The Phage



why a bacteriophage cannot infect a human

Can a bacteriophage infect a human cell?

It’s an intriguing question that has scientists scratching their heads over the possibility of these “minute guys” (phages) wreaking havoc on our bodies. This same question would be asked by someone who wants to know if phages are safe for humans, especially when used as a treatment alternative. Concerns about their safety when used live (without deactivation or being killed) never left the minds of those in charge of approving drugs for human/animal use. For so long, this has been a nightmare for phage-based pharmaceutical companies, but rules are finally allowing many phage products to enter the market.
Bacteriophage trying to infect human cell
Bacteriophages can not infect human cells. ©Raphael Hans Lwesya 

Bacteriophages, which are viruses that infect bacteria, have resurfaced as powerful regulators of bacterial populations in natural ecosystems. Phages infiltrate the human body in the same way that they do other natural environments, to the point where they are the most numerous in the human virome. Despite the fact that phages in the human body have been reported for decades, this was only revealed in recent metagenomic studies. The impact of phage presence in humans has yet to be determined. Still, as in marine environments, a clear role in regulating bacterial populations is possible, which could have an impact on human health.
Furthermore, phages are excellent vehicles for genetic transfer, and they aid in the evolution of bacterial cells in the human body by horizontally spreading and acquiring DNA. The abundance of phages in the human body does not go unnoticed, and the immune system reacts to them, though to what extent is unknown. Finally, unnoticed phage presence in human samples can influence and bias microbiological and molecular results. Given the evidence, some studies suggest that their interference requires more attention.

What type of bacteria do bacteriophages infect?

Despite bacteriophages’ specificity in infecting a specific species of host bacteria, there are no known bacteria that do not have phages to infect them. Bacteria evolve to resist attacks, whereas bacteriophages, as living entities, evolve new attack strategies.

why a bacteriophage cannot infect a human

A bacteriophage must attach to specific receptors in order to initiate an infection. Eukaryotic cells lack these types of receptors, which is why these viruses cannot infect humans. Bacteria, on the other hand, have these receptors, which allow phages to attach and attack. Bacteriophages are not harmful to humans;. However, they may indirectly cause undesired activities like transferring antibiotic resistance genes (ARGs) from one bacteria to another, driven mainly by lysogenic phages.

What is the role of bacteriophages and the human microbiome?

The bacteriophage (“phage”) is a virus that eats bacteria; however, a better term would be natural bacteria predator. Phages can be found in all types of microbial environments. The conflict between phages and bacteria dates back to the dawn of life. Bacteriophages are very picky about the bacteria they attack. Because of this selectivity, phages can eliminate a specific type of harmful bacteria while leaving all other bacteria alone, with no known side effects on the human body.

The majority of the viral population in the human gut microbiome is made up of phages. Caudovirales are the most common order of bacteriophages found in the gut microbiota. The order is made up of three families of lytic viruses that attack specific types of bacteria and archaea: Myoviridae (long contractile tails), Siphoviridae (long non-contractile tails), and Podoviridae (short non-contractile tails) (short non-contractile tails).

Phages are truly magnificent, and the process by which they reproduce is fascinating. A phage attaches to a bacterium and injects its DNA into it. The bacterium then undergoes a phage factory transformation, producing up to 100 new phages before bursting and releasing the phages to attack other bacteria. This means that phages multiply much more quickly than bacteria. In some countries, particularly in Eastern Europe, phages are used to treat bacterial infections. Because each phage can only infect and kill one type of bacteria, a doctor may be able to give a patient a phage that can infect and kill that type of bacteria if the doctor knows which bacteria is infecting the patient.

How does a phage based vaccine work?

During the COVID-19 pandemic, many scientists investigated various types of vaccine production in the hopes of saving the world. Other effective vaccines have been developed as a result of these scientists’ outstanding work in research and development, which has resulted in some of the most widely used vaccine technologies. The World Health Organization has approved several vaccines to aid in the fight against this pandemic (To read more information about COVID-19 vaccines, please visit World Health Organisation Page by clicking here). Despite the fact that they have not yet been approved, phage-based vaccines have sparked interest due to their potential to protect against Covid-19. According to the research data, their efficiency was sufficient to qualify them as potential candidates.

What are phage-based vaccines?

Phage-based vaccines, also known as phage display vaccines, are phages that have been genetically modified to have peptide or protein antigens genetically displayed on their surfaces, as well as those that have antigens chemically conjugated or biologically bound on their surfaces. As a result, they can elicit an immune response and cause memory cell production. Vaccines based on phages are among the least popular.

How are phage-based vaccines made?

