Huong Q. McLean

Summary: Coinfections may influence the clinical outcome of respiratory illness. Data are limited regarding RSV coinfections in adults with high‐risk conditions. Residual respiratory specimens from community‐dwelling adults (≥ 18 years) with ≥ 1 high‐risk condition were retested using a multiplex panel for multiple viral pathogens. We compared demographic and clinical characteristics between those with RSV coinfection versus RSV single infection. RSV coinfections comprised 5.9% of all RSV infections among adults with ≥ 1 high‐risk condition. No statistically significant differences were observed between those with RSV coinfections and single infections according to presence of specific high‐risk conditions or clinical disease presentation.

Background: Influenza B vaccine effectiveness (VE) has varied by season, lineage, antigenic drift, and vaccine composition. After B/Yamagata detection ceased globally, trivalent vaccines containing B/Victoria were reintroduced in 2024–25. We evaluated influenza B circulation and VE across eight analyzed seasons spanning this transition. Methods: Ambulatory patients aged ≥6 months with acute respiratory illness were enrolled at U.S. Flu VE Network sites during eight influenza seasons from 2016–17 through 2024–25; 2020–21 was excluded because influenza circulation was negligible. Participants were tested by RT-PCR. Lineage-specific VE was estimated using a test-negative design and logistic regression adjusted for age, sex, race/ethnicity, calendar time, and study site. VE was reported for season-lineage strata with ≥50 influenza B cases. Results: Among 65,773 participants, 3,629 influenza B cases were included in lineage-specific VE analyses (1,507 B/Yamagata; 2,122 B/Victoria). Six of 10 season-lineage strata met the reporting threshold. B/Victoria VE was 58% (95% CI, 28%–77%) in 2016–17, 51% (43%–57%) in 2019–20, 78% (71%–84%) in 2023–24, and 39% (14%–56%) in 2024–25. B/Yamagata VE was 55% (46%–63%) in 2016–17 and 49% (40%–56%) in 2017–18. Conclusions: Influenza vaccines protected against medically attended outpatient influenza B illness, although VE varied by season. Continued VE monitoring and genetic surveillance are needed to detect emerging influenza B viruses and inform vaccine strain selection.

Background: The extent to which influenza vaccination may temper disease remains uncertain. We compared symptoms between influenza vaccinated and unvaccinated ambulatory persons with influenza. Methods: We conducted household transmission studies across multiple US sites during consecutive influenza seasons from 2017–2018 through 2022–2023 (excluding 2020–2021 season with minimal influenza activity). We collected daily symptom diaries and respiratory specimens. Three scores were calculated, varying weights on specific symptoms: (1) influenza-like illness (ILI); (2) lower respiratory; and (3) all symptoms. For each score, we examined the daily mean score between those vaccinated and unvaccinated against influenza using weighted multivariable linear mixed effects and frailty models. Results: The study included 869 children (41% vaccinated, 47% female, 58% White, non-Hispanic) and 653 adults (42% vaccinated, 65% female, 72% White, non-Hispanic) with laboratory-confirmed influenza. In multivariable analyses, the mean difference in the daily ILI score was −0.16 (95% CI, −.32 to −.01) between vaccinated and unvaccinated children and −0.18 (95% CI, −.34 to −.01) for the lower respiratory score. There was no significant difference among adults. Influenza vaccination was not associated with time to symptom alleviation among children. However, ILI symptom alleviation occurred earlier among vaccinated (HR: 1.30; 95% CI, 1.04–1.62) adults. Conclusions: Ambulatory children with influenza who were vaccinated experienced less ILI symptom burden compared to those who were not vaccinated against influenza, but vaccination was not associated with symptom duration. Conversely, among ambulatory adults with influenza, vaccination and symptom burden were not associated, but vaccination was associated with faster alleviation of ILI symptoms.

