Part 1: Introduction to mRNA Vaccines

1.4. Why Target Bacteria?

Most people associate vaccines with targeting disease caused by viruses - but vaccines can target conditions caused by bacteria and parasites as well! In fact, in Part 2, we’ll select possible antigens for a vaccine against the A. baumannii bacteria.

Vaccines against bacteria are a very useful tool in humanity’s arsenal. In 2019, bacterial infections were the 2nd leading cause of death, being responsible for around 9% of all global deaths, with over 50% of the fatalities being caused by one of only five strains. Humanity has been fighting bacteria since the discovery of the first antibiotic, penicillin. However, bacteria can ‘fight back’ by building resistance to antibiotics - a phenomenon called antimicrobial resistance (AMR). When people use antibiotics against bacteria, they’re trying to combat a bacterial infection that usually contains millions, if not billions, of slightly different bacteria from the same strain. Due to natural variation introduced when bacteria divide, a few specimens may be resistant to the used antibiotic. Sometimes, antibiotics wipe out the majority of the population, leaving space for the remaining, resistant bacteria to grow - suddenly, the infection is back to its previous size, but all the bacteria are now resistant to the antibiotic that was just used. AMR is a growing threat because bacteria can become immune to most and even all antibiotics known to mankind - in 2019, it was indirectly responsible for almost 5 million deaths, more than HIV and malaria combined. The number of AMR-related deaths is projected to increase substantially by 2050 if not addressed.

AMR has initially been observed in high-income countries and mainly attributed to antibiotic misuse and overuse. However, reports from low- and middle-income countries have rapidly risen from 2011 to 2021, primarily due to increased antibiotic usage but also thanks to the rise of adequate surveillance programs.

Healthcare environments, such as hospitals, are where the most resistant pathogens can be found. It’s easy to acquire new resistance in such environments and persist by constantly infecting new patients. Moreover, such environments usually contain young (<5 years), old (>65 years), and weak/immunocompromised patients, to whom AMR poses the most threat. Yearly, about 214.000 neonatal deaths are attributed to AMR. Moreover, antimicrobial resistance also threatens the outcomes of some surgeries, such as organ transplantations, where it raises treatment failure and mortality by “cancelling” the effect of antibiotics.

Bacteria have multiple resistance mechanisms, from reduced membrane permeability (which makes it harder for antibiotics to enter bacteria) to the use of efflux pumps (actively pumping out antibiotic molecules) and antibiotic degradation (producing machinery to break down antibiotics). Overall, these mechanisms can successfully lower the efficacy of all known antibiotics. Since the discovery of penicillin in 1928, just 20 structural classes of antibiotics have been developed in 1930-1960. The pace of discovery has significantly slowed down, with only 29 total antibiotics receiving marketing authorization since 2010 - most of them were slightly modified molecules belonging to previously-discovered classes. Because of this similarity, bacteria with a high degree of resistance may already be resistant to them. The problem is made worse by the process required to develop new antibiotics, which requires a long time for approval, as well as substantial financial resources. Bacteria can, regrettably, develop resistance much faster than new antibiotics can be developed.

Antibiotic discovery alone cannot fight the rapid evolution of antimicrobial resistance (AMR) much longer. Resistance mechanisms have been identified for all existing antibiotics, and few new drugs are in development. Vaccines can be an effective tool in the fight against AMR, as highlighted by WHO, but have been historically underutilized. They can do so directly - by inducing immunity against strains of bacteria, even if they are resistant to antibiotics - and also indirectly - by reducing the need of antibiotics. Moreover, vaccination rates above a certain threshold could induce herd immunity to strains of bacteria. Vaccines also build immunity against bacteria before infection, preventing growth after infection, which should lead to substantially less buildup of resistance to vaccines.

Generally, antibiotics are small molecules that disrupt some essential processes in bacterial cells. Due to random mutations, some cells may develop resistance mechanisms. Once an antibiotic is administered, all bacteria but those that are resistant die - leading to positive selection pressure, meaning the few surviving cells have a lot of space to develop and grow (assuming the immune system does not kill all of them in time). At the end of the cycle, the whole population of bacteria is resistant to the initial antibiotic (minus those with mutations disrupting the mechanism) since those that weren’t were selectively killed. What’s worse, some bacterial species may exchange genes, including those encoding resistance mechanisms, with others.

There are three main categories of antibiotic resistance. First, bacteria may prevent the antibiotic from reaching its target, which it binds to in order to disrupt the process. They may do that by minimizing the overall permeability of their membrane, causing fewer molecules to get inside the cell. They may also have special pumps that actively take antibiotic molecules out of the cell. Second, bacteria may develop special machinery that changes antibiotic targets, preventing their normal activity. The most common ways to modify antibiotics are hydrolysis and transferring a chemical group, preventing the molecule from binding to its target. Lastly, bacteria may protect the antibiotic target by changing its structure so the antibiotic cannot bind as well (or at all) anymore. In this case, the target still performs its function in the vital bacterial process.

There are currently only around 10 approved vaccines for bacterial disease. However, the response to COVID-19 unlocked new possibilities in the field, opening up the ability to target more molecular targets (longer proteins, as previously discussed in Part 1.3).

There are still a few unknowns when it comes to using mRNA vaccines against bacteria. To avoid the same phenomenon as the one underlying AMR, antigens have to be carefully chosen as essential proteins, so bacteria can’t “change them” easily (in reality, the bacteria with modified antigens - which would be likely to exist if the protein was not essential - would thrive after a vaccine, as it would not be targeted by the antibodies induced by the vaccine). Even so, experts are looking at vaccines containing more than one antigen to bring the possibility of an AMR-like mechanism even lower. While promising, this type of mRNA vaccines that combine multiple antigens has not yet been licensed to target any pathogen. mRNA vaccines also cannot solve unrelated scientific challenges in vaccine development, such as understanding how the immune response against a specific bacterium is triggered. Ultimately, there are very intricate mechanisms underlying bacterial infections compared to viral ones, and a deeper understanding is required to unlock the full potential of antibacterial mRNA vaccines. Some specific domains where more research is needed are how protection against bacteria manifests (correlates of protection), the biology of complex bacterial pathogens, and finding out which responses are necessary for effective immunity. With all these gaps, combined with the vast number of possible proteins a bacterium may express, rational antigen selection is essential in the production of working antibacterial vaccines.