Adjuvant Immunotherapies as a Novel Approach to Bacterial Infections

Elisa T Helbig; Bastian Opitz; Leif E Sander


Immunotherapy. 2013;5(4):365-81. 

In This Article

Abstract and Introduction


The rapid emergence of multidrug-resistant pathogens, especially Gram-negative bacteria and mycobacteria, represents one of the major medical challenges of the 21st century. The gradual loss of effective classical antibiotics for many bacterial pathogens, combined with an increasing population density and mobility, urgently calls for the development of novel treatments. Here, we discuss the potential of adjuvant immunotherapies to selectively stimulate protective immune responses as a treatment option for bacterial infections. In order to elicit appropriate immune responses and to avoid unwanted inflammatory tissue damage, it is essential to identify ligands and receptor pathways that specifically control protective responses at the site of infection. We summarize existing data and discuss suitable candidate targets for future immunotherapies of infectious diseases.


In light of the sweeping success of antibiotics and vaccines in the mid-20th century, there was the widespread fallacious notion in the 1960s and 1970s that infectious diseases had been defeated once and for all. One of the world's leaders in infectious diseases at that time, Petersdorf, predicted a millennium in which clinical infectious disease fellows would have to "culture themselves".[1,2] Unfortunately, these and other anecdotal prophecies were false. Today, infectious diseases continue to represent one of the largest medical problems and socio-economic challenges worldwide.[3] In low-income countries, infectious diseases represent the leading cause of death. While in middle- and high-income countries most people die from chronic conditions such as cardiovascular diseases and cancer, mortality rates of infectious diseases such as pneumonia remain stubbornly high despite easy access to healthcare and antimicrobials.[201] Why did the optimistic prophecies of the mid-last century fail? The reasons are probably simple: as environments and hosts change, so do the microorganisms and their vectors, creating new host–microbe interactions and new diseases. Simply speaking, modern medicine was unable to outrun microbial evolution. In the past century alone, several hundred documented infectious diseases have emerged or re-emerged.[4] The most prominent examples are viral diseases such as HIV/AIDS, SARS or Ebola; however, strikingly, bacterial infections represent the majority of all emerging infectious diseases.[4]

Introduction of antibiotic therapy in the 1930s was undoubtedly one of the greatest medical breakthroughs of all time, which saved millions of lives because infectious disease (e.g., pneumonia)-related mortality was dramatically reduced.[5] Today, many standard procedures such as abdominal surgery are hard to imagine without the ability to prevent and treat bacterial infections with broad-spectrum antibiotics. However, the easy availability and widespread (mis-)use of antibiotics has come at the price of a sharply increasing bacterial drug resistance due to Darwinian selection. Unfortunately, at the same time, the antibiotic pipeline has successively dried up in the past few decades.[6]

Antibiotic resistance is a rapidly growing global problem; however, with specific geographic distribution patterns.[202] For instance, eastern Europe and Asia are experiencing alarmingly high rates of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis infections,[7,8] which, in combination with an increased population mobility, is likely to lead to a renaissance of tuberculosis in western countries. Antibiotic-resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococci have drawn significant public attention.[9] Fortunately, infection rates are slowly decreasing in recent years[10] and most isolates are still sensitive to second- and third-line antibiotics such as linezolid. By contrast, the drastic increase of multidrug resistance among Gram-negative bacteria, especially Enterobacteriaceae such as Escherichia coli, Klebsiella spp. and nonfermenters such as Pseudomonas and Acinetobacter spp., is a cause for major concern.[11–13] As extended-spectrum β-lactamase (ESBL) rates are soaring in parts of Asia, Latin America and southern Europe, with frequencies of ESBL for E. coli and Klebsiella spp. reaching >80% of clinical isolates in India,[11] classical antibiotics such as third-generation cephalosporins are falling by the wayside. Rising cephalosporin resistance has in turn greatly increased carbapenem consumption. Until recently, carbapenems were typical reserve antibiotics with near-universal activity against all Enterobacteriaceae, most other Gram-negative and several Gram-positive bacterial species. Lately, several different carbapenemases have been isolated. Carbapenemase-producing strains are on the rise and they are usually resistant to most antibiotics with the (partial) exception of tigecycline and some old and sub-optimal agents such as colistin or fosfomycin.[14,15] However, tigecycline has little or no activity against Pseudomonas and tigecycline-resistant Enterobacteriaceae are also emerging.[16] Furthermore, tigecycline has shown limited clinical effectiveness in treating severe infections, possibly due to its pharmacokinetic/pharmacodynamic profile and its bacteriostatic rather than bacteriolytic activity.[17] Moreover, even completely colistin-resistant carbapenemase-producing Klebsiella pneumoniae strains have already emerged,[18] leaving no more arrows in the antibiotic quiver. These scenarios have led WHO and leading infectious disease professionals to warn that modern medicine is on the verge of a postantibiotic era,[203] an ironic contrast to the euphoric predictions of the 1960s.

