bims-inflim 2018-06-17 papers

Issue of 2018–06–17
five papers selected by
Christine Oshansky-Weilnau

Vaccine. 2018 Jun 07. pii: S0264-410X(18)30818-1. [Epub ahead of print]

Protection by universal influenza vaccine is mediated by memory CD4 T cells.

Sophie A Valkenburg, Olive T W Li, Athena Li, Maireid Bull, Thomas A Waldmann, Liyanage P Perera, Malik Peiris, Leo L M Poon.

There is a diverse array of influenza viruses which circulate between different species, reassort and drift over time. Current seasonal influenza vaccines are ineffective in controlling these viruses. We have developed a novel universal vaccine which elicits robust T cell responses and protection against diverse influenza viruses in mouse and human models. Vaccine mediated protection was dependent on influenza-specific CD4+ T cells, whereby depletion of CD4+ T cells at either vaccination or challenge time points significantly reduced survival in mice. Vaccine memory CD4+ T cells were needed for early antibody production and CD8+ T cell recall responses. Furthermore, influenza-specific CD4+ T cells from vaccination manifested primarily Tfh and Th1 profiles with anti-viral cytokine production. The vaccine boosted H5-specific T cells from human PBMCs, specifically CD4+ and CD8+ T effector memory type, ensuring the vaccine was truly universal for its future application. These findings have implications for the development and optimization of T cell activating vaccines for universal immunity against influenza.

Keywords: IL-15; Influenza virus; T cells; Universal vaccine; Vaccinia

DOI: https://doi.org/10.1016/j.vaccine.2018.06.007

Antiviral Res. 2018 Jun 06. pii: S0166-3542(18)30007-X. [Epub ahead of print]

MPL and CpG combination adjuvants promote homologous and heterosubtypic cross protection of inactivated split influenza virus vaccine.

Eun-Ju Ko, Youri Lee, Young-Tae Lee, Yu-Jin Kim, Ki-Hye Kim, Sang-Moo Kang.

Annual vaccination is not effective in conferring cross-protection against antigenically different influenza viruses. Therefore, it is of high priority to improve the cross protective efficacy of influenza vaccines. We investigated the adjuvant effects of monophosphoryl lipid A (MPL) and oligodeoxynucleotide CpG (CpG) on promoting homologous protection and cross-protection after vaccination of C57BL/6 and BALB/c mice with inactivated split virus. Combination adjuvant effects of MPL and CpG on improving homologous and cross protective vaccine efficacy were evident as shown by higher levels of homologous and cross-reactive binding IgG and hemagglutination inhibiting antibodies. Combination adjuvant effects on enhancing the protective efficacy against homologous and heterosubtypic virus were demonstrated by less weight loss, lower airway inflammatory disease, and better control of viral loads as well as prevention of inflammatory cytokines and cellular infiltrates. Overall, the findings in this study suggest that a combination adjuvant of different toll-like receptor ligands exhibits a unique pattern of innate and adaptive immune responses, contributing to improved homologous and heterosubtypic cross-protection by inactivated split virion influenza vaccination.

Keywords: Adjuvant; CpG; Cross-protection; Influenza virus; MPL

DOI: https://doi.org/10.1016/j.antiviral.2018.06.004

Vaccine. 2018 Jun 06. pii: S0264-410X(18)30758-8. [Epub ahead of print]

Multi-clade H5N1 virus-like particles: Immunogenicity and protection against H5N1 virus and effects of beta-propiolactone.

Peter Pushko, Irina Tretyakova, Rachmat Hidajat, Xiangjie Sun, Jessica A Belser, Terrence M Tumpey.

During the past decade, H5N1 highly pathogenic avian influenza (HPAI) viruses have diversified genetically and antigenically, suggesting the need for multiple H5N1 vaccines. However, preparation of multiple vaccines from live H5N1 HPAI viruses is difficult and economically not feasible representing a challenge for pandemic preparedness. Here we evaluated a novel multi-clade recombinant H5N1 virus-like particle (VLP) design, in which H5 hemagglutinins (HA) and N1 neuraminidase (NA) derived from four distinct clades of H5N1 virus were co-localized within the VLP structure. The multi-clade H5N1 VLPs were prepared by using a recombinant baculovirus expression system and evaluated for functional hemagglutination and neuraminidase enzyme activities, particle size and morphology, as well as for the presence of baculovirus in the purified VLP preparations. To remove residual baculovirus, VLP preparations were treated with beta-propiolactone (BPL). Immunogenicity and efficacy of multi-clade H5N1 VLPs were determined in an experimental ferret H5N1 HPAI challenge model, to ascertain the effect of BPL on immunogenicity and protective efficacy against lethal challenge. Although treatment with BPL reduced immunogenicity of VLPs, all vaccinated ferrets were protected from lethal challenge with influenza A/VietNam/1203/2004 (H5N1) HPAI virus, indicating that multi-clade VLP preparations treated with BPL represent a potential approach for pandemic preparedness vaccines.

