Tularaemia, sometimes referred to as "rabbit fever or “deer fly fever”, is a rare but serious infectious disease caused by the Francisella tularensis bacterium.¹ This disease is highly infectious since Francisella tularensis can spread easily and the disease can be caused by a even 10-15 bacteria.¹ Even though it is rare, preventing tularemia is crucial because if it is not treated with the right antibiotics, tularaemia might be lethal. Therefore, it is crucial to look into tularaemia prevention strategies, including vaccination. Vaccines work by teaching the immune system to recognise and combat Francisella tularensis if exposed in the future.² In this article we will explore the role of vaccination in preventing tularemia. We will also discuss the different vaccine strategies currently being developed and their mechanisms.

What is tularemia and how can people catch it?

Tularaemia is a disease with several paths of transmission as there are multiple ways in which this bacterium can infect humans.¹ Animals are usually affected by tularaemia, particularly rodents, rabbits, and hares. Therefore, you could get infected by handling infected animals, like rabbits, hares, and rodents.¹ You may also get the bacterium by being bitten by infected insects, like ticks or deer flies. Tularaemia can occasionally be contracted by breathing in air that carries the bacterium or by consuming contaminated food or drink.¹

In particular, tularaemia can be easily acquired in some settings, such as rural or wooded places where the bacteria are carried by wild animals and insects.¹ 

What are the symptoms?

The way a person is exposed to tularaemia determines the symptoms and indicators they experience. Skin ulcers, painful and enlarged lymph glands, inflamed eyes, sore throats, mouth sores, diarrhoea, or pneumonia are some possible symptoms. Inhaling bacteria can cause symptoms such as a sudden rise of fever, chills, headache, joint pain, muscular pains, dry cough, and gradually worsening weakness.¹ 

Certain groups are at a higher risk of exposure to Francisella tularensis. These include people such as veterinary professionals, workers in laboratories, landscapers and farmers, people who deal with sheep and other animals as well as people who work with meat. Therefore especially for these people, taking appropriate preventative measures is crucial. We can prevent major consequences, lessen the transmission, and create safer conditions for individuals by being aware of the hazards and taking precautions to prevent tularaemia, especially in these high-risk occupations.³

How does the vaccine work?

Vaccines against tularaemia are designed to train your immune system to identify and combat Francisella tularensis.These vaccines expose the body to tiny or weakened portions of the bacteria, such as proteins or sugars, which triggers the production of T cells and antibodies by the immune system that specifically target the pathogen. In addition to the adaptive immune response, which remembers the bacteria for future defense, effective tularaemia vaccines also activate the innate immune system, which offers a quick initial reaction.²

Vaccines to prevent tularemia

Unfortunately, there is currently no FDA-approved vaccination for humans, despite advancements in our understanding of immunity against the bacteria that causes tularaemia. Live-attenuated, conjugate, and subunit vaccines have all shown promise in preliminary studies, but none have been successful enough to be made generally accessible.² Furthermore, because Francisella tularensis behaves differently depending on how it enters the body (e.g., through the skin or lungs), developing an effective tularaemia vaccine is challenging.² Some of the current approaches in preventing tularemia through vaccination are discussed below.

Live attenuated vaccines

Live viruses or bacteria that have been weakened so they can no longer spread illness but still boost immunity are used to make live attenuated vaccines. The purpose of these vaccinations is to assist the body identify and combating the actual virus in the event that it is eventually encountered.²

The live vaccine strain (LVS), the most extensively researched vaccine, has a modest level of effectiveness. When tested on humans, these novel LVS variants have produced robust immune responses and exhibited moderate side effects (such as headache and sore throat), while information on the precise immune cells involved is still lacking.² However, LVS may be less effective against highly virulent strains because it lacks several components, such as type IV pili, which often aid in immune system stimulation.^2,4

Genetically engineered strains are used in many experimental vaccines, especially Type A or LVS knockout strains.² ΔclpB, a potential LVS knockout, demonstrated good protection in mice with enhanced bacterial clearance and immune response.⁵ A different strategy that used a Type A mutant strain called ΔaroD shielded mice by boosting their immune systems' cellular and antibody-based defences.⁶ According to studies, the immune response may differ based on the animal model (for instance, mice versus rabbits), suggesting that distinct immune responses are required for various species to be effectively protected. Live-attenuated vaccines are a promising but challenging field of tularaemia vaccine research as researchers continue to try different gene alterations to determine the ideal combination for a potent immune response with few adverse effects.²

Subunit and conjugate vaccines

Although they haven't yet shown as much efficacy as live attenuated vaccines, researchers are also exploring conjugate and subunit vaccinations to prevent tularemia. Subunit vaccines make use of particular bacterial components that the immune system can identify. Researchers have focused on the lipopolysaccharide (LPS) and proteins (like Tul4 or FopA) found on the surface of Francisella. Unfortunately, these vaccines haven't fully protected against tularaemia yet, especially when it comes to inhaled infections, which are the most severe kind.

Subunit vaccinations need adjuvants, or substances that stimulate the immune system, to increase the immunological response. A robust, well-balanced immune response depends on the adjuvant selection. Adjuvant combinations have been employed in certain vaccine trials to assist activate both antibody-based and cellular immunity, but none have offered total protection to date.^2,4

By attaching bacterial parts — like fragments of Francisella's LPS — to a carrier protein, conjugate vaccines frequently enhance the immune response. For instance, mice were somewhat protected against low-dose infections when portions of LPS were bound to Pseudomonas aeruginosa proteins or tetanus toxin.²

Targeting the vaccine to particular immune cells, such as antigen-presenting cells, which are essential for triggering immunological responses, is another of the more recent approach.⁷ To enhance the vaccine's absorption and processing, scientists have created vaccinations that attach directly to receptors on these immune cells. These methods have some potential, but they also show that in order to completely activate the immune system, Francisella antigens may need to be combined with the appropriate adjuvant and targeting techniques.²

Killed whole cell vaccines

These vaccines are made from bacteria that have been killed so they can’t cause disease. Although these bacteria are no longer infectious, they still contain important components that the immune system can recognise. This helps the body learn how to defend itself against the actual pathogen if it’s encountered in the future.⁴

Nanoparticle vaccines

To prevent tularaemia, researchers are investigating vaccinations made of nanoparticles. Following the success of COVID-19 mRNA vaccines, which employ a similar approach, nanoparticles—tiny particles that can efficiently carry vaccine components—are attracting more interest.² A potential method that shielded mice and rats from airborne infection was the use of glucan nanoparticles loaded with Francisella proteins and portions of its LPS.^8,2

Summary

Tularemia is a bacterial disease caused by the bacteria Francisella tularensis. The bacteria can infect you through animal contact (like handling infected rabbits or rodents), bites from ticks or deer flies, inhaling contaminated air, or eating/drinking tainted food. Although various vaccines are being developed, there isn't one that the FDA has approved for humans. Live-attenuated vaccines, which employ weakened bacteria, have potential but require more research to determine their efficacy. Subunit and conjugate vaccines do not yet provide complete protection against severe forms of tularaemia, although they do target certain bacterial components. Vaccinations based on nanoparticles are being investigated for their effective administration and possible long-term protection. These methods have promise, however, since Francisella tularensis exhibits distinct behaviours depending on how it affects various parts of the body, research for developing effective vaccines is still undergoing.