Influenza Vaccination Strategies Research Articles

Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection.

Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection or immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed.

Management of the vaccination campaign in a population of frail older outpatients affected by cognitive or endocrinological conditions: a pilot study in Italy

Vaccination, particularly against pneumococcus and influenza, is a low-cost primary prevention, useful to avoid hard complications, particularly among frail older people. In this pilot study, we aimed to assess the effect of a strategy for influenza and pneumococcal vaccination for outpatients mainly affected by cognitive or endocrinological conditions, evaluating what could stimulate or demotivate vaccination among older people. This study was conducted during the 2023–2024 influenza season at the outpatient clinics in Palermo, Italy. A total 76 patients were included. More than half of the patients could be considered as pre-frail and about 20% frail, according to a comprehensive geriatric evaluation. Among patients, 46.05% received only vaccination against pneumococcus, 28.95% both vaccinations, and 25.0% only against influenza. Compared with the previous seasons, a 19.5% increase of influenza and 90.2% of pneumococcal vaccine uptake was observed. Side effects of vaccination were the main reason of the previous rejection, namely 76.9% for influenza and 53.8% for anti-pneumococcal vaccination. In conclusion, our study indicates how a new vaccination strategy in different settings could be feasible. Proposing influenza and pneumococcal vaccination for frail older outpatients could be an effective instrument to improve immunization coverage that is still low among older people.

COVID-19 Vaccination Strategies in the Endemic Period: Lessons from Influenza.

Coronavirus disease 2019 (COVID-19) is a highly contagious zoonotic respiratory disease with many similarities to influenza. Effective vaccines are available for both; however, rapid viral evolution and waning immunity make them virtually impossible to eradicate with vaccines. Thus, the practical goal of vaccination is to reduce the incidence of serious illnesses and death. Three years after the introduction of COVID-19 vaccines, the optimal vaccination strategy in the endemic period remains elusive, and health authorities worldwide have begun to adopt various approaches. Herein, we propose a COVID-19 vaccination strategy based on the data available until early 2024 and discuss aspects that require further clarification for better decision making. Drawing from comparisons between COVID-19 and influenza vaccination strategies, our proposed COVID-19 vaccination strategy prioritizes high-risk groups, emphasizes seasonal administration aligned with influenza vaccination campaigns, and advocates the co-administration with influenza vaccines to increase coverage.

Antibody Response to Influenza Hemagglutinin Conserved Stalk Domain after Sequential Immunization with Old Vaccine Strains.

Hemagglutinin (HA) is the major envelope glycoprotein and antigen on the surface of influenza virions. The glycoprotein comprises a globular head and a stalk region. While immunodominant epitopes on influenza HA head are highly variable, the stalk domain is conserved. The variability of the HA head causes the antigenic drift that made the requirement of annual update of vaccine strains. Induction of antibody against the stalk domain has been proposed as an approach for a broadly protective influenza vaccine strategy. Sequential exposure to influenza strains with highly diverse HA heads but conserved stalks have been shown to induce antibody to the low immunogenic stalk domain. Here, we tested this approach by using old influenza vaccine strains that are decades apart in evolution. Inactivated whole virion vaccine of influenza A/Puerto Rico/8/1934, A/USSR/92/1977, and A/Thailand/102/2009 (H1N1) was sequentially immunized into BALB/c mice in comparison to immunization using single strain (A/Thailand/102/2009 (H1N1)). The sequentially immunized mice developed higher levels of binding antibody to the stalk domain. These suggested that using old vaccine strains in sequential vaccination may be a possible approach to induce antibody to the conserved stalk domain.

Acceptability, cost-effectiveness, and capacity of a facility-based seasonal influenza vaccination among high-risk groups: a study protocol in selected tertiary care hospitals of Bangladesh

