This report updates the 2020-21 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2020;69[No. RR-8]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. During the 2021-22 influenza season, the following types of vaccines are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).The 2021-22 influenza season is expected to coincide with continued circulation of SARS-CoV-2, the virus that causes COVID-19. Influenza vaccination of persons aged ≥6 months to reduce prevalence of illness caused by influenza will reduce symptoms that might be confused with those of COVID-19. Prevention of and reduction in the severity of influenza illness and reduction of outpatient visits, hospitalizations, and intensive care unit admissions through influenza vaccination also could alleviate stress on the U.S. health care system. Guidance for vaccine planning during the pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html. Recommendations for the use of COVID-19 vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html, and additional clinical guidance is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.Updates described in this report reflect discussions during public meetings of ACIP that were held on October 28, 2020; February 25, 2021; and June 24, 2021. Primary updates to this report include the following six items. First, all seasonal influenza vaccines available in the United States for the 2021-22 season are expected to be quadrivalent. Second, the composition of 2021-22 U.S. influenza vaccines includes updates to the influenza A(H1N1)pdm09 and influenza A(H3N2) components. U.S.-licensed influenza vaccines will contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Third, the approved age indication for the cell culture-based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), has been expanded from ages ≥4 years to ages ≥2 years. Fourth, discussion of administration of influenza vaccines with other vaccines includes considerations for coadministration of influenza vaccines and COVID-19 vaccines. Providers should also consult current ACIP COVID-19 vaccine recommendations and CDC guidance concerning coadministration of these vaccines with influenza vaccines. Vaccines that are given at the same time should be administered in separate anatomic sites. Fifth, guidance concerning timing of influenza vaccination now states that vaccination soon after vaccine becomes available can be considered for pregnant women in the third trimester. As previously recommended, children who need 2 doses (children aged 6 months through 8 years who have never received influenza vaccine or who have not previously received a lifetime total of ≥2 doses) should receive their first dose as soon as possible after vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For nonpregnant adults, vaccination in July and August should be avoided unless there is concern that later vaccination might not be possible. Sixth, contraindications and precautions to the use of ccIIV4 and RIV4 have been modified, specifically with regard to persons with a history of severe allergic reaction (e.g., anaphylaxis) to an influenza vaccine. A history of a severe allergic reaction to a previous dose of any egg-based IIV, LAIV, or RIV of any valency is a precaution to use of ccIIV4. A history of a severe allergic reaction to a previous dose of any egg-based IIV, ccIIV, or LAIV of any valency is a precaution to use of RIV4. Use of ccIIV4 and RIV4 in such instances should occur in an inpatient or outpatient medical setting under supervision of a provider who can recognize and manage a severe allergic reaction; providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. For ccIIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or any component of ccIIV4 is a contraindication to future use of ccIIV4. For RIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or any component of RIV4 is a contraindication to future use of RIV4. This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2021-22 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration-licensed indications. Updates and other information are available from CDC's influenza website (https://www.cdc.gov/flu); vaccination and health care providers should check this site periodically for additional information.

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Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-21 Influenza Season.

Summary Background Influenza vaccine effectiveness (VE) can vary by type and subtype. Over the past decade, the test-negative design has emerged as a valid method for estimation of VE. In this design, VE is calculated as 100% × (1 – odds ratio) for vaccine receipt in influenza cases versus test-negative controls. We did a systematic review and meta-analysis to estimate VE by type and subtype. Methods In this systematic review and meta-analysis, we searched PubMed and Embase from Jan 1, 2004, to March 31, 2015. Test-negative design studies of influenza VE were eligible if they enrolled outpatients on the basis of predefined illness criteria, reported subtype-level VE by season, used PCR to confirm influenza, and adjusted for age. We excluded studies restricted to hospitalised patients or special populations, duplicate reports, interim reports superseded by a final report, studies of live-attenuated vaccine, and studies of prepandemic seasonal vaccine against H1N1pdm09. Two reviewers independently assessed titles and abstracts to identify articles for full review. Discrepancies in inclusion and exclusion criteria and VE estimates were adjudicated by consensus. Outcomes were VE against H3N2, H1N1pdm09, H1N1 (pre-2009), and type B. We calculated pooled VE using a random-effects model. Findings We identified 3368 unduplicated publications, selected 142 for full review, and included 56 in the meta-analysis. Pooled VE was 33% (95% CI 26–39; I 2 =44·4) for H3N2, 54% (46–61; I 2 =61·3) for type B, 61% (57–65; I 2 =0·0) for H1N1pdm09, and 67% (29–85; I 2 =57·6) for H1N1; VE was 73% (61–81; I 2 =31·4) for monovalent vaccine against H1N1pdm09. VE against H3N2 for antigenically matched viruses was 33% (22–43; I 2 =56·1) and for variant viruses was 23% (2–40; I 2 =55·6). Among older adults (aged >60 years), pooled VE was 24% (−6 to 45; I 2 =17·6) for H3N2, 63% (33–79; I 2 =0·0) for type B, and 62% (36–78; I 2 =0·0) for H1N1pdm09. Interpretation Influenza vaccines provided substantial protection against H1N1pdm09, H1N1 (pre-2009), and type B, and reduced protection against H3N2. Vaccine improvements are needed to generate greater protection against H3N2 than with current vaccines. Funding None.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(16)00129-8.pdf

Variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of test-negative design studies

Influenza virus infections are a major public health concern and cause significant morbidity and mortality worldwide. Current influenza virus vaccines are an effective countermeasure against infection but need to be reformulated almost every year owing to antigenic drift. Furthermore, these vaccines do not protect against novel pandemic strains, and the timely production of pandemic vaccines remains problematic because of the limitations of current technology. Several improvements have been made recently to enhance immune protection induced by seasonal and pandemic vaccines, and to speed up production in case of a pandemic. Importantly, vaccine constructs that induce broad or even universal influenza virus protection are currently in preclinical and clinical development.

