An information-theoretic approach for the assessment ofacontinuous outcome as a surrogate for a binary trueendpoint based on causal inference: Application tovaccine evaluation.

Prevention and Control of Seasonal Influenza With Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2014–15 Influenza Season

In a causal inference framework, a new metric has been proposed to quantify surrogacy for a continuous putative surrogate and a binary true endpoint, based on information theory. The proposed metric, termed the individual causal association (ICA), was quantified using a joint causal inference model for the corresponding potential outcomes. Due to the non-identifiability inherent in this type of models, a sensitivity analysis was introduced to study the behavior of the ICA as a function of the non-identifiable parameters characterizing the aforementioned model. In this scenario, to reduce uncertainty, several plausible yet untestable assumptions like monotonicity, independence, conditional independence or homogeneous variance-covariance, are often incorporated into the analysis. We assess the robustness of the methodology regarding these simplifying assumptions via simulation. The practical implications of the findings are demonstrated in the analysis of a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine.

Co-circulation of two antigenically and genetically distinct lineages of influenza B virus, represented by prototype viruses B/Victoria/2/1987 and B/Yamagata/16/1988, has led to the development of quadrivalent influenza vaccines that contain two influenza B antigens. The inclusion of two influenza B antigens presents challenges for the production and regulation of inactivated quadrivalent vaccines, including the potential for cross-reactivity of the reagents used in identity and potency assays because of the relative close relatedness of the hemagglutinin (HA) from the two virus lineages. Monoclonal antibodies (mAbs) specific for the two lineages of influenza B HA were generated and characterized and used to set-up simple identity tests that distinguish the influenza B antigens in inactivated trivalent and quadrivalent vaccines. The lineage-specific mAbs bound well to the HA of influenza B strains included in influenza vaccines over a period of more than 10 years, suggesting that identity tests using such lineage-specific mAbs would not necessarily have to be updated with every influenza B vaccine strain change. These lineage-specific mAbs were also used in an antibody capture ELISA format to quantify HA in vaccine samples, including monovalent, trivalent, and quadrivalent vaccine samples from various manufacturers. The results demonstrated correlation with HA values determined by the traditional single radial immunodiffusion (SRID) assay. Further, the antibody-capture ELISA was able to distinguish heat-stressed vaccine from unstressed vaccine, and was similar to the SRID in quantifying the resultant loss of potency. These mAb reagents should be useful for further development of antibody-based alternative influenza B identity and potency assays.

