Search

Introduction A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. Methods Healthy adults (n = 180), ages 19–50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 μg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. Results Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6–212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. Conclusions Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807. [ABSTRACT FROM AUTHOR]

Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continued to occur in annual waves. In the 2016/2017 fifth wave, Yangtze River Delta (YRD) lineage viruses, which differed antigenically from those of earlier waves, predominated. In this phase 2 double-blinded trial we randomized 720 adults ≥ 19 years of age to receive two injections of a YRD lineage inactivated A/Hong Kong/125/2017 fifth-wave H7N9 vaccine, given 21 days apart, at doses of 3.75, 7.5, and 15 µg of hemagglutinin (HA) with AS03A adjuvant and at doses of 15 and 45 µg of HA without adjuvant. Two doses of adjuvanted vaccine were required to induce HA inhibition (HI) antibody titers ≥ 40 in most participants. After two doses of the 15 µg H7N9 formulation, given with or without AS03 adjuvant, the proportion achieving a HI titer ≥ 40 against the vaccine strain at 21 days after the second vaccination was 65 % (95 % CI, 57 %-73 %) and 0 % (95 % CI, 0 %-4%), respectively. Among those who received two doses of the 15 µg adjuvanted formulation the proportion with HI titer ≥ 40 at 21 days after the second vaccination was 76 % (95 % CI, 66 %-84 %) in those 19–64 years of age and 49 % (95 % CI, 37 %-62 %) in those ≥ 65 years of age. Responses to the adjuvanted vaccine formulations did not vary by HA content. Antibody responses declined over time and responses against drifted H7N9 strains were diminished. Overall, the vaccines were well tolerated but, as expected, adjuvanted vaccines were associated with more frequent solicited systemic and local adverse events. AS03 adjuvant improved the immune responses to an inactivated fifth–wave H7N9 influenza vaccine, particularly in younger adults, but invoked lower responses to drifted H7N9 strains. These findings may inform future influenza pandemic preparedness strategies. [ABSTRACT FROM AUTHOR]

Knowledge regarding the frequency of ocular abnormalities and abnormal visual function in children exposed to Zika virus (ZIKV) in utero but born without congenital Zika syndrome (CZS) is limited. We hypothesized that children exposed to ZIKV in utero born without CZS may have visual impairments in early childhood. We performed ophthalmic examination between 16 and 21 months of age and neurodevelopment assessment at 24 months of age with the Mullen Scales of Early Learning test (MSEL) on children enrolled in a cohort born to women pregnant during and shortly after the ZIKV epidemic in Nicaragua (2016–2017). ZIKV exposure status was defined based on maternal and infant serological testing. Visual impairment was defined as abnormal if the child had an abnormal ophthalmic exam and/or low visual reception score in the MSEL assessment. Of 124 children included in the analysis, 24 (19.4%) were classified as ZIKV-exposed and 100 (80.6%) unexposed according to maternal or cord blood serology. Ophthalmic examination showed that visual acuity did not differ significantly between groups, thus, 17.4% of ZIKV-exposed and 5.2% of unexposed had abnormal visual function (p = 0.07) and 12.5% of the ZIKV-exposed and 2% of the unexposed had abnormal contrast testing (p = 0.05). Low MSEL visual reception score was 3.2-fold higher in ZIKV-exposed than unexposed children, but not statistically significant (OR 3.2, CI: 0.8–14.0; p = 0.10). Visual impairment (a composite measure of visual function or low MESL visual reception score) was present in more ZIKV-exposed than in unexposed children (OR 3.7, CI: 1.2, 11.0; p = 0.02). However, the limited sample size warrants future investigations to fully assess the impact of in utero ZIKV exposure on ocular structures and visual function in early childhood, even in apparently healthy children. Author summary: Vertical transmission of Zika virus (ZIKV) during pregnancy has the potential to cause vision abnormalities even in the absence of overt ocular structural abnormalities or congenital Zika syndrome. We were able to classify infants' ZIKV exposure status by applying a serological algorithm of Zika antibodies in maternal and umbilical cord blood samples. We evaluated the ophthalmological abnormalities in children born in Nicaragua during the American ZIKV epidemic of 2015–2017 with no clinical abnormality detected at birth. We performed eye examinations on the children at 16–21 months of age, and neurocognitive testing by the Mullens Scales of Early Learning (MSEL) was performed at 24 months of age. Visual impairment, a composite measure of abnormal visual function and/or visual reception score was significantly more common in ZIKV-exposed than in unexposed children. We found a nonsignificant trend for a higher proportion of children exposed to ZIKV in utero had abnormal visual function and abnormal contrast testing than unexposed children. The visual reception score from the MSEL was also higher in Zika-exposed children, but these relationships did not reach statistical significance. These impairments could have implications for later academic performance, specifically reading. Early intervention may limit the morbidity associated with congenital ZIKV exposure. [ABSTRACT FROM AUTHOR]

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019. [ABSTRACT FROM AUTHOR]

