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In phase 2 and 3 randomized, controlled trials, baloxavir — an inhibitor of influenza cap-dependent endonuclease — showed evidence of clinical symptom relief and antiviral activity against influenza. However, influenza-resistant variants appeared to develop with treatment.

During influenza epidemics, Japanese clinicians routinely perform rapid influenza diagnostic tests (RIDTs) in the examination of patients who have an influenza-like illness, and patients with positive test results, including otherwise healthy individuals, are treated with anti-influenza drugs. However, it was recently reported that the sensitivity of RIDTs was extremely low in adult patients. We examined the sensitivity and specificity of an RIDT that is widely used in Japan, ImunoAce Flu (TAUNS, Shizuoka, Japan), in comparison to reverse transcriptase polymerase chain reaction (RT-PCR). The sensitivity and specificity of the ImunoAce Flu test were 97.1% (95%CI: 93.8-98.9) and 89.2% (95%CI: 84.1-93.1), respectively. The ImunoAce Flu test is designed to not only detect influenza A or B, but also to detect H1N1pdm09 with the use of an additional test kit (Linjudge FluA/pdm). Its sensitivity and specificity for A/H1N1pdm09 were 97.6% (95%CI: 87.4-99.9) and 92.6% (95%CI: 82.1-97.9), respectively. Thus, by consecutively testing patients with the ImunoAce Flu test followed by the Linjudge FluA/pdm test, we are able to diagnose whether a patient has A/H1N1pdm09 or A/H3N2 infection within a short time. The reliability of rapid test results seems to be much higher in Japan than in other countries, because approximately 90% of influenza patients are tested and treated within 48 hours after the onset of illness, when the influenza viral load in the upper respiratory tract is high. From the Japanese experience, RIDTs are sufficiently sensitive and highly useful, if patients are tested within 48 hours after the onset of illness.

•Three-season vaccine effectiveness in preventing influenza illness was 45% (N = 12,888).•Three-season vaccine effectiveness in preventing hospitalization was 52%.•Vaccine effectiveness was highest in young group and declined with age thereafter.•Low or no significant VE was demonstrated in infants or in adolescents. We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age in 2015/16 season. In addition, based on the data obtained during the three seasons from 2013 to 2016, we estimated the three-season VE in preventing influenza illness and hospitalization. Our study was conducted according to a test-negative case-control design (TNCC) and as a case-control study based on influenza rapid diagnostic test results. During 2015/16 season, the quadrivalent IIV was first used in Japan. The adjusted VE in preventing influenza illness was 49% (95% confidence interval [CI]: 42–55%) against any type of influenza, 57% (95% CI: 50–63%) against influenza A and 34% (95% CI: 23–44%) against influenza B. The 3-season adjusted VE was 45% (95% CI: 41–49%) against influenza virus infection overall (N = 12,888), 51% (95% CI: 47–55%) against influenza A (N = 10,410), and 32% (95% CI: 24–38%) against influenza B (N = 9232). An analysis by age groups showed low or no significant VE in infants or adolescents. By contrast, VE was highest in the young group (1–5 years old) and declined with age thereafter. The 3-season adjusted VE in preventing hospitalization as determined in a case-control study was 52% (95% CI: 42–60%) for influenza A and 28% (95% CI: 4–46%) for influenza B, and by TNCC design, it was 54% (95% CI: 41–65%) for influenza A and 34% (95% CI: 6–54%) for influenza B. We demonstrated not only VE in preventing illness, but also VE in preventing hospitalization based on much larger numbers of children than previous studies.

