AstraZeneca Bets on Bioconjugation Without Human Data to Revive Bacterial Vaccines

AstraZeneca Acquires Omniose for Bioconjugation Technology

AstraZeneca has acquired Omniose, a vaccine startup and development partner, to integrate its proprietary "bioconjugation" technology. This technology is described as a more efficient method for creating conjugate vaccines, which involve attaching a protein to an immune system-provoking antigen. Omniose claimed this approach could lead to higher-quality conjugate vaccines. AstraZeneca intends to utilize this technology to develop new vaccines targeting serious bacterial infections, building upon a vaccine-focused alliance established between the two companies in January 2024. The specific financial terms of the acquisition were not disclosed.

• AstraZeneca's acquisition of Omniose strategically enhances its vaccine development capabilities by integrating Omniose's proprietary bioconjugation technology. This technology is touted as a more efficient method for manufacturing conjugate vaccines, which are crucial for targeting complex bacterial infections.
• The acquired bioconjugation technology is expected to enable AstraZeneca to produce "higher-quality" conjugate vaccines. This advancement is specifically aimed at developing new immunizations for serious bacterial infections, addressing a significant unmet medical need in infectious disease prevention.
• The acquisition formalizes and expands upon an existing collaboration between AstraZeneca and Omniose, which began in January 2024 as a vaccine-focused alliance. This prior partnership laid the groundwork for the current transaction, indicating a successful and deepening relationship between the two entities.

Addressing the Limitations in Serious Bacterial Infection Treatments

Current treatment of serious bacterial infections is constrained by escalating antimicrobial resistance, significant drug toxicities, and persistent pharmacokinetic and evidence gaps. These limitations affect both Gram-positive and Gram-negative pathogens and complicate therapy in critically ill and immunocompromised populations.

• Oxazolidinone toxicity and resistance: Linezolid, the first oxazolidinone antibiotic approved by FDA, is still used in therapy despite common adverse events, such as myelosuppression and serotonergic toxicity, as well as the increasing percentage of linezolid-resistant bacteria (Staphylococcus aureus, enterococci and methicillin-resistant S. aureus).

• Vancomycin limitations in staphylococcal infections: There has been an alarming increase in the rates of methicillin-resistant S. aureus (MRSA) over the past two decades, and the more recent emergence of heterogenous vancomycin-intermediate (hVISA), vancomycin-intermediate (VISA) and vancomycin-resistant S. aureus (VRSA) strains limits the use of vancomycin, the current standard of care for MRSA infections. Tolerance to vancomycin, which represents a lack of bactericidal activity of vancomycin, increasing MICs of vancomycin for staphylococci, poor tissue penetration by the drug and a slow rate of bactericidal action of the drug have also raised concerns about its efficacy.

• Polymyxin toxicity and narrow utility: Polymyxins were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and knowledge on polymyxins had been scarce until recently. Current use is limited by nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin.

• Aminoglycoside organ toxicity: Although aminoglycosides are clinically-essential antibiotics, the mechanisms underlying their selective toxicity to the kidney and inner ear continue to be unraveled despite more than 70 years of investigation. Serious bacterial infections induce systemic inflammatory responses that also potentiate the degree of ototoxicity and permanent hearing loss.

• Beta-lactam pharmacokinetic variability in critical illness: In critically ill orthotopic liver transplant (OLT) recipients, pathophysiological issues potentially affecting the pharmacokinetics of beta-lactams and beta-lactam penetration in the lung, ascitic fluid, and bile affect attainment of adequate pharmacokinetic/pharmacodynamic (PK/PD) targets. Several research gaps still exist in assessing the PK behavior of beta-lactams in critical OLT recipients, including the impact of specific OLT-associated pathophysiological alterations and the relationship between aggressive beta-lactam PK/PD target attainment and clinical outcome.

• High mortality from carbapenem- and colistin-resistant Gram-negative infections: Overall, the 28-day mortality rate was 66% in carbapenem-resistant K. pneumoniae bacteremia, with colistin resistance significantly increased with duration of hospital stay and prior colistin use, and age and colistin resistance significantly increased 28-day mortality. Among carbapenem resistant K. pneumoniae isolated from bacteremia, 74.1% and 67.9% mortality were seen among string test positives and isolates meropenem MIC of ≥16µg/ml respectively, and isolates with both string positivity and meropenem MIC of ≥16µg/ml had a very high mortality rate of 84.2%.

