Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Pravesh D. Kara, Arshad S. Mather, Alri Pretorius, Thireshni Chetty, Shawn Babiuk, David B. Wallace Lumpy skin disease virus (LSDV) is responsible for causing severe economic losses to cattle farmers throughout Africa, the Middle East, and more recently, South-Eastern Europe and Russia. It belongs to the Capripoxvirus genus of the Poxviridae family, with closely related sheeppox and goatpox viruses. Like other poxviruses, the viral genome codes for a number of genes with putative immunomodulatory capabilities. Current vaccines for protecting cattle against lumpy skin disease (LSD) based on live-attenuated strains of field isolates passaged by cell culture, resulting in random mutations. Although generally effective, these vaccines can have drawbacks, including injection site reactions and/or limited immunogenicity. A pilot study was conducted using a more targeted approach where two putative immunomodulatory genes were deleted separately from the genome of a virulent LSDV field isolate. These were open reading frame (ORF) 005 and ORF008, coding for homologues of an interleukin 10-like and interferon-gamma receptor-like gene, respectively. The resulting knockout constructs were evaluated in cattle for safety, immunogenicity and protection. Severe post-vaccinal reactions and febrile responses were observed for both constructs. Two calves inoculated with the ORF008 knockout construct developed multiple lesions and were euthanised. Following challenge, none of the animals inoculated with the knockout constructs showed any external clinical signs of LSD, compared to the negative controls. Improved cellular and humoral immune responses were recorded in both of these groups compared to the positive control. The results indicate that at the high inoculation doses used, the degree of attenuation achieved was insufficient for further use in cattle due to the adverse reactions observed.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Gillian K. SteelFisher, Robert J. Blendon, Rustam Haydarov, William Lodge, Hannah Caporello, Sherine Guirguis, Saumya Anand, Julianne Birungi, Matthew R. Williams, Eran N. Ben-Porath, Denise O'Reilly, Christoph Sahm Background Using a survey conducted during the 2013–2014 polio outbreak in Somalia, this study examines attitudinal and knowledge-based threats to oral polio vaccine acceptance and commitment. Findings address a key gap, as most prior research focuses on endemic settings. Methods Between November 19 and December 21, 2013, we conducted interviews among 2003 caregivers of children under 5 years in select districts at high risk for polio transmission. Within each district, sample was drawn via a multi-stage cluster design with random route household selection. We calculated the percentage of caregivers who could not confirm recent vaccination and those uncommitted to future vaccination. We compared these percentages among caregivers with varying knowledge and attitudes, focusing on variables identified as threats in endemic settings, using controlled and uncontrolled comparisons. We also examined absolute levels of threat variables. Results Only 10% of caregivers could not confirm recent vaccination, but 32% were uncommitted to future vaccination. Being unvaccinated or uncommitted were related to multiple threat variables. For example, compared with relevant counterparts, caregivers were more likely to be unconfirmed and uncommitted if they did not trust vaccinators “a great deal” (unconfirmed: 9% vs. 2%; uncommitted: 49% vs. 28%), which is also true in endemic settings. Unlike endemic settings, symptom knowledge was related to commitment while rumor awareness was low and unrelated to past acceptance or commitment. Levels of trust and perceptions of OPV effectiveness were high, though perceptions of community support and awareness of logistics were lower. Conclusions As in endemic settings, outbreak responses will benefit from communications strategies focused on enhancing trust in vaccinators, institutions and the vaccine, alongside making community support visible. Disease facts may help motivate acceptance, and enhanced logistics information may help facilitate caregiver availability at the door. Quelling rumors early may be important to prevent them from becoming threats.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Rachael Biggart, Adam Finn, Robin Marlow Observational studies have linked a reduction in childhood seizures (CS) to the introduction of rotavirus vaccination (RV). England is opportunely placed to explore this due to well-defined introduction, high uptake of RV and centralised Hospital Episodes Statistics recording all admissions. We investigated the association between seizures and vaccine use through interrupted time-series analysis of all CS admissions in children 〈3 years old (ICD-10 codes; G40 ∗ -G41 ∗ , R56.0 ∗ ) during 2007–2017. We did not detect a statistically significant association between the introduction of RV and admission with febrile (p = 0.84), afebrile (p = 0.83) or all CS (p = 0.93), even when limited to peak rotavirus seasonality (March). This is the first ecological study in a country that exclusively uses the monovalent vaccine. Although a negative finding, we would argue that if an effect cannot be detected at this population level then it is unlikely to be clinically or economically significant but generates hypotheses of potential non-specific effects.