Search

Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of preexisting immunity on vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analyzed 66 test-negative design studies that examined VE against infection or severe disease (hospitalization, intensive care unit admission, or death) for primary vaccination series. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (77%; 95% CI, 72-81) and severe disease (86%; 95% CI, 83-89) compared with studies that excluded people with prior COVID-19 infection (pooled VE against infection: 87% [95% CI, 85-89]; pooled VE against severe disease: 93% [95% CI, 91-95]). There was a negative correlation between VE estimates against infection and severe disease, and the cumulative incidence of cases before the start of the study or incidence rates during the study period. We found clear empirical evidence that higher levels of preexisting immunity were associated with lower VE estimates. Prior infections should be treated as both a confounder and effect modificatory when the policies target the whole population or are stratified by infection history, respectively. [ABSTRACT FROM AUTHOR]

We estimated XBB.1.5 vaccine effectiveness (VE) against symptomatic SARS‐CoV‐2 infection among adults aged ≥ 65 years during the 2023/2024 JN.1 lineage‐predominant period in a European multi‐country test‐negative case–control study at primary care level. We estimated VE adjusted by study site, age, sex, chronic conditions and onset date. We included 220 cases and 1733 controls. The VE was 48% (95% CI: 12–71), 23% (95% CI: −11–48) and 5% (95% CI: −92–56) among those with symptom onset 1–5, 6–11, and ≥ 12 weeks after vaccination, respectively. XBB.1.5 vaccine provided short and moderate protection against JN.1 symptomatic infection. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to estimate the effectiveness of original and bivalent COVID-19 vaccines in reducing COVID-19-associated hospitalizations among the adult population of Turin, Italy. Methods: We conducted a retrospective, test-negative, case–control study of 5768 adults aged ≥50 years who had symptoms that were consistent with COVID-19-like illness and were admitted to the hospitals of the Turin Health Unit network from 1 January 2021 to 31 January 2023. We evaluated the effectiveness of the vaccines that at the time of the study were authorized in the European Union (original/bivalent BNT162b2; original mRNA-1273; ChAdOx1-S; Ad26.COV2.S) by comparing the odds of a positive test for SARS-CoV-2 in vaccinated patients with the odds of a positive test in unvaccinated patients. The association between vaccination status, hospitalization, ICU admission and positive SARS-CoV-2 test was estimated by building multivariate adjusted logistic regression models. Results: During the predominance of the pre-Omicron variants, the vaccine effectiveness of two and three doses received in the last 120 days against COVID-19-associated hospitalizations was 93.6% (95% CI: 90.1 to 95.9) and 97.1% (95% CI: 90.8 to 99.1), respectively. During the predominance of the Omicron variant, the vaccine effectiveness of two and three doses was 26.6% (95% CI: −0.6 to 46.5) and 75.2% (95% CI: 68.1 to 80.7), respectively, and it rose to 88% (95% CI: 78.2 to 93.3) for four or five doses of the bivalent vaccine. Conclusions: Our study confirms that the COVID-19 vaccines protect adult patients from hospitalizations, including the subgroup ≥80 years, also during the period of the Omicron variant's predominance. [ABSTRACT FROM AUTHOR]

Background: During the 2022–2023 influenza season, the influenza activities in most regions of China were postponed, including Beijing. The unusually delayed influenza epidemic posed a challenge to the effectiveness of the influenza vaccine. Methods: Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022–2023 influenza season against influenza A-associated outpatient and emergency-department-attended influenza-like illness (ILI) in Beijing, China, from 9 January to 30 April 2023. Results: The analysis included 8301 medically attended ILI patients, of which 1342 (46.2%) had influenza A(H1N1)pdm09, 1554 (53.4%) had influenza A(H3N2), and 11 (0.4%) had co-infection of the two viruses. VE against influenza A-associated ILI patients was 23.2% (95% CI: −6.5% to 44.6%) overall, and 23.1%, 9.9%, and 33.8% among children aged 6 months to 17 years, adults aged 18–59 years, and adults aged ≥60 years, respectively. VE against influenza A(H1N1)pdm09 and against influenza A(H3N2) were 36.2% (95% CI: −1.9% to 60.1%) and 9.5% (95% CI: −34.1% to 39.0%), respectively. VE of the group with vaccination intervals of 14–90 days (70.1%, 95% CI: −145.4 to 96.4) was higher than that of the groups with a vaccination interval of 90–149 days (18.7%, 95% CI: −42.4% to 53.6%) and ≥150 days (21.2%, 95% CI: −18.8% to 47.7%). Conclusions: A moderate VE against influenza A(H1N1)pdm09 and a low VE against influenza A(H3N2) were observed in Beijing during the 2022–2023 influenza season, a season characterized with a delayed and high-intensity influenza epidemic. VE appears to be better within three months after vaccination. Our findings indicate a potential need for the optimization of vaccination policies and underscore the importance of continuous monitoring of influenza to enhance vaccines and optimizing vaccination timing. [ABSTRACT FROM AUTHOR]

Objectives: We estimated vaccine effectiveness (VE) against SARS-CoV-2 infection among a statewide cohort of people with HIV (PWH) and compared the estimates with a matched cohort of people without HIV (PWoH) in South Carolina (SC), USA. Methods: A population-based cohort was retrieved from statewide electronic health records between January 2, 2021, and April 14, 2022, during which several variants were circulating in SC (i.e., Alpha, Delta, Omicron). We compared the odds of vaccination between test-positive cases and test-negative controls using logistic regression models for both SARS-CoV-2 infection and severe COVID-19 outcomes. The VE was derived as (1 − adjusted odds ratio) × 100%. Results: A total of 7279 test episodes in PWH and 72,790 matched test episodes in PWoH were included for analysis, representing 6561 unique PWH and 67,521 unique PWoH. The peak level of VE against SARS-CoV-2 infection occurred 7-59 days after receipt of the second dose of vaccine (PWH: 61.20%; PWoH: 67.09%), followed by a waning protective effect 90-119 days after the second dose in both PWH (35.80%) and PWoH (47.57%), where PWH had a proportionally lower and declined faster VE. Regarding the VE against severe outcomes of SARS-CoV-2 infection, a relatively higher level of protection was maintained in both populations (complete primary series: PWH: 69.06%; PWoH: 60.63%). Conclusions: A complete primary series of COVID-19 vaccines offered significant protection against SARS-CoV-2 infection and severe outcomes in both PWH and PWoH populations, although this wanes with time. However, the estimate of VE against SARS-CoV-2 infection appeared lower in PWH than in PWoH and the degree of waning over time was relatively quicker in PWH.

Abstract The test-negative design (TND) is an observational study design to evaluate vaccine effectiveness (VE) that enrolls individuals receiving diagnostic testing for a target disease as part of routine care. VE is estimated as one minus the adjusted odds ratio of testing positive versus negative comparing vaccinated and unvaccinated patients. Although the TND is related to case–control studies, it is distinct in that the ratio of test-positive cases to test-negative controls is not typically pre-specified. For both types of studies, sparse cells are common when vaccines are highly effective. We consider the implications of these features on power for the TND. We use simulation studies to explore three hypothesis-testing procedures and associated sample size calculations for case–control and TND studies. These tests, all based on a simple logistic regression model, are a standard Wald test, a continuity-corrected Wald test, and a score test. The Wald test performs poorly in both case–control and TND when VE is high because the number of vaccinated test-positive cases can be low or zero. Continuity corrections help to stabilize the variance but induce bias. We observe superior performance with the score test as the variance is pooled under the null hypothesis of no group differences. We recommend using a score-based approach to design and analyze both case–control and TND. We propose a modification to the TND score sample size to account for additional variability in the ratio of controls over cases. This work enhances our understanding of the data generating mechanism in a test-negative design (TND) and how it is distinct from that of a case-control study due to its passive recruitment of controls.

