Vaccine makers seek a role in the fight against antibiotic resistance

Take the current pneumococcal conjugate vaccines (PCV), which have been highly effective in reducing the prevalence of drug-resistant S pneumoniae infections. Five years after the PCV vaccine was introduced in the United States, invasive pneumococcal disease caused by drug-resistant strains in children under 2 was reduced by 84%; in South Africa, the rate of penicillin-resistant pneumococcal disease in children fell by 82%.

"In the case of the pneumococcal vaccine, we've seen there is significant potential to reduce the burden of resistant infections," said One Health Trust Director Ramanan Laxminarayan, PhD, MPH.

But global uptake of licensed bacterial vaccines needs to be higher; uptake of the PCV vaccine, for example, is only at 60%. In a study published in BMJ Global Health, Hasso-Agopsowicz and colleagues from the International Vaccine Institute, the Novo Nordisk Foundation, and the London School of Hygiene & Tropical Medicine estimated that getting to 90% global coverage for the PVC vaccine could avert 59,000 AMR deaths.

"I think this is precisely why we wanted to highlight that these vaccines already exist, and that we can do so much more already with the existing tools," Hasso-Agopsowicz said. "We still have 40% of children who do not get vaccinated [with] this important vaccine."

Current S pneumoniae vaccines in the pipeline aim to increase serotype coverage and reduce manufacturing costs, which could boost uptake.

The typhoid conjugate vaccine (TCV) is another bacterial vaccine with high efficacy but low uptake. More than 110,000 deaths from typhoid fever occur each year, and multidrug-resistant strains have become prevalent in parts of South Asia and Africa. A One Health Trust report estimated that an infant TCV program could prevent approximately 53.5 million cases of drug-resistant typhoid in 73 LMICs over 10 years.

"Improving vaccine coverage with existing, licensed vaccines, like PCV and TCV, is a priority—both to reduce the overall mortality associated with these infections, as well as to reduce AMR," Padmini Srikantiah, MD, MPH, who leads the AMR strategy at the Gates Foundation, said in an email.

The problem of endemic bacteria

Then there are several pathogens for which no licensed vaccine exists, but which have drawn interest from vaccine developers because of their potential impact on morbidity, mortality, and antibiotic use.

Among them is Shigella, one of the leading causes of diarrheal disease in children under 5 and a common cause of antibiotic use in LMICs. A recent study published in PLOS Medicine found that a 2-dose Shigella vaccine modeled on the candidates in the pipeline and with 60% efficacy, given at 9 and 12 months, could cut antibiotic course for Shigella diarrhea by 34.5% in low-income settings.

"These kids get a lot of Shigella, and they have a lot of antibiotic use for Shigella," said lead study author Elizabeth Rogawski McQuade, PhD, MSPH, of Emory University's Rollins School of Public Health. "In terms of absolute magnitude, this is an important and I think significant reduction."

In addition to driving antibiotic use, Shigella is one of the endemic bacterial pathogens that contribute to high childhood mortality rates in LMICs, and it caused an estimated 93,000 deaths in children under 5 in 2019.

"Shigella is the biggest cause of diarrheal deaths that doesn't currently have a vaccine," MacLennan said.

MacLennan, who's also a clinician with experience working in hospitals in Kenya and Malawi, says the child deaths caused by Shigella and other endemic bacteria are commonplace in these settings, though they don't get the same attention as those that occur during "in-your-face" epidemics like Ebola. These are the deaths that MacLennan believes bacterial vaccines could help prevent.

"It's an absolute tragedy if you lose a child in a hospital in a high-income country, but it happens all the time in LMIC settings," he said. "And a lot of this is endemic bacterial disease."

Shigella, E coli and K pneumoniae are among the pathogens with vaccine candidates listed in the third group (Group C) of the WHO pipeline report, based on the fact that the candidates are still in the early stages of clinical development and the feasibility for development is considered moderate. In other words, they're a long way off.

"Vaccines against these pathogens might be available in the long term, however, short term solutions to prevent resistance should focus on other interventions to reduce AMR," the WHO wrote.

A chance to protect newborns from deadly infections

But even though it could be many years until such a vaccine exists, the Gates Foundation believes that a maternal vaccine that could target K pneumoniae could have a profound impact.

"Klebsiella pneumoniae is the leading cause of neonatal sepsis and related deaths in low- and middle-income countries," Srikantiah said. "Because of the outsize burden of Klebsiella pneumoniae infections in neonates in these geographies, we have prioritized the development of a maternal vaccine that could be given to a pregnant woman in the second or third trimester to provide protective antibodies to the newborn infant."

