The first mRNA vaccine against Lyme disease

Messenger RNA vaccines (mRNA vaccines) were the big players in the arms race against the SARS-CoV-2 virus and the first to be commercialized.

But their story began at least twenty years before the pandemic. While the first studies focused on applications against cancer, today these vaccines are finding increasing use against infectious diseases as well.

Researchers from the National Institute of Health (NIH) in the United States have tested in the laboratory the first mRNA vaccine against Lyme disease, a bacterial infection transmitted by tick bites of the Ixodes genus. The vaccine, however, does not target the bacterium that causes the disease (Borrelia burgdoferi), but the proteins in the tick's saliva. In vaccinated animals, the inflammation generated at the bite site prevents the tick from feeding and transmitting the bacterium. This strategy, the researchers say, could also be extended to other tick-borne diseases or other vectors.

Lyme disease

Tick-borne diseases are spreading widely in North America and Europe. Approximately 40,000 cases are reported in the United States each year. Lyme disease is the most common in Europe, with an average incidence of 22 cases per 100,000 inhabitants per year, especially children and young adults living in wooded areas. The countries with the highest incidence are Croatia, Bulgaria, Hungary and Finland. The number of infections has grown steadily: over 360,000 cases have been reported in the two decades from 1990 to 2010. The disease affects not only humans, but also many wild or domestic animals, such as dogs.

Lyme disease is caused by the bacterium Borrelia burgdoferi, which is transmitted to humans by the bite of an infected tick belonging to the Ixodes genus - the most common are Ixodes ricinus in Europe and Ixodes scapularis in North America. Ticks become infected during a blood meal on an animal that carries the bacterium, typically small mammals such as rodents or some bird species. In risk areas, 5-40% of ticks are infected.

Initial symptoms include skin rash, fever, headache, and fatigue. But if not treated in time, the infection can also extend to muscles, joints, nervous system and heart. The infection is treatable with antibiotics: cephalosporins, amoxicillins, macrolides. Antibiotic treatment works against the disease at an early stage and avoids complications affecting the organs. The first symptoms, however, are non-specific and the diagnosis is sometimes delayed: in this case, antibiotic therapy is only partially effective. Complications, in fact, can cause permanent tissue damage

Vaccines: where are we?

However, tick diseases can be prevented, first of all by adopting correct behaviors, such as wearing protective clothing, using repellents and removing ticks before infection occurs. But it would also be important to have a vaccine that protects against infection or at least its complications. To date, there are approved Lyme disease vaccines for dogs, but not for humans. The only one currently in phase 2 of the clinical trial is a vaccine produced by Valneva and Pfizer, which targets a protein expressed on the surface of the pathogen Borrelia burgdoferi.

Vaccines against Sars-CoV-2 also work in a similar way: they are directed against the spike protein expressed on the surface of the virus. However, Borrelia has a peculiarity, which makes it particularly difficult to design effective vaccines. This bacterium continuously modifies the expression of its surface proteins in the different stages of infection.

While still in the gut of the tick, Borrelia expresses the OspA protein, which is the main target of veterinary vaccines currently on the market in the United States. When the tick feeds on the blood of a vaccinated specimen, it also ingests antibodies against OspA, which neutralize the bacterium when it is still in its intestine. After the tick starts feeding, however, Borrelia travels to the salivary glands and expresses a new protein called OspC. This variant has become the target of a second generation of vaccines, which provide a further barrier to infection when the bacterium has already entered the mammalian host. In the late stages of infection, Borrelia expresses different proteins, including OspF.

mRNA vaccines

The vaccine designed by the NIH researchers has a different mechanism of action, because it does not target any of the Borrelia surface protein.

It is a messenger RNA vaccine, the first of its kind against Lyme disease. You have surely heard of this technology because it is the basis of the Pfizer / Biontech and Moderna vaccines against Covid-19. They were the first to arrive on the market and immediately demonstrated an efficacy of over 90% in preventing infections and especially severe forms.

These vaccines work differently from traditional ones: they do not contain live, attenuated viruses or bacteria or fragments of viral proteins. Instead, they use messenger ribonucleic acid (mRNA) molecules to teach our cells how to make a protein or protein fragment of the pathogen. From this point on, the mechanism is similar to that of other vaccines: the immune system recognizes the foreign protein and produces antibodies capable of neutralizing the virus or bacterium and memory cells which will produce an immune response to each subsequent encounter with the same pathogen.

Why precisely RNA? This nucleic acid is the genetic material that contains the instructions for the synthesis of proteins. RNA copies the genetic information contained in DNA in a process called "transcription" and transports it out of the nucleus, into the cytoplasm - for this reason it is called "messenger". Its recipients are ribosomes, cellular machines that carry out the instructions printed on the RNA molecule to assemble proteins, a process called “translation”. RNA vaccines, therefore, use a widely tested cell system. They are also quick and easy to produce from nothing but the genetic sequence of the pathogen

A vaccine against the tick bite

The Lyme disease vaccine that is being tested in the NIH laboratories is called 19ISP and is an mRNA vaccine, in which messenger RNA molecules are incorporated within fat nanoparticles - a system also exploited by Pfizer / Biontech and Moderna to deliver the vaccine content inside cells.
As we had anticipated, however, this vaccine has a different mechanism of action. Its target, in fact, is not the surface protein of the pathogen, but the vector itself, that is the tick is responsible for its transmission. The vaccine contains mRNAs that code for 19 different proteins found in the saliva of Ixodes scapularis, one of the vector ticks for Lyme disease.
Researchers have observed that several animals repeatedly exposed to a tick bite develop a so called “tick immunity”. Ticks detach almost immediately after biting or cause itching and redness of the skin - normally absent - which alert the animal to remove them immediately. The saliva of the tick therefore contains immunogenic proteins: the immune system becomes aware of their presence and even generate a memory response, which makes the animal immune to subsequent bites.
The vaccine induces the production of antibodies against the proteins contained in the saliva of Ixodes. When the tick bites, the antibodies bind to the proteins, generating local inflammation that also attracts other cells of the immune system.
The result is that the tick is unable to feed and detaches itself practically immediately, without transmitting the infection. The researchers tested the vaccine on animals, particularly guinea pigs. None of the vaccinated animals contracted the infection after a bite from an infected tick and all developed an immune reaction. In the unvaccinated, instead, 50% tested positive for Lyme disease

Perspective

The researchers now plan to test their vaccine on other animals, such as rabbits. In fact, different animals seem to have different immune responses and some, such as mice, do not develop immunity to ticks at all. This phenomenon has not yet been directly observed in humans. However, people who are repeatedly exposed to tick bites appear to develop redness and itching, which in animals is associated with tick immunity.

New studies on people who have contracted the infection or have been in contact with the tick repeatedly will allow us to understand whether humans also develop antibodies against the proteins contained in 19ISP. The researchers also believe they can adapt the mRNA vaccine against other vector-borne diseases, including other tick species or mosquitoes.

Erika Salvatori

Translated from:

Microbiologia Italia. Il primo vaccino a mRNA contro la malattia di Lyme.

Vitares presented a project, together with the Evvivax company, to develop  a veterinary vaccine for dogs, which simultaneously protects against Lyme disease and opportunistic infections that can affect the animal when it is already debilitated. The project involves the development of a genetic DNA vaccine, which will protect dogs from the risk of a multiple and life-threatening infection. For more information click here.