Heterogeneity of SARS-CoV-2 immune responses after the nationwide Omicron wave in China.

It remains unclear how previous infections and vaccinations influenced and shaped heterogeneous immune responses against Omicron and its variants in diverse populations in China. After the national wave of Omicron in early 2023, we evaluated serum levels of neutralizing antibodies (nAbs) against Omicron (B.1.1.529) and its variants (BA.5, BF.7, and CH1.1) in 33 COVID-19 convalescents and 40 uninfected vaccinees, using vesicular stomatitis virus-based pseudovirus neutralizing assay. In addition, we followed 34 Delta convalescent patients to compare their immune responses against Omicron before (late 2021) and after the Omicron wave (early 2023). NAbs at the acute phase of the disease were investigated in 50 Omicron inpatients, including 24 vaccinated and 26 unvaccinated patients. Among them, nasal mucosal IgA levels were measured in 42 subjects. Compared to vaccination, breakthrough infections significantly increased the breadth and magnitude of serum nAbs and mucosal IgA levels against Omicron variants. Exposure to Omicron but not Delta elicited stronger pan-Omicron responses. In Omicron inpatients, nAbs continued to rise as vaccination doses increased. However, in both vaccinees and convalescents, a fourth dose vaccination did not elicit higher nAbs against Omicron. Furthermore, nAbs against Omicron variants lasted longer than nAbs against WT SARS-CoV-2. Breakthrough infections of Omicron variants elicited specific immune responses against Omicron compared to vaccination and Delta infection. Although repeated vaccination revealed limited impacts on serum nAbs, populations at high risk of hospitalization may still benefit from continued vaccination.IMPORTANCEThe study described the specific humoral immunity against Omicron and its variants (BA.5, BF.7, and CH1.1) in diverse populations, including Delta-positive convalescent patients, Omicron-infected patients with a previous or current confirmed Delta infection, Omicron-positive patients, and healthy controls. In addition, we followed Delta convalescents for 1 year to evaluate the effect of a booster vaccine, breakthrough infection, and reinfection. Nasal mucosal IgA levels against SARS-CoV-2 were also examined. The findings of this study demonstrated the varied responses of individuals in different states following the outbreak of Omicron, highlighting the potential advantages of ongoing immunization for groups that are more vulnerable and have a greater likelihood of being hospitalized.

Characteristics and factors of repeated influenza vaccination among elderly individuals in Shanghai, China from 2020 to 2022.

Elderly individuals face a high risk of hospitalization and death related to influenza, thus prioritizing them for influenza vaccination. Due to variations in the influenza virus and waning protective antibodies, annual influenza vaccination is recommended. However, research on repeated influenza vaccination among elderly individuals in China is limited. From 2020 to 2022, the average influenza vaccination coverage among registered elderly individuals in Shanghai was 4.1%, showing a declining trend over time. In 2020, the rate of repeated influenza vaccination among elderly individuals was 28.35%, which rose to almost two-thirds both in 2021 and 2022. No increased risk of adverse events following immunization was observed after repeated influenza vaccination during this period. Our study also found that elderly individuals with Shanghai household registration, managed by community clinics, and older age tended to receive more doses of repeated influenza vaccination throughout the period from 2020 to 2022. Increasing influenza vaccine coverage among elderly individuals in Shanghai is both urgent and challenging. Health authorities should intensify educational and promotional campaigns to encourage uptake of annual repeated influenza vaccination among elderly individuals.

Neutralizing antibody responses against contemporary and future influenza A(H3N2) viruses in paradoxical clades elicited by repeated and single vaccinations.

