If Only Santa Would be Real…When Are We Going to Have a Universal Flu Vaccine?

 

By Jesica Levingston Mac leod, PhD

Wouldn’t it be great if the answer to that question was “next year” (yep, only a 1 month wait). Sadly, besides all the astonishing efforts of various researchers groups we are just entering the clinical studies that might lead towards a safe and effective vaccine.

Probably you already heard about the antigenic mismatch with the current vaccine (for the strain H3N2): this means that the strains used in the vaccine could potentially not completely cover one or more of the seasonal influenza virus varieties. Therefore, if you got the flu shot, you might get sick anyways.

The concept behind the universal vaccine is to bypass the antigenic mismatch problem and other issues related with the way in which the vaccines are formulated nowadays. As Drs. Natali Pica and Peter Palese explained last year (Pica et al. 2013), the vaccines are prepared year by year with the aim to protect against the virus strains that are predicted to circulate in the next period. But, and there is always a “but” in predictions, an unexpected mutation in the virus not contemplated in the vaccine production, could conclude in a pandemic.

The clue came from thinking outside of the box, and breaking with the traditional dogmas in flu vaccine production. When you get infected with the influenza virus, your immune system targets the head domain of the HA (Hemagglutinin) protein, so the current vaccine production approach was to aim for this antigen. The bad news is that this domain changes every year. The flu vaccines are based on inactivated viruses , when you receive this vaccine, you will generate antibodies to fight these specific HA proteins. In Dr. Palese’s lab they are focus on regions of influenza HA protein that are highly conserved across virus subtypes, like the stalk domain of the HA protein. Also, he is engineering different HA chimeras. This strategy has been really successful, showing protection in animal models (mice and ferrets), and the vaccines were approved to go to clinical trial next year. This universal vaccine offered good protection for pandemics H5N1 and H7N9 influenza viruses.

Another strategy, published in Nature Medicine (Sridhar et al.) reports that targeting conserved core proteins using virus-specific CD8+ T cells (lymphocytes or white blood cells with a vital role in the immune system) could provide a draft for a universal influenza vaccine. But… even the scientists implicated in the research were not very positive about how long is going to take to translate this technique to the “outside the lab” world.

The third strategy is coming from an Italian group (Vitelli et al. 2013), and this potential universal influenza vaccine is been tested in animal models by the FDA.  This vaccine uses as a vector the virus PanAd3 (it was isolated from a great ape), which carries 2 genes that express proteins conserved among a variety of influenza viruses. The 2 viral proteins, the matrix protein (M1) and the nucleoprotein (NP), could be expressed for the human cells infected with the recombinant PanAd3 virus and immunize the patient against different influenza viruses.

Other entrepreneurial ideas are blooming around the world in order to solver the “influenza virus infection” problem. The influenza virus kills around 500,000 people annually worldwide (WHO), and affects very negatively the life of other hundreds of thousands. In fact, I do not know anybody who did not got the flu at least ones, I encourage to try to find somebody who was never sick with flu symptoms. This points out how universal this problem is and therefore it should get an universal solution soon.

What We Can Learn About The Flu From Elderberries

 

By Lori Bystrom

Flu season is still upon us and many of us will fall under influenza’s nasty spell, if we have not already. Folklore suggests that elderberries can ward off evil spirits and many illnesses, and although they may not be the first remedy that comes to mind when you have the flu, these fruits may be worth a second look. Recent research suggests that these dark purple berries have antiviral properties and the mechanisms that contribute to their effects may provide additional clues on how to fight off this winter virus.

 

Currently, there are relatively few antivirals on the market, and their widespread use has led to increasing resistance and declining efficacy.  As a result, scientists are trying to better understand influenza and what confers resistance. Moreover, the specter of a deadly influenza pandemic is leading many researchers to explore diverse and novel treatment options.