BackgroundIn Bangladesh, seasonal influenza imposes considerable disease and economic burden, especially for those at high-risk of severe disease. The most successful approach for influenza prevention is the administration of a vaccine. Many poor and middle-income nations, including Bangladesh, do not have a national strategy or program in place for seasonal influenza vaccines, despite the World Health Organization’s (WHO) advice to prioritize high-risk populations. Additionally, there is a scarcity of substantial data on the cost-effectiveness of seasonal influenza vaccination in these countries. The aim of our study is to determine acceptability, health beliefs, barriers, and intention of receiving influenza vaccine among high-risk populations, assess the cost-effectiveness of implementing a facility-based seasonal influenza vaccination programme, and investigate the required capacity for a potential seasonal influenza vaccination programme.MethodsWe will undertake this study following STROBE guidelines. We will conduct the study in inpatient and outpatient departments of three selected tertiary-level hospitals leveraging the ongoing hospital-based influenza surveillance (HBIS) platform. The study population will include the WHO-defined four high-risk groups excluding healthcare workers: children six months to eight years, pregnant women, elderly ≥ 60 years, and adults with chronic diseases. We will collect quantitative data on participants’ acceptability, health beliefs, barriers, and vaccination intentions using the health belief model (HBM) from patients meeting the criteria for high-risk populations attending two public tertiary-level hospitals. In one of the two public tertiary-level hospitals, we will arrange an influenza vaccination campaign before the influenza season, where the vaccine will be offered free of cost to high-risk patients, and in the second hospital, vaccination will not be offered. Both the vaccinated and unvaccinated participants will then be followed-up once a month for one year to record any influenza-like illness, hospitalization, and death. Additional data for objective two will be collected from patients with symptoms of influenza-like illness (ILI) and severe acute respiratory infection (SARI) at one public and one private hospital to determine both direct and indirect costs associated with influenza illness. We will estimate the required number of influenza vaccines, safe injections, and total storage volume utilizing secondary data. We will use a deterministic Markov decision-analytic model to estimate the cost-effectiveness of facility-based influenza vaccination in Bangladesh.DiscussionThe results of this study will enable the National Immunization Technical Advisory Group and the Ministry of Health & Family Welfare of Bangladesh to decide what steps to take to develop and implement an influenza vaccination strategy targeting high-risk populations.Trial registrationThe Clinicaltrials.gov registration number is NCT05996549. The registration for the protocol version 2.0 took place in August 2023, with the initial participant being enrolled in March 2022.

Comparing performance of year-round and campaign-mode influenza vaccination strategies among children aged 6–23 months in Kenya: 2019–2021

IntroductionIn 2016, the Kenya National Immunization Technical Advisory Group requested additional programmatic and cost effectiveness data to inform the choice of strategy for a national influenza vaccination program among children aged 6–23 months of age. In response, we conducted an influenza vaccine demonstration project to compare the performance of a year-round versus campaign-mode vaccination strategy. Findings from this demonstration project will help identify essential learning lessons for a national program. MethodsWe compared two vaccine delivery strategies: (i) a year-round vaccination strategy where influenza vaccines were administered throughout the year at health facilities. This strategy was implemented in Njoro sub-county in Nakuru (November 2019 to October 2021) and Jomvu sub-county in Mombasa (December 2019 to October 2021), (ii) a campaign-mode vaccination strategy where vaccines were available at health facilities over four months. This strategy was implemented in Nakuru North sub-county in Nakuru (June to September 2021) and Likoni sub-county in Mombasa (July to October 2021). We assessed differences in coverage, dropout rates, vaccine wastage, and operational needs. ResultsWe observed similar performance between strategies in coverage of the first dose of influenza vaccine (year-round strategy 59.7 %, campaign strategy 63.2 %). The coverage obtained in the year-round sub-counties was similar (Njoro 57.4 %; Jomvu 63.1 %); however, more marked differences between campaign sub-counties were observed (Nakuru North 73.4 %; Likoni 55.2 %). The campaign-mode strategy exceeded the cold chain capacity of participating health facilities, requiring thrice monthly instead of once monthly deliveries, and was associated with a two-fold increase in workload compared to the year-round strategy (168 vaccines administered per day in the campaign strategy versus 83 vaccines administered per day in the year-round strategy). ConclusionAlthough both strategies had similar coverage levels, the campaign-mode strategy was associated with considerable operational needs that could significantly impact the immunization program.

