Interview Questions for Brad Spellberg
For Developing a Broad-Spectrum Vaccine:
- Your work on a broad-spectrum vaccine represents a significant innovation in preventing healthcare-associated infections. Can you delve into the latest advancements in its development and explain how this vaccine leverages innate immunity to offer protection against multiple pathogens simultaneously?
The AMMA vaccine that was published a few months ago in Science Translational Medicine (https://www.science.org/doi/10.1126/scitranslmed.adf9556) is a first-in-class mechanism vaccine. It works not by inducing antibody or T cell responses to protect against pathogens, but rather by inducing Trained Immunity. Trained Immunity remains a relatively new concept in Immunology. It was first described less than 15 years ago, and its nuances are still being worked out. Trained Immunity is a form of short-term memory that occurs in innate immune cells, rather than lymphocytes. During Trained Immunity, genetic transcriptional changes occur in macrophages or other innate cells (e.g., NK cells) that enable them to respond differently to a second contact with an immune stimulus than the first. The molecular mechanism of this memory is acetylation and/or methylation of histones, which result in altered transcription factor access to various genes. The phenomenon lasts for weeks to months, generally, rather than years to decades like traditional lymphocyte mediated adaptive (memory) immunity does.
The trade-off of this shorter term memory immunity is that it is much broader in pathogen scope. Adaptive lymphocyte-mediated immunity is incredibly specific to single epitopes from pathogens, with efficacy mediated by highly specific antibody or T cell receptor binding. But Trained Immunity results in more general protective effects. The AMMA vaccine, for example, induces macrophages to more effectively phagocytize microbes, both Gram positive and Gram negative bacterial pathogens. It also induces a net anti-inflammatory phenotype, rather than a pro-inflammatory phenotype. The result is a very unusual combination of enhanced clearance of pathogens with a damping down of systemic sepsis response. We have likened it to the vaccine converting macrophages in the Incredible Hulk, which can “smash” the bad guys. But not only the Incredible Hulk, it’s the smart version of Incredible Hulk—the “Smart Hulk”. Because they smash the bad guys while keeping the inflammation down that normally would cause host injury from sepsis.
Efficacy has been established against numerous high priority antibiotic-resistant pathogens, including MRSA, VRE, carbapenem-resistant Pseudomonas, Acinetobacter, and Klebsiella, ESBL E. coli, and the fungi Candida and Rhizopus (one of the etiologic agents of the mold infection mucormycosis). Efficacy persists in mice with no lymphocytes and in neutropenic mice, but is completely ablated in mice lacking macrophages. We also demonstrated hallmark changes to histones and gene expression typical of Trained Immunity.
Other vaccines are known to cause a Trained Immunity effect, but they are not used for that Trained Immunity effect. For example, the BCG vaccine against TB has been published in large studies to result in a reduced risk of other, non tuberculous infections for approximately 12 months and possibly up to 24 months after receipt of the vaccine, and this effect is known to be due to Trained Immunity. The reason the Trained Immunity effect lasts so long is that BCG is a live bacterial vaccine, and the bacteria continues to replicate in the host for months after immunization. In contrast, we are using inert vaccine components that are non viable. So we expect shorter term protection, on the order of weeks. But that is long enough to protect against hospital acquired infections, since most hospitalizations last less than 1 week.
We are now looking to move the vaccine towards the clinic, and hope to begin clinical trials possibly in 2025.
For Challenging Conventional Antibiotic Dogma:
- In recent years, the approach to antibiotic use has been evolving. What are the most critical new insights about antibiotic duration and specificity that healthcare professionals should be aware of, and how might these change current clinical practices?
What we have witnessed in the last 15 years is a fundamental revolution in thinking about antibiotics based on one overarching theme, which has multiple ripple effects. The overarching theme, quite simply stated, is that virtually everything we thought we knew about antibiotics was based either on no data, or low quality data such as uncontrolled case series from the 1940s and 1950s, rather than the high quality data many of us have long presumed to exist. It doesn’t. Antibiotics were among the earliest effective therapies in all of medicine, preceded only by ether for surgery, opiate for pain, digitalis for heart failure, and impure insulin harvested from pig pancreas. They emerged on the scene so early, in the 1930s with sulfonamides and then 1940s with other classes, that randomized controlled trials were not yet being used to assess the efficacy of therapeutics. So dogmas became established about antibiotic practices in the absence of high quality data.
The ripple effect of this is that we have learned in the last 15 years that many cherished dogmas are simply wrong. Remember static and cidal as a concept for antibiotics? Yeah, that’s done. Cidal antibiotics are not more effective than static antibiotics, based on an analysis of more than 50 randomized controlled trials in which static and cidal antibiotics were compared head to head.
Durations of therapy are another widespread example. Most doctors prescribe antibiotics in 7 day increments, and some doctors prescribe in 5 day increments. 10-14 days is a commonly used range. The evidence for these durations? It turns out, the 7 days derives from the fact that in 321 C.E., Roman Emperor Constantine the Great decreed there would be 7 days in a week (based on the Old Testament, since he was an early convert to Christianity). Had good old Constantine decreed a 4 day work week, we’d be giving 4-8 days of therapy instead of 7-14 (and we would also have only 2 work days before the weekend, which would have been nice). There are no other data to validate a 7-14 day duration. It’s just the arbitrariness of our definition of a week, which does actually derive from an actual decree from Constantine in 321 C.E. But as we know, some doctors prefer 10 day increments. What’s the evidence for 10 days? Well, it’s actually based on the number of fingers that evolved on the hominid hand. That’s the evidence. Seriously. This has led some of us to speculate that the world would be a better place, with less antibiotic resistance, if we had instead evolved as 3-toed sloths. But here’s the thing. We no longer need to use Constantine units and hominid metacarpal bone numbers to select durations of therapy for many infections. In the last 20 years, there have been more than 130 randomized controlled trials comparing durations of therapy for many types of acute infections. In virtually every one of those trials, the shorter duration of therapy (typically in the 3-5 day range) has been equal in efficacy to longer durations (typically in the 10-14 day duration). From this new evidence base, the Shorter Is Better movement has been born. It is now mainstream, and standard of care for many types of infections, resulting in the same cure rate, but with fewer harmful adverse events and less selective pressure driving resistance than longer courses of therapy.
Another recent example of toppled antibiotic dogma is the “Oral Is the New IV” movement. Since the 1940s, one of the most deeply held beliefs in all of medicine is that IV antibiotics are “more powerful” than oral antibiotics, and that for many types of invasive infections, they must be treated with intravenous antibiotics rather than oral antibiotics. The consequence of this is IV therapy dogma that patients are either kept in the hospital for prolonged periods of time, or sent home with an invasive catheters for prolonged times. There are real harms from this practice. But numerous randomized controlled trials conducted in the last 20 years have confirmed, without exception, that oral therapy is as effective as IV-only therapy for infections ranging from bone infections, blood infections, abdominal infections, and even heart valve infections, which have long been considered sacrosanct and requiring IV therapy.
What we have learned, ultimately, is that medicine has long been based on eminence rather than evidence—it is the famousness of the old teachers of decades past, propagated by more recent famous practitioners who write national guidelines that demand care be delivered in specific ways without meaningful evidence to support these demands, that has created care standards. Not evidence. And we are challenging that and changing it, so that Medicine can move to evidenced-based evolution of practice, rather than eminence-based consistency of practice.
