A new analysis of a randomized trial for an experimental respiratory syncytial virus (RSV) vaccine suggests there is potential for RSV vaccines to reduce antimicrobial prescribing in infants.
While the vaccine, a recombinant RSV F nanoparticle vaccine (RSV F) developed by Novavax, did not perform as well in the trial as was hoped and was not licensed, the analysis, published yesterday in the Proceedings of the National Academy of Sciences, found that among infants of mothers randomized to receive the vaccine, any antimicrobial prescribing over the first 90 days of life was reduced by nearly 13% compared with infants whose mothers' received a placebo.
The analysis also found that RSV is a major contributor to antimicrobial prescribing in infants, whether for lower respiratory tract infections (LRTIs) or other infections precipitated by RSV.
The authors of the study say the findings suggest that impact on antimicrobial prescribing should be considered in evaluations of future RSV vaccine candidates.
A leading cause of respiratory infections in kids
The results of the randomized, placebo-controlled trial, which was conducted in 87 sites in 11 countries from December 2015 to May 2018, showed that the vaccine efficacy (VE) of the RSV F vaccine was 39.4% against RSV-associated, medically significant LRTI in the first 90 days of life compared with placebo.
"The results with respect to the primary end point did not meet prespecified criteria for vaccine efficacy," the investigators wrote in the New England Journal of Medicine in 2020.
The initial trial did not consider impact on antimicrobial prescribing among its outcomes. But the follow-up data on adverse events, and the comprehensive medical history of the mothers and the infants in the trial, were all there. That provided researchers with an opportunity to go back and looks at rates of antimicrobial prescribing among infants in the two trial arms, explains lead study author Joseph Lewnard, PhD, an assistant professor of epidemiology at the University of California Berkeley.
"It was a particular priority scientifically because we recognized that acute respiratory tract infections are really the leading single driver of antibiotic consumption, which is of course a significant driver of resistance selection in pathogens relevant to humans," Lewnard told CIDRAP News.
RSV is a leading cause of respiratory diseases in children worldwide, causing an estimated 34 million acute LRTIs in children annually, with the highest incidence of severe disease occurring in infants 1 to 3 months old, according to the World Health Organization. "Everybody in early life pretty much gets exposed to, and infected with, RSV," Lewnard said.
In addition, Lewnard and his colleagues note that previous studies conducted in the United Kingdom have reported increases in pediatric antimicrobial prescribing during periods with greater RSV circulation.
Significant reduction in antimicrobial prescribing
Analysis of the follow-up data from the trial, which included 2,978 infants randomized to the RSV F vaccine arm and 1,546 randomized to the placebo arm, showed that over the first 90 days of life, antimicrobial prescribing incidence among infants whose mothers received the RSV F vaccine was 133.7 prescription courses per 100 person-years at risk, compared with 148.7 in children whose mothers received placebo.
The corresponding VE estimate was 12.9% (95% confidence interval [CI], 1.3% to 23.1%). VE against LRTI-associated antimicrobial prescribing was even higher—16.9% (95% CI, 1.4% to 29.4%).
Among infants in the high-income countries (HICs) in the trial (Australia, Argentina, Chile, New Zealand, Spain, the United States, and the United Kingdom), VE against all antimicrobial prescribing and LRTI-associated prescribing (20.2% and 49.4%, respectively) was higher than it was in low- and middle-income countries (10.9% and 12.8%, respectively, in Bangladesh, Mexico, the Philippines, and South Africa).
Accounting for differences in antimicrobial prescribing across settings, maternal vaccination prevented an estimated 3.6 prescription courses per 100 infants over the first 90 days of life in HICs and 5.1 per 100 infants in LMICs. LRTI episodes accounted for 69% to 73% of all antimicrobial prescribing prevented by maternal vaccination.
"The results are really quite encouraging, in so far as they identify that a very sizable chunk of all antimicrobial prescribing that occurred in early life—which is a critical developmental period for infants, their immune systems, and their microbiome—is preventable by a single vaccine," Lewnard said.
Another interesting finding was that in HICs, VE against antimicrobial prescriptions associated with ear infections (acute otitis media, AOM) was 71.3% (95% CI, 28.1% to 88.6%). It was notably higher in wealthier countries, the study notes, because ear infections tend to be underdiagnosed and undertreated in lower-income settings.
But Lewnard said it speaks to the impact that RSV—which is one of the most prominent viral causes of AOM—and an effective RSV vaccine could have on antimicrobial prescribing for ear infections, particularly in the United States, which accounted for more than 23% of infants in the study.
"A very substantial proportion of all the antibiotic-treated acute otitis media cases that were occurring [in the trial] could be prevented by an RSV vaccine," he said.
A potential stewardship tool
While the RSV F vaccine did not meet its primary endpoint, more are in development and may prove more effective at preventing both the disease burden caused by RSV and the accompanying antibiotic use. But even so, Lewnard said the findings from their analysis of this unsuccessful vaccine candidate, when compared with other antimicrobial stewardship efforts, highlight the significant role that vaccines could play in preventing unnecessary antibiotic use.
For example, he noted that intensive antimicrobial stewardship campaigns that target healthcare providers or patients, even when successful, have only reduced outpatient antibiotic prescribing by single digits.
"This is really a paltry figure and underscores the difficulty that we've had over decades with tackling antimicrobial prescribing through that avenue alone," Lewnard said. "Seeing here that a very sizable chunk of prescribing could be prevented by an RSV vaccine alone really suggests that we could have a strong new tool at our disposal for achieving this objective."