From Injection to Ingestion: can yeast make vaccines more accessible?

In recent years, the scientific community has increasingly acknowledged that even when effective and safe vaccines exist, their accessibility often remains insufficient. As doctoral researcher Emilija Vasiliunaite explains, the reasons are diverse – ranging from complex, costly manufacturing processes to logistical challenges.

“This became especially evident during the COVID–19 pandemic: although modern mRNA technology made it possible to develop vaccines at record speed, their production and distribution required complex conditions, including ultra–low storage temperatures, which in some parts of the world became a difficult obstacle to overcome,” she explains.

At the same time, another trend is emerging: vaccination coverage is declining in many countries. Even the continuously growing body of data on the safety and effectiveness of injectable vaccines has so far failed to reverse this trend. The human factor also plays a role: some people are afraid of needles, others are sceptical of the pharmaceutical industry, and some grow weary of intensive vaccination schedules, especially when it comes to infants.

Vasiliunaite  acknowledges that intensive infant vaccination schedules can be emotionally challenging for parents as well. As the mother of a young baby herself, she confirms this and notes that an orally administered, pleasant tasting rotavirus vaccine, which babies often sip eagerly, usually does not feel as emotionally difficult for parents as standard injectable vaccines, which sometimes must be administered in both legs during a single visit.

Some people are afraid of needles, others are sceptical of the pharmaceutical industry, and some grow weary of intensive vaccination schedules

It is therefore no coincidence that attention is turning to so called edible or oral vaccines. Such a format could not only reduce psychological barriers but also pave the way for simpler and cheaper production. Vasiliunaite explains that a vaccine perceived not as a medicine, but as a food product or dietary supplement, could theoretically reach people faster and at lower cost – there would be no need to fully purify the antigen, and the manufacturing process itself would be more flexible than that of traditional injectable vaccines.

Yeasts – the unexpected allies

In experiments conducted by VU LSC and U.S. National Cancer Institute scientists, a technology previously used by LSC researchers was adapted for vaccine development. In this approach, the genetic material encoding a target antigen – a viral protein – is “written” into yeast cells using circular DNA molecules. “This means that the yeasts were given a recipe according to which they themselves began producing the desired protein. These genetically modified yeasts became a kind of vaccine ‘container’,” Vasiliunaite explains.

A vaccine perceived not as a medicine, but as a food product or dietary supplement, could theoretically reach people faster and at lower cost

To select precisely those yeasts that truly produce the vaccine antigen, Lithuanian scientists have used a genetic engineering technique since 1992: after briefly exposing the yeasts to formaldehyde, only cells carrying a protective genetic instruction survive.

“Formaldehyde is not a component of the final product – after selection, the yeasts are grown and prepared without it, and the final concentration is lower than what is permitted in drinking water. This is considered an advantage compared with the antibiotics often used for selection,” the scientist notes.

According to her, studies in mice showed that vaccines administered either as fresh yeast biomass or as dried yeast 'crisps' induced an immune response. Importantly, the mice willingly ate this 'food'. For humans, yeasts could also be delivered in capsule form, but the possibility of integrating them into fermented beverages – such as kvass or beer – is not ruled out.

This unconventional solution was chosen by U.S. based virologist Chris Buck, who attempted to apply vaccine–antigen–producing yeasts in beer brewing. When he analysed his own blood samples before and after consuming such beer, an increase in specific antibody levels was observed.

These results encouraged Buck to continue his experiments even after encountering a prohibition from the National Institutes of Health ethics committee against experimenting on himself during work hours. To proceed, he decided to act as a private individual and founded the nonprofit organization Gusteau Research Corporation. Moreover, together with VU LSC scientists, he published the results of their research on the open platform Zenodo, where guidelines for brewing such beer are also provided.

Although this experiment must currently be regarded as a single case and does not meet the criteria for a clinical trial, the data obtained suggest that the principle itself may work not only under laboratory conditions, but also in the human body. 

According to Vasiliunaite, the main reason vaccines are usually administered by injection is related to the characteristics of the digestive system. During digestion in the stomach, vaccine antigens are broken down along with food, so oral immunization typically does not work. Cells that recognize vaccines are also not present in the stomach – they are located further along the digestive tract, in the intestines. For this reason, it is crucial that the antigen, protected from stomach acid, reach the intestines and activate the immune cells there.

Until now, vaccination through food has been effective almost exclusively with 'live', attenuated vaccines that protect against intestinal infections. One modern example is the rotavirus vaccine for infants. In this case, the strength of the immune response is determined by the fact that the vaccine contains not individual viral components, but the entire, albeit weakened, virus, which actively stimulates the immune system. It is also important that the rotavirus itself is naturally adapted to infect the intestines. For this reason, it was easier for scientists to develop an oral vaccine capable of serving as an alternative to injectable ones.

By contrast, component or so–called 'inactivated' vaccines, consisting only of individual parts of a pathogen, often fail to induce a sufficient immune response. Even when protected from stomach acid – for example, by encapsulation – they often generate only local immunity in the intestines. The gut operates immune tolerance mechanisms that prevent excessive immune reactions to food antigens and the gut microbiota. As a result, systemic immune responses, in which antibodies are also detected in the blood, usually do not develop.

In the case of yeast–based vaccines, Vasiliunaite suggests that yeast cells carrying the vaccine inside them likely play a dual role: they not only protect the antigen from stomach acids, but also act as an additional activator of intestinal immune cells – a so–called adjuvant.

However, the exact mechanism behind this effect is not yet fully understood and will be the subject of further research. The viral antigen used to develop these vaccines is the major capsid protein of polyomaviruses. This is a convenient model protein that forms virus–like particles in yeast cells – structures that mimic the shape of a virus and consist of hundreds of copies of the protein. Previous studies have shown that such purified particles, when used in injectable vaccines, are highly immunogenic and induce very strong, long–lasting immune responses. In this case, however, it is the yeast cells themselves that determine the effectiveness of the edible vaccine. This was confirmed by experiments in mice – when disrupted yeast cells containing the viral antigen were fed to them, no immune response developed.

'Beer vaccine' scepticism

As the researcher notes, scepticism toward the idea of a 'beer vaccine' is inevitable. No similar studies have been conducted so far, and the idea itself emerged as a kind of curiosity–driven scientific experiment that unexpectedly produced tangible results. It remains unclear whether this method is suitable only for polyomaviruses or could also be applied to other diseases. Regulatory issues are also important – within the European Union, the use of genetically modified microorganisms in food is strictly regulated.

On the other hand, there are already examples in the United States of fermented beverages produced with genetically modified yeasts that are legally consumed. This shows that technological possibilities exist, but the path toward a widely used vaccine will be long and will require many additional, independent studies.

A successful Fulbright fellowship and collaboration with U.S. scientists became a starting point for further polyomavirus research in Lithuania. Vasiliunaite continues this work together with a VU LSC research group, and the promise of this research direction is further demonstrated by a project funded by the Research Council of Lithuania – Studies of Polyomavirus Pathogenicity and Host Specificity Factors – which will ensure continued financial support for future studies.

Pic: Boonrom Pranidchakan