Source: LE TEMPS by Aurélie Coulon (written in French)

Chemist Chi-Huey Wong, who has won several awards for his work on protein glycosylation - the attachment of sugars to proteins in cells - is developing a universal vaccine against COVID-19 and other coronaviruses.

Many scientists are currently pursuing the same goal: to find the universal vaccine formula against COVID-19, one that would no longer require a booster shot and which, at the same time, would protect against other known serious diseases linked to a coronavirus, such as SARS, MERS-CoV, and also against future emerging viruses. Among these researchers is Chi-Huey Wong, professor of chemistry at the Scripps Research Institute in California, winner of several prestigious scientific awards including the Wolf Prize in 2014 and the Welch Award in Chemistry in 2021.

Honoured for his fundamental research work on protein glycosylation - the cellular process of adding monosaccharide or polysaccharide to proteins - and its role in the progression of cancers and viral and bacterial infections, Prof. Chi-Huey Wong has transferred his knowledge to the field of the vaccination. The Taiwanese-American chemist was in Geneva this Sunday, on the side-lines of the 76th World Health Assembly, to talk about his concept of a universal low-sugar vaccine, during an event organized by the STUF United Fund, non-profit and charitable support organization in the fields of culture, education, public health and environmental protection.

Why is it difficult to develop a lastingly effective vaccine against COVID-19?

Prof. Chi-Huey Wong: Since the outbreak of the COVID-19 epidemic in 2019, this virus has not stopped mutating. In October 2021, there were at least five main variants of SARS-CoV-2, the coronavirus responsible for COVID-19: Alpha, Beta, Delta, Gamma and Omicron. Omicron became the dominant strain, and it too has continued to mutate ever since. The speed of mutation is much faster than the pace of vaccine development. About 400 of them are in development and 30 have been approved for humans. But none of these vaccines are universal. They are based on the circulating variant of the virus and, for the most part, made from its spike protein [editor’s note: protein which serves as the key to the virus to enter the human cells] where the mutations take place. So they generally do not protect against the emerging variant.

What approach does your universal vaccine take?

Our approach is to identify the conserved sequence in the spike protein that does not mutate. We analysed more than 15 million variants of this viral protein in coronaviruses and found around 18 small protein sequences – called peptides – that are systematically conserved. Each represents 10 to 15 amino acids.

Unfortunately, of these 18 peptides, 17 are covered by polysaccharides; they are therefore not fully exposed to our immune system. Also, polysaccharides are made by host cells, not the virus, so the immune system sees them as self-antigens. The virus uses these polysaccharides to evade the immune system and facilitate infection. So we need to remove the polysaccharides to produce a spike protein with less sugars for vaccination.

Why has this not been done before?

Scientists have already tried and failed. They made the spike protein from the bacterium Escherichia coli, which does not glycosylate. However, this is essential for the protein to be able to fold in 3D and be recognized by white blood cells and antibodies. Our “trick” is that you don’t have to remove all the sugar. Just a little should be kept to ensure that the structure of the protein is correct, hence the concept of a universal low-sugar vaccine. It's simple to remove polysaccharides, it only takes one step with specific-enzymes, but first we had to study glycosylation and understand the role of these polysaccharides in immunology. This is an area that has been ignored for many years.

Is this universal “low sugar” vaccine easy to produce?

We have two options, one is to use the protein directly, the other with messenger RNA (mRNA). For the protein vaccine, we express the spike protein in human cells in which it is glycosylated. Then we treat it with specific-enzymes to remove the polysaccharides layer. It is placed in a buffer with an adjuvant to be used as a vaccine.

What about taking advantage of messenger RNA?

It is enough to change the genetic sequence of the mRNA, with a single nucleotide change, at the place where one does not want the peptide produced in the cell to be glycosylated. Then, the mRNA is delivered with lipid-nanoparticles in a targeted manner. We designed nanoparticles that deliver mRNA directly to immune cells to avoid any possible side effects. Otherwise, the mRNA can go anywhere. We also found that the vaccine is safer when the sugars are removed.

What stage are you in clinical trials?

We have already obtained positive results in three animal models. Phase 1 clinical trials are being prepared and we expect to have preliminary results by the end of the year.

Can we imagine applying the same principle for other viruses?

The same concept of vaccine can be developed for influenza virus, HIV, dengue virus...We have already made a good progress with our universal influenza vaccine, which will enter the clinical trial in humans. I hope this vaccine will be effective for a long time, without the need for a booster. If there is a mutation again in the conserved peptide, then we will have to redesign the vaccine. So far, there has been no change.