The genomes of influenza A and B viruses comprise eight segmented, single-stranded, negative-sense viral RNAs (vRNAs). Although segmentation of the virus genome complicates the packaging of infectious progeny into virions, it provides an evolutionary benefit in that it allows viruses to exchange vRNAs with other strains. Influenza A viruses are believed to package their eight different vRNAs in a specific manner. However, several studies have shown that many viruses are noninfectious and fail to package at least one vRNA. Therefore, the genome-packaging mechanism is not fully understood. In this study, we used electron microscopy to count the number of ribonucleoproteins (RNPs) inside the virions of different influenza A and B virus strains. All eight strains examined displayed eight RNPs arranged in a “7+1” configuration in which a central RNP was surrounded by seven RNPs. Three-dimensional analysis of the virions showed that at least 80% of the virions packaged all eight RNPs; however, some virions packaged only five to seven RNPs, with the exact proportion depending on the strain examined. These results directly demonstrate that most viruses package eight RNPs, but some do indeed package fewer. Our findings support the selective genome-packaging model and demonstrate the variability in the number of RNPs incorporated by virions, suggesting that the genome-packaging mechanism of influenza viruses is more flexible than previously thought. IMPORTANCE The genomes of influenza A and B viruses contain segmented RNAs, which complicates genome packaging but provides the evolutionary advantage of allowing the exchange of individual genome segments with those of other strains. Some studies have shown that influenza A viruses package all eight genome segments in a specific manner, whereas others have shown that many virions are noninfectious and fail to package at least one genome segment. However, such viruses have never been directly observed. Here, we used electron microscopy to provide the first direct visual evidence of virions packaging an incomplete set of ribonucleoproteins. The percentage of these noninfectious virions varied from 0 to 20, depending on the virus strain, indicating that most virions package all eight genome segments. These results extend our knowledge about how infectious and noninfectious virions coordinate for successful virus infection. The genomes of influenza A and B viruses contain segmented RNAs, which complicates genome packaging but provides the evolutionary advantage of allowing the exchange of individual genome segments with those of other strains. Some studies have shown that influenza A viruses package all eight genome segments in a specific manner, whereas others have shown that many virions are noninfectious and fail to package at least one genome segment. However, such viruses have never been directly observed. Here, we used electron microscopy to provide the first direct visual evidence of virions packaging an incomplete set of ribonucleoproteins. The percentage of these noninfectious virions varied from 0 to 20, depending on the virus strain, indicating that most virions package all eight genome segments. These results extend our knowledge about how infectious and noninfectious virions coordinate for successful virus infection.

•First season (2022/23) of co-circulation of flu and COVID-19 in Japan.•Among 536 hospitalized children with fever, none were positive for both viruses.•The vaccine effectiveness (VE) for preventing flu A was 34 % (p = 0.15).•Flu VE in 6–12 year olds and those with underlying diseases was observed (p < 0.05).•Only 1 of 35 COVID-19 cases, and 42 out of 429 controls, had been vaccinated. We have analyzed the inactivated vaccine effectiveness (VE)for preventing influenza hospitalization by test-negative design in the 2022/23 season. This is the first season of co-circulation of influenza and COVID-19, and a unique period because all inpatients received COVID-19 screening. Among 536 children hospitalized with fever, none were positive for both influenza and SARS-CoV-2. The adjusted VE for preventing influenza A for all children, the 6–12-year-old group, and those with underlying diseases was 34 % (95 ％CI, −16 %–61 %, n = 474), 76 % (95 ％ CI, 21 %–92 %, n = 81), and 92 % (95 ％ CI, 30 %–99 %, n = 86), respectively. Only 1 out of 35 hospitalized cases with COVID-19, and 42 out of 429 controls, had been immunized with COVID-19 vaccine. This is the first report showing influenza VE by age group in children in this limited season. We still recommend the inactivated influenza vaccine for children based on the significant VE in subgroup analysis.

