Universal Influenza Vaccine DT-Headless HA
"A universal flu vaccine would eliminate the need to update and administer the seasonal flu vaccine each year and could provide protection against newly emerging flu strains, potentially including those that could cause pandemics."
A true universal flu vaccine would protect us from all subtypes and strains of influenza. Influenza strains are differentiated by two glycoproteins on the exterior surface of the virus: (i) neuraminidase (NA) and (ii) hemagglutinin (HA). We have identified 18 HA variations and 11 NA variations. The nomenclature for coding each influenza strain is the HA variation number + NA variation number. Flus of subtype A can be contracted and carried by both animals and humans, whereas subtype B is only human. For example, the Spanish Flu of 1918 was caused by Influenza virus A H1N1. Further, influenza virus strains have subtype strains which occur as the virus mutates.
HA is what enables viral cells to enter human cells. Each influenza virus has an HA head and HA stalk.
Our current influenza vaccine works by stimulating our immune systems to produce antibodies that target the HA head. The head of the HA glycoprotein mutates and varies constantly, and significantly between seasons. Flu vaccines today target HA heads of strains from the previous year. As there are many possible strains, the small subset of strains for each year's flu vaccine is determined by a the WHO's global consortium represented by scientists across many nationalities, and the covered strains vary from year to year.
While HA heads are variable, HA stalks generally remain unchanged. Therefore, what we call a "universal flu" vaccine would create antibodies for targeting the HA stalk.
Hemagglutinin (HA) is the primary protein on the surface of the Influenza virus that the immune system mounts antibodies against. The “head” domain of HA is highly variable: it mutates and changes each season, and as a result, current Influenza vaccines are strain-specific, meaning that they each only protect against one prevalent, seasonal strain. For this reason new vaccine cocktails must be designed and manufactured before each winter season. In contrast, the “stalk” domain of HA is highly conserved across Influenza strains and antibodies generated against the stalk of HA therefore protect against many strains. However, the head domain acts as a decoy and distracts the immune system from reacting to the stalk; and as a result very few stalk antibodies are elicited in infected patients.
For this reason, there has been a concerted effort in the Influenza vaccine field to design a “Headless-HA” vaccine consisting of only the conserved stalk domain, with the head domain removed. Headless HA would focus immune responses on only the highly conserved stalk domain and thus elicit broad protection not just against multiple strains of seasonal influenza, but also against the risk of future pandemic influenza strains.
To date, it has otherwise not been technically feasible in the field to design a Headless HA molecule comprising the full-length HA stalk trimer, that is correctly folded in its native prefusion conformation. Calder has used DT conformational locking to render this feasible. By introducing DT crosslinks into the stalk of HA, our patented process first locks the stalk of HA in its native, trimeric, prefusion conformation. Then, once the stalk is locked, we remove the head domain with a protease, using targeted/engineered cleavage sites.
" The resulting molecule, ‘DT-Headless HA’ can be produced at high yields, and shows intact stalk antigenicity."
Our tests show it binds to a panel of key stalk antibodies, and yet does not bind to head-specific antibodies. DT-Headless HA is now being manufactured in our lab so it can be tested in mouse immunogenicity studies.
We aim to demonstrate that DT-Headless HA elicits broad protection against multiple influenza strains.
Collaborators
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James Crowe, M.D., Director, Vanderbilt Vaccine Center
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Indresh Srivastava, Ph.D., Vice President, Product Realization, Protein Sciences Corp., now Sanofi Pasteur.