Influenza is an acute respiratory infectious disease that is caused by the influenza virus, which seriously affects human health. The influenza virus has frequent antigenic drifts that can facilitate escape from pre-existing population immunity and lead to the rapid spread and annual seasonal epidemics. Influenza outbreaks occur in crowded settings, such as schools, kindergartens, and nursing homes. Seasonal influenza epidemics can cause 3-5 million severe cases and 290 000-650 000 respiratory disease-related deaths worldwide every year. Pregnant women, infants, adults aged 60 years and older, and individuals with comorbidities or underlying medical conditions are at the highest risk of severe illness and death from influenza. China has experienced a influenza epidemic season dominated by A (H1N1) pdm09 subtype from mid-February to the end of April 2023, and the intensity was slightly higher than the epidemic year before the COVID-19. We may face the risk of interaction or co-circulation of respiratory infectious diseases such as COVID-19 and influenza during the coming season. Annual influenza vaccination is an effective way to prevent influenza, reduce influenza-related severe illness and death, and reduce the harm caused by influenza-related diseases and the use of medical resources. The currently approved influenza vaccines in China include trivalent inactivated influenza vaccine (IIV3), quadrivalent inactivated influenza vaccine (IIV4), and trivalent live attenuated influenza vaccine (LAIV3). IIV3 and IIV4 are produced as a split virus vaccine and subunit vaccine; LAIV3 is a live, attenuated virus vaccine. The influenza vaccine is a non-immunization program vaccine, which means that residents are voluntarily vaccinated. China CDC has issued "Technical guidelines for seasonal influenza vaccination in China" every year from 2018 to 2022. Over the past year, new research evidence has been published at home and abroad, and new influenza vaccines have been approved for marketing in China. To better guide the prevention and control of influenza and vaccination in China, the National Immunization Advisory Committee (NIAC) Technical Working Group (TWG), Influenza Vaccination TWG updated and revised the 2022-2023 technical guidelines with the latest research progress into the "Technical guidelines for seasonal influenza vaccination in China (2023-2024)." The new version has updated five key areas: (1) new research evidence－especially research conducted in China-has been added, including new estimates of the burden of influenza disease, assessments of influenza vaccine effectiveness and safety, and analyses of the cost-effectiveness of influenza vaccination; (2) policies and measures for influenza prevention and control were issued by the National Health Commission of the People's Republic of China and National Disease Control and Prevention Administrationy over the past year; (3) influenza vaccines approved for marketing in China this year; (4) composition of trivalent and quadrivalent influenza vaccines for the 2023-2024 northern hemisphere influenza season; and (5) recommendations for influenza vaccination during the 2023-2024 influenza season. The 2023-2024 guidelines recommend that all people aged 6 months and above who have no contraindications should get the influenza vaccination. For adults aged ≥18 years, co-administration of inactivated SARS-CoV-2 and influenza vaccines in separate arms is acceptable regarding immunogenicity and reactogenicity. For people under 18 years of age, there should be at least 14 days between influenza vaccination and COVID-19 vaccination. The guidelines express no preference for influenza vaccine type or manufacturer-any approved, age-appropriate influenza vaccines can be used. Combining the influenza epidemic tendency and the prevention and control strategy of multiple diseases, the technical guidelines recommend priority vaccination of the following high-risk groups during the upcoming 2023-2024 influenza season to minimize harm from influenza: (1) healthcare workers, including clinical doctors and nurses, public health professionals, and quarantine professionals; (2) adults ≥60 years of age; (3) individuals with comorbidities; (4) people living in nursing homes or welfare homes and staff who take care of vulnerable, at-risk individuals; (5) pregnant women; (6) children 6-59 months of age; (7) family members and caregivers of infants under 6 months of age; and (8) people who work in nursery institutions, primary and secondary schools, and supervision places. Children 6 months to 8 years of age who receive inactivated influenza vaccine for the first time should receive two doses, with an inter-dose interval of 4 or more weeks. Children who previously received the influenza vaccine and anyone aged 9 years or older need only one dose. LAIV is recommended only for a single dose regardless of the previous influenza vaccination. Vaccination should begin as soon as influenza vaccines become available, and preferably should be completed before the onset of the local influenza season. Repeated influenza vaccination during a single influenza season is not recommended. Vaccination clinics should provide immunization services throughout the epidemic season. Pregnant women can receive inactivated influenza vaccine at any stage of pregnancy. These guidelines are intended for use by staff of CDCs, healthcare workers, maternity and child care institutions and immunization clinic staff members who work on influenza control and prevention. The guidelines will be updated periodically as new evidence becomes available.

ABSTRACTAt the beginning of the 21st century, a new paradigm was introduced for the evaluation of surrogate endpoints based on meta-analysis. In this paradigm, the putative surrogate is assessed at two different levels, the so-called, trial and individual level. Trial level surrogacy is defined as the association between the expected causal treatment effects across different trials populations, whereas the individual level is defined as the association between the surrogate and true endpoints, after adjusting by trial and treatment. It has been argued that the individual level surrogacy does not have a causal interpretation and, consequently, it is a poor metric of surrogacy. In the present work, an alternative definition of individual level surrogacy is introduced based on individual causal treatment effects. In addition, using the maximum entropy principle, a direct link between the individual level surrogacy, as defined in the meta-analytic approach, and the newly proposed definition is established. This new perspective sets the individual level surrogacy in a more coherent framework with respect to the trial level and bridges the two main schools of thought in this domain, namely, the causal inference and meta-analytic schools.

