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.

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.

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.

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.

Immunogenicity and Viral Shedding of Russian-Backbone, Seasonal, Trivalent, Live, Attenuated Influenza Vaccine in a Phase II, Randomized, Placebo-Controlled Trial Among Preschool-Aged Children in Urban Bangladesh.

BACKGROUND: We evaluated a Russian-backbone, live, attenuated influenza vaccine (LAIV) for immunogenicity and viral shedding in a randomized, placebo-controlled trial among Bangladeshi children. METHODS: Healthy children received a single, intranasal dose of LAIV containing the 2011-2012 recommended formulation or placebo. Nasopharyngeal wash (NPW) specimens were collected on days 0, 2, 4, and 7. Reverse transcription polymerase chain reactions and sequencing identified the influenza virus (vaccine or wild-type). On days 0 and 21, blood specimens were collected to assess immunogenicity using hemagglutination inhibition, microneutralization, and immunoglobulin A (IgA) and G enzyme-linked immunosorbent assays (ELISAs); NPW specimens were also collected to assess mucosal immunogenicity using kinetic IgA ELISA. RESULTS: We enrolled 300 children aged 24 through 59 months in the immunogenicity and viral shedding analyses. Among children receiving LAIV, 45% and 67% shed A/H3N2 and B vaccine strains, respectively. No child shed A/H1N1 vaccine strain. There were significantly higher day 21 geometric mean titers (GMTs) for the LAIV, as compared to the placebo groups, in all immunoassays for A/H3N2 and B (log10 titer P < .0001; GMT Ratio >2.0). Among immunoassays for A/H1N1, only the mucosal IgA GMT was significantly higher than placebo at day 21 (log10 titer P = .0465). CONCLUSIONS: Children vaccinated with LAIV had serum and mucosal antibody responses to A/H3N2 and B, but only a mucosal IgA response to A/H1N1. Many children shed A/H3N2 and B vaccine strains, but none shed A/H1N1. More research is needed to determine the reason for decreased LAIV A/H1N1 immunogenicity and virus shedding. CLINICAL TRIALS REGISTRATION: NCT01625689.

Kinetics of Serological Responses in Critically Ill Patients Hospitalized With 2009 Pandemic Influenza A(H1N1) Virus Infection in Canada, 2009-2011.

Background: The kinetics of the antibody response during severe influenza are not well documented. Methods: Critically ill patients infected with 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09), confirmed by reverse-transcription polymerase chain reaction analysis or seroconversion (defined as a ≥4-fold rise in titers), during 2009-2011 in Canada were prospectively studied. Antibody titers in serially collected sera were determined using hemagglutinin inhibition (HAI) and microneutralization assays. Average antibody curves were estimated using linear mixed-effects models and compared by patient outcome, age, and corticosteroid treatment. Results: Of 47 patients with A(H1N1)pdm09 virus infection (median age, 47 years), 59% had baseline HAI titers of <40, and 68% had baseline neutralizing titers of <40. Antibody titers rose quickly after symptom onset, and, by day 14, 83% of patients had HAI titers of ≥40, and 80% had neutralizing titers ≥40. Baseline HAI titers were significantly higher in patients who died compared with patients who survived; however, the antibody kinetics were similar by patient outcome and corticosteroid treatment. Geometric mean titers over time in older patients were lower than those in younger patients. Conclusions: Critically ill patients with influenza A(H1N1)pdm09 virus infection had strong HAI and neutralizing antibody responses during their illness. Antibody kinetics differed by age but were not associated with patient outcome.

Influence of Immune Priming and Egg Adaptation in the Vaccine on Antibody Responses to Circulating A(H1N1)pdm09 Viruses After Influenza Vaccination in Adults.

Background: Although ferret antisera used in influenza surveillance did not detect antigenic drift of A(H1N1)pdm09 viruses during the 2015-2016 season, low vaccine effectiveness was reported in adults. We investigated the immune basis of low responses to circulating A(H1N1)pdm09 viruses after vaccination. Methods: Prevaccination and postvaccination serum samples collected from >300 adults (aged 18-49 years) in 6 seasons (2010-2011 to 2015-2016) were analyzed using hemagglutination inhibition assays to evaluate the antibody responses to 13 A(H1N1) viruses circulated from 1977 to 2016. Microneutralization and serum adsorption assays were used to verify the 163K and 223R specificity of antibodies. Results: Individual antibody profiles to A(H1N1) viruses revealed 3 priming patterns: USSR/77, TW/86, or NC/99 priming. More than 20% of adults had reduced titers to cell-propagated circulating 6B.1 and 6B.2 A(H1N1)pdm09 viruses compared with the A/California/07/2009 vaccine virus X-179A. Significantly reduced antibody reactivity to circulating viruses bearing K163Q was observed only in the USSR/77-primed cohort, whereas significantly lower reactivity caused by egg-adapted Q223R change was detected across all 3 cohorts. Conclusion: Both 163K specificity driven by immune priming and 223R specificity from egg-adapted changes in the vaccine contributed to low responses to circulating A(H1N1)pdm09 viruses after vaccination. Our study highlights the need to incorporate human serology in influenza surveillance and vaccine strain selection.

Influence of Birth Cohort on Effectiveness of 2015-2016 Influenza Vaccine Against Medically Attended Illness Due to 2009 Pandemic Influenza A(H1N1) Virus in the United States.

Background: The effectiveness of influenza vaccine during 2015-2016 was reduced in some age groups as compared to that in previous 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09 virus)-predominant seasons. We hypothesized that the age at first exposure to specific influenza A(H1N1) viruses could influence vaccine effectiveness (VE). Methods: We estimated the effectiveness of influenza vaccine against polymerase chain reaction-confirmed influenza A(H1N1)pdm09-associated medically attended illness from the 2010-2011 season through the 2015-2016 season, according to patient birth cohort using data from the Influenza Vaccine Effectiveness Network. Birth cohorts were defined a priori on the basis of likely immunologic priming with groups of influenza A(H1N1) viruses that circulated during 1918-2015. VE was calculated as 100 × [1 - adjusted odds ratio] from logistic regression models comparing the odds of vaccination among influenza virus-positive versus influenza test-negative patients. Results: A total of 2115 A(H1N1)pdm09 virus-positive and 14 696 influenza virus-negative patients aged ≥6 months were included. VE was 61% (95% confidence interval [CI], 56%-66%) against A(H1N1)pdm09-associated illness during the 2010-2011 through 2013-2014 seasons, compared with 47% (95% CI, 36%-56%) during 2015-2016. During 2015-2016, A(H1N1)pdm09-specific VE was 22% (95% CI, -7%-43%) among adults born during 1958-1979 versus 61% (95% CI, 54%-66%) for all other birth cohorts combined. Conclusion: Findings suggest an association between reduced VE against influenza A(H1N1)pdm09-related illness during 2015-2016 and early exposure to specific influenza A(H1N1) viruses.