UVA Today

UVA’s Dr. Steven L. Zeichner, left, is working with Virginia Tech’s Dr. Xiang-Jin Meng on a vaccine that could fight multiple coronaviruses. (Zeichner photo by Sanjay Suchak, University Communications; Meng photo courtesy of Virginia Tech)

“We are continuing to work very hard,” Zeichner said. “Since those early results, we have been systemically testing how we can best administer the vaccine, either orally, intranasally or intramuscularly, and how we can optimize the immune response with different versions of the pieces of the viruses that are used get the body to make an effective immune response against the virus.”

Zeichner and Meng are also in talks with the World Health Organization’s International Vaccine Institute in Seoul, South Korea, which is charged with making vaccines available around the world, particularly in disadvantaged countries or for potentially pandemic diseases.

“Once we get our process established, we will send materials to them so that they can scale it up and do more advanced trials, hopefully including human trials,” Zeichner said.

How It Works

The vaccine Zeichner and Meng are working on is a killed whole-cell vaccine. To make it, the researchers use a new platform Zeichner invented to rapidly develop vaccines, which involves synthesizing the DNA that directs the production of a piece of the COVID-19 virus.

The synthesized DNA, which can instruct the immune system in how to mount a protective response, is inserted into a common bacteria, usually E. coli, that is grown in a fermenter, much like the machines used in breweries. The DNA instructs the bacteria to place pieces of protein on cell surfaces. Those antigens form the basis of the vaccine. Importantly, the proteins are placed on the surfaces of bacteria that have had many of their genes deleted, including genes that are responsible for the production of other proteins that are on the surface of the bacteria. This makes the vaccine antigen much more visible to the immune system. Scientists then kill the bacteria, which now function as the vaccine.

Growing bacteria is fast and inexpensive, and uses common, inexpensive starting materials. There are several other vaccines made from killed bacteria already in use around the world – for example, vaccines for cholera and pertussis – so the industrial capacity required to make a new killed whole-cell vaccine is readily available.

While the currently available COVID-19 vaccines – which Zeichner has received and wholeheartedly endorses – focus on the COVID-19 virus’ entire spike protein, Zeichner and Meng’s vaccine focuses more closely on two regions of that spike protein: the fusion peptide region and the stalk region.

“The current vaccines use the entire spike protein, and they have been remarkably effective so far – everyone should get one,” Zeichner said. “However, there are potential challenges as more variants emerge, because the spike protein has some immunodominant regions that the body’s immune system focuses on first.”

Future mutations of the virus, Zeichner said, could alter those immunodominant regions and allow the virus to evade vaccines that focus on them.

“To survive, pathogens need to get the immune system to create an immune response to something that the pathogen can then change,” he said. “It is like waving a shiny object in front of the body’s immune system, attracting the immune system to that region so that it ignores other regions the virus cannot change so easily.”

Among the regions the coronavirus cannot easily change are the fusion peptide region and the stalk region that Zeichner and Meng have chosen to focus on. Those particular regions are present in every sequence of the COVID-19 virus identified so far – tens of thousands of them – indicating that the virus needs those regions to survive. These regions show no to minimal variation across all the viruses studied so far.

“We are trying to make a vaccine against a piece of the virus that cannot mutate,” Zeichner said. “The fusion peptide region, for example, is so invariant that every single coronavirus we know of has the same six amino acids in the center of that region – not just in humans, but in animals.”

Results So Far – and an HIV Link

In March, the team announced that vaccinating pigs with vaccines against either SARS-CoV-2, the virus caused by COVID-19, or porcine epidemic diarrhea virus, another coronavirus that causes a severe and economically consequential pig viral disease, successfully prevented pigs from becoming severely ill when they were experimentally infected with porcine epidemic diarrhea virus.

Although SARS-CoV-2 and porcine epidemic diarrhea virus are only distantly related genetically (SARS-CoV-2 is classified as a beta coronavirus, while porcine epidemic diarrhea virus is classified as an alpha coronavirus) the two viruses share those six amino acids and other amino acids in the fusion peptide region, leading Zeichner and Meng to believe that a human vaccine targeting the fusion peptide region could protect people from severe COVID-19 disease, from multiple SARS-CoV-2 variants, and even from other coronaviruses. Other human coronaviruses that have been identified include SARS-CoV, the virus that causes severe acute respiratory syndrome, or SARS; MERS-CoV, which causes Middle East Respiratory Syndrome; and several coronaviruses that cause the common cold.

“Though it is very early on, these results were somewhat surprising and definitely encouraging,” Zeichner said.

Energized, the team is now in the process of optimizing its vaccine, testing different ways to deliver the vaccine and different additions or subtractions that might make it more or less effective.

“We think we have a few ways of making it even more immunogenic,” Zeichner said.

They are also applying for grants to fund the next stage of the project, which will need a fresh surge of resources to continue. Among the grants Zeichner is applying for is a National Institutes of Health grant that asks different labs to work together on a universal coronavirus vaccine. Another grant asks for promising developments in making an HIV vaccine. HIV and COVID, share some structural similarities even though they cause very different illnesses.

“Scientists have been trying to make an HIV vaccine for more than 35 years,” Zeichner said. “We are hopeful that some lessons from our efforts on COVID-19 might spill over into that effort.”

A Dollar a Dose, a Vaccine for the World

In addition to broad protection, Zeichner and Meng’s vaccine offers another critical advantage: it’s cheap to produce.

The process, from identifying a vaccine target to producing and killing the bacteria needed for the vaccine, takes about two to three weeks and uses cheap, commonly available materials, totaling about $1 per dose.

Additionally, the technology needed to make killed whole-cell vaccines like this one is already available not only in developed countries, but in many developing countries.

“When developing countries begin to create their own indigenous biotech capabilities, the capability to make a killed whole-cell bacteria vaccine is one of the first things they start with,” Zeichner said, citing cholera and pertussis vaccines as examples of other vaccines that have been developed in this manner.

“In many low- and middle-income countries, the factories needed to produce these vaccines already exists,” he said. “If we can get the right immunogen, and get help from the WHO to find the right producers, this vaccine could be produced indigenously in developed countries for about $1 a dose, instead of being produced in developed countries and sold and shipped to developing countries.”

Having that production capability would save money and, crucially, time. The Delta variant is already surging around the world, and we don’t know what problems future variants might cause.

“Each time the virus undergoes replication, there is an opportunity for new mutations, and right now we have a lot of replication,” Zeichner said. “It’s scary, because there is more opportunity for the virus to become resistant to current vaccines. It really underscores the need for projects like this one.”