Antibody-Mediated Suppression Regulates the Humoral Immune Response to Influenza Vaccination in Humans.

BACKGROUND: Preexisting immunity, including memory B cells and preexisting antibodies, can modulate antibody responses to influenza in vivo to antigenically related antigens. We investigated whether preexisting hemagglutination inhibition (HAI) antibodies targeting the K163 epitope on the hemagglutinin (K163 antibodies) could affect antibody responses following vaccination with A/California/07/2009-like A(H1N1)pdm09 influenza viruses in humans. METHODS: Pre- and postvaccination sera collected from 300 adults (birth years, 1961-1998) in 6 seasons (2010-2016) were analyzed by HAI assays with 2 reverse genetics viruses and A(H1N1) viruses circulated from 1977 to 2018. Antibody adsorption assays were used to verify the preexisting K163 antibody-mediated suppression effect. RESULTS: Preexisting K163 antibody titers ≥80 affected HAI antibody responses following influenza vaccination containing A/California/07/2009-like antigens. At high K163 antibody concentrations (HAI antibody titers ≥160), all HAI antibody responses were suppressed. However, at moderate K163 antibody concentrations (HAI antibody titer, 80), only K163 epitope-specific antibody responses were suppressed, and novel HAI antibody responses targeting the non-K163 epitopes were induced by vaccination. Novel antibodies targeting non-K163 epitopes cross-reacted with newly emerging A(H1N1)pdm09 strains with a K163Q mutation rather than historic 1977-2007 A(H1N1) viruses. CONCLUSIONS: K163 antibody-mediated suppression shapes antibody responses to A(H1N1)pdm09 vaccination. Understanding how preexisting antibodies suppress and redirect vaccine-induced antibody responses is of great importance to improve vaccine effectiveness.

[The study on biological exposure index of occupational exposure to arsenic and its inorganic compounds].

Objective: To establish biological exposure index (BEI) of occupational exposure to arsenic and its inorganic compounds through occupational epidemiology and the regression analysis of internal and external exposure of workers. Methods: In November 2021, 125 workers with occupational exposure to arsenic and its inorganic compounds and 49 office administrators in a non-ferrous metal smelter in Yunnan Province were selected as the exposure group and control group, respectively. Air samples from the workplace of the study subjects on weekdays were collected and arsenic concentrations were determined. Urine samples were collected in end-of-work weekend and high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) was used to detect the levels of trivalent inorganic arsenic (iAs(3+)) , pentavalent inorganic arsenic (iAs(5+)) , monomethyl arsenic (MMA) and dimethyl arsenic (DMA) in urine. The correlations between arsenic concentration in the workplace air and arsenic species in urine of workers were analyzed. Arsenic exposure concentration and the level of urinary arsenic (ΣiAs+MMA+DMA) of workers was analyzed by linear regression and the BEI of arsenic and its inorganic compounds in the workplace was proposed based on the results of micronucleus test. Results: The median of time-weighted average concentration (C(TWA)) of arsenic in the workplace air of the exposure group was 0.0116 mg/m(3), and the over-standard rate was 71.2% (89/125) . The concentrations of iAs(3+), iAs(5+), inorganic arsenic (iAs=ΣiAs(3+)+iAs(5+)) 、MMA、DMA and urinary arsenic in the exposure group were higher than those in the control group at the end of shift, and the differences were statistically significant (P<0.05) . The concentration of arsenic in the workplace air had the strongest correlation with the concentration of urinary arsenic at the end of the shift (r(s)=0.909, P<0.001) . The regression equation was lg (y) =7.662+2.968lg (x) (r=0.821, P<0.05) . According to the occupational exposure limit (OEL) of arsenic in China, the concentration of urinary arsenic in the end-of-work weekend was calculated to be 53.2 µg/L. Combined with the results of micronucleus test, the BEI of occupational exposure to arsenic and its inorganic compounds in the workplace was proposed to be 50 µg/L. Conclusion: The urinary arsenic in the end-of-work weekend can be used as a biomarker of occupational exposure to arsenic, and its BEI is recommended to be 50 µg/L.

[Correlation analysis of urinary arsenic species and health effect indicators of occupational arsenic exposure workers].