BackgroundThe effects of repeated influenza vaccination in children are not well understood. In this study, we evaluated previous vaccination effects on antibody response after vaccination with trivalent inactivated influenza vaccine (IIV) or quadrivalent live-attenuated influenza vaccine (LAIV) among school-aged children (5–17 years) across 3 seasons.MethodsChildren were enrolled in the fall of 2013, 2014, and 2015. The participants received IIV or LAIV according to parent preference (2013–2014) or our randomization scheme (2014–2015). All study children received IIV in 2015–2016. Hemagglutination-inhibition assays measured antibody response to egg-grown vaccine strains from prevaccination and postvaccination serum samples. Geometric mean titers (GMTs) and increases in GMTs from before to after vaccination (geometric mean fold rise [GMFR]) were estimated from repeated-measures linear mixed models.ResultsWe enrolled 161 children in 2013–2014, 128 in 2014–2015, and 126 in 2015–2016. Among the IIV recipients, responses to the influenza A(H1N1)pdm09 and B vaccine strains were lowest among children who had received a previous-season IIV. The GMFRs for strains A(H1N1)pdm09 and B were 1.5 to 2.3 for previous-season IIV and 4.3 to 12.9 for previous-season LAIV or no previous vaccine. GMFRs were lower for strain A(H3N2), and differences according to previous-season vaccination history were smaller and not significant in most seasons. Most children had a post-IIV vaccination titer of ≥40 for vaccine strains in all seasons, regardless of previous-season vaccination history. Little to no increase in antibody levels was observed after vaccination with LAIV.ConclusionsSerologic response to vaccination was greatest for IIV, but previous-season vaccination modified IIV response to A(H1N1)pdm09 and B. Influenza A(H3N2) responses were low in all groups, and LAIV generated minimal serologic response against all strains.

Enhanced Passive Safety Surveillance (EPSS) was conducted for quadrivalent inactivated split-virion influenza vaccines (IIV4) in Germany (high dose [HD]) and Finland (standard dose [SD]) for the northern hemisphere (NH) 2022/23 influenza season. The primary objective was to assess adverse events following immunization (AEFI) occurring ≤7 days post-vaccination. In each country, the EPSS was conducted at the beginning of the NH influenza season. Exposure information was documented using vaccination cards (VC), and AEFI were reported via an electronic data collection system or telephone. AEFI were assessed by seriousness and age group (Finland only). The vaccinee reporting rate (RR) was calculated as the number of vaccinees reporting ≥ 1 AEFI divided by the total vaccinees. In Germany, among 1041 vaccinees, there were 31 AEFI (ten vaccinees) during follow-up, including one serious AEFI. Of 16 AEFI (six vaccinees) with reported time of onset, 15 occurred ≤7 days post-vaccination (RR 0.58%, 95% confidence interval [CI] 0.21, 1.25), which was lower than the 2021/22 season (RR 1.88%, 95% CI: 1.10, 3.00). In Finland, among 1001 vaccinees, there were 142 AEFI (51 vaccinees) during follow-up, none of which were serious. Of 133 AEFI (48 vaccinees) with time of onset reported, all occurred ≤7 days post-vaccination (RR 4.80%, 95% CI: 3.56, 6.31), which was similar to the 2021/22 season (RR 4.90%, 95% CI: 3.65, 6.43). The EPSS for HD-IIV4 and for SD-IIV4 in the 2022/23 influenza season did not suggest any clinically relevant changes in safety beyond what is known/expected for IIV4s.

This study aimed to evaluate the immunogenicity non-inferiority and safety of the quadrivalent inactivated split-virion influenza vaccine in participants ≥ 3 years old. A total of 3,328 participants were enrolled. Participants 3–8 years old were administered one or two doses of the investigational vaccine or one dose of the control vaccine, whereas the other participants were administered only one dose of the investigational or control vaccine. The immunogenicity and occurrence of adverse events (AEs) after 30 days of full-course vaccination and serious adverse events (SAEs) within 6 months after full-course vaccination were assessed. The sero-conversion rates (SCRs) of anti-H1N1, H3N2, B(Y), and B(V) antibodies in the test group were 74.64%, 87.40%, 82.66%, and 78.89%, respectively, and their geometric mean titers were 1:250.13, 1:394.54, 1:200.84, and 1:94.91, respectively, which were non-inferior to those in the control group. The SCRs and sero-protection rates in the two-dose group of participants 3–8 years old were greater than those in the one-dose group. The incidences of total AEs and adverse reactions in the test group were 31.6% and 21.7%, respectively, which were close to those in the control group. In the two-dose group, the incidence of adverse reactions was considerably lower in the second dose (5.5%) than in the first dose (14.7%). Most AEs were grade 1 in severity, and no SAEs were recorded. The investigational vaccine had immunogenicity non-inferior to the control vaccine, and two doses were more effective than one dose in participants 3–8 years old, with a good overall safety. Trial registration: CTR20200715.