Immunogenicity and Safety of Alternative Influenza Vaccination Strategies in Repeated Seasons in Pediatric Hematopoietic-Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant (HCT) recipients are at increased risk for morbidity and mortality from influenza infection. Annual influenza vaccination is recommended; however, HCT recipients have diminished immune responses to vaccination. Our recent trial demonstrated that two doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart post-HCT were more immunogenic than two doses of standard dose quadrivalent influenza vaccine (SD-QIV). We assessed the impact of this strategy in a consecutive season post-HCT. Methods The initial trial was a multi-center double-blinded phase II randomized controlled trial comparing two doses of HD-TIV to two doses of SD-QIV in children 3-17 years old given 3-35 months post-allogeneic HCT. Participants completing the initial trial could re-enroll the subsequent influenza season to receive the same two-dose vaccine formulation. Hemagglutinin inhibition (HAI) titers were measured at baseline and 28-42 days following each dose. Injection-site and systemic adverse events were assessed. The immunogenicity endpoints were the post-dose 1 and post-dose 2 geometric mean HAI titers (GMTs) in the second year of participation. Results A total of 170 participants were enrolled in the initial trial, with 65 re-enrolling for a second year (n=33 SD-QIV and n=32 HD-TIV). Post-dose 1 and 2 GMTs were higher for both the SD-QIV and HD-TIV groups in the second year compared the first year (Table 1). In year two, the adjusted geometric mean ratio (aGMR) comparing HD-TIV to SD-QIV was higher post-dose 1 for A/H1N1 (aGMR=1.99, 95% CI:[1.07, 3.68]). The HD-TIV group demonstrated a higher frequency of four-fold titer rise after a single dose compared to two doses of SD-QIV for A/H3N2 (61% vs. 48%) and B/Victoria (77% vs. 65%). Frequency of injection site and systemic reactions were similar between the HD-TIV and SD-QIV groups in year two. Conclusions The post-dose 1 and 2 GMTs were consistently higher for HD-TIV compared to SD-QIV in year two, and aGMR reached statistical significance after a single dose of HD-TIV for A/H1N1. Year two reactogenicity was comparable for both vaccination strategies. Further studies with larger numbers of participants are needed to demonstrate if one or two doses of HD-TIV are needed in subsequent influenza seasons post-HCT when a two-dose vaccination series is given in the first post-HCT season. Table 1. Point estimates and 95% CIs for geometric mean HAI titer, titer ≥1:40, and proportion with ≥4-fold rise from baseline for each vaccine regimen, stratified for each antigen. Also included is the ratio of the observed values (n) to the number of evaluable subjects (N) at each visit. Baseline titers are measured prior to first vaccine dose, post-dose 1 titers are measured 28-42 days following first dose (prior to the second dose), post-dose 2 titers are measured 28-42 days following second dose. Table 1 Note: If 100% achieved seroprotection or seroconversion, “n/a” was entered as a two-sided 95% CI could not be calculated.

Heterologous prime-boost H1N1 vaccination exacerbates disease following challenge with a mismatched H1N2 influenza virus in the swine model

Influenza A viruses (IAVs) pose a significant threat to both human and animal health. Developing IAV vaccine strategies able to elicit broad heterologous protection against antigenically diverse IAV strains is pivotal in effectively controlling the disease. The goal of this study was to examine the immunogenicity and protective efficacy of diverse H1N1 influenza vaccine strategies including monovalent, bivalent, and heterologous prime-boost vaccination regimens, against a mismatched H1N2 swine influenza virus. Five groups were homologous prime-boost vaccinated with either an oil-adjuvanted whole-inactivated virus (WIV) monovalent A/swine/Georgia/27480/2019 (GA19) H1N2 vaccine, a WIV monovalent A/sw/Minnesota/A02636116/2021 (MN21) H1N1 vaccine, a WIV monovalent A/California/07/2009 (CA09) H1N1, a WIV bivalent vaccine composed of CA09 and MN21, or adjuvant only (mock-vaccinated group). A sixth group was prime-vaccinated with CA09 WIV and boosted with MN21 WIV (heterologous prime-boost group). Four weeks post-boost pigs were intranasally and intratracheally challenged with A/swine/Georgia/27480/2019, an H1N2 swine IAV field isolate. Vaccine-induced protection was evaluated based on five critical parameters: (i) hemagglutination inhibiting (HAI) antibody responses, (ii) clinical scores, (iii) virus titers in nasal swabs and respiratory tissue homogenates, (iv) BALf cytology, and (v) pulmonary pathology. While all vaccination regimens induced seroprotective titers against homologous viruses, heterologous prime-boost vaccination failed to enhance HAI responses against the homologous vaccine strains compared to monovalent vaccine regimens and did not expand the scope of cross-reactive antibody responses against antigenically distinct swine and human IAVs. Mismatched vaccination regimens not only failed to confer clinical and virological protection post-challenge but also exacerbated disease and pathology. In particular, heterologous-boosted pigs showed prolonged clinical disease and increased pulmonary pathology compared to mock-vaccinated pigs. Our results demonstrated that H1-specific heterologous prime-boost vaccination, rather than enhancing cross-protection, worsened the clinical outcome and pathology after challenge with the antigenically distant A/swine/Georgia/27480/2019 strain.

The role of vaccination in COPD: influenza, SARS-CoV-2, pneumococcus, pertussis, RSV and varicella zoster virus.