As one of the most effective measures to prevent seasonal influenza viruses, annual influenza vaccination is globally recommended. Nevertheless, evidence regarding the impact of repeated vaccination to contemporary and future influenza has been inconclusive. A total of 100 subjects singly or repeatedly immunized with influenza vaccines including 3C.2a1 or 3C.3a1 A(H3N2) during 2018-2019 and 2019-2020 influenza season were recruited. We investigated neutralization antibody by microneutralization assay using four antigenically distinct A(H3N2) viruses circulating from 2018 to 2023, and tracked the dynamics of B cell receptor (BCR) repertoire for consecutive vaccinations. We found that vaccination elicited cross-reactive antibody responses against future emerging strains. Broader neutralizing antibodies to A(H3N2) viruses and more diverse BCR repertoires were observed in the repeated vaccination. Meanwhile, a higher frequency of BCR sequences shared among the repeated-vaccinated individuals with consistently boosting antibody response was found than those with a reduced antibody response. Our findings suggest that repeated seasonal vaccination could broaden the breadth of antibody responses, which may improve vaccine protection against future emerging viruses.

Repeated vaccination does not appear to significantly weaken the protective effect of influenza vaccine in the elderly: A test-negative case-control study in China.

BACKGROUND: The impact of repeated influenza vaccination on vaccine effectiveness has been a topic of debate. Conducting more multinational, multicenter studies in different influenza seasons is crucial for a better understanding of this issue. There is a lack of comprehensive related research reports in China. METHODS: Using the Regional Health Information Platform, we conducted a test-negative case-control study to evaluate the impact of repeated vaccination on the prevention of laboratory-confirmed influenza in individuals aged 60 and above in Ningbo during four influenza seasons from 2018-19 to 2021-22. Influenza-positive cases and negative controls were matched in a 1:1 ratio based on the visiting hospital and the date of influenza testing. Propensity score adjustment and multivariable logistic regression were used to estimate risk and address confounding effects. RESULTS: During the study period, a total of 30,630 elderly patients underwent influenza virus nucleic acid or antigen testing. After exclusions, we included 1976 cases of influenza-positive and 1976 cases of influenza-negative controls. Multivariable logistic regression analysis revealed that individuals receiving the vaccine in two consecutive seasons did not exhibit a significantly increased risk of influenza illness compared to those receiving the vaccine only in the current season (adjusted odds ratio: 1.22, 95% confidence interval: 0.94-1.58). However, the risk of influenza illness was found to be elevated in individuals who received the vaccine only in the previous season (adjusted odds ratio: 1.56, 95% confidence interval: 1.15-2.10) and even further elevated in those who had not received the vaccine in either of the consecutive two seasons (adjusted odds ratio: 3.39, 95% confidence interval: 2.80-4.09). CONCLUSIONS: Regardless of the vaccination history in the previous season, receiving the current season influenza vaccine is the best choice for the elderly population. Our study supports the initiative to vaccinate elderly individuals against influenza annually.

Standard-dose versus MF59-adjuvanted, high-dose or recombinant-hemagglutinin influenza vaccine immunogenicity in older adults: comparison of A(H3N2) antibody response by prior season's vaccine status.

BACKGROUND: Annual influenza vaccination is recommended for older adults but repeated vaccination with standard-dose influenza vaccine has been linked to reduced immunogenicity and effectiveness, especially against A(H3N2) viruses. METHODS: Community-dwelling Hong Kong adults aged 65-82 years were randomly allocated to receive 2017/18 standard-dose quadrivalent, MF59-adjuvanted trivalent, high-dose trivalent, and recombinant-HA quadrivalent vaccination. Antibody response to unchanged A(H3N2) vaccine antigen was compared among participants with and without self-reported prior year (2016/17) standard-dose vaccination. RESULTS: Mean fold rise (MFR) in antibody titers from Day 0 to Day 30 by hemagglutination inhibition and virus microneutralization assays were lower among 2017/18 standard-dose and enhanced vaccine recipients with (range, 1.7-3.0) vs. without (range, 4.3-14.3) prior 2016/17 vaccination. MFR was significantly reduced by about one half to four fifths for previously vaccinated recipients of standard-dose and all three enhanced vaccines (ß range, 0.21-0.48). Among prior-year vaccinated older adults, enhanced vaccines induced higher 1.43 to 2.39-fold geometric mean titers and 1.28 to 1.74-fold MFR vs. standard-dose vaccine by microneutralization assay. CONCLUSIONS: In the context of unchanged A(H3N2) vaccine strain, prior-year vaccination was associated with reduced antibody response among both standard-dose and enhanced influenza vaccine recipients. Enhanced vaccines improved antibody response among older adults with prior-year standard-dose vaccination.