• Persister-cell tolerance and treatment failure: Persister cells comprise a phenotypic variant that shows extreme antibiotic tolerance resulting in treatment failures of bacterial infections, while mechanisms underlying their formation in Staphylococcus aureus remain largely unknown.

• Stewardship and evidence gaps: Fifty-seven percent of broad spectrum empiric therapy was continued despite culture results allowing de-escalation in young infants with serious bacterial infection. For daptomycin in hematological malignancies, there was a notable scarcity of studies, lack of comparative studies, and no randomized comparative trials in patients with febrile neutropenia.

Emerging Mechanisms of Action in Serious Bacterial Infection Therapies

Recent literature highlights diverse emerging mechanisms for serious bacterial infections, spanning direct bacterial targeting and host innate immune modulation. Activity spans methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant (MDR) bacteria, and multidrug-resistant Gram-negative bacteria (MDR-GNB).

• Inhibition of bacterial protein synthesis via peptidyl transferase center binding: 22-((2-methyl-1-(1H-pyrrole-2-carboxamido)propan-2-yl)thio)-deoxypleuromutilin exhibited potent antibacterial activity against Gram-positive bacteria (MRSA, MRSE, Staphylococcus aureus, Streptococcus agalactiae and Staphylococcus dysgalactiae), demonstrating a remarkably low MIC of 0.008 μg/mL, which was superior to both reference drugs tiamulin and valnemulin, with molecular docking demonstrating favorable binding to the peptidyl transferase center and inhibition of bacterial protein synthesis indirectly demonstrated through GFP expression inhibition assays.

• Hydrolysis of peptidoglycan in the cell wall: Staphylococcus simulans secretes lysostaphin, which destroys staphylococci through the hydrolysis of peptidoglycan in the cell wall, with recombinant lysostaphin-A-based ointment effective on excisional wound healing in an animal model and SEM results showing intense wrecking effects on bacterial cells.

• Nonspecific targeting of bacterial membranes leading to permeabilization and rupture: The gecko-derived cathelicidin from Gekko japonicus exhibited broad-spectrum antibacterial activity against both Gram-negative and Gram-positive bacteria, with minimal inhibitory concentrations ranging from 2.34 to 4.69 μg/mL, with lead peptide RH-16 adopting an amphipathic α-helical conformation and killing via rapid bacterial membrane permeabilization and rupture while retaining antibacterial activity in plasma.

• Antimicrobial peptide activity with immunomodulation: Brevinin-1E-OG9c-De-NH, derived from brevinin-1E-OG9 isolated from skin secretions of Odorrana grahami, showed potent antibacterial activity especially against S. aureus and attenuated inflammatory responses induced by lipoteichoic acid and heat-killed microbes.

• Siderophore cephalosporin and beta-lactam/beta-lactamase inhibitor combinations for MDR-GNB: Cefiderocol, a novel siderophore cephalosporin, demonstrated non-inferiority compared with standard-of-care therapies in complicated urinary tract infections, nosocomial pneumonia, and bloodstream infections sustained by GNB, while imipenem-relebactam (I-R), a novel beta-lactam/beta-lactamase inhibitor combination given with cilastatin, has in vitro activity against multidrug-resistant organisms including carbapenem-resistant Pseudomonas aeruginosa and extended-spectrum beta-lactamase and carbapenem-resistant Enterobacterales.

• Host-directed boosting of neutrophil killing and reactive adipogenesis: Retinoic acid (RA) stimulated primary human neutrophils to produce reactive oxygen species, neutrophil extracellular traps, and the antimicrobial peptide cathelicidin (LL-37) and directly inhibited growth of group A Streptococcus (GAS), reducing skin lesion size and bacterial burden in a murine model of GAS skin infection, while dermal Candida albicans infection triggered the dermal reactive adipogenesis response and induced cathelicidin expression in preadipocytes through the FGFR-MEK-ERK pathway.

