Thomas Kupper (right) and team members Tian Tian (left) and Jason Williams are working toward a universal coronavirus vaccine.

Thomas Kupper, MD, chief of Dermatology at the Brigham wants to develop a vaccine to not only protect against COVID-19 but to also protect against past, current and future strains of coronavirus. And, by building on his lab’s recent work to develop a universal influenza vaccine, Kupper may have a head start.

“We’re excited to be in the right place at the right time to address this terrible pandemic,” said Kupper.

Auditors to the Rescue

When the human body fights a viral infection, two components of the immune system are critical. One is the generation of antibodies — proteins that are created to bind specifically to a virus and kill it directly or bring it to cells that can envelop and destroy the virus. Most vaccines, including the current seasonal flu vaccine, focus exclusively on helping the body generate antibodies.

But there is a second and important way that the immune system responds to infection.

“Our immune system and viruses have co-evolved,” said Kupper. “We conquer viral infections not only with antibodies but also by attacking cells that are infected.”

To do so, the immune system uses T cells. Every cell in the body takes the proteins made within it, chops them up and then displays them on its surface. T cells bind to these chopped up proteins and if they detect a foreign protein, such as proteins from a virus, they flag the cell for destruction.

“T cells are a bit like ninja auditors, looking for irregularities,” said Kupper. “Most vaccines out there right now focus entirely on making antibodies. But what we and a couple of other groups are thinking about is how to get the T cell part of the immune system working against coronaviruses.”

By enlisting the help of T cells, Kupper and his team are working on an approach to elicit lasting protection against past, current and future coronavirus strains. They plan to target regions conserved across coronaviruses, including SARS, bat coronavirus and SARS-CoV-2 (the virus that causes COVID-19) in addition to the SARS-CoV-2 spike protein, which is unique to SARS-CoV-2.

Learning from a History of Vaccine Development

One of the unique aspects of the vaccine in development is its use of an established delivery method known as MVA (Modified Vaccinia virus Ankara). Vaccinia virus was used during the smallpox eradication campaign, which began in 1959.  The original Vaccinia virus caused illness in immunocompromised people, but MVA is a safer version. Today, MVA is being used as a recombinant viral vector — a tool for delivering synthetic viral genes — to develop vaccines against other infectious diseases and cancer. MVA has been administered to more than 300,000 people and used in commercial products available today.

MVA vaccines are almost always delivered by injection into the muscle.  Kupper and colleagues found that MVA delivery using a bifurcated needle that disrupts the skin elicits much more powerful immunity. The team is also working with a group at Georgia Institute of Technology to deliver the vaccine via skin-disrupting microneedle patches.

“This is an old-fashioned way to deliver vaccines,” said Kupper. “By delivering through the top layer of skin, we’re able to get a powerful immune response.”

In their work to develop a universal vaccine against influenza, Kupper’s lab found that this vaccine technique could also get T cells to traffic to the lungs — a critical site for both the flu and for COVID-19.

“We were very interested in getting protective T cells to the lungs because viruses like the flu cause lung infections and pneumonia,” said Kupper. “When COVID-19 came along, we recognized the same issue was at play.”

Rapid Response

One of the limitations of the currently available influenza vaccine is that researchers must predict which strains are likely to appear next season and produce vaccines to target these strains. A vaccine that is able to target regions of a virus that don’t change — conserved regions — could solve this conundrum. Kupper’s lab is working to identify and clone the most promising, highly conserved regions of the coronaviruses to target and will then work with a viral vector collaborator to produce MVA vaccines.

The National Institute of Allergy and Infectious Diseases has funded Kupper’s work on a universal flu vaccine for 4 years, and recently awarded him a supplemental grant to make the universal coronavirus vaccine for COVID-19 and test them in a murine model. Many steps remain along the path to bringing the vaccines into human clinical trials and toward approval by the Federal Drug Administration, but these are being pursued in parallel.

“We will need sufficient quantity of high-quality vaccine to proceed to Phase I trials, which means that additional funding sources are needed to make the next steps happen. We are already bringing together the right people through virtual meetings — we’re working on everything we can because we know we need to make this happen,” said Kupper.

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