Exacerbations of COPD are associated with worsening of the airflow obstruction, hospitalisation, reduced quality of life, disease progression and death. At least 70% of COPD exacerbations are infectious in origin, with respiratory viruses identified in approximately 30% of cases. Despite long-standing recommendations to vaccinate patients with COPD, vaccination rates remain suboptimal in this population.Streptococcus pneumoniae is one of the leading morbidity and mortality causes of lower respiratory tract infections. The Food and Drug Administration recently approved pneumococcal conjugate vaccines that showed strong immunogenicity against all 20 included serotypes. Influenza is the second most common virus linked to severe acute exacerbations of COPD. The variable vaccine efficacy across virus subtypes and the impaired immune response are significant drawbacks in the influenza vaccination strategy. High-dose and adjuvant vaccines are new approaches to tackle these problems. Respiratory syncytial virus is another virus known to cause acute exacerbations of COPD. The vaccine candidate RSVPreF3 is the first authorised for the prevention of RSV in adults ≥60 years and might help to reduce acute exacerbations of COPD. The 2023 Global Initiative for Chronic Lung Disease report recommends zoster vaccination to protect against shingles for people with COPD over 50 years.

Humoral Response to the Acetalated Dextran M2e Vaccine is Enhanced by Antigen Surface Conjugation.

The influenza A virus causes substantial morbidity and mortality worldwide every year and poses a constant threat of an emergent pandemic. Seasonal influenza vaccination strategies fail to provide complete protection against infection due to antigenic drift and shift. A universal vaccine targeting a conserved influenza epitope could substantially improve current vaccination strategies. The ectodomain of the matrix 2 protein (M2e) of influenza is a highly conserved epitope between virus strains but is also poorly immunogenic. Administration of M2e and the immunostimulatory stimulator of interferon genes (STING) agonist 3'3'-cyclic guanosine-adenosine monophosphate (cGAMP) encapsulated in microparticles made of acetalated dextran (Ace-DEX) has previously been shown to be effective for increasing the immunogenicity of M2e, primarily through T-cell-mediated responses. Here, the immunogenicity of Ace-DEX MPs delivering M2e was further improved by conjugating the M2e peptide to the particle surface in an effort to affect B-cell responses more directly. Conjugated or encapsulated M2e co-administered with Ace-DEX MPs containing cGAMP were used to vaccinate mice, and it was shown that two or three vaccinations could fully protect against a lethal influenza challenge, while only the surface-conjugated antigen constructs could provide some protection against lethal challenge with only one vaccination. Additionally, the use of a reducible linker augmented the T-cell response to the antigen. These results show the utility of conjugating M2e to the surface of a particle carrier to increase its immunogenicity for use as the antigen in a universal influenza vaccine.

Factors associated with hospitalization for seasonal influenza in Morocco.

Morocco is actively working towards expanding its influenza vaccine policy to cover high-risk groups, as recommended by the World Health Organization (WHO). We assessed the risk factors for influenza-associated hospitalization for severe acute respiratory infections (SARI) that occurred during the last 5 seasons. We conducted a retrospective, analytical study among patients recruited in the ambulatory and hospital sites of the influenza sentinel surveillance system in Morocco between 2014 and 2019. Using multiple logistic regression, we compared the characteristics of influenza-positive patients with SARI to those with influenza-like illness (ILI) to identify factors associated with severe disease. We included 1323 positive influenza patients with either SARI (41.7%) or ILI diagnosis (58.3%). A(H1N1)pdm09, A(H3N2) and influenza B, respectively, contributed 49.2%, 29.5% and 20.6% of the cases. The main risk factors considered in the bivariate analysis were found in the multivariate analysis to be significantly associated with influenza-related hospitalization (SARI): age < 2 years (aOR = 7.08, P < 0.001); age ≥ 65 years (aOR = 3.59, P < 0.001); diabetes (aOR = 1.98, P = 0.017); obesity (aOR = 2.94, P = 0.034); asthma or chronic respiratory disease (aOR = 4.99, P < 0.001); chronic renal failure (aOR = 4.74, P = 0.005); pregnancy (aOR = 7.49, P < 0.001); and the A(H1N1)pdm09 subtype (aOR = 1.82, P < 0.001). This study provides epidemiological evidence for the expected benefit of an influenza vaccination strategy for high-risk groups as recommended by the WHO.

Impact of Influenza Vaccination on the Burden of Severe Influenza in the Elderly: Spain, 2017-2020.