There are many different influenza vaccines authorized for use in Canada and new evidence on influenza and vaccines is emerging all the time. The National Advisory Committee on Immunization (NACI) provides recommendations annually regarding seasonal influenza vaccines to the Public Health Agency of Canada (PHAC). To summarize the NACI recommendations regarding the use of seasonal influenza vaccines for the 2018-2019 influenza season in light of two NACI reviews conducted on 1) the risk of serious influenza-related complications in children and adults with neurologic and neurodevelopment conditions and 2) the efficacy/effectiveness of high-dose and adjuvanted inactivated influenza vaccines in persons 65 years of age and older. For both topics, NACI's Influenza Working Group developed a predefined search strategy to identify all eligible studies, assessed their quality, summarized and analyzed the findings, proposed recommendations and identified the Grade of evidence that supported them. In light of the evidence, the recommendations were then considered and approved by NACI. NACI concludes there is fair evidence to recommend that children and adults with neurologic and neurodevelopment conditions are groups for whom influenza immunization is particularly recommended (Evidence Grade B recommendation). On choosing influenza vaccines for persons 65 years of age and older, at a programmatic level, NACI recommends that any of the four influenza vaccines available for use should be used. There is insufficient evidence to make a comparative recommendation on the use of these vaccines at a programmatic level (Grade I). At an individual level, NACI recommends that high-dose trivalent inactivated influenza vaccine (TIV) should be offered over standard-dose TIV to persons 65 years of age and older (Grade A). There is insufficient evidence to make comparative recommendations on the use of MF59-adjuvanted TIV and quadrivalent inactivated influenza vaccine over standard-dose TIV (Grade I). NACI continues to recommend annual influenza vaccination for all individuals aged six months and older, with particular focus on people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, people who provide essential community services and people in direct contact during culling operations with poultry infected with avian influenza.

Quadrivalent influenza inactivated vaccine (IIV4) is more likely to provide wider protection against yearly circulating influenza viruses than trivalent inactivated influenza vaccine (IIV3). In this study, a total of 320 participants were allocated to four age cohorts (6–35 months, 3–8 years, 9–17 years, and ≥ 18 years; 80 participants/cohort) according to their actual date of birth. Participants in each cohort were randomly assigned to two groups to receive intramuscular injection of the trial vaccine or the comparative vaccine in a one-dose (3–8 years, 9–17 years,and ≥ 18 years) schedule on day 0 or two-dose (6–35 months cohort) schedule on day 0 and 28. The first objective is to evaluate the safety and immunogenicity of the full-dose subunit non-adjuvanted IIV4 (FD-subunit NAIIV4) we developed versus an active-control, China-licensed split-virion NAIIV4, in people ≥ 3 years. The second objective is to evaluate the safety and immunogenicity of FD-subunit NAIIV4 versus the half-dose (HD-subunit NAIIV4) in toddlers aged 6–35 months. Results showed that all adverse reactions noted were rare, mild, and self-limited. In ≥ 3 years cohorts, systemic adverse reactions in FD-subunit NAIIV4 groups were less than the active control split-virion NAIIV4 groups ([Systemic adverse reaction rates (95%CI)], 15.0 (8.6–21.4) versus 19.2(12.1–26.2), p = 0.391). The overall seroprotection efficacy after vaccination were comparable between FD-subunit NAIIV4 and the active control split-virion NAIIV4([Seroprotection rates (95%CI)], H1N1, 99.2(81.3–100.0) versus 94.9(90.9–98.9), p = 0.117; H3N2, 81.7(74.7–88.6) versus 82.1(75.1–89.0), p = 0.939; BV, 75.8(68.2–83.5) versus 74.4(66.4–82.3), p = 0.793; BY, 94.2(90.0–98.4) versus 92.3(87.5–97.1), p = 0.568). Additionally, FD-subunit NAIIV4 has comparable safety and better seroprotection versus that of the half-dose in 6–35 months toddlers groups ([Total adverse reaction rates (95%CI)], 37.5(18.5–56.5) versus 47.5(26.1–68.9), p = 0.366) ([Seroprotection rates (95%CI)], H1N1, 85(56.4–100.0) versus 75.7(47.6–100.0), p = 0.117; H3N2, 50(28.1–71.9) versus 29.7(12.2–47.3), p = 0.070; BV, 75(48.2–100.0) versus 29.7(12.2–47.3), p < 0.001; BY, 75(48.2–100.0) versus 56.8(32.5–81.0), p = 0.091). As a result, the FD-subunit NAIIV4 we developed is safe and effective to provide broader and adequate protection against the circulating influenza viruses during 2018–2019, which could be an essential component of the global preventive strategy for influenza pandemic.

