Review article
The global surge in antimicrobial resistance presents a critical threat to public health, emphasizing the urgent need for the development of new and more effective bacterial vaccines. Since the success of mRNA vaccines during the COVID-19 pandemic, this vaccine strategy has rapidly advanced, with most efforts focused on cancer immunotherapy and targeting viral pathogens. Recently, mRNA vaccines have entered the early phases of clinical development for bacterial diseases. However, bacteria present greater biological complexity compared with viruses, posing additional challenges for vaccine design, such as antigen selection, immune response and mRNA construct design. Here, we discuss critical aspects in the development of bacterial mRNA vaccines, from antigen selection to construct design. We also highlight the current preclinical landscape and discuss remaining translational challenges and future potential for mRNA vaccines against bacterial infections.
Main
Antibiotics have been successfully used to treat bacterial infections for decades. However, recently, antimicrobial resistance (AMR) has been rising to dangerously high levels1,2,3,4. Bacterial vaccines represent an attractive tool to combat AMR as they can confer protection against infection and disease, while preventing the emergence and transmission of bacterial infections. This directly impacts on antibiotic prescription and overuse, and might thus limit the selection and dissemination of antibiotic-resistant strains5,6.
Bacterial vaccines are typically based on whole-cell vaccines (inactivated or live attenuated pathogens), polysaccharides alone or conjugated to proteins, and protein subunit vaccines. Whole-cell bacterial vaccines have the advantage of inducing immunity against a wide repertoire of bacterial antigens. Within this category, live attenuated vaccines are often more effective compared to inactivated vaccines because they retain the ability to replicate, thereby inducing a broader immune response. This feature, however, limits their use in immunocompromised individuals. Several successful bacterial subunit vaccines have been licensed in recent years. Among them, glycoconjugate vaccines, created by covalently linking polysaccharides to an antigenic protein, have proven particularly effective and cost-efficient in preventing bacterial infections, such as Haemophilus influenzae type B, Streptococcus pneumoniae, Neisseria meningitidis and Salmonella Typhi7. These vaccines also contribute to herd immunity by reducing transmission within the population8. Other successful bacterial vaccines have been based on protein subunits, including inactivated toxins (as for diphtheria and tetanus vaccines), virulence factors (as for the serogroup B meningococcus) or can be combined (as in the acellular pertussis vaccine). In addition, innovative approaches are currently in development, including engineered outer membrane vesicles (OMVs), derived from Gram-negative bacteria, and whole-cell vaccines developed using synthetic biology, as reviewed elsewhere9. Novel immune stimulants have also been investigated to enhance T cell-mediated immunity, boost immunogenicity and counteract immunosenescence in bacterial subunit vaccines. One example is the clinically approved AS01 adjuvant, a liposomal formulation of monophosphoryl lipid A with the purified saponin QS-2110. As a key final step in the development of the first new anti-tuberculosis vaccine in over a century, a phase III clinical trial is currently evaluating the efficacy of a vaccine candidate, composed of the M72 recombinant fusion protein—comprising two Mycobacterium tuberculosis (Mtb) antigens (Mtb32A and Mtb39A)—formulated with the AS01 adjuvant11. This vaccine is aimed at preventing pulmonary tuberculosis in adults and adolescents. Previous clinical data have already demonstrated that M72, formulated with AS01E, which enhances immune responses, provides over 50% protection against active pulmonary tuberculosis disease in Mtb-infected adults12.
Ilke Aernout,
Rein Verbeke,
Fabien Thery,
Patrick Willems,
Uri Elia,
Stefaan C. De Smedt,
Rino Rappuoli,
Dan Peer,
Francis Impens &
Ine Lentacker