Annual influenza vaccination is the main strategy to reduce the burden of seasonal influenza epidemics and is recommended for the elderly in most countries with influenza vaccination strategies, with the main objective of preventing hospitalizations and mortality associated with seasonal influenza in this age group. Studies from different countries have estimated the benefits of seasonal influenza vaccination programs in the elderly, preventing a considerable number of cases, hospitalizations and deaths every year. A study measured the number of medically attended confirmed influenza cases in primary care that are prevented annually by vaccination in the population aged 65 and older in Spain, the Netherlands and Portugal, but estimates of the impact of the national influenza vaccination program in the prevention of severe disease in Spain are lacking. The two objectives of this study were to estimate the burden of severe influenza disease in the Spanish population and to measure the impact of influenza vaccination in the prevention of these outcomes in the population aged 65 years and older. Using influenza surveillance systems put in place before the COVID-19 pandemic, we conducted a retrospective observational study to estimate the burden of hospitalizations and ICU admissions in Spain between 2017-18 and 2019-20, by season and age group. Burden estimates for the 65+ group, combined with vaccine effectiveness (VE) and vaccination coverage (VC) data, were used as input data in an ecological, observational study to estimate the impact of the influenza vaccination program on the elderly. We found a higher burden of severe influenza disease in seasons 2017-18 and 2018-19, with A(H3N2) circulation, and in the youngest and oldest age groups. In those aged 65 and older, we estimated an average of 9900 influenza hospitalizations and 1541 ICU admissions averted by vaccination each year. Seasonal influenza vaccination was able to prevent between 11 and 26% influenza hospitalizations and around 40% ICU admissions in the elderly in the three pre-pandemic seasons. In conclusion, our study complements previous analyses in the primary care setting in Spain and demonstrates the benefits of the annual influenza vaccination program in the prevention of severe influenza disease in the elderly, even in seasons with moderate VE.

Humoral Response After Five Successive Doses of SARS-CoV-2 mRNA Vaccine in Kidney Transplant Patients.

The poor humoral response after vaccination against SARS-CoV-2 in kidney transplant (KT) patients led to the approval of successive booster doses.1 In recent weeks, the administration of a fifth dose of bivalent vaccines to KT, including components of the original virus strain and of the Omicron variant, was approved in Spain.2 The information about the effect of this new dose of messenger RNA (mRNA) vaccine on KT humoral response is limited and inaccurate.3,4 In our center, the humoral response to mRNA vaccine was prospectively studied in 16 stable KT recipients who received 5 successive doses between March 2021 and December 2022 (Table 1). They had not received monoclonal antibodies against the virus previously. No prior SARS-CoV-2 infection was confirmed by negative IgG antibodies against the nucleocapsid in all of them. The level of SARS-CoV-2 IgG anti-S antibodies at baseline and 1 mo after 2, 3, 4, and 5 doses was quantified by SARS-CoV-2 IgG chemiluminescent microparticle immunoassay (Abbott). Seroconversion was considered with an anti-S antibody titer greater than 260 BAU/mL. The seroconversion rate was 12.5% after 2 doses, 56.2% after the third, 81.2% after the fourth, and 93.8% after the fifth one. Only 1 KT did not develop antibodies after the fifth dose, who is the oldest in this series (73 y). Patients who seroconverted after 2 doses (n = 2) doubled the antibody titer after the third one; in those who seroconverted after 3 doses (n = 7), it increased by 380% after the fourth, and by 60% after the fifth one in those who seroconverted after 4 doses (n = 4). No patients presented acute rejection or serious adverse effects. TABLE 1. - Clinical and analytical characteristics of the patients N = 16 mRNA vaccine type, n (mRNA-1273/BNT162b2) 15/1 Male gender, n (%) 12 (75) Age, median [IQR] 61.5 [52.2–68] Diabetes, n (%) 9 (56.2) Time from KT to SARS-CoV-2 vaccine (mo), median [IQR] 50 [19.8–207] Serum creatinine at first dose, median [IQR] 1.3 [1–1.47] Induction immunosuppressive therapy, n (%) 9 (56.3) Tacrolimus, n (%) 15 (93.8) MPA, n (%) 11 (68.8) mTOR inhibitors, n (%) 3 (18.7) Prednisone, n (%) 16 (100) Thymoglobulin in the 2 y before SARS-CoV-2 vaccine, n (%) 5 (31.3) Rituximab in the year before SARS-CoV-2 vaccine, n (%) 0 Belatacept, n (%) 0 Non-heart-beating donor, n (%) 4 (25) Anti-S antibody titer after the second dose (BAU/mL), median 1070 Anti-S antibody titer after the third dose (BAU/mL), median [IQR] 1218 [689–2474] Anti-S antibody titer after the fourth dose (BAU/mL), median [IQR] 2029 [1021–5250] Anti-S antibody titer after the fifth dose (BAU/mL), median [IQR] 3105 [1466–5680] Time between KT and first dose (mo), median [IQR] 50 [19.7–207] Time between second and third doses (d), median [IQR] 127 [124.2–128.7] Time between third and fourth doses (d), median [IQR] 199 [196–204.7] Time between fourth and fifth doses (d), median [IQR] 202.5 [199.2–210] IQR, interquartile range; KT, kidney transplant; MPA, mycophenolic acid; mRNA, messenger RNA. An early experience in 8 KTs was reported with encouraging results, although not all received mRNA vaccines.3 Osmanodja et al retrospectively analyzed the serological response to the fifth dose in a cohort of KT patients.4 However, these patients had previously received different types of vaccines, not only mRNA, and mycophenolic acid dose adjustments was performed before the fourth dose, hindering the interpretation of their results. Our experience includes stable patients followed up prospectively without changes in their immunosuppressive therapy, which allows to analyze the effect of successive vaccine doses with fewer confounding factors. Our results support that successive doses progressively increase the seroconversion rate, allowing the majority of KT patients to maintain an adequate serological response. The limitations of our study include the small number of patients and the lack of information on cellular immunity. However, we present for the first time the evolution of the humoral response after 5 doses of mRNA vaccine in KT. In our opinion, it seems necessary to continue with the vaccination booster given the high seroconversion rate achieved. We must also identify those nonresponders who could benefit from passive immunization. However, the continuous mutations of the virus decrease the efficacy of monoclonal antibody-based prevention,5 so if the infection becomes endemic, it may be beneficial to continue with periodic vaccination boosters in KT patients, similar to the influenza vaccination strategies.