Background In China, the 2022–2023 influenza season began earlier and was characterized by higher levels of influenza activity and co-circulation of various respiratory pathogens compared with seasons before the coronavirus disease 2019 (COVID-19) pandemic. Timely and precise estimates of influenza vaccine effectiveness (IVE) against infections can be used to guide public health measures. Methods A test-negative study was conducted to estimate IVE against laboratory-confirmed influenza using data from the CHinese Electronic health Records Research in Yinzhou (CHERRY) study that prospectively integrated laboratory, vaccination, and health administrative data in Yinzhou, southern China. We included patients who presented influenza-like illness and received nucleic acid tests and/or antigen tests between October 2023 and March 2024. Estimates of IVE were adjusted for age, gender, month of specimen submitted, chronic comorbidities, and hospitalization status. Results A total of 205 028 participants, including 96 298 influenza cases (7.6% vaccinated) and 108 730 influenza-negative controls (13.4% vaccinated), were eligible for this analysis. The estimates of IVE were 49.4% (95% CI, 47.8%–50.9%), 41.9% (95% CI, 39.8%–44.0%), and 59.9% (95% CI, 57.9%–61.9%) against overall influenza, influenza A, and influenza B, respectively. A lower IVE was observed for individuals aged 7–17 years (38.6%), vs 45.8% for 6 months–6 years, 46.7% for 18–64 years, and 46.1% for ≥65 years. Vaccination reduced the risk of infection by 44.4% among patients with chronic comorbidities. IVEs varied by epidemic weeks with the changes in influenza activity levels and the switch of dominant influenza strains. Conclusions Influenza vaccination in the 2023–2024 season was protective against infection for the entire population. [ABSTRACT FROM AUTHOR]

Background: Vaccination is a highly effective strategy for the prevention of enterovirus A71 (EV-A71)—hand, foot, and mouth disease (HFMD). Three inactivated EV-A71 vaccines in China have demonstrated remarkable efficacy against EV-A71-HFMD during clinical trials, exhibiting vaccine effectiveness (VE) exceeding 90% and few adverse events (AEs). However, the effectiveness of vaccines in the real world and its impact on the epidemiological characteristics of HFMD after the use of EV-A71 inactivated vaccine are uncertain. Methods: The odd ratio (OR) and 95% confidence (CI) were used as the effect estimates of the meta-analysis in the test-negative design (TND), and the OR was used to calculate VE: VE = (1 − OR) × 100%. Results: According to the literature search strategy, a comprehensive search was conducted in PubMed, Web of Science (including Chinese Science Citation Database and MEDLINE), and Embase, and 18 records were ultimately included in this study. Subsequently, the overall VE and 95% CI of different vaccine doses were analyzed, with the one-dose vaccine at 66.9% (95% CI: 45.2–80.0%) and the two-dose vaccine at 84.2% (95% CI: 79.4–87.9%). Additionally, the most reported AEs were mild general reactions without any rare occurrences. Simultaneously, the widespread use of the EV-A71 vaccine would lead to a reduction in both the incidence of EV-A71-associated HFMD and severe cases caused by EV-A71. Conclusion: The administration of the two-dose EV-A71 vaccine is highly effective in preventing HFMD in the real world, and the widespread use of the EV-A71 vaccine leads to a reduction in the incidence of EV-A71-associated HFMD and that of severe cases caused by EV-A71. The findings suggest that administering the two-dose EV-A71 inactivated vaccine to children aged 6 months to 71 months can be effective in preventing EV-A71-associated HFMD, highlighting the need for developing a multivalent HFMD vaccine for preventing cases not caused by EV-A71. [ABSTRACT FROM AUTHOR]

In autumn 2023, European vaccination campaigns predominantly administered XBB.1.5 vaccine. In a European multicentre study, we estimated 2023 COVID-19 vaccine effectiveness (VE) against laboratory-confirmed symptomatic infection at primary care level between September 2023 and January 2024. Using a test-negative case–control design, we estimated VE in the target group for COVID-19 vaccination overall and by time since vaccination. We included 1057 cases and 4397 controls. Vaccine effectiveness was 40 % (95 % CI: 26–53 %) overall, 48 % (95 % CI: 31–61 %) among those vaccinated < 6 weeks of onset and 29 % (95 % CI: 3–49 %) at 6–14 weeks. Our results suggest that COVID-19 vaccines administered to target groups during the autumn 2023 campaigns showed clinically significant effectiveness against laboratory-confirmed, medically attended symptomatic SARS-CoV-2 infection in the 3 months following vaccination. A longer study period will allow for further variant-specific COVID-19 VE estimates, better understanding decline in VE and informing booster administration policies. [ABSTRACT FROM AUTHOR]

Background The 2022–2023 United States influenza season had unusually early influenza activity with high hospitalization rates. Vaccine-matched A(H3N2) viruses predominated, with lower levels of A(H1N1)pdm09 activity also observed. Methods Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022–2023 season against influenza A–associated emergency department/urgent care (ED/UC) visits and hospitalizations from October 2022 to March 2023 among adults (aged ≥18 years) with acute respiratory illness (ARI). VE was estimated by comparing odds of seasonal influenza vaccination among case-patients (influenza A test positive by molecular assay) and controls (influenza test negative), applying inverse-propensity-to-be-vaccinated weights. Results The analysis included 85 389 ED/UC ARI encounters (17.0% influenza A positive; 37.8% vaccinated overall) and 19 751 hospitalizations (9.5% influenza A positive; 52.8% vaccinated overall). VE against influenza A–associated ED/UC encounters was 44% (95% confidence interval [CI], 40%–47%) overall and 45% and 41% among adults aged 18–64 and ≥65 years, respectively. VE against influenza A–associated hospitalizations was 35% (95% CI, 27%–43%) overall and 23% and 41% among adults aged 18–64 and ≥65 years, respectively. Conclusions VE was moderate during the 2022–2023 influenza season, a season characterized with increased burden of influenza and co-circulation with other respiratory viruses. Vaccination is likely to substantially reduce morbidity, mortality, and strain on healthcare resources. [ABSTRACT FROM AUTHOR]

The test-negative design (TND) is an observational study design to evaluate vaccine effectiveness (VE) that enrolls individuals receiving diagnostic testing for a target disease as part of routine care. VE is estimated as one minus the adjusted odds ratio of testing positive versus negative comparing vaccinated and unvaccinated patients. Although the TND is related to case–control studies, it is distinct in that the ratio of test-positive cases to test-negative controls is not typically pre-specified. For both types of studies, sparse cells are common when vaccines are highly effective. We consider the implications of these features on power for the TND. We use simulation studies to explore three hypothesis-testing procedures and associated sample size calculations for case–control and TND studies. These tests, all based on a simple logistic regression model, are a standard Wald test, a continuity-corrected Wald test, and a score test. The Wald test performs poorly in both case–control and TND when VE is high because the number of vaccinated test-positive cases can be low or zero. Continuity corrections help to stabilize the variance but induce bias. We observe superior performance with the score test as the variance is pooled under the null hypothesis of no group differences. We recommend using a score-based approach to design and analyze both case–control and TND. We propose a modification to the TND score sample size to account for additional variability in the ratio of controls over cases. This work enhances our understanding of the data generating mechanism in a test-negative design (TND) and how it is distinct from that of a case-control study due to its passive recruitment of controls. [ABSTRACT FROM AUTHOR]

Case–control studies involving test-negative (TN) and syndrome-negative (SN) controls are reliable for evaluating influenza and rotavirus vaccine effectiveness (VE) during a random vaccination process. However, there is no empirical evidence regarding the impact in real-world mass vaccination campaigns against SARS-CoV-2 using TN and SN controls. To compare in the same population the effectiveness of SARS-CoV-2 vaccination on COVID-19-related hospitalization rates across a cohort design, TN and SN designs. We conducted an unmatched population-based cohort, TN and SN case–control designs linking data from four data sources (public primary healthcare system, hospitalization registers, epidemiological surveillance systems and the national immunization program) in a Chilean municipality (Rancagua) between March 1, 2021 and August 31, 2021. The outcome was COVID-19-related hospitalization. To ensure sufficient sample size in the unexposed group, completion of follow-up in the cohort design, and sufficient time between vaccination and hospitalization in the case–control design, VE was estimated comparing 8-week periods for each individual. Among the 191,505 individuals registered in the primary healthcare system of Rancagua in Chile on March 1, 2021; 116,453 met the cohort study's inclusion criteria. Of the 9,471 hospitalizations registered during the study period in the same place, 526 were COVID-19 cases, 108 were TN controls, and 1,628 were SN controls. For any vaccine product, the age- and sex-adjusted vaccine effectiveness comparing fully and nonvaccinated individuals was 67.2 (55.7–76.3) in the cohort design, whereas it was 67.8 (44.1–81.4) and 77.9 (70.2–83.8) in the TN and SN control designs, respectively. The VE of a COVID-19 vaccination program based on age and risk groups tended to differ across the three observational study designs. The SN case-control design may be an efficient option for evaluating COVID-19 VE in real-world settings. [ABSTRACT FROM AUTHOR]