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Advances in the development of influenza virus vaccines.

The adaptive immune response to influenza virus infection is multifaceted and complex, involving antibody and cellular responses at both systemic and mucosal levels. Immune responses to natural infection with influenza virus in humans are relatively broad and long-lived, but influenza viruses can escape from these responses over time owing to their high mutation rates and antigenic flexibility. Vaccines are the best available countermeasure against infection, but vaccine effectiveness is low compared with other viral vaccines, and the induced immune response is narrow and short-lived. Furthermore, inactivated influenza virus vaccines focus on the induction of systemic IgG responses but do not effectively induce mucosal IgA responses. Here, I review the differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection. A better understanding of how natural infection induces broad and long-lived immune responses will be key to developing next-generation influenza virus vaccines. Developing universal influenza virus vaccines will require understanding how broad and long-lived antibody responses to natural infection with influenza A virus are generated, a topic that has benefited greatly from technologies that enable the analysis of single human B cells.

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The human antibody response to influenza A virus infection and vaccination.

Background. During the 2012–2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza B lineage viruses in the United States. Methods. Patients with acute cough illness for ≤7 days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as [100% × (1 − adjusted odds ratio)] for vaccination in cases versus test-negative controls. Results. Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval [CI], 43%–55%) overall, 39% (95% CI, 29%–47%) against influenza A(H3N2), 66% (95% CI, 58%–73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%–63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50–64 years (52%; 95% CI, 33%–65%) and persons aged 6 months– 8 years (51%; 95% CI, 32%–64%) and lowest among persons aged ≥65 years (11%; 95% CI, −41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011–2012 vaccine 1 year earlier. Conclusions. The 2012–2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.

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Influenza Vaccine Effectiveness in the United States During 2012–2013: Variable Protection by Age and Virus Type

Within the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) project we conducted a multicentre case-control study in eight European Union (EU) Member States to estimate the 2011/12 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza A(H3) among the vaccination target groups. Practitioners systematically selected ILI / acute respiratory infection patients to swab within seven days of symptom onset. We restricted the study population to those meeting the EU ILI case definition and compared influenza A(H3) positive to influenza laboratory-negative patients. We used logistic regression with study site as fixed effect and calculated adjusted influenza vaccine effectiveness (IVE), controlling for potential confounders (age group, sex, month of symptom onset, chronic diseases and related hospitalisations, number of practitioner visits in the previous year). Adjusted IVE was 25% (95% confidence intervals (CI): -6 to 47) among all ages (n=1,014), 63% (95% CI: 26 to 82) in adults aged between 15 and 59 years and 15% (95% CI: -33 to 46) among those aged 60 years and above. Adjusted IVE was 38% (95%CI: -8 to 65) in the early influenza season (up to week 6 of 2012) and -1% (95% CI: -60 to 37) in the late phase. The results suggested a low adjusted IVE in 2011/12. The lower IVE in the late season could be due to virus changes through the season or waning immunity. Virological surveillance should be enhanced to quantify change over time and understand its relation with duration of immunological protection. Seasonal influenza vaccines should be improved to achieve acceptable levels of protection. 
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Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case–control study

In the fifth season of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE), we undertook a multicentre case-control study (MCCS) in seven European Union (EU) Member States to measure 2012/13 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory confirmed as influenza. The season was characterised by substantial co-circulation of influenza B, A(H1N1)pdm09 and A(H3N2) viruses. Practitioners systematically selected ILI patients to swab ≤7 days of symptom onset. We compared influenza-positive by type/subtype to influenza-negative patients among those who met the EU ILI case definition. We conducted a complete case analysis using logistic regression with study as fixed effect and calculated adjusted vaccine effectiveness (AVE), controlling for potential confounders (age, sex, symptom onset week and presence of chronic conditions). We calculated AVE by type/subtype. Study sites sent 7,954 ILI/acute respiratory infection records for analysis. After applying exclusion criteria, we included 4,627 ILI patients in the analysis of VE against influenza B (1,937 cases), 3,516 for A(H1N1)pdm09 (1,068 cases) and 3,340 for influenza A(H3N2) (730 cases). AVE was 49.3% (95% confidence interval (CI): 32.4 to 62.0) against influenza B, 50.4% (95% CI: 28.4 to 65.6) against A(H1N1)pdm09 and 42.2% (95% CI: 14.9 to 60.7) against A(H3N2). Our results suggest an overall low to moderate AVE against influenza B, A(H1N1)pdm09 and A(H3N2), between 42 and 50%. In this season with many co-circulating viruses, the high sample size enabled stratified AVE by type/subtype. The low estimates indicate seasonal influenza vaccines should be improved to achieve acceptable protection levels. 
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Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicentre case-control study, influenza season 2012/13.

M. Głuchowska

Papers

Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case–control study

Influenza vaccine effectiveness estimates in Europe in a season with three influenza type/subtypes circulating: the I-MOVE multicentre case-control study, influenza season 2012/13.