 

Elderberries have a long history of medicinal and dietary use. As well as being used to make pies, jellies, wine and liqueurs, they have also been used to make various medicinal concoctions. These berries have also shown activity against both bacterial and viral pathogens, including several strains of influenza.There are also many commercial preparations of elderberry that are available (e.g., syrups and lozenges), some of which have alleviated flu symptoms in clinical trials.1,2

Despite mounting evidence that elderberries might be valuable for treating the flu, their mechanistic effects are not well understood, especially at the molecular level. Swaminathan et al., demonstrated that an anthocyanin pigment (cyanidin-3-sambubiocide), found in European elderberries (Sambucus nigra), have unique antiviral effects. As with several commercial antivirals, the anthocyanin inhibits viral neuraminidases — enzymes that allow progeny viruses to be released from the host cell. Specifically, viral neuraminidases cleave sialic acid groups, which enable the virus to detach from the host and spread the virus. In a video that demonstrates these effects, the neuraminidases are portrayed as blue monster-like enzymes with teeth that cleave sialic acid groups. This study shows for the first time that cyanidin-3-sambubiocide binds to an active site of influenza neuraminidase and potentially blocks the enzyme’s effects (similar to the yellow objects in the video).

 

The authors used mass spectrometry to measure the mass fragments released from unbound and anthocyanin-bound neuraminidases. Based on these results, the researchers were able to predict which residues of the influenza neuraminidase bound to the anthocyanin. The precise location was further elucidated by computational studies that evaluated the interaction between the anthocyanin component  (excluding sugar groups) and the N1 neuraminidase from the 2009 H1N1 pandemic strain.  The antiviral effects of the compound were also confirmed to be effective by a neuraminidase inhibition assay. These experiments indicated that the anthocyanin favored binding to a so-called “430-cavity”, which is different from the region where standard antiviral drugs bind.  Furthermore, the results showed that the bound anthocyanin was located away from two residues that that are known to regulate neuraminidase resistance.

 

Although the results are promising, more research is warranted to confirm that cyanidin-3-sambubiocide has antiviral effects in clinical studies, and whether or not other compounds in elderberries enhance, synergize or alter the activity of this compound. Nevertheless, elderberries may help scientists find more effective and less resistant-prone treatments that may prevent influenza from casting a dark shadow on our health.

 

One Flu Over the Cuckoo’s Nest: Has the New Avian Influenza Virus Achieved Human-to-Human Transmission?

 

By Asu Erden

Human cases of H7N9 – a new avian influenza A virus – were first reported in China between February and March 2013. It is believed that infection with this virus requires exposure to poultry but when and how the virus crossed the species barrier remains elusive. The Centers for Disease Control (CDC) originally estimated that up to 20% of the people that become infected with this virus die. There are currently no vaccines available against this avian flu virus, although clinical trials are under way with the help of the World Health Organization (WHO). The disease caused is severe and mainly affects the respiratory tract. Li et al. recently published a study in the New England Journal of Medicine that sheds light on the epidemiology of the disease caused by H7N9 and suggests that the virus might have achieved human-to-human transmission.

 

In their study, Li et al. investigated 139 confirmed cases of H7N9 from 12 different areas in China (including Shanghai and Beijing). Their aim was to better understand the epidemiology of the lower respiratory illness caused by this avian flu virus newly infecting humans. They were able to identify cases thanks to the Chinese surveillance system for pneumonia of unknown origin, which was put in place in 2004 at the time of the H5N1 avian influenza outbreak. The study confirmed that infection with H7N9 is most likely caused by exposure to live animals (poultry, birds, or swine). Most of the studied cases (77%) occurred in older individuals with the median age of patients being 61. Despite an older age distribution, the H7N9 virus seems to infect people from a broader age range than H5N1 did a decade ago.

 

This emerging zoonosis seems to be particularly virulent. After an incubation period of 7 days, H7N9 caused an acute illness characterized by severe lower respiratory symptoms – including pneumonia and respiratory failure – in all studied patients. The case fatality rate was also high, with 34% of patients dying. This rate is significantly higher than originally estimated by the WHO but remains lower than for H5N1. Further studies are required to establish the true case fatality rate of the disease caused by H7N9 in the overall population.