Within influenza vaccine effectiveness (VE) studies at primary care level with a laboratory-confirmed outcome, clinical case definitions for recruitment of patients can vary. We used the 2022–23 VEBIS primary care European multicentre study end-of-season data to evaluate whether the clinical case definition affected IVE estimates. We estimated VE using a multicentre test-negative case-control design. We measured VE against any influenza and influenza (sub)types, by age group (0–14, 15–64, ≥65 years) and by influenza vaccine target group, using logistic regression. We estimated IVE among patients meeting the European Union (EU) acute respiratory infection (ARI) case definition and among those meeting the EU influenza-like illness (ILI) case definition, including only sites providing information on specific symptoms and recruiting patients using an ARI case definition (as the EU ILI case definition is a subset of the EU ARI one). We included 24 319 patients meeting the EU ARI case definition, of whom 21 804 patients (90 %) meet the EU ILI case definition, for the overall pooled VE analysis against any influenza. The overall and influenza (sub)type-specific VE varied by ≤2 % between EU ILI and EU ARI populations. Among all analyses, we found similar VE estimates between the EU ILI and EU ARI populations, with few (10%) additional non-ILI ARI patients recruited. These results indicate that VE in the 2022–23 influenza season was not affected by use of a different clinical case definition for recruitment, although we recommend investigating whether this holds true for next seasons. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has highlighted the need to use infection testing databases to rapidly estimate effectiveness of prior infection in preventing reinfection (⁠|$P{E}_S$|⁠) by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Mathematical modeling was used to demonstrate a theoretical foundation for applicability of the test-negative, case–control study design to derive |$P{E}_S$|⁠. Apart from the very early phase of an epidemic, the difference between the test-negative estimate for |$P{E}_S$| and true value of |$P{E}_S$| was minimal and became negligible as the epidemic progressed. The test-negative design provided robust estimation of |$P{E}_S$| and its waning. Assuming that only 25% of prior infections are documented, misclassification of prior infection status underestimated |$P{E}_S$|⁠ , but the underestimate was considerable only when > 50% of the population was ever infected. Misclassification of latent infection, misclassification of current active infection, and scale-up of vaccination all resulted in negligible bias in estimated |$P{E}_S$|⁠. The test-negative design was applied to national-level testing data in Qatar to estimate |$P{E}_S$| for SARS-CoV-2. |$P{E}_S$| against SARS-CoV-2 Alpha and Beta variants was estimated at 97.0% (95% CI, 93.6-98.6) and 85.5% (95% CI, 82.4-88.1), respectively. These estimates were validated using a cohort study design. The test-negative design offers a feasible, robust method to estimate protection from prior infection in preventing reinfection. [ABSTRACT FROM AUTHOR]

Previous research suggested that the inactivated influenza vaccine (IIV) may protect against SARS-CoV-2 infection or a severe course of COVID-19. These findings were however based on cohort studies, that are prone to confounding by indication. We examined the association between IIV and SARS-Cov-2 infection in a Dutch population using a test-negative design. This test-negative case-control study was conducted in adults (≥60) who tested because of COVID-19 like symptoms at community SARS-CoV-2 testing locations in the Netherlands during the period of November 8th 2021-March 11th 2022. Information on receipt of IIV in October-November 2021 was routinely collected at each visit. Logistic regression was used to calculate unadjusted, partially (sex, age, education level) and fully adjusted (COVID-19 vaccination, IIV 2020) odds ratios (ORs) for receipt of IIV in SARS-CoV-2 positive versus negative subjects. Differential effects on SARS-CoV-2 risk by time since IIV were investigated by including an interaction term for calendar time: November 2021-January 2022 vs February-March 2022. In total, 1,832 participants were included in the main analysis, of whom 336 (18.3 %) had a positive SARS-CoV-2 test. No significant association between IIV and SARS-CoV-2 infection was found; fully adjusted OR of 1.07 (95 % CI: 0.78–1.49). The interaction term for time periods was not significant (1.04 [95 % CI: 0.51–2.15], p = 0.91). Results were robust in sensitivity analyses. While earlier observational studies suggested a protective non-specific effect of IIV and SARS-CoV-2 infections, this smaller, but well controlled test-negative design study does not suggest an effect, either positive or negative. Larger test-negative design studies, or alternative designs such as the self-controlled case series design are needed to confirm these findings and provide more definite answers on the topic. [ABSTRACT FROM AUTHOR]

Hungary provides the opportunity to evaluate the effectiveness of COVID-19 vaccination in a setting where naturally acquired immunity and hybrid immunity are likely to play a greater role due to suboptimal vaccination coverage. Methods: A test-negative study was conducted during the 2022–2023 respiratory season at the primary care level to determine the effectiveness of at least one COVID-19 booster dose in preventing medically attended symptomatic RT-PCR-confirmed SARS-CoV-2 infection in adults. Unvaccinated patients were used as a reference group. Results: A total of 247 cases and 1073 controls were included in the analysis. CVE was 56.8% (95% CI: 11.9–78.8%) in the population aged 60 years and older and 2.3% (95% CI: −50.0–36.3%) in the younger adults against COVID-19 caused by Omicron subvariants, mainly BA.5, BQ.1, and XBB.1. Self-reported COVID-19 in the 60–365 days prior to the current illness did not confer protection against reinfection without vaccination, but together with booster vaccination, it reduced the risk of COVID-19 by 63.0% (95% CI: −28.0–89.3%) and 87.6% (95% CI: 26.4–97.9%) among the 18–59 and 60+ age groups, respectively. Conclusions: CVE against COVID-19 was moderately high in the 60+ age groups. Because of the benefit of hybrid immunity, persons with previous SARS-CoV-2 infection should still be considered for vaccination campaigns. [ABSTRACT FROM AUTHOR]

BackgroundEstimates of coronavirus disease 2019 (COVID-19) vaccine effectiveness under real-world conditions, and understanding of barriers to uptake, are necessary to inform vaccine rollout.MethodsWe enrolled cases (testing positive) and controls (testing negative) from among the population whose SARS-CoV-2 molecular diagnostic test results from 24 February to 29 April 2021 were reported to the California Department of Public Health. Participants were matched on age, sex, and geographic region. We assessed participants' self-reported history of mRNA-based COVID-19 vaccine receipt (BNT162b2 and mRNA-1273). Participants were considered fully vaccinated 2 weeks after second dose receipt. Among unvaccinated participants, we assessed willingness to receive vaccination. We measured vaccine effectiveness (VE) via the matched odds ratio of prior vaccination, comparing cases with controls.ResultsWe enrolled 1023 eligible participants aged ≥18 years. Among 525 cases, 71 (13.5%) received BNT162b2 or mRNA-1273; 20 (3.8%) were fully vaccinated with either product. Among 498 controls, 185 (37.1%) received BNT162b2 or mRNA-1273; 86 (16.3%) were fully vaccinated with either product. Two weeks after second dose receipt, VE was 87.0% (95% confidence interval: 68.6-94.6%) and 86.2% (68.4-93.9%) for BNT162b2 and mRNA-1273, respectively. Fully vaccinated participants receiving either product experienced 91.3% (79.3-96.3%) and 68.3% (27.9-85.7%) VE against symptomatic and asymptomatic infection, respectively. Among unvaccinated participants, 42.4% (159/375) residing in rural regions and 23.8% (67/281) residing in urban regions reported hesitancy to receive COVID-19 vaccination.ConclusionsAuthorized mRNA-based vaccines are effective at reducing documented SARS-CoV-2 infections within the general population of California. Vaccine hesitancy presents a barrier to reaching coverage levels needed for herd immunity.