Influenza remains a significant public health burden in India, causing seasonal outbreaks and substantial morbidity across all age groups. Despite available effective vaccines, uptake remains low, and comprehensive safety and immunogenicity data for quadrivalent influenza vaccines in Indian populations are limited. This open-label phase III study evaluated the immunogenicity and safety of a quadrivalent inactivated split-virion influenza vaccine (QIV) in participants aged 6 months and older across five Indian sites. Participants received one or two 0.5 mL doses based on age and prior vaccination history. A total of 401 participants were enrolled in the study. Geometric mean titers increased from baseline across all age groups for all four strains. Hemagglutination inhibition (HAI) geometric mean titer ratios (GMTRs) comparing post-vaccination to baseline values showed higher responses to A/H1N1 in adults aged 18 years and older, while A/H3N2 responses were similar across age groups. Younger participants demonstrated higher GMTRs for B/Yamagata and B/Victoria strains. Seroconversion rates at day 29 were generally highest against A/H1N1 across all ages. Solicited injection site reactions were comparable among age groups, though younger participants reported fewer local reactions. No vaccine-related serious adverse events occurred. These findings demonstrate that QIV induced HAI titer increases in pediatric populations comparable to or somewhat higher adult responses against all four vaccine strains. QIV immunization against influenza was generally safe and well tolerated in both adults and children. Clinical Trials Registry – India: CTRI/2021/11/037841.

MF59®-adjuvanted trivalent inactivated influenza vaccine (aIIV3) and high-dose trivalent inactivated influenza vaccine (HD-IIV3) elicit an enhanced immune response in older adults compared to standard, quadrivalent inactivated influenza vaccines (IIV4). We sought to determine the relative vaccine effectiveness (rVE) of aIIV3 versus IIV4 and HD-IIV3 in preventing influenza-related medical encounters in this retrospective cohort study involving adults ≥65 years with ≥1 health condition during the 2017–2018 and 2018–2019 influenza seasons. Data were obtained from primary and specialty care electronic medical records linked with pharmacy and medical claims. Adjusted odds ratios (OR) were derived from an inverse probability of treatment-weighted sample adjusted for age, sex, race, ethnicity, geographic region, vaccination week, and health status. rVE was determined using the formula (% rVE = 1 − ORadjusted) × 100. Analysis sets included 1,755,420 individuals for the 2017–2018 season and 2,055,012 for the 2018–2019 season. Compared to IIV4, aIIV3 was 7.1% (95% confidence interval 3.3–10.8) and 20.4% (16.2–24.4) more effective at preventing influenza-related medical encounters in the 2017–2018 and 2018–2019 seasons, respectively. Comparable effectiveness was observed with HD-IIV3 across both seasons. Our results support improved effectiveness of aIIV3 vs IIV4 in a vulnerable population of older adults at high risk of influenza and its complications.