Keywords: H5N1; Influenza; Propiolactone; VLP; Vaccine

DOI: https://doi.org/10.1016/j.vaccine.2018.05.092

Cell Syst. 2018 Jun 01. pii: S2405-4712(18)30196-0. [Epub ahead of print]

Dissection of Influenza Infection In Vivo by Single-Cell RNA Sequencing.

Yael Steuerman, Merav Cohen, Naama Peshes-Yaloz, Liran Valadarsky, Ofir Cohn, Eyal David, Amit Frishberg, Lior Mayo, Eran Bacharach, Ido Amit, Irit Gat-Viks.

The influenza virus is a major cause of morbidity and mortality worldwide. Yet, both the impact of intracellular viral replication and the variation in host response across different cell types remain uncharacterized. Here we used single-cell RNA sequencing to investigate the heterogeneity in the response of lung tissue cells to in vivo influenza infection. Analysis of viral and host transcriptomes in the same single cell enabled us to resolve the cellular heterogeneity of bystander (exposed but uninfected) as compared with infected cells. We reveal that all major immune and non-immune cell types manifest substantial fractions of infected cells, albeit at low viral transcriptome loads relative to epithelial cells. We show that all cell types respond primarily with a robust generic transcriptional response, and we demonstrate novel markers specific for influenza-infected as opposed to bystander cells. These findings open new avenues for targeted therapy aimed exclusively at infected cells.

Keywords: bystander versus infected cells; immune and non-immune cell types; influenza infection in vivo; single-cell RNA sequencing

DOI: https://doi.org/10.1016/j.cels.2018.05.008

Vaccine. 2018 Jun 06. pii: S0264-410X(18)30815-6. [Epub ahead of print]

A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among older adults.

Marc Baay, Kaatje Bollaerts, Thomas Verstraeten.

INTRODUCTION: New adjuvants have been developed to improve the efficacy of vaccines and for dose-sparing capacity and may overcome immuno senescence in the elderly. We reviewed the safety of newly-adjuvanted vaccines in older adults.
METHODS: We searched Medline for clinical trials (CTs) including new adjuvant systems (AS01, AS02, AS03, or MF59), used in older adults, published between 01/1995 and 09/2017. Safety outcomes were: serious adverse events (SAEs); solicited local and general AEs (reactogenicity); unsolicited AEs; and potentially immune-mediated diseases (pIMDs). Standard random effects meta-analyses were conducted by type of safety event and adjuvant type, reporting Relative Risks (RR) with 95% confidence intervals (95% CI).
RESULTS: We identified 1040 publications, from which we selected 7, 7, and 12 CTs on AS01/AS02, AS03 and MF59, respectively. 47,602 study participants received newly-adjuvanted vaccine and 44,521 control vaccine, or placebo. Rates of SAEs (RR = 0.99, 95% CI = 0.96-1.02), deaths (RR = 0.99, 95% CI = 0.92-1.06) and pIMDs (RR = 0.94, 95% CI = 0.79-1.1) were comparable in newly-adjuvanted and control groups. Vaccine-related SAEs occurred in <1% of the subjects in both groups. The reactogenicity of AS01/AS02 and AS03 adjuvanted vaccines was higher compared to control vaccines, whereas MF59-adjuvanted vaccines resulted only in more pain. Grade 3 reactogenicity was reported infrequently, with fatigue (RR = 2.48, 95% CI = 1.69-3.64), headache (RR = 2.94, 95% CI = 1.24-6.95), and myalgia (RR = 2.68, 95% CI = 1.86-3.80) occurring more frequently in newly-adjuvanted groups. Unsolicited AEs occurred slightly more frequently in newly-adjuvanted groups (RR = 1.04, 95% CI = 1.00-1.08).
CONCLUSIONS: Our review suggests that, within the clinical trial setting, the use of new adjuvants in older adults has not led to any safety concerns, with no increase in SAEs or fatalities. Higher rates for solicited AEs were observed, especially for AS01/AS02 and AS03 adjuvanted vaccines, but AEs were mostly mild and transient. Further evidence will need to come from the use of new adjuvants in the real-world setting, where larger numbers can be studied to potentially detect rare reactions.

Keywords: Adjuvants; Older adults; Safety; Vaccine

DOI: https://doi.org/10.1016/j.vaccine.2018.06.004