Antibiotic resistance is often encoded on promiscuous plasmids, which can be easily transferred among strains and species, thereby facilitating the fast spread of drug resistance. Gut resident microflora[19] or contaminated food and water[20,21] have been shown to serve as a reservoir and source of spread for antibiotic resistance such as ESBL. Misuse of antibiotics creates selective pressure which favors the development of drug resistance. Some authors have estimated up to 50% of all antibiotic prescriptions worldwide to be considered inappropriate.[22] Such misuse includes antibiotic treatment of viral infections, prescription of broad-spectrum antibiotics for banal infections, too low dosing or too short intake periods, all of which create ideal conditions for Darwinian selection of antibiotic- resistant mutants. Another cause for concern is the massive consumption of broad-spectrum antibiotics in animal farming. In addition to, for example, high ESBL carriage rates in poultry, published evidence suggests that soil resident bacteria are becoming increasingly antibiotic-resistant as a result of uncontrolled antibiotic use in meat production and plant agriculture.[23] In an excellent study, Forsberg et al. recently demonstrated that soil bacteria may serve as an important environmental source of resistance genes.[24] The authors found perfect sequence identity in several resistance genes and flanking mobile elements of soil bacteria and human pathogens as a direct indicator of horizontal gene transfer of resistance genes.[24]

The combination of rapidly emerging multidrug resistance and increasing global population density urgently calls for novel, broadly effective and cost-efficient therapies for infectious diseases. While the development of new antibiotics is sorely needed, the pipeline may still fail to keep pace with the emergence of resistance.[6] It will therefore be important to design strategies to limit our dependence on antibiotics as the sole therapeutic option for bacterial infections. Instead of the traditional pathogen-centered therapies, we discuss the prospects of host-focused approaches to selectively stimulate protective antimicrobial immune responses. Such treatments are referred to as adjuvant immunotherapies and could be used as an alternative or a potent addition to conventional antibiotics.[25] Intentional induction of antimicrobial immunity is an old and very efficient prophylactic concept, first introduced by Edward Jenner in 1798 and widely known as vaccination.[26] Specific vaccines against problematic pathogens known to frequently carry antibiotic resistance could critically limit their spread. However, besides technical obstacles to develop efficient targeted vaccines, there is growing vaccination reluctance in the population due to safety concerns.[27] In addition, acute bacterial infections demand quick-acting therapies. Classical vaccines confer protection by generating adaptive immune responses, which normally require several days or even weeks to fully unfold. By contrast, the innate immune system possesses a large arsenal of antimicrobial effectors, which can be activated within minutes or hours. Furthermore, innate immune responses are antigen-independent, allowing a broader application of adjuvant immunotherapies, at least against the same class of pathogens (e.g., Gram-negative extracellular bacteria). It has also been suggested that immunotherapies may be favorable for managing chronic infections such as M. tuberculosis infections.[28] Here, we discuss novel strategies for targeted activation of innate immunity and review previously published studies on innate immune stimulants as adjuvant immunotherapeutic agents. We will particularly focus on novel insights into the immunological decision-making mechanisms that govern antimicrobial responses and means to manipulate them therapeutically.