Objective: To explore the correlation between urinary arsenic and health effects through the determination and analysis of urinary arsenic levels in occupational arsenic exposed workers. Methods: In November 2021, 95 workers exposed to arsenic and its inorganic compounds and 31 administrative personnel from a non-ferrous metal smelter in Yunnan Province were selected as the contact group and control group, respectively. Urine forms of arsenic, blood tumor markers, liver function were detected, and micronucleus test was used to analyze the chromosome damage. The correlation between urine forms of arsenic and health effects were analyzed. Results: Compared with the control group, the concentrations of urinary trivalent inorganic arsenic (iAs(3+)) , pentavalent inorganic arsenic (iAs(5+)) , inorganic arsenic (iAs=ΣiAs(3+)+iAs(5+)) , monomethyl arsenic (MMA) , dimethyl arsenic (DMA) and urinary arsenic (ΣiAs+MMA+DMA) at the end of class in contact group were higher (P<0.05) . There was no statistically significant difference in blood tumor markers and liver function indicators between the two groups (P>0.05) . Compared with the control group, the peripheral blood micronucleus rate and cell micronucleus rate in the contact group were significantly increased (P<0.05) . The urinary arsenic, iAs(5+), inorganic arsenic and DMA were positively correlated with peripheral blood micronucleus rate in contact group (r(s)=0.48, 0.34, 0.37, 0.23, P<0.05) , and the urinary arsenic, iAs(5+), DMA were positively correlated with peripheral blood micronucleus rate (r(s)=0.48, 0.34, 0.26, P<0.05) . Conclusion: There is a significant correlation between different valence states of arsenic in the urine and abnormal health effects of occupational arsenic exposed workers. It is necessary to strengthen the detection of arsenic species in the urine of occupational arsenic exposed workers to better protect their health.

Effect of Repeat Vaccination on Immunogenicity of Quadrivalent Cell-Culture and Recombinant Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years: A Randomized, Open-Label Trial.

BACKGROUND: Antibody responses to non-egg-based standard-dose cell-culture influenza vaccine (containing 15 µg hemagglutinin [HA]/component) and recombinant vaccine (containing 45 µg HA/component) during consecutive seasons have not been studied in the United States. METHODS: In a randomized trial of immunogenicity of quadrivalent influenza vaccines among healthcare personnel (HCP) aged 18-64 years over 2 consecutive seasons, HCP who received recombinant-HA influenza vaccine (RIV) or cell culture-based inactivated influenza vaccine (ccIIV) during the first season (year 1) were re-randomized the second season of 2019-2020 (year 2 [Y2]) to receive ccIIV or RIV, resulting in 4 ccIIV/RIV combinations. In Y2, hemagglutination inhibition antibody titers against reference cell-grown vaccine viruses were compared in each ccIIV/RIV group with titers among HCP randomized both seasons to receive egg-based, standard-dose inactivated influenza vaccine (IIV) using geometric mean titer (GMT) ratios of Y2 post-vaccination titers. RESULTS: Y2 data from 414 HCP were analyzed per protocol. Compared with 60 IIV/IIV recipients, 74 RIV/RIV and 106 ccIIV/RIV recipients showed significantly elevated GMT ratios (Bonferroni corrected P < .007) against all components except A(H3N2). Post-vaccination GMT ratios for ccIIV/ccIIV and RIV/ccIIV were not significantly elevated compared with IIV/IIV except for RIV/ccIIV against A(H1N1)pdm09. CONCLUSIONS: In adult HCP, receipt of RIV in 2 consecutive seasons or the second season was more immunogenic than consecutive egg-based IIV for 3 of the 4 components of quadrivalent vaccine. Immunogenicity of ccIIV/ccIIV was similar to that of IIV/IIV. Differences in HA antigen content may play a role in immunogenicity of influenza vaccination in consecutive seasons. CLINICAL TRIALS REGISTRATION: NCT03722589.

Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure-Minnesota, 2021.

BACKGROUND: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture-based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection. METHODS: We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts. RESULTS: Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP. CONCLUSIONS: This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture-based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Risk for Infection in Humans after Exposure to Birds Infected with Highly Pathogenic Avian Influenza A(H5N1) Virus, United States, 2022.

