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Journal articleSiggins MK, Gill SK, Langford PR, et al., 2015,
PHiD-CV induces anti-Protein D antibodies but does not augment pulmonary clearance of nontypeable Haemophilus influenzae in mice
, Vaccine, Vol: 33, Pages: 4954-4961, ISSN: 1873-2518BackgroundA recently-licensed 10-valent pneumococcal conjugate vaccine (PHiD-CV; Synflorix, GSK) uses Protein D from Haemophilus influenzae as a carrier protein. PHiD-CV therefore has the potential to provide additional protection against nontypeable H. influenzae (NTHi). NTHi frequently causes respiratory tract infections and is associated with significant morbidity and mortality worldwide and there is currently no vaccine.MethodsWe developed mouse models of NTHi infection and influenza/NTHi superinfection. Mice were immunized with PHiD-CV, heat-killed NTHi, or a 13-valent pneumococcal conjugate vaccine that did not contain Protein D (PCV13; Prevenar, Pfizer) and then infected intranasally with NTHi.ResultsInfection with NTHi resulted in weight loss, inflammation and airway neutrophilia. In a superinfection model, prior infection with pandemic H1N1 influenza virus (strain A/England/195/2009) augmented NTHi infection severity, even with a lower bacterial challenge dose. Immunization with PHiD-CV produced high levels of antibodies that were specific against Protein D, but not heat-killed NTHi. Immunization with PHiD-CV led to a slight reduction in bacterial load, but no change in disease outcome.ConclusionsPHiD-CV induced high levels of Protein D-specific antibodies, but did not augment pulmonary clearance of NTHi. We found no evidence to suggest that PHiD-CV will offer added benefit by preventing NTHi lung infection.
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Journal articleSantra S, Tomaras GD, Warrier R, et al., 2015,
Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques.
, Plos Pathogens, Vol: 11, ISSN: 1553-7374HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.
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Journal articleLi C, Guan X, Du T, et al., 2015,
Inhibition of HIV-1 infection of primary CD4<SUP>+</SUP> T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9
, JOURNAL OF GENERAL VIROLOGY, Vol: 96, Pages: 2381-2393, ISSN: 0022-1317- Author Web Link
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- Citations: 140
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Journal articleOkala SG, King DF, Shattock RJ, 2015,
Comparison of HIV-1 envelope specific IgA and IgG antiviral ability to prevent HIV-1 infection: additive, inhibitory and synergistic effects
, JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, Vol: 18 -
Journal articleNilsson C, Hejdeman B, Godoy-Ramirez K, et al., 2015,
HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial
, PLOS One, Vol: 10, ISSN: 1932-6203BackgroundWe compared safety and immunogenicity of intradermal (ID) vaccination with and withoutelectroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA primeHIV-MVA boost vaccine in healthy Swedish volunteers.MethodsHIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and Band RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteersreceived vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) IDEP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVACMDRexpressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performedat weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 proteinboost together with HIV-MVA.ResultsThe ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statisticallysignificant difference was seen in the IFN-γ ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV-DNA ID recipients (1/7, 14%, p=0.6158).The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-γ ELISpot responserate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrablein 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and71% responders, respectively. IFN-γ and IL-2 dominated the CD4+ T cell response to Gagand Env. The CD8+ response to Gag was broader with expression of IFN-γ, IL-2, MIP-1βand/or CD107. No differences were seen between DNA vaccine groups. Binding antibodieswere induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env,with the highest titers among EP/gp140 recipients.ConclusionIntradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediatedimmune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen,with or without intradermal electroporation use.
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Journal articleKinnear E, Caproni LJ, Tregoning JS, 2015,
A Comparison of Red Fluorescent Proteins to Model DNA Vaccine Expression by Whole Animal In Vivo Imaging
, PLOS One, Vol: 10, ISSN: 1932-6203DNA vaccines can be manufactured cheaply, easily and rapidly and have performed well inpre-clinical animal studies. However, clinical trials have so far been disappointing, failing toevoke a strong immune response, possibly due to poor antigen expression. To improveantigen expression, improved technology to monitor DNA vaccine transfection efficiency isrequired. In the current study, we compared plasmid encoded tdTomato, mCherry,Katushka, tdKatushka2 and luciferase as reporter proteins for whole animal in vivo imaging.The intramuscular, subcutaneous and tattooing routes were compared and electroporationwas used to enhance expression. We observed that overall, fluorescent proteins were not agood tool to assess expression from DNA plasmids, with a highly heterogeneous responsebetween animals. Of the proteins used, intramuscular delivery of DNA encoding either tdTomatoor luciferase gave the clearest signal, with some Katushka and tdKatushka2 signalobserved. Subcutaneous delivery was weakly visible and nothing was observed followingDNA tattooing. DNA encoding haemagglutinin was used to determine whether immuneresponses mirrored visible expression levels. A protective immune response against H1N1influenza was induced by all routes, even after a single dose of DNA, though qualitative differenceswere observed, with tattooing leading to high antibody responses and subcutaneousDNA leading to high CD8 responses. We conclude that of the reporter proteins used,expression from DNA plasmids can best be assessed using tdTomato or luciferase. But, thedisconnect between visible expression level and immunogenicity suggests that in vivowhole animal imaging of fluorescent proteins has limited utility for predicting DNA vaccineefficacy.