Impaired IL-17 and cytotolytic responses to influenza vaccine antigens in aging nonhuman primates

Abstract Despite widespread flu vaccination, influenza remains a major cause of morbidity and mortality in the elderly. The early immune response, including CD4+ helper T cells, and CD8+ CTLs, plays a critical role in efficient control of virus and initiation of adaptive immunity. However, the correlates of protection in the elderly are not well understood. Here, we sought to investigate early cellular responses to re-exposure with seasonal flu vaccine antigens in a cohort of pre-vaccinated young and old rhesus macaques (human age equivalent of 30–45 yrs, and 55–85 yrs). In vitro T cell responses were examined following overnight stimulation of PBMCs with flu vaccine antigens by flow cytometry for Th1-type and Th17-type cytokine responses, and cytolytic functions. Notably, older macaques showed significantly impaired IL-17 production and CD107a upregulation in response to vaccine antigens, along with greater HLA-DR +/PD-1 +CD8 T cells. Further, they produced significantly higher TNF-α than young macaques. These results suggest that circulating flu vaccine-specific T cells in older macaques are deficient in mucosal barrier-protective and cytotolytic functions and possess a dominant proinflammatory function. These findings suggest that re-exposure to flu vaccine antigens in older individuals likely induces a proinflammatory response that is impaired in cytolytic capacity and the ability to repair lung mucosal damage during influenza infection, thereby resulting in more severe disease outcomes. Further studies on in vivo modulation of proinflammatory T cells while enhancing IL-17 functions during vaccination could support the development of more effective influenza vaccine strategies for older adults.

Cost-Effectiveness and Health Impacts of Different Influenza Vaccination Strategies for Children in China

Authors aimed to evaluate the economic and health impacts of three influenza vaccines available in China, including trivalent inactivated vaccine, quadrivalent inactivated vaccine, and live attenuated influenza vaccine, for children aged six months to 18 years. Two decision-analytic models were developed to simulate four vaccination strategies. Outcomes included total costs from a societal perspective in 2021, quality-adjusted life-year loss, numbers of outpatient and inpatient cases, and deaths avoided using each strategy. Deterministic and probabilistic sensitivity analyses were performed to examine the uncertainty of model inputs. For children aged six months to three years, trivalent inactivated vaccine saved $48 million and avoided a loss of 17,637 quality-adjusted life-years compared with no vaccination. For children aged 3-18 years, quadrivalent inactivated vaccine was cost-effective compared with trivalent inactivated vaccine, with an incremental cost-effectiveness ratio of $32,948.5/quality-adjusted life-year (willingness-to-pay threshold=$37,653/quality-adjusted life-year), which was sensitive to the RR of vaccine effectiveness of quadrivalent inactivated vaccine versus of trivalent inactivated vaccine. When compared with quadrivalent inactivated vaccine, live attenuated influenza vaccine was $1.28 billion more costly but gained an additional 13,560 quality-adjusted life-years; its incremental cost-effectiveness ratio was $123,983.8/quality-adjusted life-year. Live attenuated influenza vaccine would be cost-effective if its vaccine effectiveness was >0.79. Probabilistic sensitivity analysis revealed that quadrivalent inactivated vaccine, trivalent inactivated vaccine, live attenuated influenza vaccine, and no vaccination were cost-effective in 55.94%, 33.09%, 10.97%, and 0% of 10,000 Monte Carlo simulations. Trivalent inactivated vaccine was cost-effective compared with no vaccination in children aged six months to 18 years. Of the three vaccination strategies for children aged 3-18 months, quadrivalent inactivated vaccine appears to be the most cost-effective.

