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Undocumented or subclinical influenza cases may explain why those who have received repeat influenza vaccines over multiple seasons are at higher risk for the disease.

The occurrence of undocumented or subclinical influenza infection may explain why patients who have received influenza vaccines repeatedly over multiple seasons face a higher risk for contracting the disease than those who have not, according to findings published in the Journal of Infectious Diseases.

The findings suggest that measurements of vaccine efficacy should account for both clinical and subclinical exposure to influenza.

“Previous studies have shown that the influenza infection risk in vaccinees repeatedly vaccinated across multiple seasons can be higher than the risk among non-repeat vaccinees, a phenomenon called repeat vaccination effect,” Qifang Bi, PhD, tells Physician’s Weekly. “However, previous studies haven’t accounted for several factors that could potentially bias the estimates. Our paper examines whether three potential factors, the timing of vaccination, recent clinical infection history, and subclinical infection history, can fully explain the repeat vaccination effect. This helps improve our understanding of the benefits of influenza vaccination.”

Evaluating Factors Linked With Reduced Vaccine Efficacy

The researchers performed a secondary analysis of data from the US Flu Vaccine Effectiveness Network, including information collected between the 2011-2012 and 2018-2019 influenza seasons. The study was conducted at five sites within the network in Michigan, Pennsylvania, Texas, Washington, and Wisconsin. Patients who received a vaccine within 14 days of the onset of illness were excluded from the analysis, and so were those who received more than one dose each season before the onset of symptoms, as well as infants younger than 1 year of age at the time of enrollment.

The study sites offered insight into 61,943 different visits, 90% of which were eligible for inclusion in the analysis. Approximately half (50.2%) of visits were from patients who received one dose of that season’s vaccine at least two weeks before the onset of illness. Among those patients vaccinated two weeks or more before falling ill, nearly three-fourths of visits (73.7%) were by patients who had been vaccinated at least once during the prior flu season, according to the researchers.

The Wisconsin Vaccine Effectiveness Network site (Marshfield Clinic) was the primary center for inpatient and outpatient care in its area, allowing for a more complete picture of patients’ influenza testing history and medical histories over multiple flu seasons than the other sites, Dr. Bi notes.

“At Marshfield Clinic, we examined the impact of known prior-season clinical infection on the effect of repeated influenza vaccination using data from our records,” Dr. Bi explains.

The researchers then conducted logistic regression analysis and mathematical modeling to examine three possible explanations for why infection rates appear higher in patients who have been repeatedly vaccinated.

Study Results

“First, we observed that repeat vaccinees tend to vaccinate a few weeks earlier in the season, and other work has shown that influenza vaccine effectiveness wanes. When we adjusted for the time of vaccination, we still estimated an increase in influenza infection rates in repeat vaccinees,” Dr. Bi says.

Patients who were repeatedly vaccinated tended to receive their vaccines 1 week earlier in the influenza season than other patients, the researchers reported (1.1 weeks, 95% CI, 1-1.2). They wrote that repeat vaccine recipients were more likely to test positive for strain A(H3N2) compared with other patients (odds ratio, 1.11, 95% CI, 1.02-1.21). However, according to Dr. Bi, patients were not more likely to test positive for influenza B or influenza A(H1N1).

“Next, we tested whether differences in the rate of recent medically attended influenza infections could explain the apparent increased infection risk in repeat vaccinees. We know that having a clinical influenza infection protects against future clinical influenza infections, and we also found that unvaccinated people who have confirmed infections, especially children, are especially likely to be vaccinated in the next year. We couldn’t explain the trend we were seeing.”

Although clinical infection did influence patients’ decisions on whether to get vaccinated the following season, “adjusting for recent documented clinical infections did not strongly influence the estimated effect of prior-season vaccination,” the researchers wrote.

“Finally, we considered that most influenza infections are not medically attended, and these infections can also protect against future infections and potentially enhance responses to future vaccination,” Dr. Bi says. “We examined scenarios in which medically unattended infections could explain estimates, and we found that non-medically attended infection could potentially explain the higher infection rates in repeat vaccinees.”

Improving Measures of Vaccine Efficacy

Dr. Bi said the results indicated that how influenza vaccine efficacy is measured needs to change.

“We need a better understanding of infection and vaccination histories. We expect follow-up studies to examine the effect of repeated vaccination after stratifying individuals by clinical and subclinical exposure history. This could be achieved by conducting longitudinal cohort studies that involve blood collection, active surveillance, and sequencing to identify subclinical infections.”

She cautions, however, that the study did not evaluate the benefits or limits of annual influenza vaccination programs.

“Our analysis doesn’t directly examine the practical benefits of the annual vaccination program and shouldn’t be considered as evidence supporting or undermining annual vaccination of influenza vaccine,” Dr. Bi says.