Influenza Vaccine Effectiveness in Preventing Laboratory-Confirmed Influenza Cases and Hospitalizations in Navarre, Spain, 2022-2023.

We estimated influenza vaccine effectiveness (IVE) in preventing outpatient and hospitalized cases in the 2022-2023 season. A test-negative design included a representative sample of outpatients and all hospitalized patients with influenza-like illness (ILI) from October 2022 to May 2023 in Navarre, Spain. ILI patients were tested by PCR for influenza virus. Influenza vaccination status was compared between confirmed influenza cases and test-negative controls. Among 3321 ILI patients tested, IVE to prevent influenza cases was 34% (95% confidence interval (CI): 16 to 48) overall, 85% (95%CI: 63 to 94) against influenza B, and 28% (95%CI: 3 to 46) against A(H3N2). Among 558 outpatients, 222 (40%) were confirmed for influenza: 55% A(H3N2), 11% A(H1N1), and 31% B. Overall, IVE to prevent outpatient cases was 48% (95%CI: 8 to 70), 88% (95%CI: 3 to 98) against influenza B, and 50% (95%CI: -4 to 76) against A(H3N2). Of 2763 hospitalized patients, 349 (13%) were positive for influenza: 64% A(H3N2), 17% A(H1N1), and 8% B. IVE to prevent hospitalization was 24% (95%CI: -1 to 42) overall, 82% (95%CI: 49 to 93) against influenza B, and 16% (95%CI: -17 to 40) against A(H3N2). No IVE was observed in preventing influenza A(H1N1). IVE was high to prevent influenza B, moderate against A(H3N2) and null against A(H1N1). A lower proportion of influenza B cases may explain the smaller IVE in hospitalized patients than in outpatients. The null IVE against A(H1N1) was consistent with the observed antigenic drift and supports the new composition of the 2023-2024 influenza vaccine.

Association of vaccine-specific regulatory T cells with reduced antibody response to repeated influenza vaccination.

Repeated annual influenza vaccinations have been associated with reduced vaccine-induced antibody responses. This prospective study aimed to explore the role of vaccine antigen-specific regulatory T (Treg) cells in antibody response to repeated annual influenza vaccination. We analyzed pre- and postvaccination hemagglutination inhibition (HI) titers, seroconversion rates, seroprotection rates, vaccine antigen hemagglutinin (HA)-specific Treg cells, and conventional T (Tconv) cells. We compared these parameters between vaccinees with or without vaccine-induced seroconversion. Our multivariate logistic regression revealed that prior vaccination was significantly associated with a decreased likelihood of achieving seroconversion for both H1N1(adjusted OR, 0.03; 95% CI, 0.01-0.13) and H3N2 (adjusted OR, 0.09; 95% CI, 0.03-0.30). Furthermore, individuals who received repeated vaccinations had significantly higher levels of pre-existing HA-specific Treg cells than those who did not. We also found that vaccine-induced fold-increases in HI titers and seroconversion were negatively correlated with pre-existing HA-specific Treg cells and positively correlated with the ratio of Tconv to Treg cells. Overall, our findings suggest that repeated annual influenza vaccination is associated with a lower vaccine-induced antibody response and a higher frequency of vaccine-specific Treg cells. However, a lower frequency of pre-existing Treg cells correlates with a higher postvaccination antibody response.