Background: The aim of this study was to estimate the effectiveness of original and bivalent COVID-19 vaccines in reducing COVID-19-associated hospitalizations among the adult population of Turin, Italy. Methods: We conducted a retrospective, test-negative, case–control study of 5768 adults aged ≥50 years who had symptoms that were consistent with COVID-19-like illness and were admitted to the hospitals of the Turin Health Unit network from 1 January 2021 to 31 January 2023. We evaluated the effectiveness of the vaccines that at the time of the study were authorized in the European Union (original/bivalent BNT162b2; original mRNA-1273; ChAdOx1-S; Ad26.COV2.S) by comparing the odds of a positive test for SARS-CoV-2 in vaccinated patients with the odds of a positive test in unvaccinated patients. The association between vaccination status, hospitalization, ICU admission and positive SARS-CoV-2 test was estimated by building multivariate adjusted logistic regression models. Results: During the predominance of the pre-Omicron variants, the vaccine effectiveness of two and three doses received in the last 120 days against COVID-19-associated hospitalizations was 93.6% (95% CI: 90.1 to 95.9) and 97.1% (95% CI: 90.8 to 99.1), respectively. During the predominance of the Omicron variant, the vaccine effectiveness of two and three doses was 26.6% (95% CI: −0.6 to 46.5) and 75.2% (95% CI: 68.1 to 80.7), respectively, and it rose to 88% (95% CI: 78.2 to 93.3) for four or five doses of the bivalent vaccine. Conclusions: Our study confirms that the COVID-19 vaccines protect adult patients from hospitalizations, including the subgroup ≥80 years, also during the period of the Omicron variant’s predominance.

• Influenza vaccines provided moderate protection against influenza-related outpatient visit and hospitalization. • The effectiveness varied substantially by influenza type/subtype, with highest effectiveness against A/H1N1 and lowest against A/H3N2. • Both young adults and elderly manifested significantly decreased influenza vaccine effectiveness compared with children. Under the global risk of epidemic rebound of influenza after COVID-19 outbreak, the study aimed to provide a comprehensive evaluation of the seasonal influenza vaccine effectiveness (IVE) and to explore the potential effect modifiers. We searched for test-negative design studies with IVE estimates published between January 1, 2017 and December 31, 2022. We estimated pooled IVE using random-effects meta-analysis, and conducted meta-regression with study site, age, sex and comorbidity as explanatory variables. We identified 2429 publications and included 191 in the meta-analysis. The pooled IVE was 41.4 % (95 % CI: 39.2–43.5 %) against any influenza. For specific strains, the IVE was 55.4 % (95 % CI: 52.7–58.1 %) against A/H1N1, 26.8 % (95 % CI: 23.5–29.9 %) against A/H3N2, 47.2 % (95 % CI: 38.1–54.9 %) against B/Yamagata, and 40.6 % (95 % CI: 23.7–53.7 %) against B/Victoria, and the effectiveness against A/H3N2 was significantly lower than A/H1N1 (p < 0.0001) and B/Yamagata (p < 0.0001). The pooled IVE was 39.2 % (95 % CI: 36.5–41.9 %) in preventing influenza-associated outpatient visit and 43.7 % (95 % CI: 39.7–47.4 %) in preventing influenza-related hospitalization. The IVE against any influenza was 48.6 % (95 % CI: 44.7–52.2 %) for children aged < 18 years, 36.7 % (95 % CI: 31.9–41.1 %) for adults aged 18–64 years, and 30.6 % (95 % CI: 26.2–34.8 %) for elderly aged ≥65 years. Meta-regression revealed that the IVE was associated with the average age of study participants, in which both young adults [relative odds ratio (ROR) = 1.225, 95 % confidence interval (CI): 1.099–1.365, p = 0.0002] and elderly (ROR = 1.245, 95 % CI: 1.083–1.431, p = 0.002) manifested a significantly decreased effectiveness compared with children. Influenza vaccines provided moderate protection against laboratory-confirmed influenza and related outpatient visit and hospitalization. However, the effectiveness may vary substantially by virus type and age group, suggesting the necessity to tailor vaccination strategies especially for older individuals and against the A/H3N2 strain, and to promote annual immunization and annual analysis of vaccine effectiveness. [ABSTRACT FROM AUTHOR]

Background During the 2022–2023 influenza season, the United States experienced the highest influenza-associated pediatric hospitalization rate since 2010–2011. Influenza A/H3N2 infections were predominant. Methods We analyzed acute respiratory illness (ARI)–associated emergency department or urgent care (ED/UC) encounters or hospitalizations at 3 health systems among children and adolescents aged 6 months–17 years who had influenza molecular testing during October 2022–March 2023. We estimated influenza A vaccine effectiveness (VE) using a test-negative approach. The odds of vaccination among influenza-A–positive cases and influenza-negative controls were compared after adjusting for confounders and applying inverse-propensity-to-be-vaccinated weights. We developed overall and age-stratified VE models. Results Overall, 13 547 of 44 787 (30.2%) eligible ED/UC encounters and 263 of 1862 (14.1%) hospitalizations were influenza-A–positive cases. Among ED/UC patients, 15.2% of influenza-positive versus 27.1% of influenza-negative patients were vaccinated; VE was 48% (95% confidence interval [CI], 44–52%) overall, 53% (95% CI, 47–58%) among children aged 6 months–4 years, and 38% (95% CI, 30–45%) among those aged 9–17 years. Among hospitalizations, 17.5% of influenza-positive versus 33.4% of influenza-negative patients were vaccinated; VE was 40% (95% CI, 6–61%) overall, 56% (95% CI, 23–75%) among children ages 6 months–4 years, and 46% (95% CI, 2–70%) among those 5–17 years. Conclusions During the 2022–2023 influenza season, vaccination reduced the risk of influenza-associated ED/UC encounters and hospitalizations by almost half (overall VE, 40–48%). Influenza vaccination is a critical tool to prevent moderate-to-severe influenza illness in children and adolescents. [ABSTRACT FROM AUTHOR]

Background: Observational studies are used for estimating vaccine effectiveness under real-world conditions. The practical performance of two common approaches--cohort and test-negative designs--need to be compared for COVID-19 vaccines. Methods: We compared the cohort and test-negative designs to estimate the effectiveness of the BNT162b2 vaccine against COVID-19 outcomes using nationwide data from the United States Department of Veterans Affairs. Specifically, we (1) explicitly emulated a target trial using follow-up data and evaluated the potential for confounding using negative controls and benchmarking to a randomized trial, (2) performed case-control sampling of the cohort to confirm empirically that the same estimate is obtained, (3) further restricted the sampling to person-days with a test, and (4) implemented additional features of a test-negative design. We also compared their performance in limited datasets. Results: Estimated BNT162b2 vaccine effectiveness was similar under all four designs. Empirical results suggested limited residual confounding by healthcare-seeking behavior. Analyses in limited datasets showed evidence of residual confounding, with estimates biased downward in the cohort design and upward in the testnegative design. Conclusion: Vaccine effectiveness estimates under a cohort design with explicit target trial emulation and a test-negative design were similar when using rich information from the VA healthcare system, but diverged in opposite directions when using a limited dataset. In settings like ours with sufficient information on confounders and other key variables, the cohort design with explicit target trial emulation may be preferable as a principled approach that allows estimation of absolute risks and facilitates interpretation of effect estimates. [ABSTRACT FROM AUTHOR]

The current influenza season started in Italy in October 2023, approaching the epidemic peak in late December (52nd week of the year). We aimed to explore the mid-term virologic surveillance data of the 2023/2024 influenza season (from 16 October 2023 to 7 January 2024) in Sicily, the fourth most populous Italian region. A test-negative design was used to estimate the effectiveness of seasonal influenza vaccine (VE) against A(H1N1)pdm09 virus, the predominant subtype in Sicily (96.2% of laboratory-confirmed influenza cases). Overall, 29.2% (n = 359/1230) of oropharyngeal swabs collected from patients with influenza-like illness (ILI) were positive for influenza. Among the laboratory-confirmed influenza cases, 12.5% (n = 45/359) were vaccinated against influenza, with higher prevalence of laboratory-confirmed diagnosis of influenza A among subjects vaccinated with quadrivalent inactivated standard dose (29.4%), live attenuated intranasal (25.1%), and quadrivalent inactivated high-dose (23.8%) influenza vaccines. Comparing influenza vaccination status for the 2023/2024 season among laboratory-confirmed influenza-positive and -negative samples, higher vaccination rates in influenza-negative samples (vs. positive) were observed in all age groups, except for 45–64 years old, regardless of sex and comorbidities. The overall adjusted VE (adj-VE) was 41.4% [95%CI: 10.5–61.6%], whereas the adj-VE was 37.9% [95%CI: −0.7–61.7%] among children 7 months–14 years old and 52.7% [95%CI: −38.0–83.8%] among the elderly (≥65 years old). [ABSTRACT FROM AUTHOR]