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Journal articleRussell RF, McDonald JU, Ivanova M, et al., 2015,
Partialattenuation of respiratory syncytial virus with a deletion of a small hydrophobic gene Is associated with elevated interleukin-1β responses
, Journal of Virology, Vol: 89, Pages: 8974-8981, ISSN: 1098-5514The small hydrophobic (SH) gene of respiratory syncytial virus (RSV), a major cause of infant hospitalization, encodes a viroporin of unknown function. SH gene knockout virus (RSV ΔSH) is partially attenuated in vivo, but not in vitro, suggesting that the SH protein may have an immunomodulatory role. RSV ΔSH has been tested as a live attenuated vaccine in humans and cattle, and here we demonstrate that it protected against viral rechallenge in mice. We compared the immune response to infection with RSV wild type and RSV ΔSH in vivo using BALB/c mice and in vitro using epithelial cells, neutrophils, and macrophages. Strikingly, the interleukin-1β (IL-1β) response to RSV ΔSH infection was greater than to wild-type RSV, in spite of a decreased viral load, and when IL-1β was blocked in vivo, the viral load returned to wild-type levels. A significantly greater IL-1β response to RSV ΔSH was also detected in vitro, with higher-magnitude responses in neutrophils and macrophages than in epithelial cells. Depleting macrophages (with clodronate liposome) and neutrophils (with anti-Ly6G/1A8) demonstrated the contribution of these cells to the IL-1β response in vivo, the first demonstration of neutrophilic IL-1β production in response to viral lung infection. In this study, we describe an increased IL-1β response to RSV ΔSH, which may explain the attenuation in vivo and supports targeting the SH gene in live attenuated vaccines.
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Journal articlePeters PJ, Gonzalez-Perez MP, Musich T, et al., 2015,
Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes
, Retrovirology, Vol: 12, ISSN: 1742-4690Background: HIV-1 variants carrying non-macrophage-tropic HIV-1 R5 envelopes (Envs) are predominantly trans‑mitted and persist in immune tissue even in AIDS patients who have highly macrophage-tropic variants in the brain.Non-macrophage-tropic R5 Envs require high levels of CD4 for infection contrasting with macrophage-tropic Envs,which can efficiently mediate infection of cells via low CD4. Here, we investigated whether non-macrophage-tropicR5 Envs from the acute stage of infection (including transmitted/founder Env) mediated more efficient infection ofectocervical explant cultures compared to non-macrophage-tropic and highly macrophage-tropic R5 Envs from latedisease.Results: We used Env+ pseudovirions that carried a GFP reporter gene to measure infection of the first cells targetedin ectocervical explant cultures. In straight titrations of Env+ pseudovirus supernatants, mac-tropic R5 Envs from latedisease mediated slightly higher infectivities for ectocervical explants although this was not significant. Surprisingly,explant infection by several T/F/acute Envs was lower than for Envs from late disease. However, when infectivity forexplants was corrected to account for differences in the overall infectivity of each Env+ pseudovirus (measured onhighly permissive HeLa TZM-bl cells), non-mac-tropic early and late disease Env+ pseudoviruses mediated signifi‑cantly higher infection. This observation suggests that cervical tissue preferentially supports non-mac-tropic Env+viruses compared to mac-tropic viruses. Finally, we show that T-cells were the main targets for infection regardless ofwhether explants were stimulated with T-cell or monocyte/macrophage cytokines. There was no evidence of mac‑rophage infection even for pseudovirions carrying highly mac-tropic Envs from brain tissue or for the highly mactropic,laboratory strain, BaL, which targeted T-cells in the explant tissue.Conclusions: Our data support ectocervical tissue as a favorable environment for non-mac-trop
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Journal articleMastelic Gavillet B, Eberhardt CS, Auderset F, et al., 2015,
MF59 Mediates Its B Cell Adjuvanticity by Promoting T Follicular Helper Cells and Thus Germinal Center Responses in Adult and Early Life.
, Journal of Immunology, Vol: 194, Pages: 4836-4845, ISSN: 0022-1767The early life influenza disease burden calls for more effective vaccines to protect this vulnerable population. Influenza vaccines including the MF59 oil-in-water adjuvant induce higher, broader, and more persistent Ab responses in adults and particularly in young, through yet undefined mechanisms. In this study, we show that MF59 enhances adult murine IgG responses to influenza hemagglutinin (HA) by promoting a potent T follicular helper cells (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. Remarkably, this enhancement of TFH and GC B cells is already fully functional in 3-wk-old infant mice, which were fully protected by HA/MF59 but not HA/PBS immunization against intranasal challenge with the homologous H1N1 (A/California/7/2009) strain. In 1-wk-old neonatal mice, MF59 recruits and activates APCs, efficiently induces CD4(+) effector T cells and primes for enhanced infant responses but induces few fully functional TFH cells, which are mostly follicular regulatory T cells, and poor GC and anti-HA responses. The B cell adjuvanticity of MF59 appears to be mediated by the potent induction of TFH cells which directly controls GC responses both in adult and early life, calling for studies assessing its capacity to enhance the efficacy of influenza immunization in young infants.
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Journal articleLiu Y, Luo S, He S, et al., 2015,
Tetherin restricts HSV-2 release and is counteracted by multiple viral glycoproteins
, VIROLOGY, Vol: 475, Pages: 96-109, ISSN: 0042-6822- Author Web Link
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- Citations: 21
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