Fast and highly selective determination of hemagglutinin content in quadrivalent influenza vaccine by reversed-phase high-performance liquid chromatography method

Limited randomized clinical trial data exist on the safety of simultaneous administration of COVID-19 and influenza vaccines. To compare the reactogenicity, safety, and changes in health-related quality of life (HRQOL) after simultaneous vs sequential receipt of messenger RNA (mRNA) COVID-19 vaccine and quadrivalent inactivated influenza vaccine (IIV4). This randomized, placebo-controlled clinical trial was conducted between October 8, 2021, and June 14, 2023, at 3 US sites. Participants were nonpregnant persons aged 5 years or older with the intention of receiving both influenza and mRNA COVID-19 vaccines. Intramuscular administration in opposite arms of either IIV4 or saline placebo simultaneously with mRNA COVID-19 vaccine at visit 1. Those who received placebo at visit 1 received IIV4 and those who received IIV4 at visit 1 received placebo 1 to 2 weeks later at visit 2. The primary composite reactogenicity outcome was the proportion of participants with fever, chills, myalgia, and/or arthralgia of moderate or greater severity within 7 days after vaccination visits 1 and/or 2, using a 10% noninferiority margin. Secondary outcomes were solicited reactogenicity events and unsolicited adverse events (AEs) for 7 days after each visit separately and HRQOL after visit 1, assessed by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index. Serious AEs (SAEs) and AEs of special interest (AESIs) were assessed for 121 days. Outcomes were compared between groups. A total of 335 persons (mean [SD] age, 33.4 [15.1] years) were randomized (169 to the simultaneous group and 166 to the sequential group); 211 (63.0%) were female, and 255 (76.1%) received bivalent BNT162b2 mRNA COVID-19 vaccine. The proportion with the primary composite reactogenicity outcome in the simultaneous group (25.6% [n = 43]) was noninferior to the proportion in the sequential group (31.3% [n = 52]) (site-adjusted difference, -5.6 percentage points [pp]; 95% CI, -15.2 to 4.0 pp). Respective proportions in each group were similar after each visit separately (visit 1, 40 [23.8%] vs 47 [28.3%]; visit 2, 5 [3.0%] vs 9 [5.4%]). No significant group differences in participants with AEs (21 [12.4%] vs 16 [9.6%]), SAEs (1 [0.6%] vs 1 [0.6%]), and AESIs (19 [11.2%] vs 9 [5.4%]) were observed in the simultaneous vs sequential groups, respectively. Among participants with severe reactogenicity, the mean (SD) EQ-5D-5L Index score decreased from 0.92 (0.08) to 0.92 (0.09) prevaccination to 0.81 (0.09) to 0.82 (0.12) postvaccination. In this randomized clinical trial assessing simultaneous vs sequential administration of mRNA COVID-19 and IIV4 vaccines, reactogenicity was comparable in both groups. These findings support the option of simultaneous administration of these vaccines. ClinicalTrials.gov Identifier: NCT05028361.

A U.S. multisite trial was conducted and explored whether blunting of mRNA COVID-19 vaccine immunogenicity occurred when administered simultaneously with influenza vaccine. Persons ≥5years of age received either quadrivalent inactivated influenza vaccine (IIV4) or saline placebo simultaneously with an initial or booster dose of mRNA COVID-19 vaccine. Those receiving placebo with mRNA COVID-19 vaccine received IIV4 7-14days later. SARS-CoV-2 antibody was assessed by pseudovirus neutralization (D614G, BA.4/BA. 5, and XBB.1.5) at baseline and 28days following mRNA COVID-19 vaccine primary series or booster dose. Of 335 randomized participants, 157 were in the simultaneous group and 150 the sequential group. Post-vaccination geometric mean SARS-CoV-2 ID50 titers for the ancestral D614G strain and BA.4/5 variant (simultaneous versus sequential) were 4357.1 versus 4492.3(p=0.79) and 1547.8 versus 1463.8(p=0.69), respectively. Blunting of mRNA COVID-19 vaccine immunogenicity was not observed when mRNA COVID-19 and influenza vaccines were administered simultaneously. TRIAL REGISTRATIONClinicalTrials.gov ID: NCT05028361.