Efectividad de la vacuna antigripal en la prevención de la gripe en personas mayores de 65 años / Effectiveness of the influenza vaccine in the prevention of influenza in people over 65 years of age

Introducción: La gripe es una de las enfermedades de mayor impacto epidemiológico y de máxima relevancia en la gestión de los servicios sanitarios. La vacuna de la gripe puede tener una gran variabilidad cada temporada, por lo que nuestro objetivo fue conocer la efectividad de la vacuna de la gripe de la temporada 2017/2018 para la prevención de casos graves de gripe en mayores de 65 años en un hospital general de agudos de 385 camas. Material y método: Estudio de casos y controles. Se incluyeron todos los pacientes hospitalizados con gripe mayores de 65 años confirmada por el laboratorio durante la temporada 2017/2018. Los que cumplieron criterios de caso grave de gripe se consideraron caso. Los que no cumplían criterios de gravedad se consideraron controles. Se calculó los factores asociados con el desarrollo de la gripe grave. Resultados: La mediana de edad fue de 68 años (DE 91,87). La tasa de ataque fue de 0,23/100 habitantes y la efectividad vacunal de 38%. Los grupos de vacunados y no vacunados fueron diferentes en cuanto a edad (p < 0,0481). El estado de vacunación frente a la gripe grave resultó ser un factor protector independiente (OR = 0,840; 0,746-0,913). Conclusiones: La efectividad de la vacunación antigripal proporcionó una mayor protección contra la infección y redujo la gravedad de la gripe en los pacientes mayores hospitalizados. Estos hallazgos deberían tenerse en cuenta para mejorar las estrategias de vacunación y alcanzar mejores coberturas vacunales en la población de riesgo. (AU)

Introduction: Influenza is one of the diseases with the greatest epidemiological impact and of maximum relevance in the management of health services. The flu vaccine can have great variability each season, so our objective was to find out the effectiveness of the flu vaccine for the 2017/2018 season for the prevention of severe cases of flu in people over 65 years of age in a 385-bed acute general hospital.Material and method: Study of cases and controls. All hospitalized patients with laboratory-confirmed influenza older than 65 years during the 2017/2018 season were included. Those who met the criteria for a severe case of influenza were considered cases. Those who did not meet the severity criteria were considered controls. Factors associated with the development of severe influenza were calculated. Results: The median age was 68 years (SD 91.87). The attack rate was 0.23 per hundred inhabitants and the vaccine effectiveness was 38%. The vaccinated and unvaccinated groups were different in terms of age (p < 0.0481). Vaccination status against severe influenza was found to be an independent protective factor (OR = 0.840; 0.746-0.913). Conclusions: The effectiveness of influenza vaccination provided greater protection against infection and reduced the severity of influenza in older hospitalized patients. These findings should be taken into account to improve vaccination strategies and achieve better vaccination coverage in the population at risk. (AU)

Repeated influenza vaccination induces similar immune protection as first-time vaccination but with differing immune responses.

BACKGROUND: Recent seasonal epidemics of influenza have been caused by human influenza A viruses of the H1N1 and H3N2 subtypes and influenza B viruses. Annual vaccination is recommended to prevent infection; however, how annual influenza vaccination influences vaccine effectiveness is largely unknown. METHODS: To investigate the impact of repeated vaccination on immune and protective effect, we performed a prospective seroepidemiologic study. Participants with or without prior vaccination (2018-2019) were enrolled during the 2019-2020 influenza season. Inactivated quadrivalent influenza vaccine (IIV4) was administered through the intramuscular route, and venous blood samples were collected regularly to test hemagglutination inhibition (HAI) titers. RESULTS: The geometric mean titers and proportion with titers ≥40 against the influenza vaccine components peaked at 30 days post-vaccination. At Day 30, the geometric mean titer and proportion with titers ≥40 in participants who had been previously vaccinated were higher for H3N2 but similar for both B lineages (Victoria and Yamagata) as compared with participants vaccinated for the first time. As for H1N1, the geometric mean titer was lower in repeated vaccinated participants, but the proportion with titers ≥40 was consistent in both groups. CONCLUSIONS: Repeated vaccination provides similar or enhanced protection as compared with single vaccination in first-time vaccinees.

[Effectiveness of the influenza vaccine in the prevention of influenza in people over 65 years of age]. / Efectividad de la vacuna antigripal en la prevención de la gripe en personas mayores de 65 años.