• PCV13 vaccination is effective in preventing vaccine-serotype community acquired pneumococcal diseases. • VE of PCV13 against specific PCV13 serotypes (6B, 6A and 19F) was higher than for other serotypes. • VEs in the matched PCV13/ S. pneumoniae -negative case-control study was higher than unmatched PCV13/non-PCV13 serotypes case-control study. • VE was higher for ≥ 2 or ≥ 3 doses of PCV13 vaccination compared to ≥ 1 dose. In 2016, China licensed 13-valent pneumococcal conjugate vaccine (PCV13) based on a study that demonstrated its immunogenicity is non-inferior to PCV7. However, the real-world effectiveness of PCV13 against vaccine-serotype pneumococcal diseases in China has limited evidence. A test-negative case-control study was conducted among children under 5 years old admitted to the Children's Hospital of Soochow University (SCH) with respiratory tract infections from January 2018 to December 2020. Cases were defined as children from whom the isolates were tested positive for Streptococcus pneumoniae (S. pneumoniae) with serotypes included in PCV13. Two control groups were included, one represented children with isolates positive for S. pneumoniae of non-PCV13 serotypes and the other comprised children who tested negative for S. pneumoniae. The S. pneumoniae -negative controls were selected by matching them to the cases based on gender, age and admission date in a 1:1 ratio. Vaccine effectiveness (VE) was calculated using a logistic regression model as (1- adjusted odds ratio) * 100 %. A total of 2371 pneumococcal isolates were included in the analysis, of which 75.0 % (1779/2371) were covered by PCV13 serotypes. Consequently, these 1779 children were classified as cases, and 592 children were designated as non-PCV13 serotype controls. Another 1779 children were correspondingly recruited as S. pneumoniae -negative controls. Overall, 40 cases (2.3 %) and 148 controls (6.2 %) had received vaccination. The overall VE in the PCV13/non-PCV13 serotypes case-control study was 50.0 % (95 % CI: 15.0, 70.7), which was lower than the VE of 74.4 % (95 % CI: 60.7, 83.3) in the matched PCV13/ S. pneumoniae -negative case-control study. VE was higher for ≥ 2 or ≥ 3 doses of vaccination compared to ≥ 1 dose. VE against specific PCV13 serotypes (6B, 6A and 19F) was higher than for other serotypes. PCV13 vaccination demonstrates effectiveness against vaccine-serotype pneumococcal diseases in children, particularly for serotypes 6B, 6A and 19F. [ABSTRACT FROM AUTHOR]

During the height of the global COVID-19 pandemic, the test-negative design (TND) was extensively used in many countries to evaluate COVID-19 vaccine effectiveness (VE). Typically, the TND involves the recruitment of care-seeking individuals who meet a common clinical case definition. All participants are then tested for an infection of interest. To review and describe the variation in TND methodology, and disclosure of potential biases, as applied to the evaluation of COVID-19 VE during the early vaccination phase of the pandemic. We conducted a systematic review by searching four biomedical databases using defined keywords to identify peer-reviewed articles published between January 1, 2020, and January 25, 2022. We included only original articles that employed a TND to estimate VE of COVID-19 vaccines in which cases and controls were evaluated based on SARS-CoV-2 laboratory test results. We identified 96 studies, 35 of which met the defined criteria. Most studies were from North America (16 studies) and targeted the general population (28 studies). Outcome case definitions were based primarily on COVID-19-like symptoms; however, several papers did not consider or specify symptoms. Cases and controls had the same inclusion criteria in only half of the studies. Most studies relied upon administrative or hospital databases assembled for a different (non-evaluation) clinical purpose. Potential unmeasured confounding (20 studies), misclassification of current SARS-CoV-2 infection (16 studies) and selection bias (10 studies) were disclosed as limitations by some studies. We observed potentially meaningful deviations from the validated design in the application of the TND during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

We conducted a multicentre hospital‐based test‐negative case–control study to measure vaccine effectiveness (VE) against PCR‐confirmed influenza in adult patients with severe acute respiratory infection (SARI) during the 2022/2023 influenza season in Europe. Among 5547 SARI patients ≥18 years, 2963 (53%) were vaccinated against influenza. Overall VE against influenza A(H1N1)pdm09 was 11% (95% CI: −23–36); 20% (95% CI: −4–39) against A(H3N2) and 56% (95% CI: 22–75) against B. During the 2022/2023 season, while VE against hospitalisation with influenza B was >55%, it was ≤20% for influenza A subtypes. While influenza vaccination should be a priority for future seasons, improved vaccines against influenza are needed. [ABSTRACT FROM AUTHOR]

Observational studies of the effectiveness of vaccines to prevent COVID-19 are needed to inform real-world use. Such studies are now underway amid the ongoing rollout of SARS-CoV-2 vaccines globally. Although traditional case-control and test-negative design studies feature prominently among strategies used to assess vaccine effectiveness, such studies may encounter important threats to validity. Here, we review the theoretical basis for estimation of vaccine direct effects under traditional case-control and test-negative design frameworks, addressing specific natural history parameters of SARS-CoV-2 infection and COVID-19 relevant to these designs. Bias may be introduced by misclassification of cases and controls, particularly when clinical case criteria include common, nonspecific indicators of COVID-19. When using diagnostic assays with high analytical sensitivity for SARS-CoV-2 detection, individuals testing positive may be counted as cases even if their symptoms are due to other causes. The traditional case-control design may be particularly prone to confounding due to associations of vaccination with healthcare-seeking behavior or risk of infection. The test-negative design reduces but may not eliminate this confounding, for instance, if individuals who receive vaccination seek care or testing for less-severe illness. These circumstances indicate the two study designs cannot be applied naively to datasets gathered through public health surveillance or administrative sources. We suggest practical strategies to reduce bias in vaccine effectiveness estimates at the study design and analysis stages.

Background: Vaccination is a highly effective strategy for the prevention of enterovirus A71 (EV-A71)—hand, foot, and mouth disease (HFMD). Three inactivated EV-A71 vaccines in China have demonstrated remarkable efficacy against EV-A71-HFMD during clinical trials, exhibiting vaccine effectiveness (VE) exceeding 90% and few adverse events (AEs). However, the effectiveness of vaccines in the real world and its impact on the epidemiological characteristics of HFMD after the use of EV-A71 inactivated vaccine are uncertain. Methods: The odd ratio (OR) and 95% confidence (CI) were used as the effect estimates of the meta-analysis in the test-negative design (TND), and the OR was used to calculate VE: VE = (1 − OR) × 100%. Results: According to the literature search strategy, a comprehensive search was conducted in PubMed, Web of Science (including Chinese Science Citation Database and MEDLINE), and Embase, and 18 records were ultimately included in this study. Subsequently, the overall VE and 95% CI of different vaccine doses were analyzed, with the one-dose vaccine at 66.9% (95% CI: 45.2–80.0%) and the two-dose vaccine at 84.2% (95% CI: 79.4–87.9%). Additionally, the most reported AEs were mild general reactions without any rare occurrences. Simultaneously, the widespread use of the EV-A71 vaccine would lead to a reduction in both the incidence of EV-A71-associated HFMD and severe cases caused by EV-A71. Conclusion: The administration of the two-dose EV-A71 vaccine is highly effective in preventing HFMD in the real world, and the widespread use of the EV-A71 vaccine leads to a reduction in the incidence of EV-A71-associated HFMD and that of severe cases caused by EV-A71. The findings suggest that administering the two-dose EV-A71 inactivated vaccine to children aged 6 months to 71 months can be effective in preventing EV-A71-associated HFMD, highlighting the need for developing a multivalent HFMD vaccine for preventing cases not caused by EV-A71.

Background: During the 2022–2023 influenza season, the influenza activities in most regions of China were postponed, including Beijing. The unusually delayed influenza epidemic posed a challenge to the effectiveness of the influenza vaccine. Methods: Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022–2023 influenza season against influenza A-associated outpatient and emergency-department-attended influenza-like illness (ILI) in Beijing, China, from 9 January to 30 April 2023. Results: The analysis included 8301 medically attended ILI patients, of which 1342 (46.2%) had influenza A(H1N1)pdm09, 1554 (53.4%) had influenza A(H3N2), and 11 (0.4%) had co-infection of the two viruses. VE against influenza A-associated ILI patients was 23.2% (95% CI: −6.5% to 44.6%) overall, and 23.1%, 9.9%, and 33.8% among children aged 6 months to 17 years, adults aged 18–59 years, and adults aged ≥60 years, respectively. VE against influenza A(H1N1)pdm09 and against influenza A(H3N2) were 36.2% (95% CI: −1.9% to 60.1%) and 9.5% (95% CI: −34.1% to 39.0%), respectively. VE of the group with vaccination intervals of 14–90 days (70.1%, 95% CI: −145.4 to 96.4) was higher than that of the groups with a vaccination interval of 90–149 days (18.7%, 95% CI: −42.4% to 53.6%) and ≥150 days (21.2%, 95% CI: −18.8% to 47.7%). Conclusions: A moderate VE against influenza A(H1N1)pdm09 and a low VE against influenza A(H3N2) were observed in Beijing during the 2022–2023 influenza season, a season characterized with a delayed and high-intensity influenza epidemic. VE appears to be better within three months after vaccination. Our findings indicate a potential need for the optimization of vaccination policies and underscore the importance of continuous monitoring of influenza to enhance vaccines and optimizing vaccination timing.