During February 7─September 3, 2022, a total of 39 US states experienced outbreaks of highly pathogenic avian influenza A(H5N1) virus in birds from commercial poultry farms and backyard flocks. Among persons exposed to infected birds, highly pathogenic avian influenza A(H5) viral RNA was detected in 1 respiratory specimen from 1 person.

Multiplex Detection of Antibody Landscapes to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)/Influenza/Common Human Coronaviruses Following Vaccination or Infection With SARS-CoV-2 and Influenza.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses continue to co-circulate, representing 2 major public health threats from respiratory infections with similar clinical presentations. SARS-CoV-2 and influenza vaccines can also now be co-administered. However, data on antibody responses to SARS-CoV-2 and influenza coinfection and vaccine co-administration remain limited. METHODS: We developed a 41-plex antibody immunity assay that can simultaneously characterize antibody landscapes to SARS-CoV-2/influenza/common human coronaviruses. We analyzed sera from 840 individuals (11-93 years), including sera from reverse transcription-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2-positive (n = 218) and -negative (n = 120) cases, paired sera from SARS-CoV-2 vaccination (n = 29) and infection (n = 11), and paired sera from influenza vaccination (n = 56) and RT-PCR-confirmed influenza infection (n = 158) cases. Last, we analyzed sera collected from 377 individuals who exhibited acute respiratory illness (ARI) in 2020. RESULTS: This 41-plex assay has high sensitivity and specificity in detecting SARS-CoV-2 infections. It differentiated SARS-CoV-2 vaccination (antibody responses only to spike protein) from infection (antibody responses to both spike and nucleoprotein). No cross-reactive antibodies were induced to SARS-CoV-2 from influenza vaccination and infection, and vice versa, suggesting no interaction between SARS-CoV-2 and influenza antibody responses. However, cross-reactive antibodies were detected between spike proteins of SARS-CoV-2 and common human coronaviruses that were removed by serum adsorption. Among 377 individuals who exhibited ARI in 2020, 129 were influenza positive; none had serological evidence of SARS-CoV-2/influenza coinfections. CONCLUSIONS: Multiplex detection of antibody landscapes can provide in-depth analysis of the antibody protective immunity to SARS-CoV-2 in the context of other respiratory viruses, including influenza.

Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment.

Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer 'Donors' (n = 52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). 'Recipients' randomized to Intervention (IR, n = 40) or Control (CR, n = 35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p = 0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols.

Impact of Immune Priming, Vaccination, and Infection on Influenza A(H3N2) Antibody Landscapes in Children.

BACKGROUND: Preexisting antibodies to influenza, shaped by early infection and subsequent exposures, may impact responses to influenza vaccination. METHODS: We enrolled 72 children (aged 7-17 years) in 2015-2016; all received inactivated influenza vaccines. Forty-one were also vaccinated in 2014-2015, with 12 becoming infected with A(H3N2) in 2014-2015. Thirty-one children did not have documented influenza exposures in the prior 5 seasons. Sera were collected pre- and postvaccination in both seasons. We constructed antibody landscapes using hemagglutination inhibition antibody titers against 16 A(H3N2) viruses representative of major antigenic clusters that circulated between 1968 and 2015. RESULTS: The breadth of the antibody landscapes increased with age. Vaccine-induced antibody responses correlated with boosting of titers to previously encountered antigens. Postvaccination titers were the highest against vaccine antigens rather than the historic A(H3N2) viruses previously encountered. Prevaccination titers to the vaccine were the strongest predictors of postvaccination titers. Responses to vaccine antigens did not differ by likely priming virus. Influenza A(H3N2)-infected children in 2014-2015 had narrower antibody landscapes than those uninfected, but prior season infection status had little effect on antibody landscapes following 2015-2016 vaccination. CONCLUSIONS: A(H3N2) antibody landscapes in children were largely determined by age-related immune priming, rather than recent vaccination or infection.

[The research progress of metabolism and occupational biological exposure index metabolism of inorganic arsenic and its compounds].