•Vaccine was effective in preventing illness, 38% against influenza A (mostly H3N2).•Vaccine was effective in preventing illness, 39% against influenza B.•Infants showed no significant vaccine effectiveness.•The children who were immunized in two consecutive seasons were more likely to have influenza.•However, the influenza vaccine should be recommended every season for children. We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age during the 2016/17 season. In addition, we estimated the impact of repeated vaccination in children on VE. Our study for VEs in preventing influenza and admission due to influenza were conducted according to a test-negative case-control design (TNCC) based on influenza rapid diagnostic test results. We also analyzed the VE by vaccine status in the current and previous seasons for the impact of repeated vaccination. During the 2016/17 season, the quadrivalent IIV was used in Japan. The adjusted VE in preventing influenza illness was 38% (95% CI, 29–46) against influenza A and 39% (95% CI, 18–54) against influenza B. Infants showed no significant VE. The VE in preventing hospitalization was not demonstrated. For the analysis of repeated vaccination, the vaccine was effective only when immunization occurred in the current season. The children who were immunized in two consecutive seasons were more likely to develop influenza compared to those immunized in the current season only (odds ratio, 1.58 [95% CI, 1.05–2.38], adjusted odds ratio, 1.53 [95% CI, 0.99–2.35]). However, the odds ratio of repeated vaccination was not significant when the analysis excluded those who developed influenza in the previous season. VE in children in the 2016/17 season was similar to values previously reported. Repeated vaccination interfered with the VE against any influenza infection in the 2016/17 season. The results of our study suggest that decreased VE by repeat vaccination phenomenon was associated with immunity by influenza infection in the previous season. However, the influenza vaccine should be recommended every season for children.

Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARS-CoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020-March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children <5 years of age was as low as 10% as of March 2022. Our study underscores the low incidence of SARS-CoV-2 infection in Japan and the effects of vaccination on immunity at the population level.

Both traditional case-control studies (TCCSs) and test-negative case-control studies (TNCCSs) are commonly used to assess influenza vaccine effectiveness (VE). To compensate for the fact that observational studies are susceptible to bias, we combined both methods to assess VE in one geographical area during the 2015/2016 season, when influenza A (H1N1)pdm was dominant. Our TNCCS covered 331 children aged 6 months to 15 years who visited our hospital with fever, including 182 with influenza, and our TCCS covered 812 pediatric outpatients aged 6 months to 15 years, including 214 with influenza. Influenza infection and vaccination history were reviewed, and VE was calculated as (1 − odds ratio) × 100. In the TNCCS, VE against influenza A was 68% (95% CI 47–81) overall, and 70% (48–83) for those given two doses; against influenza B, VE was 37% (− 12–64) overall and 49% (2–74) for two doses. In the TCCS, VE against influenza A was 44% (15–63) overall and 44% (13–64) for two doses, and VE against influenza B was 24% (− 19–52) overall and 41% (3–64) for two doses.Conclusion: Both studies confirmed significant VE against influenza A, significant two-dose VE against influenza B, and better two-dose VE than one-dose VE.What is Known:• Influenza vaccine effectiveness (VE) varies from year to year.• Observational studies are conventionally used for VE assessment. However, they are inherently susceptible to bias and confounding.What is New:• This is the first report of influenza VE assessment using more than one observational study and performed in a specific area during the same season.• VE estimates obtained in our traditional case-control study were lower than those in our test-negative case-control study, but both studies found significant VE against influenza.

•Both one- and two-doses regimens of inactivated flu vac are effective for children.•Both regimens reduced cases involving hospitalization due to influenza A.•The two-dose regimen was more effective against influenza B in some seasons. We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses. VE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed. In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A. Both one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.

During influenza epidemics, Japanese clinicians routinely conduct rapid influenza diagnostic tests (RIDTs) in patients with influenza-like illness, and patients with positive test results are treated with anti-influenza drugs within 48 h after the onset of illness. We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children (6 months–15 years old, N = 4243), using a test-negative case-control design based on the results of RIDTs in the 2018/19 season. The VE against influenza A(H1N1)pdm and A(H3N2) was analyzed separately using an RIDT kit specifically for detecting A(H1N1)pdm09. The adjusted VE against combined influenza A (H1N1pdm and H3N2) and against A(H1N1)pdm09 was 39% (95% confidence interval [CI], 30%–46%) and 74% (95% CI, 39%–89%), respectively. By contrast, the VE against non-A(H1N1)pdm09 influenza A (presumed to be H3N2) was very low at 7%. The adjusted VE for preventing hospitalization was 56% (95% CI, 16%–77%) against influenza A. The VE against A(H1N1)pdm09 was consistently high in our studies. By contrast, the VE against A(H3N2) was low not only in adults but also in children in the 2018/19 season.