INTRODUCTION: Influenza is one of the diseases with the greatest epidemiological impact and of maximum relevance in the management of health services. The flu vaccine can have great variability each season, so our objective was to find out the effectiveness of the flu vaccine for the 2017/2018 season for the prevention of severe cases of flu in people over 65 years of age in a 385-bed acute general hospital. MATERIAL AND METHOD: Study of cases and controls. All hospitalized patients with laboratory-confirmed influenza older than 65 years during the 2017/2018 season were included. Those who met the criteria for a severe case of influenza were considered cases. Those who did not meet the severity criteria were considered controls. Factors associated with the development of severe influenza were calculated. RESULTS: The median age was 68 years (SD 91.87). The attack rate was 0.23 per hundred inhabitants and the vaccine effectiveness was 38%. The vaccinated and unvaccinated groups were different in terms of age (p < 0.0481). Vaccination status against severe influenza was found to be an independent protective factor (OR = 0.840; 0.746-0.913). CONCLUSIONS: The effectiveness of influenza vaccination provided greater protection against infection and reduced the severity of influenza in older hospitalized patients. These findings should be taken into account to improve vaccination strategies and achieve better vaccination coverage in the population at risk.

Summary of the National Advisory Committee on Immunization (NACI) Statement-Recommendation on Repeated Seasonal Influenza Vaccination.

Background: Influenza vaccination is recommended annually; however, some studies have raised questions regarding whether repeated influenza vaccine administration may have unintended negative consequences for seasonal protection. Methods: The National Advisory Committee on Immunization (NACI) Influenza Working Group undertook an overview of systematic reviews on the effects of repeated influenza vaccination on vaccine effectiveness, efficacy, and immunogenicity. A systematic assessment of programmatic factors was conducted according to established NACI methods. The NACI evidence-based process was used to critically appraise the available evidence and to review recommendations. Results: The evidence base consisted of four eligible systematic reviews/meta-analyses. Repeated vaccination, including the current season, was consistently more effective than no vaccination in the current season. The evidence showed no significant difference or predictable trend in vaccine efficacy or effectiveness between vaccinations in two consecutive seasons compared to vaccination in the current season only. Conclusion: Overall, NACI concluded that there is evidence to recommend annual influenza vaccination, irrespective of whether an individual received the seasonal influenza vaccine in previous seasons. It is neither currently feasible nor warranted to modify existing annual influenza vaccination programs to account for potential negative or positive interference. NACI continues to strongly recommend that seasonal influenza vaccine should be offered annually to everyone six months of age and older who does not have contraindications to the vaccine, irrespective of previous seasons' influenza vaccination status.

Effectiveness of influenza vaccination in preventing influenza in primary care, Navarre, Spain, 2021/22.

Compared with individuals unvaccinated in the current and three previous influenza seasons, in 2021/22, influenza vaccine effectiveness at primary care level was 37% (95% CI: 16 to 52) for current season vaccination, regardless of previous doses, and 35% (95% CI: -3 to 45) for only previous seasons vaccination. Against influenza A(H3N2), estimates were 39% (95% CI: 16 to 55) and 24% (95% CI: -8 to 47) suggesting moderate effectiveness of current season vaccination and possible remaining effect of prior vaccinations.

Impact of prior infection and repeated vaccination on post-vaccination antibody titers of the influenza A(H1N1)pdm09 strain in Taiwan schoolchildren: Implications for public health.