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Joyce H.S. You, Wai-kit Ming, Chak-fei Lee, Owen Tak-yin Tsang, Paul Kay-sheung Chan Background Adjuvanted herpes zoster (HZ) subunit vaccine is recommended for adults aged ≥50 years. This study aimed to investigate cost-effectiveness of HZ subunit vaccine for older adults at different age in Hong Kong. Methods A life-long Markov model was designed to simulate outcomes of four alternatives: Vaccination at model entry (age 50 years); deferring vaccination to 60 years; deferring vaccination to 70 years; and no vaccination. Outcome measures included direct cost, indirect cost, HZ and post-herpetic neuralgia incidences, quality-adjusted life years (QALYs) loss, and incremental cost per QALY saved (ICER). Model clinical inputs were derived from literature. HZ treatment costs were collected from a cohort of HZ patients (n = 218). One-way and probabilistic sensitivity analyses were performed. Results In base-case analysis, vaccination at 50 years showed highest QALYs saved and increment cost (0.00258; USD166), followed by deferring to 60 years (0.00215 QALYs saved; USD102) and deferring to 70 years (0.00134 QALYs; USD62) when comparing to no vaccination. ICERs of vaccination arms versus no vaccine (46,267–64,341 USD/QALY) were between 1–3 × gross domestic product (GPD) per capita in Hong Kong (USD43,530–USD130,590). One-way sensitivity analyses found vaccine cost to be the common and most influential parameter for ICER of each vaccination strategy to become 〈1 × GDP per capita. In probabilistic sensitivity analysis, vaccination at 50 years, deferring to 60 years and 70 years were accepted as cost-effective in 90% of time at willingness-to-pay (WTP) of 78,400 USD/QALY, 57,680 USD/QALY and 53,760 USD/QALY, respectively. Conclusions Cost-effectiveness of each strategy is highly subject to the vaccine cost and WTP threshold per QALY saved.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Wan Liu, Yik Chun Wong, Samantha M.Y. Chen, Jiansong Tang, Haibo Wang, Allen Ka Loon Cheung, Zhiwei Chen HIV-1 diversity and latent reservoir are the major challenges for the development of an effective AIDS vaccine. It is well indicated that Gag-specific CD8 + T cells serve as the dominant host immune surveillance for HIV-1 control, but it still remains a challenge for vaccine design to induce broader and stronger cytotoxic T cell immunity against the virus. Genetic variation of the HIV-1 gag gene across different clades is one of the reasons for the reduction of antigenic epitope coverage. Here, we report an immunization strategy with heterologous vaccines expressing a mosaic Gag antigen aimed to increase antigenic breadth against a wider spectrum of HIV-1 strains. Priming using a DNA vaccine via in vivo electroporation, followed by boosting with a live replication-competent modified vaccinia TianTan (MVTT) vectored vaccine, elicited greater and broader protective Gag-specific immune responses in mice. Compared to DNA or MVTT homologous immunization, the heterologous DNA/MVTT vaccination resulted in higher frequencies of broadly reactive, Gag-specific, polyfunctional, long-lived cytotoxic CD8 + T cells, as well as increased anti-Gag antibody titer. Importantly, the DNA/MVTT heterologous vaccination induced protection against EcoHIV and mesothelioma AB1-Gag challenges. In summary, the stronger protective Gag-specific immunity induced by the heterologous regimen using two safe vectors shows promise for further development to enhance anti-HIV-1 immunity. Our study has important implications for immunogen design and the development of an effective HIV-1 heterologous vaccination strategy.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Anna Jarząb, Danuta Witkowska, Edmund Ziomek, Bartosz Setner, Aleksandra Czajkowska, Małgorzata Dorot, Zbigniew Szewczuk, Andrzej Gamian In earlier works we have described that mice immunized with outer membrane protein OmpC survive the challenge with live Shigella flexnerii 3a. We have also identified conformational epitope of this protein, that was recognized by mice antibodies. The aim of current work was to investigate whether synthetic OmpC epitope homologs can elicit immunological response sufficient in protecting mice against shigellosis. Several linear peptides containing RYDERY motif were synthesized and conjugated to poly-lysine. These conjugates appeared to be poor immunogens and to boost the immunological response an addition of the adjuvant (MPL) was required. Unfortunately, the MPL alone caused a very high immunological reaction that was masking response to peptidic epitope. Under those circumstances we used tetanus toxoid (TT) as the carrier protein for the peptides and the agent stimulating immunological response. Series of cyclic peptides, homologs of the OmpC main epitope were synthesized and conjugated to TT. The loop size in cyclic peptides varied by number of glycine residues, i.e., 1–3 residues added to the GLNRYDERYIGK motif. The linear GLNRYDERYIGC-TT was also prepared as the control. The latter conjugate gave the highest immunological response, followed by the cyclic-GGLNRYDERYIGC-TT and cyclic-GLNRYDERYIGC-TT. The third peptide, cyclic-GGGLNRYDERYIGC-TT, gave a very low response, although it was the most resistant to proteolysis. However, antibodies obtained against cyclic-GGLNRYDERYIGC-TT were more potent to recognize both OmpC and Shigella flexnerii 3a cells than the antibodies against linear GLNRYDERYIGC-TT. Furthermore, the monoclonal antibodies raised against linear GLNRYDERYIGC-TT showed 20-fold lower dissociation constant (KD) than the naturally occurring polyclonal antibodies from umbilical cord sera. Monoclonal antibodies also gave a weaker signal in electron microscope than mice and human polyclonal antibodies. In overall, our results point to cyclic peptides as better candidates for a vaccine development, since they are eliciting production of the higher affinity antibodies against Shigella cells and OmpC.