).
The antibodies protected mice from a lethal viral dose, even 60 hours post-infection.
Some of the antibodies stuck to the â€œstalkâ€ region, or hemagglutinin (H in H1N1) protein part of the virus. Because this part of the virus doesnâ€™t change as much as other regions, scientists have proposed to make it the basis for a vaccine that could provide broader protection. The antibodies could guide researchers in designing a vaccine that gives people long-lasting protection against a wide spectrum of flu viruses.
The paperâ€™s first author, Emory School of Medicineâ€™s Jens Wrammert, PhD, says â€œOur data shows that infection with the 2009 pandemic influenza strain could induce broadly protective antibodies that are very rarely seen after seasonal flu infections or flu shots. These findings show that these types of antibodies can be induced in humans, if the immune system has the right stimulation, and suggest that a pan-influenza vaccine might be feasible.”
One of the most important lessons from this past yearâ€™s pandemic, Fauci said, is the need to â€œconnect the dotsâ€ between seasonal and pandemic influenza and not view them as two separate phenomena.
â€œRather than trying to figure out one priority group over another,” Fauci said, “if we can get into a rhythm of getting most people vaccinated each year, we will have most of the population with some degree of immunity. We will get into a situation where we donâ€™t need to go from a seasonal approach to a crisis approach.
The scientists in the lab of Richard Compans, PhD, professor of microbiology and immunology at Emory, are hard at work, imagining the unimaginable: A time when patients can self-administer flu vaccines. A time when vaccination does not require exposure to inactive viruses. A time when a universal vaccine could protect from all varieties of influenza: swine, avian, seasonal and strains still emerging.
Richard Compans, PhD (right), with colleague Mark Prausnitz, PhD, from Georgia Tech
But it’s not just hope that motivates them as they work. Emory’s scientists are fighting the clock against another possible future: a time of pandemic and uncontrollable virus mutation. The recent emergence of H1N1 and H5N1, known colloquially as swine flu and avian flu, have added an even greater sense of urgency to their task.
“The H5N1â€”the virus derived from avian speciesâ€”has a 60 percent mortality,” says Emory microbiologist Sang-Moo Kang, PhD. Yet that strain of influenza hasn’t resulted in many human deaths, because, so far, avian flu spreads only to humans who are in contact with infected birds.
While in Atlanta, Chan also visited Emory to meet with President James Wagner and Emory Global Health Institute Director Koplan. She heard presentations about global health field projects by students in public health, medicine, and theology.
Chan recalled the â€œlost decade for development,â€ the 1980s, a dismal time for public health. The 1979 energy crisis followed by a recession made for tighter public health resources and few health care improvements worldwide, she explained. Some developing countries have still not recovered.
In contrast, public health has faired better in the new millennium, when the world has benefited from financial commitments backed by substantial resources, often from innovative sources, says Chan. Read more
Dr. Carlos del Rio possesses a keen view of how the novel H1N1 virus emerged last spring. Del Rio was in Mexico as the virus established itself south of the border. Its rapid, far-reaching spread marked the first influenza pandemic of the 21st century.
During Emoryâ€™s fifth annual predictive health symposium, “Human Health: Molecules to Mankind,” del Rio discussed his experiences in Mexico, what weâ€™ve learned, and what novel H1N1 has to do with predictive health.Â View a video of his presentation and five lessons learned.Â
Only a day after the virus was identified, on April 23, Mexican authorities closed schools, called off sporting events, and canceled religious gatherings. Known as â€œsocial distancing,â€ these actions led to a decrease in cases, an important lesson, says del Rio. The public knew what to do, they were cooperative, and whatâ€™s more, they applied a lot of peer pressure when it came to hand washing and sneezing hygiene.
Another lesson learned: preparation paid off. Anticipating a pandemic, The World Health OrganizationÂ had earlier mandated that countries draw up influenza pandemic plans. â€œThose plans were incredibly helpful in getting people to work together, communicate, and know what to do,â€ says del Rio.Â Interestingly, the plans in Mexico and the United States were aimed at a virus projected to originate from an avian source from southeastern Asia. â€œIt was not developed for a swine virus coming from inside the country,â€ explained del Rio.
Novel H1N1, even though itâ€™s thought of as a swine virus is in fact only about 47% swine–30% from North American swine and 17% from Eurasian swine. The virus also contains human and avian strains. Thatâ€™s important, says del Rio, because the characteristics of its genes determine how symptoms, susceptibility, and immunity manifest themselves.