BACKGROUND: The objective of this study was to evaluate the effects of prior-infection and repeated vaccination on post-vaccination antibody titers. METHODS: A(H1N1)pdm09 strain was included in 2009 pandemic monovalent, 2010-2011, and 2011-2012 trivalent influenza vaccines (MIVpdm09, TIV10/11, TIV11/12) in Taiwan. During the 2011-2012 influenza season, we conducted a prospective sero-epidemiological cohort study among schoolchildren from grades 1 - 6 in the two elementary schools in Taipei with documented A(H1N1)pdm09 vaccination records since 2009. Serum samples were collected at pre-vaccination, 1-month, and 4-months post-vaccination (T1, T2, T3). Anti-A(H1N1)pdm09 hemagglutination inhibition titers (HI-Ab-titers) were examined. We also investigated the impact of four vaccination histories [(1) no previous vaccination (None), (2) vaccinated in 2009-2010 season (09v), (3) vaccinated in 2010-2011 season (10v), and (4) vaccinated consecutively in 2009-2010 and 2010-2011 seasons (09v + 10v)] and pre-vaccination HI-Ab levels on post-vaccination HI-Ab responses as well as adjusted vaccine effectiveness (aVE) against serologically-defined infection from T2 to T3. RESULTS: TIV11/12 had zero serious adverse events reported. A(H1N1)pdm09 strain in TIV11/12 elicited seroprotective Ab-titers in 98% of children and showed promising protection (aVE: 70.3% [95% confidence interval (CI): 51.0-82.1%]). Previously unvaccinated but infected children had a 3.96 times higher T2 geometric mean titer (T2-GMT) of HI-Ab than those naïve to A(H1N1)pdm09 (GMT [95% CI]: 1039.7[585.3-1845.9] vs. 262.5[65.9-1045], p = 0.046). Previously vaccinated children with seroprotective T1-Ab-titers had a higher T2-GMT and a greater aVE than those with non-seroprotective T1-Ab-titers. Repeatedly vaccinated children had lower T2-GMT than those receiving primary doses of TIV11/12. However, after controlling prior infection and T1-Ab-titers, differences in T2-GMT among the four vaccination histories became insignificant (p = 0.16). CONCLUSION: This study supports the implementation of annual mass-vaccination with A(H1N1)pdm09 in schoolchildren for three consecutive influenza seasons when vaccine and circulating strains were well matched, and found that prior infection and pre-vaccination HI-Ab levels positively impacted post-vaccination HI-Ab responses.

[Effectiveness of influenza vaccine in preventing severe influenza]. / Efectividad de la vacuna antigripal en la prevención de la gripe grave.

INTRODUCTION: Influenza is one of the diseases with the greatest epidemiological impact and the greatest relevance in the management of health services. The flu vaccine can have great variability each season, so our objective was to know the effectiveness of the flu vaccine for the 2017/2018 season for the prevention of severe cases of flu in a general acute hospital in 385 beds. MATERIAL AND METHOD: Case control study. All hospitalized patients with laboratory confirmed influenza during the 2017/2018 season were included. Those who met the criteria for a severe case of influenza were considered cases. Those that did not meet the severity criteria were considered controls. The factors associated with the development of severe influenza were calculated. RESULTS: The effectiveness adjusted by age group and comorbidity was 60.7% (20.5-80.5). The vaccinated and unvaccinated groups were different in terms of age (P<.0381). The highest proportion of cases were concentrated in those over 65 years of age (45.5%). Vaccination status against severe influenza was found to be an independent protective factor (OR=.746; .694-.831). CONCLUSIONS: The effectiveness of influenza vaccination provided greater protection against infection and reduced the severity of influenza in hospitalized patients. These findings should be considered to improve vaccination strategies and achieve better vaccination coverage in the population at risk.

Functional and Binding H1N1pdm09-Specific Antibody Responses in Occasionally and Repeatedly Vaccinated Healthcare Workers: A Five-Year Study (2009-2014).