Arsenic is a common metal-like element. Drinking arsenic-containing water and occupational exposure to arsenic are the main ways exposure to arsenic for population. Long-term exposure to arsenic can cause various organs dysfunction and cancer. After entering the body, inorganic arsenic is mainly methylated into monomethyl arsenic and dimethyl arsenic in the liver. Only a small part of inorganic arsenic is metabolized in the kidneys and lungs, and finally the metabolites of arsenic are excreted in the urine. understanding the biological characteristics of arsenic absorption, metabolism, and distribution in the body and formulating biological indicators related to occupational exposure to arsenic and can provide a scientific basis for the prevention and treatment of arsenic-related diseases. This article will review the biological monitoring indicators of occupational exposure to arsenic and the metabolic process of arsenic in the body.

[Determination of six arsenic species in urine by high-performance liquid chromatography-inductively coupled plasma-mass spectrometr].

Objective: Establishing an analysis method for the detection of six arsenic compounds trivalent arsenic, pentavalent arsenic, methyl arsenic, dimethyl arsenic, arsenical choline and arsenical betaine in urine by high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) and providing a theoretical basis for health assessment of arsenic poisoning patients. Methods: HPLC-ICP-MS was used to detect six arsenic compounds with the hamilton PRP-X100 column and aqueous ammonium phosphate in a gradient elution as mobile phase. Results: There was a good linear relationship in the selected range of six arsenic compounds evidenced by a linear correlation coefficient greater than 0.999. The detection limit of 6 arsenic compounds was 0.46~0.57 µg/L, and the minimum quantitative concentration were 1.52~1.91 µg/L. The recovery rates of six arsenic compounds were 96.5%~106.4%, The within-run and between-run relative standard deviation was 2.9%~6.2% and 3.8%~8.7%. Conclusion: The established method with high accuracy and precision is suitable for detecting arsenic levels in urine of occupational arsenic exposure population.

Comparison of the Immunogenicity of Cell Culture-Based and Recombinant Quadrivalent Influenza Vaccines to Conventional Egg-Based Quadrivalent Influenza Vaccines Among Healthcare Personnel Aged 18-64 Years: A Randomized Open-Label Trial.

BACKGROUND: RIV4 and cell-culture based inactivated influenza vaccine (ccIIV4) have not been compared to egg-based IIV4 in healthcare personnel, a population with frequent influenza vaccination that may blunt vaccine immune responses over time. We conducted a randomized trial among healthcare personnel (HCP) aged 18-64 years to compare humoral immune responses to ccIIV4 and RIV4 to IIV4. METHODS: During the 2018-2019 season, participants were randomized to receive ccIIV4, RIV4, or IIV4 and had serum samples collected prevaccination, 1 and 6 months postvaccination. Serum samples were tested by hemagglutination inhibition (HI) for influenza A/H1N1, B/Yamagata, and B/Victoria and microneutralization (MN) for A/H3N2 against cell-grown vaccine reference viruses. Primary outcomes at 1 month were seroconversion rate (SCR), geometric mean titers (GMT), GMT ratio, and mean fold rise (MFR) in the intention-to-treat population. RESULTS: In total, 727 participants were included (283 ccIIV4, 202 RIV4, and 242 IIV4). At 1 month, responses to ccIIV4 were similar to IIV4 by SCR, GMT, GMT ratio, and MFR. RIV4 induced higher SCRs, GMTs, and MFRs than IIV4 against A/H1N1, A/H3N2, and B/Yamagata. The GMT ratio of RIV4 to egg-based vaccines was 1.5 (95% confidence interval [CI] 1.2-1.9) for A/H1N1, 3.0 (95% CI: 2.4-3.7) for A/H3N2, 1.1 (95% CI: .9-1.4) for B/Yamagata, and 1.1 (95% CI: .9-1.3) for B/Victoria. At 6 months, ccIIV4 recipients had similar GMTs to IIV4, whereas RIV4 recipients had higher GMTs against A/H3N2 and B/Yamagata. CONCLUSIONS: RIV4 resulted in improved antibody responses by HI and MN compared to egg-based vaccines against 3 of 4 cell-grown vaccine strains 1 month postvaccination, suggesting a possible additional benefit from RIV4. CLINICAL TRIALS REGISTRATION: NCT03722589.

[The role of renal tubular epithelial cells in cadmium-induced renal fibrosis].