Optimization of Elderly Influenza and Pneumococcal Immunization Programs in Beijing, China Using Health Economic Evaluations: A Modeling Study.

(1) Background: Currently, residents ≥ 60 and ≥65 years old in Beijing, China, are eligible for free influenza and pneumococcal polysaccharide vaccines (PPSV23), respectively. The present study aimed to assess the cost-effectiveness of current and alternative strategies of dual influenza and PPSV23 vaccination among the elderly in Beijing. (2) Methods: We developed a Markov state-transition model to compare the costs and the quality-adjusted life years (QALYs) associated with four influenza and PPSV23 vaccination strategies among the elderly in Beijing. The strategies were as follows: (1) no vaccination; (2) only flu vaccine for people ≥ 60 years old; (3) flu vaccine for people ≥ 60 years old and PPSV23 for people ≥ 65 years old; and (4) dual influenza vaccines and PPSV23 for people ≥ 60 years old. Incremental costs and QALYs were quantified to determine the optimal option. If dominant strategies emerged, the Chinese gross domestic product per capita in 2021 (80,976 CNY) was used as the willingness-to-pay (WTP) threshold to covert QALYs into the monetary equivalent. (3) Results: The current program saved costs and increased QALYs compared to no vaccination or flu vaccine-only strategies. However, extending free PPSV23 to people ≥ 60 years old saved 0.35 CNY additionally while increasing QALYs marginally compared with the current policy. Results were robust in all sensitivity analyses. (4) Conclusion: Beijing's current dual influenza and pneumococcal vaccination program was cost-effective among the elderly compared with the preceding policies of no vaccination and flu-only immunization programs. However, the program can further save money while enhancing the population health by extending PPSV23 to all people ≥ 60 years old.

Robust immunity to influenza vaccination in haematopoietic stem cell transplant recipients following reconstitution of humoral and adaptive immunity

AbstractObjectivesInfluenza causes significant morbidity and mortality, especially in high‐risk populations. Although current vaccination regimens are the best method to combat annual influenza disease, vaccine efficacy can be low in high‐risk groups, such as haematopoietic stem cell transplant (HSCT) recipients.MethodsWe comprehensively assessed humoral immunity, antibody landscapes, systems serology and influenza‐specific B‐cell responses, together with their phenotypes and isotypes, to the inactivated influenza vaccine (IIV) in HSCT recipients in comparison to healthy controls.ResultsInactivated influenza vaccine significantly increased haemagglutination inhibition (HAI) titres in HSCT recipients, similar to healthy controls. Systems serology revealed increased IgG1 and IgG3 antibody levels towards the haemagglutinin (HA) head, but not to neuraminidase, nucleoprotein or HA stem. IIV also increased frequencies of total, IgG class‐switched and CD21loCD27+ influenza‐specific B cells, determined by HA probes and flow cytometry. Strikingly, 40% of HSCT recipients had markedly higher antibody responses towards A/H3N2 vaccine strain than healthy controls and showed cross‐reactivity to antigenically drifted A/H3N2 strains by antibody landscape analysis. These superior humoral responses were associated with a greater time interval after HSCT, while multivariant analyses revealed the importance of pre‐existing immune memory. Conversely, in HSCT recipients who did not respond to the first dose, the second IIV dose did not greatly improve their humoral response, although 50% of second‐dose patients reached a seroprotective HAI titre for at least one of vaccine strains.ConclusionsOur study demonstrates efficient, although time‐dependent, immune responses to IIV in HSCT recipients, and provides insights into influenza vaccination strategies targeted to immunocompromised high‐risk groups.

Combining Influenza and COVID-19 Booster Vaccination Strategy to Improve Vaccination Uptake Necessary for Managing the Health Pandemic: A Systematic Review and Meta-Analysis.