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Rebecca C. Brady, Lisa A. Jackson, Sharon E. Frey, Andi L. Shane, Emmanuel B. Walter, Geeta K. Swamy, Elizabeth P. Schlaudecker, Elena Szefer, Mark Wolff, Monica Malone McNeal, David I. Bernstein, Mark C. Steinhoff Background Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are both licensed for administration to nursing mothers. Little is known about the potential for transmission of LAIV viruses from the mother to the infant and the comparative breast milk antibody responses to LAIV and IIV. Methods We performed a randomized, double-blind study comparing the immunogenicity of LAIV to IIV when administered to nursing mothers. The safety of LAIV to IIV in women and their infants was also compared. Women received LAIV + intramuscular placebo, or IIV + intranasal placebo on Day 0. Breast milk and nasal swabs (from women and infants) were collected on Days 0, 2, and 8 for detection of LAIV. Breast milk and serum antibody responses were measured at Days 0 and 28. The primary hypothesis was that LAIV would provide superior induction of breast milk IgA responses to influenza as compared to IIV when administered to nursing mothers. Results Breast milk IgG, breast milk IgA (H1N1 only), serum hemagglutination inhibition (HAI), and serum IgG responses were significantly higher following administration of IIV compared to LAIV. Receipt of either LAIV or IIV was safe in women and their infants. One (1%) LAIV recipient transmitted vaccine virus to her infant who remained well. No influenza virus was detected in breast milk. Conclusions Breast milk and serum antibody responses were higher for IIV compared to LAIV. LAIV and IIV were safe for nursing women but there was one (1%) possible transmission of LAIV to an infant. This study suggests that IIV may be the preferred vaccine for nursing mothers.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Marco Grasse, Andreas Meryk, Carina Miggitsch, Beatrix Grubeck-Loebenstein Multivalent tetanus and diphtheria toxoid containing vaccines belong to the most frequently applied vaccines. However, there is an imbalance in the degree of protection against the two antigens with insufficient long-term protection against diphtheria, particularly in the elderly population. We have previously reported a positive correlation between granulocyte macrophage-colony stimulating factor (GM-CSF) and the production of diphtheria-specific antibodies. Therefore, in the present study we analyzed the effects of in vivo applied recombinant GM-CSF on immunization with multivalent tetanus/diphtheria vaccine in mice of different age. In vivo application of GM-CSF lead to enhanced production of diphtheria-specific antibodies as well as more diphtheria-specific CD4 + T cells following vaccination with multivalent tetanus/diphtheria vaccine. In contrast, the humoral and cellular immune response to the tetanus component was unaltered. Furthermore, application of GM-CSF resulted in more splenic CD11b + dendritic cells (DCs) with a higher MHC-II expression. GM-CSF also induced a stronger recruitment of CD11b + DCs to the injected muscle. Most remarkably, GM-CSF was able to boost the diphtheria-specific immune response to the multivalent vaccine in aged mice. This study demonstrates that local administration of GM-CSF is able to improve immune responsiveness to the diphtheria component of multivalent tetanus/diphtheria vaccine in young and old mice. This information could be useful for the future design of vaccines for the elderly.

Beschreibung: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Nienke M. Scheltema, Xynthia M. Kavelaars, Kentigern Thorburn, Marije P. Hennus, Job B. van Woensel, Cornelis K. van der Ent, José A.M. Borghans, Louis J. Bont, Julia Drylewicz Background Respiratory syncytial virus (RSV) infection is an important cause of infant mortality. Here, we estimated the potential impact of maternal vaccination against RSV on life-threatening RSV infection in infants. Methods We developed a mathematical model for maternal vaccine-induced antibody dynamics and used characteristics of a maternal RSV vaccine currently in phase 3 of clinical development. The model was applied to data from two cohorts of children younger than 12 months with RSV-related paediatric intensive care unit (PICU) admission in the United Kingdom (n = 370) and the Netherlands (n = 167), and a cohort of 211 children younger than 12 months with RSV-related in-hospital death from 20 countries worldwide. Results Our model predicted that, depending on vaccine efficiency, maternal vaccination at 30 weeks’ gestational age could have prevented 62–75% of RSV-related PICU admissions in the United Kingdom and 76–87% in the Netherlands. For the global mortality cohort, the model predicted that maternal vaccination could have prevented 29–48% of RSV-related in-hospital deaths. Preterm children and children with comorbidities were predicted to benefit less than (healthy) term children. Conclusions Maternal vaccination against RSV may substantially decrease life-threatening RSV infections in infants.