Squash That Bug

The flu. Need we say more? Why yes. Yes, we do!

Last week, we examined all things flu: we talked about the influenza virus structure, how the pesky pathogen makes us feel so lousy, and why the vaccine’s effectiveness isn’t always up to sniff, er, snuff.  This WEEKLY delves deeper into the season’s favorite virus. More specifically, we look at some high-profile efforts to transform the flu vaccine into the pandemic-crusher of the WHO’s (World Health Organization) dreams.

An Alternate Flu-niverse

In February 2018, the National Institute of Allergy and Infectious Disease (NIAID) unveiled a strategic plan to create a vaccine that better protects against multiple strains of the virus for multiple years. In other words, a universal flu vaccine. Just a few months later, the Gates Foundation (Seattle, WA) announced plans to earmark up to $12 million to support the development of a universal flu vaccine. Let’s check out some of the science behind these initiatives.

The Epitope Hope

Flu prevention today relies on whole-virus vaccines. They deliver an inactivated version of the virus, which elicits an immune response in the person rubbing her or his sore arm. Vaccines typically create antibodies against the outermost portion of the hemagglutinin (HA) protein. That’s because our immune system recognizes the “head” of the protein most readily. Regrettably, that’s also the spot that mutates most rapidly—meaning that an immune response against it will typically only be good for one flu season.

Scientists at BiondVax (Jerusalem, Israel) are now targeting the HA protein’s “stalk” instead. This bit of the protein mutates much less frequently than the head. Slower mutation means the stalk is much more likely than the head to remain the same from year to year. BiondVax’s experimental vaccine, M-001, is a peptide vaccine. It consists of short stretches of the HA stalk protein called “epitopes” or sequences known to induce an immune response.

The nine epitopes selected are conserved, which means they are present on different HA proteins across different strains. So if the BiondVax vaccine successfully prompts an immune response, it should protect against different strains of the flu over multiple seasons.

Preliminary data suggests that this mixture of epitopes will induce not only an antibody response, as most vaccines do, but also a T-cell response. The current flu shot doesn’t. Once activated, T-cells quickly kill virus-infected cells. And to frost the immunity cake, the vaccine also produces Memory B- and T-cells that can quickly respond to infection by a live virus. M-001 is in Phase III clinical studies.

Beyond The Stalk: Internal Proteins

Not all efforts focus on the HA stalk. Other viral proteins also mutate somewhat infrequently. The trick is to identify which protein epitopes the immune system recognizes. Scientists at Imutex (London, U.K.) think they’ve got it. The company’s FLU-v vaccine includes conserved, immune-inducing peptides from a range of viral proteins, including M1, M2, NP-A, and NP-B.

The M2 protein is imbedded in the flu virus membrane and helps maintain the pathogen’s preferred internal pH. The NP and M1 proteins surround viral RNA. Imutex scientists determined which protein epitopes are most likely to be displayed on the surface of the infected cell through a process known as antigen presentation. In this process, viral proteins inside of infected cells are chopped up, and the resulting fragments are then “presented” or displayed on the cell surface, where they elicit an immune response. Imutex is preparing FLU-v for Phase III clinical studies.

Can mRNA Save the Day?

Another approach to generating a powerful immune response lies with viral messenger RNA (mRNA). mRNA is the molecule that cells translate into a protein. When an mRNA encoding a viral protein is delivered to someone’s cells, they translate it into viral proteins.  White blood cells then learn to recognize that protein, resulting in immunity to the virus. Encouraging cells to produce a viral protein very closely mimics natural infection. This pathogenic provocation should produce a strong immune response—including by T-cells.

Because mRNA molecules are relatively straightforward to synthesize, this type of vaccine could incorporate mRNA encoding proteins from several different strains of the flu, making it more universally protective. Moderna (Cambridge, MA) has an mRNA-based flu vaccine in Phase 1 clinical development, while BioNTech (Mainz, Germany) and CureVac (Tubingen, Germany) both have mRNA flu vaccines in preclinical development. (Article continues below)


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Term Of The Week: Pandemic Strains

The word “pandemic,” is pretty scary, even if you didn’t watch the dreadful 2016 movie of that name (we don’t recommend it) or play the amazing board game or read about the 1918 Spanish Flu Pandemic, which killed an estimated 50 million people worldwide.

What is a pandemic? Simply put, it’s an outbreak of disease that spreads rapidly over a wide geographic area, affecting an exceptionally high proportion of the population. Pandemic strains of the flu virus typically result from a pathogen that normally infects animals such as pigs or birds, but that mutate to infect people. Since these strains are often brand new to the human population, few, if any, people have immunity. Thus, the illness spreads widely and rapidly. Protection against these potentially devastating strains is on the agenda of any universal vaccine researcher.

Meanwhile, your best shot at protection from the seasonal flu remains getting an annual flu vaccine from your doctor, a health clinic, or even your neighborhood pharmacy. One day, and the sooner the better, we may get several years of protection against different flu strains from just one needle. Now that sounds almost as good as a pot of homemade chicken soup!

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