The Evolving Treatment Landscape for Serious Bacterial Infections

Cefiderocol, the first siderophore-conjugated cephalosporin approved for use in the treatment of human bacterial infections, has emerged as a central advance for drug-resistant Gram-negative pathogens. It was approved by the FDA for treatment of complicated urinary tract infection, hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia and by the European Medicines Agency (EMA) for aerobic GN infections in adults with few treatment options. In the SENTRY Antimicrobial Surveillance Program, GN isolates including 8,047 Enterobacterales, 2,282 P. aeruginosa, 650 Acinetobacter species, and 338 S. maltophilia isolates were consecutively collected from patients in 66 hospitals in 19 countries in 2020. Enterobacterales susceptibility to cefiderocol was 99.8% (CLSI), and CRE susceptibility was 98.2%. Cefiderocol was the most active antimicrobial against all P. aeruginosa isolates with MIC values of 0.12/0.5 mg/L, respectively (99.6% susceptible). A total of 256 P. aeruginosa isolates were XDR, 97.3% were susceptible to cefiderocol, and 7.4% were susceptible to meropenem. Acinetobacter susceptibility to cefiderocol was 97.7%. S. maltophilia susceptibility to cefiderocol was 100.0% (CLSI, 2021) and 97.9% (CLSI, 2022). Additional in vitro work showed cefiderocol inhibited 94.4% (119/126) of MDRAB, 100% of imipenem-resistant P. aeruginosa, 100% of DTRPA and 100% of BCC at an MIC ≤4 mg/L, and 97.9% (46/47) of S. maltophilia at ≤1 mg/L.

Clinical trial findings support several newer β-lactam-β-lactamase inhibitor combinations, notably ceftazidime-avibactam (CZA, a cephalosporin-β-lactamase inhibitor combination), which is effective in treating complicated urinary tract infections (cUTI), complicated intra-abdominal infections and hospital-acquired and ventilator-associated pneumonia caused by GNBs, with other clinically effective combinations including meropenem-vaborbactam (MVB), ceftolozane-tazobactam (C/T) and imipenem-relebactam (I-R). In a retrospective, cohort, multicentre study of 46 patients with MDR P. aeruginosa bacteremia treated with either ceftolozane-tazobactam or colistin between September 2018 and August 2021, there was no association with the use of ceftolozane-tazobactam compared to colistin and the 30-day risk-adjusted mortality (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.16-2.13, P = 0.42), while ceftolozane-tazobactam use was associated with higher clinical success than colistin (RR 1.84, 95% CI 1.11-3.06: P = 0.021). Real-life data expand cefiderocol efficacy to treat multidrug-resistant Acinetobacter baumannii infections: in 11 patients treated with cefiderocol (>48 hours) between May 1, 2021, and September 1, 2022, early clinical improvement was documented in 8/11 patients (72.7%), clinical success in 8/11 patients (72.7%), and overall 30-day mortality was 27.3% (3/11). In 17 non-critical patients treated between January 2020 and March 2023, 15 (88%) patients were clinically cured and 12 (70%) had negative cultures, with Pseudomonas aeruginosa (59%) as the main causal microorganism. Cefiderocol attained CSF concentrations that exceeded the organism-specific MIC and the CLSI susceptible breakpoint (≤4 mg/L) for 100% of the dosing interval during treatment of carbapenem-resistant Acinetobacter baumannii meningitis, with penetration into CSF estimated as the AUCCSF/AUCfree plasma ratio was 68% and 60% for 2 g IV q6h and 2 g IV q8h regimens, respectively, and a case of post-traumatic chronic osteomyelitis caused by extensively drug-resistant (XDR) Pseudomonas aeruginosa was successfully treated with cefiderocol prescribed for six weeks.

For methicillin-resistant Staphylococcus aureus bacteremia, a systematic review and meta-analysis identified 5328 patients across 2 randomized controlled trials (RCTs), 1 pooled analysis of 5 RCTs, 1 subgroup analysis (1 RCT), and 5 case-control and cohort studies (CSs), in which primary and secondary effectiveness outcomes were comparable between patients treated with LZD versus VCM, TEIC, or DAP. In a single-center, retrospective cohort study of 30 patients with persistent MRSAB receiving vancomycin plus ceftaroline for ≥24 h, median time to MRSAB clearance post-ceftaroline initiation was 2.6 days, microbiologic cure occurred in 96.7% (29/30), median hospital length of stay was 19.5 days, and 90-day all-cause mortality and MRSAB-related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively. Therapeutic drug monitoring was an independent protective factor for microbiological eradication rate (p<0.001) in 105 patients in the TDM group and 208 patients in the non-TDM group with Staphylococcus aureus bacteremia, while recent RCT results show cefazolin is not inferior to flucloxacillin in the treatment of methicillin-susceptible S. aureus (MSSA)-SAB and is less nephrotoxic, and in low-risk SAB, early oral switch therapy is possible after 5-7 days. Across severe infections, rapid diagnostic tests combined with individualised decision-making improve the selection of antibiotic therapy, rapid de-escalation to narrow-spectrum monotherapy and shortening of the duration of therapy should be the rule, and pharmacokinetic (PK) optimisation and prolonged or continuous beta-lactam use is safe and may improve outcomes.