Background: In 2009, a novel influenza A/H1N1pdm09 emerged and caused a pandemic. This strain continued to circulate and was therefore included in the seasonal vaccines up to the 2016/2017-season. This provided a unique opportunity to study the long-term antibody responses to H1N1pdm09 in healthcare workers (HCW) with a different vaccination history. Methods: HCW at Haukeland University Hospital, Bergen, Norway were immunized with the AS03-adjuvanted H1N1pdm09 vaccine in 2009 (N=55) and divided into groups according to their vaccination history; one vaccination (N=10), two vaccinations (N=15), three vaccinations (N=5), four vaccinations (N=15) and five vaccinations (N=10). HCW are recommended for influenza vaccination to protect both themselves and their patients, but it is voluntary in Norway. Blood samples were collected pre- and at 21 days, 3, 6, and 12 months after each vaccination, or annually from 2010 HCW without vaccination. ELISA, haemagglutination inhibition (HI) and microneutralization (MN) assays were used to determine the antibody response. Results: Pandemic vaccination induced a significant increase in the H1N1-specific antibodies measured by ELISA, HI and MN. Seasonal vaccination boosted the antibody response, both in HCW with only the current vaccination and those with prior and current vaccination during 2010/11-2013/14. We observed a trend of increased antibody responses in HCW with only the current vaccination in 2013/14. A two- and three-year gap before vaccination in 2013/14 provided a more potent antibody response compared to annually vaccinated HCW. Conclusions: Our long term follow up study elucidates the antibody response in HCW with different vaccination histories. Our findings contribute to our understanding of the impact of repeated vaccination upon antibody responses.

Influence of Prior Influenza Vaccination on Current Influenza Vaccine Effectiveness in Children Aged 1 to 5 Years.

BACKGROUND: Although annual influenza vaccination is an important strategy used to prevent influenza-related morbidity and mortality, some studies have reported the negative influence of prior vaccination on vaccine effectiveness (VE) for current seasons. Currently, the influence of prior vaccination is not conclusive, especially in children. METHODS: We evaluated the association between current-season VE and prior season vaccination using a test-negative design in children aged 1-5 years presenting at nine outpatient clinics in Japan during the 2016/17 and 2017/18 influenza seasons. Children with influenza-like illness were enrolled prospectively and tested for influenza using real-time RT-PCR. Their recent vaccination history was categorized into six groups according to current vaccination doses (0/1/2) and prior vaccination status (unvaccinated = 0 doses/vaccinated = 1 dose or 2 doses): (1) 0 doses in the current season and unvaccinated in prior seasons (reference group); (2) 0 doses in the current season and vaccinated in a prior season; (3) 1 dose in the current season and unvaccinated in a prior season; (4) 1 dose in the current season and vaccinated in a prior season; (5) 2 doses in the current season and unvaccinated in a prior season, and (6) 2 doses in the current season and vaccinated in a prior season. RESULTS: A total of 799 cases and 1196 controls were analyzed. The median age of the subjects was 3 years, and the proportion of males was 54%. Overall, the vaccination rates (any vaccination in the current season) in the cases and controls were 36% and 53%, respectively. The VEs of the groups were: (2) 29% (95% confidence interval: -25% to 59%); (3) 53% (6% to 76%); (4) 70% (45% to 83%); (5) 56% (32% to 72%), and (6) 61% (42% to 73%). The one- and two-dose VEs of the current season were significant regardless of prior vaccination status. The results did not differ when stratified by influenza subtype/lineage. CONCLUSION: Prior vaccination did not attenuate the current-season VE in children aged 1 to 5 years, supporting the annual vaccination strategy.

Repeated Influenza Vaccination Boosts and Maintains H1N1pdm09 Neuraminidase Antibody Titers.