One of the reasons neonatal sepsis is so deadly in LMICs is that the K pneumoniae, E coli, and other bacterial pathogens that newborns are infected with are frequently multidrug-resistant, according to Phoebe Williams, PhD, MSc, a pediatrician and infectious disease physician at the University of Sydney.

"In some of the healthcare settings that we're working in in Southeast Asia…three-quarters of babies that have a positive blood culture will die in those settings," Williams told CIDRAP's Superbugs & You podcast. "And that's because they are almost always due to multidrug-resistant pathogens. And there is just no access to antibiotics that work for those bugs."

"The treatment options are extremely, extremely limited, especially in countries where access to last-resort antibiotics is extremely limited and challenging," Hasso-Agopsowicz said. "As a result, a lot of neonates die, because they just do not have access to appropriate medications."

The lack of access to antibiotics that might treat those infections is what makes vaccines—which could prevent those infections from occurring—such an intriguing option.

Srikantiah was part of a team of researchers that estimated, in a May 2023 modeling study in PLOS Medicine, that a maternal vaccine conferring protection against K pneumoniae infection could reduce neonatal sepsis deaths in many LMICs by 15%. The study projected that the regions with the greatest reduction in neonatal sepsis deaths—sub-Saharan Africa and southeast Asia—would likely see the greatest reduction in newborn deaths from drug-resistant K pneumoniae.

Laxminarayan, who led that study, said that a vaccine that could protect newborns against Klebsiella is crucial for driving down neonatal deaths in LMICs.

"Without really tackling [Klebsiella], we don't have a way of reaching the UN Sustainable Development Goals for child survival and newborn mortality," he said. "So we need this."

That's why a vaccine that could target the pathogens that cause neonatal sepsis has been a priority both for CARB-X and the Gates Foundation, which is one of CARB-X's funders. In its most recent round of awards, CARB-X has made maternal vaccines for neonatal sepsis one of its funding priorities.

"If you can vaccinate the mother, in a way that's compatible with other vaccine regimens for pregnant women, that could really forestall the transmission of an infection that can kill a baby," CARB-X research and development chief Erin Duffy, PhD, told CIDRAP News in 2022.

A long road ahead

Back in St. Paul, Herron-Olson is pondering the many hurdles, both scientific and financial, that will need to be cleared before Alloy-EK could be given to pregnant women to help protect their newborns against those deadly infections.

"The CARB-X award gets us to phase one," she said. "Vaccine clinical development is very long and expensive, so additional investments will be needed."

Furthermore, bacterial vaccines are particularly challenging to develop, because bacteria are more complex organisms than viruses and possess a variety of antigens that could be potential targets.

"There's plenty of challenges in the bacterial vaccine space, perhaps more so than viral vaccines, where there are a number of different technologies and limited number of targets that you can go after," said MacLennan.

First, Syntiron will have to prove that Alloy-EK is safe and effective in women who experience recurrent UTIs. Testing in animal models of infection, Herron-Olson said, has shown a reduction in the severity of UTIs with the vaccine.

But the question is whether the underlying technology will work in people. Vaccines containing iron receptors have been very successful in the animal health industry, where Syntiron's affiliate veterinary company, Vaxxinova, has several bacterial vaccines on the market for livestock species. The biochemical and immunologic requirements for human vaccines, however, are different than for animal health vaccines. That required Herron-Olson and her team to re-engineer the technology.

In addition, the history of drug and vaccine development is littered with compounds that worked well in small animals, such as rodents, but not in people. On the other hand, Herron-Olson believes the lessons learned from livestock animals that are physiologically more similar to humans and naturally infected by the same bacteria give Syntiron a competitive edge.

The first-in-human trials will test whether the vaccine is safe and measure the immune response stimulated by the vaccine. Depending on the result, the next step would potentially be two phase 2 trials: one would test the efficacy of Alloy-EK in women who have recurrent UTIs, the other would look at efficacy in pregnant women.

"We really believe that the design and engineering that went into this vaccine is superior to past approaches," Herron-Olson said. "But the only way we'll really know its potential is to evaluate it in humans."

And if Alloy-EK proves successful, there are other bacterial pathogens that Syntiron hopes to target, including Salmonella and Staphylococcus aureus.

"We're really interested in getting this vaccine into clinical trials and then continuing to work on the other vaccines," Herron-Olson said. "Because AMR keeps us up at night."