Background: We assessed associations between antibody concentrations within 7 days of symptom onset and testing positive for influenza virus infection among outpatients enrolled in a test-negative study. Methods: From November 2018 to May 2019, study sites in 5 states obtained serum and respiratory specimens from outpatients aged ≥18 years presenting with acute respiratory illness. Respiratory specimens were tested for influenza virus, and viral clades were identified by means of genomic sequencing. We measured influenza antibody titers against vaccine and circulating viruses by means of hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase inhibition (NAI) assays. Reduction in the odds of influenza-associated illness at increasing HI, MN, and NAI antibody titers was estimated using logistic regression, adjusting for influenza vaccination status and time since the beginning of influenza season. Results: Among 175 patients with influenza virus infection, including 112 with influenza A(H1N1)pdm09 and 63 with A(H3N2) (44 clade 3C.3a), and 130 test-negative control patients, higher HI, MN, and NAI antibody titers against circulating influenza viruses were associated with lower odds of confirmed influenza. The odds of A(H1N1)pdm09 infection were 44% and 54% lower for each 2-fold increase in A(H1N1)pdm09 HI or NAI titer, respectively. The odds of A(H3N2) infection were 49% and 28% lower, respectively, for each 2-fold increase in MN or NAI titer against circulating A(H3N2) virus clade. NAI titers were independently associated with lower odds of influenza A(H1N1)pdm09 and A(H3N2) after controlling for HI titer. Conclusions: Higher influenza antibody titers against circulating viruses were associated with lower likelihood of influenza virus infection among adult patients with acute respiratory illness.

Background: A third dose of measles, mumps, and rubella vaccine (MMR3) may be administered in outbreak and nonoutbreak settings. However, data on long-term immunogenicity to the mumps component of MMR are limited. We examined durability of mumps antibody response among adults up to 11 years after receipt of MMR3. Methods: Persons who received MMR3 at ages 18–28 years had sera collected before (baseline), 1 month, 1, 5, and 9–11 years after vaccination. Mumps antibodies were assessed by plaque reduction neutralization, immunoassay (EIA), and immunoglobulin G (IgG) avidity. Neutralizing antibodies were assessed against the vaccine strain (Genotype A) and a wild-type virus from Genotype G. Participants with neutralizing antibody titers <31 for Genotype A and <8 for Genotype G, and with EIA index values <1.10 were considered potentially susceptible. Results: Among participants with data for all visits after MMR3 (40%, n = 262/655), susceptibility based on Genotype A titers increased from 15.7% (41/262) at baseline to 30.5% (80/262) 9–11 years after vaccination while susceptibility based on Genotype G titers remained relatively stable (30.2%–24.2%). The proportion of participants seronegative for mumps IgG by EIA increased from 0% (0/255) at baseline to 7.5% (19/255) 9–11 years after vaccination. The avidity index increased from 52% to 67% through Year 5 (P < .0001). Conclusions: By 9–11 years after receipt of MMR3, many participants had mumps antibody levels that predicted susceptibility to infection, comparable to those observed before receipt of MMR3. The antibody titers to Genotype G remained consistently lower than the titers to the vaccine strain.

Background: Estimates of the annual effectiveness of influenza vaccination combine multiple vaccine types. Reports of brand/product-specific vaccine effectiveness (VE) of egg-based and cell culture–based quadrivalent inactivated influenza vaccines (IIV4 and ccIIV4, respectively) are limited. Methods: Using an observational test-negative study design, we compared the effectiveness of selected IIV4 and ccIIV4 products among outpatients enrolled in the US Influenza Vaccine Effectiveness (Flu VE) Network from 2014–2015 to 2018–2019. We used multivariable logistic regression to estimate the product-specific and age group–specific absolute VE and relative VE (rVE) of recommended, age-appropriate vaccines against symptomatic laboratory-confirmed outpatient influenza. The rVE of ccIIV4 versus IIV4 products was estimated during 2 seasons from 2017–2019 among participants aged ≥4 years. Results: Pooling data from 5 influenza seasons when 18% and 15% of vaccinated patients had received Fluarix Quadrivalent or Fluzone Quadrivalent IIV4, respectively, the VE against influenza was 32% for Fluarix and 37% for Fluzone. Pooling 2 seasons when 11% and 28% of vaccinated patients had received ccIIV4 (Flucelvax Quadrivalent) and IIV4 (FluLaval Quadrivalent), respectively, the VE against influenza for each product was 30%. The absolute VE compared with unvaccinated patients was lowest against influenza A(H3N2) compared with that against A(H1N1)pdm09 and each B lineage; VE point estimates were lowest among patients aged ≥50 years compared with 2 younger age groups. The rVE estimates were not statistically significant, indicating similar protection across vaccine products. Conclusions: Comparisons of influenza vaccine products over multiple seasons showed benefit of both IIV4 and ccIIV4 against symptomatic laboratory-confirmed outpatient influenza, with similar absolute and relative levels of protection provided by each product.