Antibodies to influenza surface protein neuraminidase (NA) have been found to reduce disease severity and may be an independent correlate of protection. Despite this, current influenza vaccines have no regulatory requirements for the quality or quantity of the NA antigen and are not optimized for induction of NA-specific antibodies. Here we investigate the induction and durability of NA-specific antibody titers after pandemic AS03-adjuvanted monovalent H1N1 vaccination and subsequent annual vaccination in health care workers in a five-year longitudinal study. NA-specific antibodies were measured by endpoint ELISA and functional antibodies measured by enzyme-linked lectin assay (ELLA) and plaque reduction naturalisation assay. We found robust induction of NA inhibition (NAI) titers with a 53% seroconversion rate (>4-fold) after pandemic vaccination in 2009. Furthermore, the endpoint and NAI geometric mean titers persisted above pre-vaccination levels up to five years after vaccination in HCWs that only received the pandemic vaccine, which demonstrates considerable durability. Vaccination with non-adjuvanted trivalent influenza vaccines (TIV) in subsequent influenza seasons 2010/2011 - 2013/2014 further boosted NA-specific antibody responses. We found that each subsequent vaccination increased durable endpoint titers and contributed to maintaining the durability of functional antibody titers. Although the trivalent influenza vaccines boosted NA-specific antibodies, the magnitude of fold-increase at day 21 declined with repeated vaccination, particularly for functional antibody titers. High levels of pre-existing antibodies were associated with lower fold-induction in repeatedly vaccinated HCWs. In summary, our results show that durable NA-specific antibody responses can be induced by an adjuvanted influenza vaccine, which can be maintained and further boosted by TIVs. Although NA-specific antibody responses are boosted by annual influenza vaccines, high pre-existing titers may negatively affect the magnitude of fold-increase in repeatedly vaccinated individuals. Our results support continued development and standardization of the NA antigen to supplement current influenza vaccines and reduce the burden of morbidity and mortality.

Simple models to include influenza vaccination history when evaluating the effect of influenza vaccination.

BackgroundMost reports of influenza vaccine effectiveness consider current-season vaccination only.AimWe evaluated a method to estimate the effect of influenza vaccinations (EIV) considering vaccination history.MethodsWe used a test-negative design with well-documented vaccination history to evaluate the average EIV over eight influenza seasons (2011/12-2018/19; n = 10,356). Modifying effect was considered as difference in effects of vaccination in current and previous seasons and current-season vaccination only. We also explored differences between current-season estimates excluding from the reference category people vaccinated in any of the five previous seasons and estimates without this exclusion or only for one or three previous seasons.ResultsThe EIV was 50%, 45% and 38% in people vaccinated in the current season who had previously received none, one to two and three to five doses, respectively, and it was 30% and 43% for one to two and three to five prior doses only. Vaccination in at least three previous seasons reduced the effect of current-season vaccination by 12 percentage points overall, 31 among outpatients, 22 in 9-65 year-olds, and 23 against influenza B. Including people vaccinated in previous seasons only in the unvaccinated category underestimated EIV by 9 percentage points on average (31% vs 40%). Estimates considering vaccination of three or five previous seasons were similar.ConclusionsVaccine effectiveness studies should consider influenza vaccination in previous seasons, as it can retain effect and is often an effect modifier. Vaccination status in three categories (current season, previous seasons only, unvaccinated) reflects the whole EIV.

Repeated influenza vaccination provides cumulative protection from distinct H3N2 viruses.

OBJECTIVES: Current inactivated influenza vaccines provide suboptimal protection against antigenic drift, and repeated annual vaccinations shape antibody specificity but the effect on protection from infection is not well understood. METHODS: We studied the effects of cumulative and staggered vaccinations in mice to determine the effect of influenza vaccination on protection from infection and immune quality. RESULTS: We found that the timing of vaccination and antigenic change impacted the quality of immune responses. When mice received two different H3N2 strains (A/Hong Kong/4801/2014 and A/Singapore/INFIMH-16-0019/2016) by staggered timing of vaccination, there were higher H3HA antibody and B-cell memory responses than four cumulative vaccinations or when two vaccinations were successive. Interestingly, after challenge with a lethal-drifted H3N2 virus (A/Hong Kong/1/1968), mice with staggered vaccination were unable to produce high titres of antibodies specific to the challenge strain compared to other vaccination regimens because of high levels of vaccine-specific cross-reactive antibodies. All vaccination regimens resulted in protection, in terms of viral loads and survival, from lethal challenge, while lung IL-6 and inflammation were lowest in staggered or cumulative vaccination groups, indicating further advantage. CONCLUSION: Our findings help justify influenza vaccination policies that currently recommend repeat vaccination in infants and annual seasonal vaccination, with no evidence for impaired immunity by repeated seasonal vaccination.