â€œWhat weâ€™re seeing nowadays is the new strain has crowded out the seasonal influenza virus,â€ he says. Thus far, most of the deaths from novel H1N1 have been in children, young adults, and pregnant women. â€œThe people who are dying are a very different group than in previous flu seasons,â€ says del Rio.Â
Carlos del Rio, MD
Del Rio says a lot was learned early on about the novel virus thanks to frequent and transparent international communication. This flu pandemic is really the first to occur in this era of 24-hour newscasts and the Internet. So thereâ€™s a challenge for health workers: how do you continue to communicateÂ in an effective way. â€œOne thing you say one day may be contradicted the next day because you have new information. How do you make people understand that you werenâ€™t lying to them before, but you have updated information and that information is continuously changing.”
In trying to predict whatâ€™s in store for the current flu pandemic, researchers are looking back at past pandemics. Last century, there were three major flu pandemics. The largest and most important was the 1918 pandemic.
â€œA couple of things that happened back then are very important: one was there was a second wave that was actually much more severe and much more lethal than the first one.â€ says del Rio. â€œAnd over the summer, the virus actually changed. It started very much like it did this time. It started in the spring and then we had a little blip, and then we had a big blip in the second wave, and then almost a third wave. So, clearly influenza happens in waves, and weâ€™re seeing the same thing happening this time around.â€
Pregnant women are at the top of the Center for Disease Control and Preventionâ€™s priority list when it comes to vaccinating people against the novel H1N1 flu virus this year. Not only should pregnant women receive the 2009 H1N1 vaccine, they should also receive the usual seasonal flu vaccine, say Emory experts.
Staying healthy in pregnancy
Because pregnancy weakens the immune system, a pregnant woman who gets any type of flu has a greater chance for serious health problems. Pregnant women who contract H1N1 flu are more likely to be admitted to the hospital, compared with other people in general that get H1N1 flu. Pregnant women are also more likely to have serious illness, including pneumonia and death from this particular novel strain.
Both vaccines are made with a dead, or inactivated, flu virus and are given as an injection, usually in the arm. The other type of flu vaccine is a nasal spray and is not recommended for pregnant women. The nasal spray vaccine is safe for women after they have delivered, even if they are nursing.
Saad B. Omer, MBBS, MPH, PhD, assistant professor of global health at Emoryâ€™s Rollins School of Public Health, served as senior author on the report, published in the American Journal of Obstetrics & Gynecology. The study shows that there is substantial evidence that vaccination is not only safe for pregnant women but that it is critical for protecting women and their infants against serious complications from the flu.
The seasonal flu shot has been given to millions of pregnant women over several decades . Flu shots have not been shown to cause any harm to pregnant women or their babies. The 2009 H1N1 flu vaccine is being made in the same way and by the same manufacturers as the seasonal flu vaccine, explains Ault.
Ault also serves as principal investigator of a seasonal flu vaccine clinical trial underway at Emory Vaccine Center involving pregnant women.
RSPH students Nick Schaad (left) and Michael Marrone
Nick Schaad was among the students authorized to help man the CDCâ€™s Emergency Operations Center at the height of the novel H1N1 outbreak. Once the CDC began to identify influenza clusters, students began conducting phone surveys.
Schaad says he was involved in the St. Francis prep school survey in New York. Students and staff member who were sick with any flu-like symptoms were identified. The team called them and asked about the size of their household, what they might have done to protect themselves, and any recent travel. The goal was to learn as much possible about H1N1 in advance of the fall flu season.
Like the students they teach, RSPH faculty became engaged in the H1N1 epidemic. Last spring, Emory physician and microbiologist Keith Klugman, MD, PhD, was recruited to join the CDCâ€™s Team B, which includes experts from outside the CDC to quickly review and inform the agencyâ€™s efforts. CDC created Team B in the early 2000s to cope with the growing complexity of public health emergencies.
Keith Klugman, MD, PhD
Klugman says his role included the bacterial complications of influenza. Evidence from 1918, notes Klugman, clearly shows that the great majority of deaths were due to bacterial complications of the flu. In other words, the flu itself could occasionally cause death on itss own. But it caused death mostly by facilitating a synergistic lethality between itself and bacteria.
Although much has changed since 1918, the bacteria that caused so many deaths still exist but are susceptible to antibiotics.
Klugman notes the evolution of the flu. He says so far it’s generally been moderate. However, by mixing with the circulating flu in the Southern Hemisphere, it could mutate and become resistant to the first line of flu drugs. It could also become more severe. Says Klugman, â€œWe must remain ever vigilant.â€