Causal directed acyclic graphs (DAGs) are often used to select variables in a regression model to identify causal effects. Outcome-based sampling studies, such as the 'test-negative design' used to assess vaccine effectiveness, present unique challenges that are not addressed by the common back-door criterion. Here we discuss intuitive, graphical approaches to explain why the common back-door criterion cannot be used for identification of population average causal effects with outcome-based sampling studies. We also describe graphical rules that can be used instead in outcome-based sampling studies when the objective is limited to determining if the causal odds ratio is identifiable, and illustrate recent changes to the free online software Dagitty which incorporate these principles. [ABSTRACT FROM AUTHOR]

• Immune escape variants and waning immunity are major concerns for COVID-19. • Booster doses initially provided similarly high protection against BA.5 and BA.1/2. • The protection seemed shorter-lasting against BA.5, contributing to the case surge. • The added benefit of the second booster dose was low even among recent vaccinees. • Emphasize the need for vaccines with variants and/or longer duration of protection. Repeated emergence of variants with immune escape capacity and waning immunity from vaccination are major concerns for COVID-19. We examined whether the surge in Omicron subvariant BA.5 cases was due to immune escape or waning immunity through vaccine effectiveness (VE) evaluation. A test-negative case-control study was conducted in 16 clinics/hospitals during the BA.1/BA.2-dominant and BA.5-dominant periods. VE against symptomatic infection was estimated after adjusting for age, sex, comorbidity, occupation, testing frequency, prior infection, close contact history, clinic/hospital, week, and preventive measures. Absolute VE (aVE) was calculated for 2/3/4 doses, compared to the unvaccinated. Relative VE (rVE) was calculated, comparing 3 vs 2 and 4 vs 3 doses. 13,025 individuals were tested during the BA.1/BA.2-dominant and BA.5-dominant periods with similar baseline characteristics. For BA.1/BA.2, aVE was 52 % (95 %CI:34–66) 14 days-3 months post-dose 2, 42 % (29–52) > 6 months post-dose 2, 71 % (64–77) 14 days-3 months post-dose 3, and 68 % (52–79) 3–6 months post-dose 3. rVE was 49 % (38–57) 14 days-3 months post-dose 3 and 45 % (18–63) 3–6 months post-dose 3. For BA.5, aVE was 56 % (27–73) 3–6 months post-dose 2, 32 % (12–47) > 6 months post-dose 2, 70 % (61–78) 14 days-3 months post-dose 3, 59 % (48–68) 3–6 months post-dose 3, 50 % (29–64) > 6 months post-dose 3, and 74 % (61–83) ≥ 14 days post-dose 4. rVE was 56 % (45–65) 14 days-3 months post-dose 3, 39 % (27–48) 3–6 months post-dose 3, 25 % (-2–45) > 6 months post-dose 3, and 30 % (-6–54) ≥ 14 days post-dose 4. Booster doses initially provided high protection against BA.5 at a level similar to that against BA.1/BA.2. However, the protection seemed shorter-lasting against BA.5, which likely contributed to the surge. Furthermore, rVE post-dose 4 was low even among recent vaccinees. These results support the introduction of variant-containing vaccines and emphasize the need for vaccines with longer duration of protection. [ABSTRACT FROM AUTHOR]

Adults with disabilities are at increased risk for severe coronavirus disease 2019 (COVID-19). Using data across 9 states during Delta- and Omicron-predominant periods (June 2021–September 2022), we evaluated the effectiveness of the original monovalent COVID-19 messenger RNA vaccines among 521 206 emergency department/urgent care encounters (11 471 [2%] in patients with a documented disability) and 139 548 hospitalizations (16 569 [12%] in patients with a disability) for laboratory-confirmed COVID-19 illness in adults (aged ≥18 years). Across variant periods and for the primary series or booster doses, vaccine effectiveness was similar in those with and those without a disability. These findings highlight the importance of adults with disabilities staying up to date with COVID-19 vaccinations. [ABSTRACT FROM AUTHOR]

Abstract Background Influenza is a contagious viral airborne disease that adds to the clinical and economic burden on the healthcare system. It could be prevented substantially by seasonal influenza vaccination. Seasonal influenza vaccine effectiveness (SIVE) varies a lot and should therefore be monitored. This report aims to update age-stratified SIVE estimates among patients hospitalized due to severe acute respiratory infection (SARI) during the 2019–2020 influenza season. Methods We performed a test-negative case-control study between December 2019 and April 2020 influenza season. We estimated SIVE and its 95% confidence intervals (95% CI) with logistic regression as (1-odds ratio)*100%. The models were adjusted for covariates that changed the unadjusted SIVE by ≥ 10%. Results Among 84 participants, 32 (38.1%) were influenza positive, mostly with A(H1N1)pdm09 (25 cases; 78.1%). SIVE against any influenza adjusted for age and heart disease was 39.2% (95% CI: -119.3%, 83.1%). Age-stratified point estimates adjusted for heart diseases indicated different SIVE, and were 64.0% (95% CI: -309.2%, 96.8%) and 21.6% (95% CI: -252.2%, 82.6%) for 18–64 and ≥ 65 year-old participants, respectively. Conclusions The point estimates suggested low to moderate SIVE against any influenza among hospitalized 18-64-year-old SARI participants, while low estimates were found in the ≥ 65-year-old group. Although broad SIVE confidence intervals indicate a small sample size and therefore the results can serve only as indicatory, they are in line with the estimates reported by other studies during the 2019–2020 season.

ObjectiveTo evaluate the vaccine effectiveness (VE) of inactivated trivalent influenza vaccine in primary and secondary school students. MethodsRespiratory specimens were detected with PCR for influenza virus nucleic acid among 286 primary and secondary school students (6 – 15 years old) diagnosed as influenza-like illness (ILI) cases at all fever clinics in Nanshan district of Shenzhen city during an influenza season (from November 2021 to May 2022) and the ILI cases’ information on demography and influenza vaccination were collected simultaneously. The ILI cases positive for viral nucleic acid were assigned into a case group and those negative into a control group. Influenza vaccination ratio and odds ratio [OR] of viral nucleic acid positivity for the two groups were analyzed and compared to estimate the VE of influenza vaccination. ResultsOf the 286 ILI cases, 68 (23.78%) were positive for influenza nucleic acid (all belonging to B strain) and 218 (76.22%) were negative. The ratio of seasonal influenza vaccination was 5.88% (4/64) for the cases and 15.14% (33/216) for the controls, and the OR of being virus nucleic acid positive was 0.3886 (95% confidence interval [CI]: 0.1528 – 0.9880) for the vaccinated ILI cases. The estimated VE was 61.14% (95%CI: 1.20% – 84.72%) for seasonal influenza vaccination. ConclusionSeasonal influenza vaccination can protect primary and secondary school students from influenza virus infection. The result suggests that seasonal influenza vaccination needs to be promoted among school age children.

Abstract Safe and effective vaccines are crucial for the control of Covid-19 and to protect individuals at higher risk of severe disease. The test-negative design is a popular option for evaluating the effectiveness of Covid-19 vaccines. However, the findings could be biased by several factors, including imperfect sensitivity and/or specificity of the test used for diagnosing the SARS-Cov-2 infection. We propose a simple Bayesian modeling approach for estimating vaccine effectiveness that is robust even when the diagnostic test is imperfect. We use simulation studies to demonstrate the robustness of our method to misclassification bias and illustrate the utility of our approach using real-world examples.