Background: The uptake of COVID-19 booster vaccines has been significantly low. Therefore, it is questionable whether combining the COVID-19 booster vaccines with influenza vaccines can increase the population’s interest in taking such vaccines and manage the health pandemic effectively. Methodology: In this systematic review and meta-analysis, a synthesis of the findings and summary of a total of 30 research articles based on the topic, ‘combining influenza and COVID-19 booster vaccination strategy’ was undertaken. The research articles were identified from three databases, namely, PubMed, Cochran Library, and Google Scholar using specific keywords and inclusion criteria. However, research articles that were not peer-reviewed and not published in English were excluded from the systematic review and meta-analysis. The average risk ratio of the intervention group getting a combination of COVID-19 booster and influenza vaccines from the samples of the included studies was 0.78 with regard to a 95% CI. Such risk ratio is based on the null hypothesis of the current study that combining COVID-19 booster and influenza vaccines can increase the uptake of COVID-19 booster vaccines. On the other hand, the heterogeneity between such studies was I2 = 35%, while the statistical significance of their findings occurred at p < 0.05. The average p-value of the included research studies was p = 0.62 with the proportion of studies with significant p-values being 63.33% which is equivalent to 19 out of 30 studies. Therefore, the null hypothesis was not rejected in more than half of the studies. Results: A synthesis of the chosen research articles revealed that when influenza and COVID-19 booster vaccines are combined, there is potential for an increase in the uptake of the latter, mainly because many populations have already been accustomed to taking influenza vaccines on an annual basis. Conclusions: In this way, through such findings, medical health experts can make informed decisions to increase the population’s willingness to receive the COVID-19 booster vaccines.

Hospital admissions with influenza and impact of age and comorbidities on severe clinical outcomes in Brazil and Mexico.

The risk of hospitalization or death after influenza infection is higher at the extremes of age and in individuals with comorbidities. We estimated the number of hospitalizations with influenza and characterized the cumulative risk of comorbidities and age on severe outcomes in Mexico and Brazil. We used national hospital discharge data from Brazil (SIH/SUS) from 2010-2018 and Mexico (SAEH) from 2010-2017 to estimate the number of influenza admissions using ICD-10 discharge codes, stratified by age (0-4, 5-17, 18-49, 50-64, and ≥65 years). Duration of hospital stay, admission to the intensive care unit (ICU), and in-hospital case fatality rates (CFRs) defined the severe outcomes. Rates were compared between patients with or without pre-specified comorbidities and by age. A total of 327,572 admissions with influenza were recorded in Brazil and 20,613 in Mexico, with peaks period most years. In Brazil, the median hospital stay duration was 3.0 days (interquartile range, 2.0-5.0), ICU admission rate was 3.3% (95% CI, 3.2-3.3%), and in-hospital CFR was 4.6% (95% CI, 4.5-4.7). In Mexico, the median duration of stay was 5.0 days (interquartile range, 3.0-7.0), ICU admission rate was 1.8% (95% CI, 1.6-2.0%), and in-hospital CFR was 6.9% (95% CI, 6.5-7.2). In Brazil, ICU admission and in-hospital CFR were higher in adults aged ≥50 years and increased in the presence of comorbidities, especially cardiovascular disease. In Mexico, comorbidities increased the risk of ICU admission by 1.9 (95% CI, 1.0-3.5) and in-hospital CFR by 13.9 (95% CI, 8.4-22.9) in children 0-4 years. The SIH/SUS and SAEH databases can be used to estimate hospital admissions with influenza, and the disease severity. Age and comorbidities, especially cardiovascular disease, are cumulatively associated with more severe outcomes, with differences between countries. This association should be further analyzed in prospective surveillance studies designed to support influenza vaccination strategy decisions.

Monophosphoryl lipid A-adjuvanted nucleoprotein-neuraminidase nanoparticles improve immune protection against divergent influenza viruses

Universal influenza vaccines are urgently needed to prevent recurrent influenza epidemics and inevitable pandemics. We generated double-layered protein nanoparticles incorporating two conserved influenza antigens—nucleoprotein and neuraminidase—through a two-step desolvation-crosslinking method. These protein nanoparticles displayed immunostimulatory properties to antigen-presenting cells by promoting inflammatory cytokine (IL-6 and TNF-α) secretion from JAWS II dendric cells. The nanoparticle immunization induced significant antigen-specific humoral and cellular responses, including antigen-binding and neutralizing antibodies, antibody- and cytokine (IFN-γ and IL-4)-secreting cells, and NP147–155 tetramer-specific cytotoxic T lymphocyte (CTL) responses. Co-administration of monophosphoryl lipid A (MPLA, a toll-like receptor 4 agonist) with the protein nanoparticles further improved immune responses and conferred heterologous and heterosubtypic influenza protection. The MPLA-adjuvanted nanoparticles reduced lung inflammation post-infection. The results demonstrated that the combination of MPLA and conserved protein nanoparticles could be developed into an improved universal influenza vaccine strategy.