Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

Abstract

Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine developments targeting nosocomial bacterial pathogens; it further highlights the specific challenges associated with demonstrating clinical efficacy of these vaccines and the facts to be considered in future study designs. Notably, these vaccines are mainly applied to subjects with preexistent immunity to the target pathogen, transient or chronic immunosuppression and ill-defined microbiome status. Unpredictable attack rates and changing epidemiology as well as highly variable genetic and immunological strain characteristics complicate the development. In views of the clinical need, rethinking of the study designs and expectations seems warranted: first of all, vaccine development needs to be footed on a clear rationale for choosing the immunological mechanism of action and the optimal time point for vaccination, e.g., (1) prevention (or reduction) of colonization vs. prevention of infection and (2) boosting of a preexistent immune response vs. altering the quality of the immune response. Furthermore, there are different, probably redundant, immunological and microbiological defense mechanisms that provide protection from infection. Their interplay is not well-understood but as a consequence their effect might superimpose vaccine-mediated resolution of infection and lead to failure to demonstrate efficacy. This implies that improved characterization of patient subpopulations within the trial population should be obtained by pro-and retrospective analyses of trial data on subject level. Statistical and systems biology approaches could help to define immune and microbiological biomarkers that discern populations that benefit from vaccination from those where vaccines might not be effective.

The role of bacterial vaccines in the fight against antimicrobial resistance: an analysis of the preclinical and clinical development pipeline

“…

Challenges of developing vaccines against pathogens causing hospital-acquired infections Many of the WHO bacterial priority pathogens cause hospital-acquired infections, in particular Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus , extra-intestinal pathogenic Escherichia coli, Clostridioides difficile, Enterococcus faecium , and Enterobacter spp. There are multiple challenges 35 for the clinical development of vaccines against these pathogens: The relatively low incidence of infections in the vaccine target population makes efficacy trials prohibitively large in terms of trial sites and patient numbers, and expensive 3 Potential target populations tend to be critically ill, with multiple comorbidities and severely compromised immune systems, making clinical endpoints hard to establish 36 , 37 Identification of populations at risk of hospital-acquired infections at intensive care unit admission is impracticable, due to the little time available to mount an effective immune response 38 At present there is no regulatory or policy precedent for a vaccine against hospital-acquired infections Despite these limitations, it could be possible to identify patients at high risk, such as those scheduled for elective surgery or hospital treatment, which would allow enough time for their immune systems to respond to vaccine administration. Given these challenges, regulators could explore the use of correlates of protection in phase 3 trials followed by the collection of post-licensure effectiveness data and real-world evidence.

…”

Nanobiotics against antimicrobial resistance: harnessing the power of nanoscale materials and technologies

“…Immunization by vaccine remains the most effective method to provide protection against infectious diseases [197]. However, clinical applicability of many new potential vaccine candidates is limited due to low immunogenicity and inability to stimulate an effective long-lasting immunity [198,199]. In particular, subunit vaccines are less immunogenic and often fail to evoke desirable immune reactions.…”

Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents

“…Antimicrobial resistance is recognized as one of the greatest threats to human health ( World Health Organization [WHO], 2017 ; Morehead and Scarbrough, 2018 ; Murray et al, 2022 ). Thus, new antimicrobial therapies are urgently needed, although few are currently being developed ( Hughes and Karlén, 2014 ; Bekeredjian-Ding, 2020 ; Theuretzbacher et al, 2020 ). Due to numerous challenges, including long research timelines and limited financial reward, most large pharmaceutical companies are no longer investing in research and development of new antibiotics.…”