Phage-based vaccines are created by chemically/biologically/genetically modifying the structure of a bacteriophage with an antigenic but harmless structure from another organism, such as a potential pathogen. The added structure must have antigenic properties in order to elicit an immune response. Modifying phages to produce spikes for a coronavirus is an excellent example of a phage-based vaccine. Those spikes can elicit an immune response, which will act on secondary infection to protect the body from the primary infectious particle.

Mode of action of phage-based vaccines

The modes of action of phage-based vaccines are identical to those of other vaccines. Vaccines train our immune systems to produce proteins that fight disease, known as ‘antibodies,’ in the same way that they would if we were exposed to an illness, but – crucially – vaccines work without making us sick. In phage-based vaccines, the phage serves only as a vehicle for transport, while the antigenic structure is in charge of eliciting (“teaching”) the immune system.

Is the phage-based vaccine safe?

Vaccines are safe as long as they have undergone rigorous clinical trials and have been approved by the World Health Organization or local authorities such as the American Centers for Disease Control and Prevention. It is recommended that only vaccines that have been deemed safe by professional bodies and the World Health Organization be used.

Do unmodified phages elicit an immune response?

Yes, once introduced into the body, typical phages elicit an immune response. They do not, however, cause disease and, in fact, can be beneficial to human health when used professionally and purposefully (phage therapy).

Design and applications of phage-based vaccines

Design and applications of phage-based vaccines
An overview chart of the phage-based vaccine. Photo by Sanger et al., 1977

An overview of design and application of Phage based vaccines

(Refer to the diagram above)
  • (A)Vaccines derived from DNA. The entire phage particle serves as a vehicle for the gene encoding a protective antigenic peptide. The genetic material will be released into the host’s body, causing an antigen to be expressed and immune responses to be triggered. 
  • (B) Vaccines with phage-displayed peptides or proteins are made by genetically displaying peptides or proteins. Foreign peptides or proteins can be efficiently and economically fused with the relevant coat protein using phage display. The phage particles can then be used to stimulate the host immune system as effective vaccines. 
  • (C) Phage-displayed vaccines are made by allowing pre-displayed antigen-binding peptides to capture the antigens. An antigen can be directly linked to the phage surface using an artificial linker. Alternatively, an antigen-binding peptide can be identified and displayed on the phage surface before it is used to capture the antigen that has been linked to a substrate via a cleavable linker. This strategy has the potential to broaden the range of phage-displayed vaccines while also ensuring that foreign antigens are in the correct exceptional conformation. Using the techniques described above, phage-based vaccines can be designed to stimulate the host immune system and produce specific antibodies against a wide range of diseases, including viral infection, cancer, bacterial infection, fungal infection, and parasitism.

Can the Bacteriophage Mutants be the Next Generation Carriers for Conjugate Vaccines?

Passing through several waves of the deadly pandemic brought the human race into consideration of doing extensive research on vaccines. It is no doubt that they are very crucial components in controlling and eradicating disease outbreak. Different technologies have so far been developed to manufacture and administer these substances to the human body. Vaccines work by mimicking the real antigen in eliciting immune response without causing a disease (Taking into account that some people may experience temporary discomfort just after taking the jab). There have been a number of modifications done to improve the efficiency in eliciting an immune response and minimizing the side effects of the substances incorporated into vaccines. Conjugate vaccine technology uses weak and strong antigens so that many antibodies will be stimulated against a weak antigen. Carrier is very important in this technology and it’s a strong determinant of successful vaccination although only a few of them are available for clinical application. Bacteriophages are among the particles used as conjugation substances (carriers).
Illustration of conjugate vaccine development. by Jing et al (2021).

A study done by Sungsuwan et al (2022) revealed that having structurally modified bacteriophages provided better conjugation compared to wild ones. The study was purposely aimed at developing a better carrier that will elicit less immune response compared to the target antigen. Researchers designed novel mutants of bacteriophage Qβ (mQβ) and prepared a conjugated with tumour-associated carbohydrate antigens (TACAs). This combination produced very powerful antigen (TACAs) specific antibodies (IgG) and less for the carrier mQβ compared with the wild type bacteriophage Qβ and antigen conjugation which performed poorly. Using mice induced with an aggressive form of breast cancer, researchers reported 100% mortality just within 12 days for unimmunized subjects while 80% of the immunized ones were reported to be free of tumour. In addition, the mQβ based conjugate vaccine was reported to induce high levels of IgG antibodies against peptide antigens from the SARS-CoV-2 virus. This technology may play a big role in shaping the development of vaccine carriers.

Phages have as well been used to make vaccines by displaying the antigen on their surfaces (Read more about phage-based vaccines here)