 

Li’s group also carried out family cluster analyses based on four families in which two or more individuals had confirmed cases of H7N9. In each cluster, one of the individuals became infected due to close contact with poultry (e.g. visits at poultry markets) but the other infected individuals never came in close contact with live animals. This suggests that the virus might have evolved to achieve human-to-human transmission. On the other hand, Li et al. also followed over 2500 close contacts of their 139 confirmed cases and only 1% developed respiratory symptoms, none of which tested positive for H7N9. Of note, however, is that these individuals were only followed for 7 days after contact and only single swabs were collected from them. This likely decreased the likeliness of detecting H7N9 cases among close contacts.

 

The most significant finding from this study also happens to be the only negative data that were presented:  Li et al. were unable to discard the possibility that H7N9 can transmit from human to human. Given the virulence, case fatality rate, and ongoing outbreak of the H7N9 avian influenza virus, the possibility of human-to-human transmission is cause for concern. The establishment of a putative human reservoir would allow for fast spread of the virus worldwide and should be scrutinized by public health officials.

A Marvellous Month of Infectious Science

Stephanie Swift

Cold weather helps to spread flu across the country

Credit: Michael Mistretta (Flcikr)
Credit: Michael Mistretta (Flcikr)

A very cool new study from McMaster University researchers shows how weather patterns impact the spread of influenza A virus across Canada. Using outbreak data gathered over more than 13 years, the virus could be tracked over time and space. Influenza A tended to first emerge in the colder, less humid provinces of Western Canada (British Columbia and Alberta), and then spread across the country to the East. Schools also represented hotbeds of infection – when they were shut during the Summer, there were significantly fewer cases of flu recorded.

Investigating the ‘ouch’ factor during a bacterial infection

When a bacterial infection takes hold, it’s usually a painful experience. During a normal immune response, immune cells infiltrate the infected area, pummel the invading bacteria and in doing so release molecules that cause swelling and pain. Yet new research from Harvard Medical School shows that it’s not only the immune system that is to blame: at least some of the pain comes from the bacteria themselves secreting factors that can interact directly with our nervous system.

 

The immune system’s need for speed

Credit: Éole Wind (Flickr)
Credit: Éole Wind (Flickr)

Our beautiful human bodies have several portals where nasty pathogens, such as bacteria, can enter and wreak havoc. Once inside the human body, bacteria start reproducing straight away, doubling their numbers around once every 20 minutes. Yet our immune T cells constantly patrol such vulnerable open-access areas, sampling their environment to identify threatening material. A reassuring new study has now come out showing that reactive T cells sense such foreign material within a few seconds, and make the decision to respond to malevolent threats within a speedy minute.

 

Edible vaccines, om nom nom!

Rotavirus infection is one of the major nasty causes of childhood diarrhea, but can happily be prevented with an oral vaccine. Vaccinated children in industrialized countries develop 85-98% immune protection, while those in the third world develop a much lower protection level of 50-60%. The reasons behind this startling difference are not well characterized, but third world kiddies would obviously benefit from a boost in their rotavirus immune protection.

 

Credit: Yamanaka Tamaki (Flcikr)
Credit: Yamanaka Tamaki (Flcikr)

One team has come up with a new way of administering such an immune upgrade – by loading rice, a staple food in the third world, with anti-rotavirus immune-boosting antibodies. This tasty dish could conceivably be consumed regularly during childhood to maintain protection levels.

 

 

Marvelous Microbes Round-Up

Stephanie Swift

An experimental TB vaccine identifies a cool new way to boost immune protection

Researchers from Canada tested out two new inhaled vaccines against adult tuberculosis, based on adenovirus or vesicular stomatitis virus. While both vaccines generated similar levels of adaptive immunity, only the adenovirus vaccine was also able to robustly activate innate immunity. Innate immunity exists in a state of constant readiness to repel pathogenic invaders, while adaptive immunity requires stimulation, activation and expansion before it can be fully engaged. Continue reading “Marvelous Microbes Round-Up”