Objective: To investigate the role of renal tubular epithelial cells in cadmium-induced renal fibrosis. Methods: Established a sub-chronic cadmium exposure mouse model and analyzed the progress of renal fibrosis induced by cadmium exposure through Masson staining and immunohistochemistry, and then a co-culture system of renal tubular epithelial cells and renal fibroblasts was established, the levels of proliferation and activation of renal fibroblasts were detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting. Results: Sub-chronic cadmium exposure led to weight loss in mice (P<0.05) , and the levels of ß-microglobulin (ß-MG) and N-acetyl ß-D-glucosaminidase (NAG) in urine were increased in mice exposed to cadmium (P<0.05) ; pathological analysis revealed that sub-chronic cadmium exposure damaged renal tubular structure, causing infiltration of inflammatory cells and deposition of collagen fiber by Masson (P<0.05) , which in turn induced kidney fibrosis in mice; the results of in vitro co-culture experiments showed that cadmium-exposed renal tubular epithelial cells accelerated the synthesis of collagen in renal fibroblasts and promoted the proliferation and activation of renal fibroblasts (P<0.05) . Conclusion: In the progression of cadmium-induced renal fibrosis, a deleterious renal epithelial-fibroblast cross talk was formed, which may be one of the important mechanisms of cadmium-induced renal fibrosis.

Heterologous Antibody Responses Conferred by A(H3N2) Variant and Seasonal Influenza Vaccination Against Newly Emerged 2016-2018 A(H3N2) Variant Viruses in Healthy Persons.

BACKGROUND: Swine origin A(H3N2) variant [A(H3N2)v] viruses continue to evolve and remain a public health threat. Recent outbreaks in humans in 2016-2018 were caused by a newly emerged A(H3N2)v cluster 2010.1, which are genetically and antigenically distinct from the previously predominant cluster IV. To address the public health risk, we evaluated the levels of heterologous cross-reactive antibodies to A(H3N2)v cluster 2010.1 viruses induced from an existing cluster IV A(H3N2)v vaccine and several seasonal inactivated influenza vaccines (IIVs) in adults, elderly individuals, and children. METHODS: Human vaccine sera and ferret antisera were analyzed by hemagglutination inhibition (HI) and neutralization assays against representative A(H3N2)v viruses from clusters IV and 2010.1 and seasonal A(H3N2) viruses. RESULTS: Ferret antisera detected no or little cross-reactivity between the 2 A(H3N2)v clusters or between A(H3N2)v and seasonal A(H3N2) viruses. In humans, cluster IV A(H3N2)v vaccine induced antibodies cross-reactive to cluster 2010.1 viruses in approximately one-third of the 89 adult and elderly vaccinees. Seasonal IIVs did not induce seroprotective antibodies (≥40) to A(H3N2)v viruses in young children, but induced higher antibodies to A(H3N2)v viruses in cluster 2010.1 than those in cluster IV in adults. CONCLUSIONS: Cluster IV A(H3N2)v vaccine did not provide sufficient heterologous antibody responses against the new 2010.1 cluster A(H3N2)v viruses. Seasonal IIV could not induce seroprotective antibodies to 2010.1 cluster A(H3N2)v viruses in young children, suggesting that young children are still at high risk to the newly emerged A(H3N2)v viruses. Continued surveillance on A(H3N2)v viruses is critical for risk assessment and pandemic preparedness.

Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial.

