A history of failure should not discourage new research. What we need is a new strategy, says Isabelle Bekeredjian-Ding, Head of Microbiology at Paul-Ehrlich-Institut and member of the IMI Scientific Committee
Vaccines could be a valuable string in our bow in the fight against drug-resistant bacterial infections, but clinical testing of such vaccines has a long history of failure. There are a few reasons for this: because resistant bacteria are often picked up in hospitals, the vaccines that have been tested have mostly been administered to people who already have some level of pre-existing immunity to the bug in question. Others are immunosuppressed, and thus are at high risk for infection, while others may have changes in their microbiome that also lead to an increased risk of infection.
It’s also hard to predict when and to what extent a particular pathogen is going to show up and wreak havoc. Trying to target different strains of the same pathogen - which can be highly genetically diverse - makes things even more complicated. Clinical trials as they are currently designed are unable to overcome these problems. That’s why we need to rethink our tactics, learn from past failures and take advantage of new data, all while following a few guiding principles.
Time to change tactics
Vaccine development is based on a clear understanding which type of immune response will achieve the intended effect, whether that’s preventing colonisation outright, or preventing illness; boosting the immune response, or altering it. The first step is to establish a solid rationale for the mechanism the vaccine should use to do its job as well as the best time to administer it. However, what’s missing is a clear understanding of the immune response to most of the hospital-acquired bacterial pathogens. This needs to change.
One of the complicating factors comes from the body’s own built-in defense mechanisms deployed by the immune system to protect us from infection: we don’t know enough about how these mechanisms interact with vaccines. If someone gets better, we often can’t tell if it’s thanks to the their own natural defenses, or whether it’s the vaccine. The result is that a clinical trial can’t return a clear verdict as to whether or not the vaccine works.
The way to overcome this would be to better analyse the individuals participating in a clinical study, and try to group them into sub-populations based on different biological characteristics (biomarkers), as this would help us figure out who might benefit from a vaccine and who might not.
Don’t give up on vaccines for AMR just yet
We need to take advantage of new scientific data, get better at defining disease outcomes that are pathogen-specific, and choose the immunological mechanism wisely. For example, vaccines can either target selective strains that pose the biggest threat in a particular hospital setting (instead of the whole species), or in the context of pneumonia, they could focus on triggering specific local T cells (instead of systemic immunity), which are white blood cells the immune system uses to fight infection.
This will require a better understanding of what T cell responses to look out for, which route of administration will work best for the different parts of the body, and when to vaccinate, among other questions. The tangled interplay between immune status and microbiome resilience and influence also needs to be investigated more thoroughly. On top of this, we need to paint a more detailed picture of individual patients and patient subpopulations in future trials. Being able to identify the people most likely (and unlikely) to benefit from vaccination would be a huge advantage.
This may cost a lot of money, but it seems like the only way to make sure that the results obtained in the clinical trials are meaningful. This is not a new idea, but it’s in line with the growing drive for personalised medicine and individualised treatment, concepts recently introduced to the field of infectious diseases, antibiotics and vaccination.
The different biology of individual patients, added to the variety of bacterial strains, disease progression and the unique situation in each hospital, have all complicated vaccine development for tackling antimicrobial resistance, leading to many vaccine development programmes getting dropped. However, the power of vaccines to prevent such infections has been demonstrated, and a renewed effort is warranted.