Influenza is a respiratory disease caused by the influenza virus, which is highly transmissible in humans. This paper presents a systematic review and meta-analysis of randomized controlled trials (RCTs) and test-negative designs (TNDs) to assess the vaccine effectiveness (VE) of seasonal influenza vaccines (SIVs) in humans aged 15 to 64 years. An electronic search to identify all relevant studies was performed. The outcome measure of interest was VE on laboratory-confirmed influenza (any strain). Quality assessment was performed using the Cochrane risk-of-bias tool for RCTs and the ROBINS-I tool for TNDs. The search identified a total of 2993 records, but only 123 studies from 73 papers were included in the meta-analysis. Of these studies, 9 were RCTs and 116 were TNDs. The pooled VE was 48% (95% CI: 42–54) for RCTs, 55.4% (95% CI: 43.2–64.9) when there was a match between the vaccine and most prevalent circulating strains and 39.3% (95% CI: 23.5–51.9) otherwise. The TNDs' adjusted VE was equal to 39.9% (95% CI: 31–48), 45.1 (95% CI: 38.7–50.8) when there was a match and 35.1 (95% CI: 29.0–40.7) otherwise. The match between strains included in the vaccine and strains in circulation is the most important factor in the VE. It increases by more than 25% when there is a match with the most prevalent circulating strains. The laboratorial method for confirmation of influenza is a possible source of bias when estimating VE. [ABSTRACT FROM AUTHOR]

• 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. [ABSTRACT FROM AUTHOR]

Background Following historically low influenza activity during the 2020–2021 season, the United States saw an increase in influenza circulating during the 2021–2022 season. Most viruses belonged to the influenza A(H3N2) 3C.2a1b 2a.2 subclade. Methods We conducted a test-negative case-control analysis among adults ≥18 years of age at 3 sites within the VISION Network. Encounters included emergency department/urgent care (ED/UC) visits or hospitalizations with ≥1 acute respiratory illness (ARI) discharge diagnosis codes and molecular testing for influenza. Vaccine effectiveness (VE) was calculated by comparing the odds of influenza vaccination ≥14 days before the encounter date between influenza-positive cases (type A) and influenza-negative and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–negative controls, applying inverse probability-to-be-vaccinated weights, and adjusting for confounders. Results In total, 86 732 ED/UC ARI-associated encounters (7696 [9%] cases) and 16 805 hospitalized ARI-associated encounters (649 [4%] cases) were included. VE against influenza-associated ED/UC encounters was 25% (95% confidence interval (CI), 20%–29%) and 25% (95% CI, 11%–37%) against influenza-associated hospitalizations. VE against ED/UC encounters was lower in adults ≥65 years of age (7%; 95% CI, −5% to 17%) or with immunocompromising conditions (4%; 95% CI, −45% to 36%). Conclusions During an influenza A(H3N2)-predominant influenza season, modest VE was observed. These findings highlight the need for improved vaccines, particularly for A(H3N2) viruses that are historically associated with lower VE. [ABSTRACT FROM AUTHOR]

• Japanese manufacturers produce seasonal influenza vaccines of uniform formulation. • The Ministry of Health designates a single strain for each vaccine component. • The A(H3) strain selected in 2017 showed substantially low vaccine productivity. • Japan's system for strain selection has not always been beneficial for the public. • The Health Ministry reformed the scheme of vaccine strain selection in 2018. In Japan, the Ministry of Health, Labour and Welfare (MHLW) designates one specific virus strain for each component of the quadrivalent seasonal influenza vaccine, and four domestic manufacturers produce egg-based influenza vaccines with the same formulation (inactivated, split-virus) using uniform vaccine strains. Thus, discussions of the development of effective seasonal influenza vaccines so far has focused solely on the antigenic match between the vaccine strains and epidemic viruses. However, in 2017, the Japanese selection system of vaccine viruses demonstrated that even a candidate vaccine virus that is antigenically similar to the predicted circulating viruses is not necessarily suitable for vaccine production, given lower productivity of the vaccine. Taking this experience into account, the MHLW reformed the scheme of vaccine strain selection in 2018, and instructed the Vaccine Epidemiology Research Group created by the MHLW to probe how the virus strains for the seasonal influenza vaccine should be selected in Japan. In this context, a symposium, entitled "Issues of the Present Seasonal Influenza Vaccines and Future Prospects", was held as part of the 22nd Annual Meeting of the Japanese Society for Vaccinology in 2018, and subjects related to the influenza vaccine viruses were discussed among relevant administrators, manufacturers, and researchers. This report summarizes the presentations given at that symposium in order to convey the present scheme of vaccine virus selection, the evaluation of the resulting vaccines, and the efforts at new vaccine formulation in Japan. Notably, from March 2022, the MHLW has launched a discussion of the merits of the seasonal influenza vaccines produced by foreign manufacturers. [ABSTRACT FROM AUTHOR]

Hungary provides the opportunity to evaluate the effectiveness of COVID-19 vaccination in a setting where naturally acquired immunity and hybrid immunity are likely to play a greater role due to suboptimal vaccination coverage. Methods: A test-negative study was conducted during the 2022–2023 respiratory season at the primary care level to determine the effectiveness of at least one COVID-19 booster dose in preventing medically attended symptomatic RT-PCR-confirmed SARS-CoV-2 infection in adults. Unvaccinated patients were used as a reference group. Results: A total of 247 cases and 1073 controls were included in the analysis. CVE was 56.8% (95% CI: 11.9–78.8%) in the population aged 60 years and older and 2.3% (95% CI: −50.0–36.3%) in the younger adults against COVID-19 caused by Omicron subvariants, mainly BA.5, BQ.1, and XBB.1. Self-reported COVID-19 in the 60–365 days prior to the current illness did not confer protection against reinfection without vaccination, but together with booster vaccination, it reduced the risk of COVID-19 by 63.0% (95% CI: −28.0–89.3%) and 87.6% (95% CI: 26.4–97.9%) among the 18–59 and 60+ age groups, respectively. Conclusions: CVE against COVID-19 was moderately high in the 60+ age groups. Because of the benefit of hybrid immunity, persons with previous SARS-CoV-2 infection should still be considered for vaccination campaigns.

As a simple, rapid and effective research method, test-negative design (TND) has been widely used to support the evaluation of post-marketing effectiveness of vaccines and efficacies of interventions in healthcare institutions, showing a magnificent prospect of application. With the emergence of new derivative types such as real-time TND and cluster-randomized TND, TND has also been gradually applied to the exploration of disease risk factors and effectiveness evaluation of interventions. However, there are still few related research reports in China. We introduced the basic principles, methods and essentials of implementation, newly derivative types such as real-time TND and cluster-randomized TND, advantages and limitations of TND, as well as its applications in assessing post-marketing effectiveness for vaccines and efficacies of interventions, providing a theoretical and practical basis for researchers in China to carry out relevant research.

IntroductionDevelopment of Robust and Innovative Vaccine Effectiveness (DRIVE) was a European public–private partnership (PPP) that aimed to provide annual, brand-specific estimates of influenza vaccine effectiveness (IVE) for regulatory and public health purposes. DRIVE was launched in 2017 under the umbrella of the Innovative Medicines Initiative (IMI) and conducted IVE studies from its pilot season in 2017–2018 to its final season in 2021–2022.MethodsIn 2021–2022, DRIVE conducted four primary care-based test-negative design (TND) studies (Austria, Italy, Iceland, and England; involving >1,000 general practitioners), nine hospital-based TND studies (France, Iceland, Italy, Romania, and Spain, for a total of 21 hospitals), and one population-based cohort study in Finland. In the TND studies, patients with influenza-like illness (primary care) or severe acute respiratory infection (hospital) were enrolled, and laboratory tested for influenza using RT-PCR. Study contributor-specific IVE was calculated using logistic regression, adjusting for age, sex, and calendar time, and pooled by meta-analysis.ResultsIn 2021–2022, pooled confounder-adjusted influenza vaccine effectiveness (IVE) estimates against laboratory-confirmed influenza (LCI) overall and per type and subtype/lineage was produced, albeit with wide confidence intervals (CI). The limited circulation of influenza in Europe did not allow the network to reach the optimal sample size to produce precise IVE estimates for all the brands included. The most significant IVE estimates were 76% (95% CI 23%−93%) for any vaccine and 81% (22%−95%) for Vaxigrip Tetra in adults ≥65 years old and 64% (25%−83%) for Fluenz Tetra in children (TND primary care setting), 85% (12%−97%) for any vaccine in adults 18–64 years (TND hospital setting), and 38% (1%−62%) in children 6 months−6 years (population-based cohort, mixed setting).DiscussionOver five seasons, DRIVE collected data on >35,000 patients, more than 60 variables, and 13 influenza vaccines. DRIVE demonstrated that estimating brand-specific IVE across Europe is possible, but achieving sufficient sample size to obtain precise estimates for all relevant stratifications remains a challenge. Finally, DRIVE's network of study contributors and lessons learned have greatly contributed to the development of the COVID-19 vaccine effectiveness platform COVIDRIVE.