Objective: To understand the dynamics of Zika virus (ZIKV)-specific antibody immunity in children born to mothers in a flavivirus-endemic region during and after the emergence of ZIKV in the Americas. Methods: We performed serologic testing for ZIKV cross-reactive and type-specific IgG in two longitudinal cohorts, which enrolled pregnant women and their children (PW1 and PW2) after the beginning of the ZIKV epidemic in Nicaragua. Quarterly samples from children over their first two years of life and maternal blood samples at birth and at the end of the two-year follow-up period were studied. Results: Most mothers in this dengue-endemic area were flavivirus-immune at enrollment. ZIKV-specific IgG (anti-ZIKV EDIII IgG) was detected in 82 of 102 (80.4%) mothers in cohort PW1 and 89 of 134 (66.4%) mothers in cohort PW2, consistent with extensive transmission observed in Nicaragua during 2016. ZIKV-reactive IgG decayed to undetectable levels by 6–9 months in infants, whereas these antibodies were maintained in mothers at the year two time point. Interestingly, a greater contribution to ZIKV immunity by IgG3 was observed in babies born soon after ZIKV transmission. Finally, 43 of 343 (13%) children exhibited persistent or increasing ZIKV-reactive IgG at ≥9 months, with 10 of 30 (33%) tested demonstrating serologic evidence of incident dengue infection. Conclusions: These data inform our understanding of protective and pathogenic immunity to potential flavivirus infections in early life in areas where multiple flaviviruses co-circulate, particularly considering the immune interactions between ZIKV and dengue and the future possibility of ZIKV vaccination in women of childbearing potential. This study also shows the benefits of cord blood sampling for serologic surveillance of infectious diseases in resource-limited settings. [ABSTRACT FROM AUTHOR]

Unadjuvanted A/H7N9 vaccines are poorly immunogenic. The immune response is improved with the addition of MF59, an oil-in-water adjuvant. However, the cellular immunologic responses of MF59-adjuvanted A/H7N9 vaccine are not fully understood. 37 participants were vaccinated with 2 doses of 2013 influenza A/H7N9 vaccine (at Days 1 and 21) with or without MF59 and enrolled in an immunology substudy. Responses were assessed at multiple timepoints (Days 0, 8, 21, 29, and 42) for hemagglutination inhibition (HAI) and neutralizing antibody (Neut) assays, memory B cell responses by enzyme-linked ImmunoSpot; circulating follicular helper T cells (cT FH) and CD4 + T cells by intracellular cytokine staining. MF59-adjuvanted influenza A/H7N9 vaccine induced significantly higher hemagglutination inhibition (HAI) and neutralizing antibody (Neut) responses when compared to unadjuvanted vaccine. The adjuvanted vaccine elicited significantly higher levels of Inducible T-cell Co-Stimulator (ICOS) expression by CXCR3+CXCR5+CD4+ cT FH cells, compared to unadjuvanted vaccine. The magnitude of increase in cT FH cells (from baseline to Day 8) and in IL-21 expressing CD154+CD4+ T cells (from baseline to Days 8 and 21) correlated with HAI (at Day 29) and Neut antibody (at Days 8 and 29) titers. The increase in frequency of IL-21 expressing CD154+CD4+T cells (from baseline to Day 21) correlated with memory B cell frequency (at Day 42). cT FH activation is associated with HAI and Neut responses in recipients of MF59-adjuvanted influenza A/H7N9 vaccine relative to unadjuvanted vaccine. Future studies should focus on optimizing the cT FH response and use cT FH as an early biomarker of serological response to vaccination. This trial was registered at clinicaltrials.gov , trial number NCT01938742. [ABSTRACT FROM AUTHOR]

Influenza A/H7N9 viruses have pandemic potential. We conducted an open-label, randomized, controlled trial of AS03-adjuvanted 2017 inactivated influenza A/H7N9 vaccine (H7N9 IIV) in healthy adults. Group 1 received H7N9 IIV and seasonal quadrivalent influenza vaccine (IIV4) simultaneously, followed by H7N9 IIV three weeks later. Group 2 received IIV4 alone and then two doses of H7N9 IIV at three-week intervals. Group 3 received one dose of IIV4. We used hemagglutination inhibition (HAI) and microneutralization (MN) assays to measure geometric mean titers and seroprotection (≥1:40 titer) to vaccine strains and monitored for safety. Among 149 subjects, seroprotection by HAI three weeks after H7N9 IIV dose 2 was 51% (95 %CI 37%-65%) for Group 1 and 40% (95 %CI 25%-56%) for Group 2. Seroprotection by MN at the same timepoint was 84% (95 %CI 72%-93%) for Group 1 and 74% (95 %CI 60%-86%) for Group 2. By 180 days after H7N9 IIV dose 2, seroprotection by HAI or MN was low for Groups 1 and 2. Responses measured by HAI and MN against each IIV4 strain three weeks after IIV4 vaccination were similar in all groups. Solicited local and systemic reactions were similar after a single vaccination, while those receiving simultaneous H7N9 and IIV4 had slightly more reactogenicity. There were no serious adverse events or medically-attended adverse events related to study product receipt. Adjuvanted H7N9 IIV was modestly immunogenic whether administered simultaneously or sequentially with IIV4, though responses declined by 180 days. IIV4 was immunogenic regardless of schedule. Clinical Trials Registration: NCT03318315 [ABSTRACT FROM AUTHOR]

A long-standing question in evolutionary biology asks whether the genetic changes contributing to phenotypic evolution are predictable. Here, we identify a genetic change associated with segregating variation in flower color within a population of Mimulus lewisii. To determine whether these types of changes are predictable, we combined this information with data from other species to investigate whether the spectrum of mutations affecting flower color transitions differs based on the evolutionary time-scale since divergence. We used classic genetic techniques, along with gene expression and population genetic approaches, to identify the putative, loss-of-function mutation that generates rare, white flowers instead of the common, pink color in M. lewisii. We found that a frameshift mutation in an anthocyanin pathway gene is responsible for the white-flowered polymorphism found in this population of M. lewisii. Comparison of our results with data from other species reveals a broader spectrum of flower color mutations segregating within populations relative to those that fix between populations. These results suggest that the genetic basis of fixed differences in flower color may be predictable, but that for segregating variation is not. [ABSTRACT FROM AUTHOR]