Vaccines are often overlooked and only got much-needed attention during the Covid-19 pandemic. Now, it's time some of that spotlight shifts over to bacterial infections.

Bacterial vaccines often receive less attention compared to viral infectious diseases because bacterial infections are not perceived as harmful as viruses, which can rapidly spread and cause pandemics like Covid-19. 

However, it is important to note that bacterial infections can also be silent killers, especially with the rise of antimicrobial resistance (AMR) on a global scale.

The AMR phenomenon occurs as bacteria develop mutations that protect them against antibiotics. It is a complex and integrated issue as it involves humans, animals, and environmental health which all use antimicrobials.

The World Health Organization (WHO) recognizes the full value of vaccines and advocates for their use in preventing and controlling bacterial infections and antimicrobial resistance (AMR). 

The WHO's Global Vaccine Action framework is focused on expanding the use of licensed vaccines to maximize their impact on AMR. It also emphasizes the development of new vaccines that contribute to the prevention and control of AMR, while promoting a greater understanding of the impact of vaccines on AMR.

However, it is often argued that the full value of vaccines is not marketed. For example, influenza vaccines do not only prevent influenza but in older patient populations, they can have more widespread effects protecting against diseases like stroke and coronary diseases.

Likewise, bacterial vaccines can help contribute to the fight against AMR by preventing infections and reducing antimicrobial use.

Vaccines vs AMR

The potential of vaccines in combating AMR was initially discovered through observation of an 84 percent reduction in invasive disease caused by drug-resistant forms of Streptococcus pneumoniae, which were specifically targeted by a pneumococcal vaccine in children under the age of two.

They can directly impact AMR issues by preventing infection, carriage, and spread of resistant organisms. They can also indirectly reduce antibiotic use and selective pressures which are responsible for an increase in drug resistance.

In particular, typhoid conjugate vaccines (TCVs) have confirmed their impact in preventing drug-resistant typhoid cases and deaths in Pakistan, Bangladesh, Nepal, and Malawi. 

The Global Alliance for Vaccines and Immunization (GAVI) has also recognized the importance of TCVs in combating antimicrobial resistance (AMR) and has committed to supporting their deployment in regions where they are most needed.

Modeling studies on the TCV’s impact on resistant typhoid in 73-GAVI countries showed that routine immunization at 9 months until 15 years of age could reduce the prevalence of antimicrobial-resistant typhoid fever by 16 percent to avert 42.5 million cases and 506,000 deaths caused by typhoid fever with fluoroquinolones and similarly, 21.2 million cases and 342,000 deaths from multidrug-resistant typhoid fever.

Most promising bacterial vaccine candidates

At the current pace, AMR is expected to kill 10 million people each year by 2050, with a yearly cost of $100 trillion, according to the WHO. In 2019, there were 4.95 million deaths globally associated with AMR, making bacterial AMR the 12th leading underlying cause of death globally, ahead of HIV, tuberculosis, and malaria.

Particularly, six pathogens including Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa led to 72 percent of deaths associated with bacterial AMR.

However, among these leading pathogens, only Streptococcus pneumoniae has a vaccine.

Fortunately, there are currently about 61 bacterial vaccines in active clinical development with the highest number of candidates with 16, 13, and 6 for S. pneumoniae, tuberculosis (TB), and Shigella flexneri respectively.

At the recently concluded Global Vaccines and Immunization Research Forum (GVIRF) in Korea, the progress of the most promising vaccine candidates was announced which included the Group B Streptococcus (GBS) maternal vaccine from Pfizer which is scheduled to enter phase 3 trials this year.

“An efficacy trial is going to be unlikely as it's too costly and time-consuming to undertake,” an official at Pfizer said. “We will instead aim for licensure by conducting a serocorrelate of protection but are unsure how regulatory bodies would react to this.”

Regarding Enterotoxigenic E. coli (ETEC) vaccines, the most promising candidates are two live attenuated vaccines, ETVAX and ACE527, and a fimbrial tip adhesins vaccine which are all in phase 2. Meanwhile, the most advanced Shigella vaccine, ShigETEC, completed phase 1 trials last year.

Additionally, the International Vaccines Institute (IVI) is also engaged in the development of an invasive non-typhoidal salmonella (iNTS) vaccine for which no vaccine yet exists. In 2022, the trivalent, multidose drug product vaccine formulation was optimized, and the technology transferring process was completed with its manufacturing partner SK Bioscience.

The iNTS disease is known to cause gastroenteritis, high fever, bloodstream infections, sepsis, and even death in severe cases.

“The iNTS vaccine is expected to undergo toxicology studies and will embark on an investigational new drug (IND) authorization for a phase 1 clinical trial plan in 2023,” remarked an IVI official.

Other innovative approaches

While the Covid-19 pandemic underscored the importance of vaccines, it also contributed to exacerbating AMR as antimicrobials were widely prescribed to manage the unfamiliar virus.

The WHO’s most recent report on Global Antimicrobial Resistance and Use Surveillance System (GLASS) linked the Covid-19 pandemic with a 15 percent increase in AMR rates in 2020 compared with 2017 for bacteriologically confirmed infection (BCI)s caused by meropenem and third-generation cephalosporin resistance in bloodstream E. coli, ciprofloxacin resistance in Salmonella spp., and azithromycin resistance in gonorrhea.

Aside from vaccines and antibiotics, rapid diagnostics for decision-making and monitoring resistant genes, new antibiotics, phage therapies, monoclonal antibodies, and microbiota-based interventions to target resistant pathogens were suggested to reduce AMR impacts.

Additionally, whole genome sequencing should be leveraged to investigate AMR genes and their resistance mechanisms to inform treatment guidelines and control strategies for other bacterial vaccines like the case for new typhoid conjugate vaccines.