In this multicenter, prospective, test-negative, case-control study in Japan, the effectiveness of both BA.1-containing and BA.4/BA.5-containing bivalent coronavirus disease 2019 mRNA vaccines against symptomatic infection during the BA.5-dominant period was high compared with no vaccination (65% and 76%) and moderate compared with monovalent vaccines administered over half a year earlier (46% combined). [ABSTRACT FROM AUTHOR]

Background Two- and 3-dose BNT162b2 vaccine effectiveness (VE) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including Delta and Omicron variants, was assessed among adolescents in Canada, where first and second doses were spaced longer than the manufacturer-specified 3-week interval. Methods Test-negative design estimated VE against laboratory-confirmed SARS-CoV-2 infection ≥14 days after vaccination among 12–17-year-olds in Quebec and British Columbia, Canada, between 5 September 2021 and 30 April 2022 (epidemiological weeks 36–17). VE was explored by the interval between first and second doses, time since the second dose, and with a third dose. Results The VE against Delta was ≥90% until at least 5 months after the second dose. The VE against Omicron decreased from about 65%–75% at 2–3 weeks to ≤50% by the third month after vaccination, restored to approximately 65% by a third dose. Although confidence intervals overlapped, VE against Omicron was about 5%–7% higher (absolute) when first and second doses were spaced ≥8 versus 3–4 weeks apart. Conclusions In adolescents, 2 BNT162b2 doses provided strong and sustained protection against Delta but reduced and rapidly waning VE against Omicron. A longer interval between first and second doses and a third dose marginally improved Omicron protection. [ABSTRACT FROM AUTHOR]

Background: Influenza is a contagious viral airborne disease that adds to the clinical and economic burden on the healthcare system. It could be prevented substantially by seasonal influenza vaccination. Seasonal influenza vaccine effectiveness (SIVE) varies a lot and should therefore be monitored. This report aims to update age-stratified SIVE estimates among patients hospitalized due to severe acute respiratory infection (SARI) during the 2019–2020 influenza season. Methods: We performed a test-negative case-control study between December 2019 and April 2020 influenza season. We estimated SIVE and its 95% confidence intervals (95% CI) with logistic regression as (1-odds ratio)*100%. The models were adjusted for covariates that changed the unadjusted SIVE by ≥ 10%. Results: Among 84 participants, 32 (38.1%) were influenza positive, mostly with A(H1N1)pdm09 (25 cases; 78.1%). SIVE against any influenza adjusted for age and heart disease was 39.2% (95% CI: -119.3%, 83.1%). Age-stratified point estimates adjusted for heart diseases indicated different SIVE, and were 64.0% (95% CI: -309.2%, 96.8%) and 21.6% (95% CI: -252.2%, 82.6%) for 18–64 and ≥ 65 year-old participants, respectively. Conclusions: The point estimates suggested low to moderate SIVE against any influenza among hospitalized 18-64-year-old SARI participants, while low estimates were found in the ≥ 65-year-old group. Although broad SIVE confidence intervals indicate a small sample size and therefore the results can serve only as indicatory, they are in line with the estimates reported by other studies during the 2019–2020 season. [ABSTRACT FROM AUTHOR]

The current influenza season started in Italy in October 2023, approaching the epidemic peak in late December (52nd week of the year). We aimed to explore the mid-term virologic surveillance data of the 2023/2024 influenza season (from 16 October 2023 to 7 January 2024) in Sicily, the fourth most populous Italian region. A test-negative design was used to estimate the effectiveness of seasonal influenza vaccine (VE) against A(H1N1)pdm09 virus, the predominant subtype in Sicily (96.2% of laboratory-confirmed influenza cases). Overall, 29.2% (n = 359/1230) of oropharyngeal swabs collected from patients with influenza-like illness (ILI) were positive for influenza. Among the laboratory-confirmed influenza cases, 12.5% (n = 45/359) were vaccinated against influenza, with higher prevalence of laboratory-confirmed diagnosis of influenza A among subjects vaccinated with quadrivalent inactivated standard dose (29.4%), live attenuated intranasal (25.1%), and quadrivalent inactivated high-dose (23.8%) influenza vaccines. Comparing influenza vaccination status for the 2023/2024 season among laboratory-confirmed influenza-positive and -negative samples, higher vaccination rates in influenza-negative samples (vs. positive) were observed in all age groups, except for 45–64 years old, regardless of sex and comorbidities. The overall adjusted VE (adj-VE) was 41.4% [95%CI: 10.5–61.6%], whereas the adj-VE was 37.9% [95%CI: −0.7–61.7%] among children 7 months–14 years old and 52.7% [95%CI: −38.0–83.8%] among the elderly (≥65 years old).

ObjectiveTo evaluate influenza vaccine effectiveness (VE) in preventing laboratory confirmed influenza illness among children aged 6 – 59 months during 2011 – 2021, and to provide evidences for improving vaccination recommendation and policy-making. MethodsBased on a prospective influenza surveillance conducted at the Soochow University Affiliated Children′s Hospital in Suzhou city, Jiangsu province from October 2011 to May 2021, we conducted a test-negative case-control study. The participants of the study were selected from 5 554 influenza-like illness (ILI) and 7 737 severe acute respiratory infection (SARI) outpatients/inpatients aged 6 – 59 months and with nasopharyngeal swab/sputum specimen test for influenza virus nucleic acid in the surveillance and influenza vaccination records of all the ILI and SARI patients were checked retrospectively. The cases of the study were influenza virus-positive ILI (n = 517) and SARI (n = 582) patients aged 6 – 59 months; the controls were 1 : 2 age- and clinic attending/hospital admission date-matched influenza virus-negative ILI/SARI patients. The adjusted odds ratio (aOR) of vaccination and VE were estimated using conditional logistic regression. ResultsThe vaccination records were available for 73.3% (9 747) of the registered patients and the observed vaccination rate was 1.79% (174/9 747). The overall VE for all the ILI/SARI patients was 36.8% (95% confidence interval [95% CI]: – 4.7% – 61.9%); the VE was 26.7% (95% CI: – 34.8% – 60.2%) for the ILI and 53.1% (95% CI: – 17.0% – 81.2%) for the SARI. The VE were 28.9% (95% CI: – 31.2% – 61.5%) and 51.2% (95% CI: – 21.3% – 80.4%) for the patients aged 6 – 35 months and 36 – 59 months. The VE of partial vaccination and full vaccination for children aged 6 – 35 months were 21.6% (95% CI = – 65.1% – 62.7%) and 40.6% (95% CI = – 66.0% – 78.8%), respectively. ConclusionThe overall VE of influenza vaccination was 36.8% among 6 – 59 months old children, with a higher VE against SARI than that against ILI and a higher VE among the children aged 36 – 59 months than that among those aged 6 – 35 months. Full dose influenza vaccination provided better protection than partial dose vaccination for children aged 6 – 35 months.

Test-negative designs are commonplace in assessments of influenza vaccination effectiveness, estimating this value from the exposure odds ratio of vaccination among individuals treated for acute respiratory illness who test positive for influenza virus infection. This approach is widely believed to recover the vaccine direct effect by correcting for differential health-care-seeking behavior among vaccinated and unvaccinated persons. However, the relationship of the measured odds ratio to true vaccine effectiveness is poorly understood. We derived the odds ratio under circumstances of real-world test-negative studies. The odds ratio recovers the vaccine direct effect when 2 conditions are met: 1) Individuals' vaccination decisions are uncorrelated with exposure or susceptibility to the test-positive or test-negative conditions, and 2) vaccination confers "all-or-nothing" protection (whereby certain individuals have no protection while others are perfectly protected). Biased effect-size estimates arise if either condition is unmet. Such bias might suggest misleading associations of vaccine effectiveness with time since vaccination or the force of infection of influenza. The test-negative design could also fail to correct for differential health-care-seeking behavior among vaccinated and unvaccinated persons without stringent criteria for enrollment and testing. Our findings demonstrate a need to reassess how data from test-negative studies can inform policy decisions.