BACKGROUND: Enhanced influenza vaccines may improve protection for older adults, but comparative immunogenicity data are limited. Our objective was to examine immune responses to enhanced influenza vaccines, compared to standard-dose vaccines, in community-dwelling older adults. METHODS: Community-dwelling older adults aged 65-82 years in Hong Kong were randomly allocated (October 2017-January 2018) to receive 2017-2018 Northern hemisphere formulations of a standard-dose quadrivalent vaccine, MF59-adjuvanted trivalent vaccine, high-dose trivalent vaccine, or recombinant-hemagglutinin (rHA) quadrivalent vaccine. Sera collected from 200 recipients of each vaccine before and at 30-days postvaccination were assessed for antibodies to egg-propagated vaccine strains by hemagglutination inhibition (HAI) and to cell-propagated A/Hong Kong/4801/2014(H3N2) virus by microneutralization (MN). Influenza-specific CD4+ and CD8+ T cell responses were assessed in 20 participants per group. RESULTS: Mean fold rises (MFR) in HAI titers to egg-propagated A(H1N1) and A(H3N2) and the MFR in MN to cell-propagated A(H3N2) were statistically significantly higher in the enhanced vaccine groups, compared to the standard-dose vaccine. The MFR in MN to cell-propagated A(H3N2) was highest among rHA recipients (4.7), followed by high-dose (3.4) and MF59-adjuvanted (2.9) recipients, compared to standard-dose recipients (2.3). Similarly, the ratio of postvaccination MN titers among rHA recipients to cell-propagated A(H3N2) recipients was 2.57-fold higher than the standard-dose vaccine, which was statistically higher than the high-dose (1.33-fold) and MF59-adjuvanted (1.43-fold) recipient ratios. Enhanced vaccines also resulted in the boosting of T-cell responses. CONCLUSIONS: In this head-to-head comparison, older adults receiving enhanced vaccines showed improved humoral and cell-mediated immune responses, compared to standard-dose vaccine recipients. CLINICAL TRIALS REGISTRATION: NCT03330132.

Stockpiled Avian Influenza A(H7N9) Vaccines Induce Robust, Nonneutralizing Functional Antibodies Against Antigenically Drifted Fifth-Wave A(H7N9) Viruses.

Human infections caused by avian influenza A(H7N9) viruses have raised concerns of a pandemic. The capability of the current stockpiled A(H7N9) vaccines to induce cross-protective, nonneutralizing functional antibodies against antigenically drifted A(H7N9) viruses has not been evaluated before. Here we show that vaccination with either MF59- or AS03-adjuvanted inactivated A(H7N9) vaccines elicited robust, cross-reactive antibody-dependent cell-mediated cytotoxicity-mediating and neuraminidase-inhibiting functional antibodies against the antigenically drifted A(H7N9) viruses that emerged recently during the fifth-wave outbreak in China, including a highly pathogenic A(H7N9) human isolate. Such cross-reactive humoral immunity may provide vital first-line defense against fatal outcomes in case of an A(H7N9) pandemic.

Antibodies Against Egg- and Cell-Grown Influenza A(H3N2) Viruses in Adults Hospitalized During the 2017-2018 Influenza Season.

BACKGROUND: Influenza vaccine effectiveness was low in 2017-2018, yet circulating influenza A(H3N2) viruses were antigenically similar to cell-grown vaccine strains. Notably, most influenza vaccines are egg propagated. METHODS: Serum specimens were collected shortly after illness onset from 15 influenza A(H3N2) virus-infected cases and 15 uninfected hospitalized adults. Geometric mean titers against egg- and cell-grown influenza A/Hong Kong/4801/2014(H3N2) virus vaccine strains and representative circulating viruses (including A/Washington/16/2017) were determined by a microneutralization (MN) assay. Independent effects of strain-specific titers on susceptibility were estimated by logistic regression. RESULTS: MN titers against egg-grown influenza A/Hong Kong virus were significantly higher among vaccinated individuals (173 vs 41; P = 0.01). In unadjusted models, a 2-fold increase in titers against egg-grown influenza A/Hong Kong virus was not significantly protective (29% reduction; P = .09), but a similar increase in the cell-grown influenza A/Washington virus antibody titer (3C.2a2) was protective (60% reduction; P = .02). Higher egg-grown influenza A/Hong Kong virus titers were not significantly associated with infection, when adjusted for antibody titers against influenza A/Washington virus (15% reduction; P = .61). A 54% reduction in the odds of infection was observed with a 2-fold increase in titer against influenza A/Washington virus (P = not significant), adjusted for the titer against egg-grown influenza A/Hong Kong virus titer. CONCLUSION: Individuals vaccinated in 2017-2018 had high antibody titers against the egg-adapted vaccine strain and lower titers against circulating viruses. Titers against circulating but not egg-adapted strains were correlated with protection.

Detection of Avian Influenza A(H7N2) Virus Infection Among Animal Shelter Workers Using a Novel Serological Approach-New York City, 2016-2017.