New influenza vaccine products might be licensed in coming years. Ideally, these vaccines would generate more broadly cross-reactive and longer-lasting protection than those currently licensed. Recommendations for the use of and potential preference for new influenza vaccines should be informed by absolute and comparative effectiveness evaluations. Absolute vaccine effects are commonly evaluated pre- and postlicensure, but more complex comparative evaluations have special considerations discussed in this Viewpoint. Relative vaccine effectiveness (rVE) can be assessed in clinical trials, cluster-randomized trials, and a variety of observational designs. Cluster-randomized trials have reduced potential for bias compared to observational studies, but operational barriers may limit feasibility. Observational rVE studies may utilize prospectively collected data or real-world evidence from large healthcare databases. Advantages of observational rVE studies include timeliness and lower cost, but uptake of novel influenza vaccines that is low and variable by age, health status, and other characteristics is a major challenge.

Background: The cell culture-based inactivated influenza vaccine (ccIIV) was first approved for use in children aged 4-17 years in 2016 in the United States. The approved age indication for ccIIV was expanded to include children 6 months and older beginning the 2022-2023 season. There is limited real-world data on ccIIV effectiveness in children. We assessed ccIIV effectiveness using the test-negative design during the 2023-2024 season. Methods: Patients aged 6 months to 64 years who sought outpatient or telehealth care for acute respiratory illness were actively recruited between October 2023 and May 2024. Symptom eligibility criteria included cough, with an illness duration of ≤ 7 days. Respiratory samples were tested by reverse transcription polymerase chain reaction to identify influenza cases. Vaccination dates and products were determined by immunization records. Analyses were restricted to ccIIV recipients and unvaccinated participants. Cell culture-based inactivated influenza vaccine effectiveness was estimated as [100% × (1 − odds ratio)] for vaccination in cases versus test-negative controls, with adjustment for age and calendar time. Results: Among 1850 participants, 12% were age 6 months to 3 years, 32% were age 4-17 years, and 56% were age 18-64 years. Influenza was detected in 505 (27%) participants; 267 had influenza A/H1N1pdm09; 149 had influenza B; 56 had influenza A/H3N2; and 33 had influenza A with unknown subtype. A total of 470 (25%) received ccIIV. Among children (age 6 months to 17 years), ccIIV effectiveness was 64% [95% confidence interval (CI), 37%-81%] against influenza A/H1N1pdm09, 75% (95% CI, 43%-91%) against influenza B, and 76% (95% CI, 4%-97%) against influenza A/H3N2. Among adults (age 18-64 years), ccIIV effectiveness was 56% (95% CI, 31%-73%) against influenza A/H1N1pdm09, 62% (95% CI, 13%-86%) against influenza B, and 33% (95% CI, −62% to 76%) against influenza A/H3N2. Young children aged 6 months to 3 years had the highest point estimates (88%-98%). Conclusion: Cell culture-based inactivated influenza vaccine generated substantial real-world effectiveness against medically attended, laboratory-confirmed influenza in children and adults during a season when influenza A/H1N1pdm09 viruses predominated and influenza B and influenza A/H3N2 co-circulated at lower levels.