Vaccines elicit variable immune responses in different people. A multitude of reasons can make a vaccine less effective against disease, a consequence that can be dangerous or even fatal. Correlations between microbiota and immune response to vaccination are recognized as a factor associated with vaccine failures. Unfortunately, evidence supporting the benefit of probiotics to modulate vaccine response is inconclusive (most likely due to the heterogeneity of probiotic strains, dosages, and routes of administration). However, another promising area of research is the use of probiotics as vaccine adjuvants.
In this article, we will look at the evidence in that regard.
Vaccine adjuvants, in brief
A vaccine stimulates an individual’s immune system to produce immunity to a specific disease, protecting the person from that disease. Immunization currently prevents 4-5 million deaths every year from diseases such as diphtheria, tetanus, pertussis, influenza, measles as well as COVID-19.
Two components comprise a vaccine: antigens and adjuvants.
- Antigens typically consist of proteins or carbohydrates derived from the pathogen, against which an adaptive immune response is desired. In the case of mRNA vaccines, the body produces the antigen.
- Adjuvants are substances used in conjunction with vaccines to increase the humoral and/or cellular response to a delivered antigen.
Combining the correct antigen and adjuvant can induce faster, more robust, and more durable immune responses, and may also reduce the amount of antigen needed to induce protection. Following its introduction in the 1920s, alum remained the only adjuvant licensed for human use for the next 70 years. Since the 1990s, a further five adjuvants have been included in licensed vaccines, but the molecular mechanisms by which these adjuvants work remain only partially understood.
Most pathogens enter the body at mucosal sites. The defense of these barrier tissues is mediated by innate and adaptive immune responses, making mucosal vaccine delivery attractive due to the ease of administration and the common-mucosal immune system.
The use of lactic acid bacteria (LAB) as an oral vaccine platform has been explored against many pathogens and toxins.
Lactic acid bacteria as vaccine adjuvants
LAB have many advantages that make them promising candidates for mucosal vaccine delivery vectors.
These advantages include simple, non-invasive oral or intranasal mucosal administration and low cost. LAB tend to elicit minimal immune responses against themselves, instead inducing high levels of systemic and mucosal antibodies against the expressed foreign antigen following uptake via the mucosal immune system. Furthermore, some orally administered LAB could be used to induce specific immunity not only in the intestinal mucosa but also in the respiratory tract, a feature that may be harnessed in creating vaccines for SARS-CoV2.
The potential of LAB as mucosal vaccine adjuvants has been known for more than 30 years. LAB for use as vaccine vectors generally include Streptococcus gordonii, Lactococcus lactis, and multiple lactobacilli species.
Unfortunately, due to the risk of reversion to virulence by the attenuated pathogen in the vaccine, there are few available for use worldwide.
Because of these safety issues, new types of mucosal vaccine vectors are needed, such as recombinant LAB as next-generation mucosal vaccine vectors, due to their natural acid and bile resistance, stability at room temperature, and their ability to beneficially modulate mucosal innate and adaptive immune responses.
Based on this idea, several probiotic-based vaccines have been developed; a few are listed below.
- A recombinant Streptococcus gordonii vector has been used effectively against pertussis toxin in mice.
- Recombinant Bacillus subtilis strains via the oral route could be recognized and neutralize the native toxin, produced by enterotoxigenic Escherichia coli in vaccinated mice.
- Engineered Lactococcus lactis vaccine demonstrated significant humoral immunity against gastric Helicobacter pylori infection in mice.
- Recombinant Lacticaseibacillus casei vaccine has shown potential against porcine epidemic diarrhea in newborn piglets.
- A study on adults reported that strains of Lacticaseibacillus rhamnosus could be an influential adjuvant to improve influenza vaccine immunogenicity.
- Recombinant Lactobacillus lactis vector showed positive results after vaccination for human papillomavirus in healthy women volunteers.
- In a study that compared the potential of eight Lactobacillus species as immunogenic carriers of the antigen from Mycobacterium tuberculosis, Lactiplantibacillus plantarum and Levilactobacillus brevis were considered the most promising carriers of TB vaccines.
The SARS-CoV2 virus —where respiratory mucosa plays a key role— has highlighted the need for better mucosal vaccinations. Recombinant probiotics, particularly lactic acid bacteria, show promise as vaccine carriers because of their intrinsic immunomodulatory features, natural adjuvanticity, and feasible expression of relevant antigens in the mucosal surface. Furthermore, some LAB can induce protective immunity in both the intestinal and respiratory tracts, which would be of great importance against SARS-CoV-2.
- Recombinant Lactiplantibacillus plantarum was able to express viral antigens, including the spike protein of SARS-CoV-2 as well as differentially modulate the innate and adaptive immune responses in both the intestinal and respiratory mucosa after its oral administration.
- Another probiotic with abilities to express spike proteins Bifidobacteria longum was chosen as an adjuvant for a new oral vaccine currently under investigation in a clinical trial.
It is important to note that vaccine-induced immune responses are highly variable between individuals and populations in different regions of the world. The development of probiotic-based vaccines will need to take into account these differences.
For decades, probiotic-based recombinant vaccines have shown encouraging results, albeit most research was done in animals. Their use in humans has been largely limited by the risk of reversion to virulence by the attenuated pathogen. However, the SARS-CoV-2 pandemic has invigorated research into the development of safe next-generation recombinant mucosal vaccines. Bioengineered probiotic vaccines stand out among other platforms for their affordability and targeting of the SARS-CoV-2 spike protein. However, more studies are needed to define their efficacy and to investigate their role in human immunological pathways to ensure their safety and durable immunity.
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