BACKGROUND: In 2016, an influenza A(H7N2) virus outbreak occurred in cats in New York City's municipal animal shelters. One human infection was initially detected. METHODS: We conducted a serological survey using a novel approach to rule out cross-reactive antibodies to other seasonal influenza viruses to determine whether additional A(H7N2) human infections had occurred and to assess exposure risk. RESULTS: Of 121 shelter workers, one had serological evidence of A(H7N2) infection, corresponding to a seroprevalence of 0.8% (95% confidence interval, .02%-4.5%). Five persons exhibited low positive titers to A(H7N2) virus, indicating possible infection; however, we could not exclude cross-reactive antibody responses to seasonal influenza viruses. The remaining 115 persons were seronegative. The seropositive person reported multiple direct cat exposures without using personal protective equipment and mild illness with subjective fever, runny nose, and sore throat. CONCLUSIONS: We identified a second case of A(H7N2) infection from this outbreak, providing further evidence of cat-to-human transmission of A(H7N2) virus.

Birth Cohort Effects in Influenza Surveillance Data: Evidence That First Influenza Infection Affects Later Influenza-Associated Illness.

BACKGROUND: The evolution of influenza A viruses results in birth cohorts that have different initial influenza virus exposures. Historically, A/H3 predominant seasons have been associated with more severe influenza-associated disease; however, since the 2009 pandemic, there are suggestions that some birth cohorts experience more severe illness in A/H1 predominant seasons. METHODS: United States influenza virologic, hospitalization, and mortality surveillance data during 2000-2017 were analyzed for cohorts born between 1918 and 1989 that likely had different initial influenza virus exposures based on viruses circulating during early childhood. Relative risk/rate during H3 compared with H1 predominant seasons during prepandemic versus pandemic and later periods were calculated for each cohort. RESULTS: During the prepandemic period, all cohorts had more influenza-associated disease during H3 predominant seasons than H1 predominant seasons. During the pandemic and later period, 4 cohorts had higher hospitalization and mortality rates during H1 predominant seasons than H3 predominant seasons. CONCLUSIONS: Birth cohort differences in risk of influenza-associated disease by influenza A virus subtype can be seen in US influenza surveillance data and differ between prepandemic and pandemic and later periods. As the population ages, the amount of influenza-associated disease may be greater in future H1 predominant seasons than H3 predominant seasons.

The Effect of Preexisting Immunity on Virus Detection and Immune Responses in a Phase II, Randomized Trial of a Russian-Backbone, Live, Attenuated Influenza Vaccine in Bangladeshi Children.

BACKGROUND: In a 2012 Phase II clinical trial, 300 Bangladeshi children aged 24 to 59 months with no prior influenza vaccine exposure were randomized to receive a single intranasally-administered dose of either trivalent, Russian-backbone, live, attenuated influenza vaccine (LAIV) or placebo. Protocol-defined analyses, presented in the companion manuscript, demonstrate decreased viral detection and immunogenicity for A/H1N1pdm09, relative to the A/H3N2 and B strains. This post hoc analysis of the trial data aims to investigate the LAIV strain differences by testing the hypothesis that preexisting humoral and mucosal immunity may influence viral recovery and immune responses after LAIV receipt. METHODS: We used logistic regressions to evaluate the relations between markers of preexisting immunity (ie, hemagglutination inhibition [HAI], microneutralization, and immunoglobulin G and immunoglobulin A (both serum and mucosal antibodies) and LAIV viral recovery in the week post-vaccination. We then tested for potential effect modification by baseline HAI titers (ie, <10 versus ≥10) and week 1 viral recovery on the LAIV-induced serum and mucosal immune responses, measured between days 0 and 21 post-vaccination. RESULTS: Higher levels of preexisting immunity to influenza A/H3N2 and B were strongly associated with strain-specific prevention of viral shedding upon LAIV receipt. While evidence of LAIV immunogenicity was observed for all 3 strains, the magnitudes of immune responses were most pronounced in children with no evidence of preexisting HAI and in those with detectable virus. CONCLUSIONS: The results provide evidence for a bidirectional association between viral replication and immunity, and underscore the importance of accounting for preexisting immunity when evaluating virologic and immunologic responses to LAIVs. CLINICAL TRIALS REGISTRATION: NCT01625689.