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

Description: 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.

Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Xinyu Liu, Danhua Zhao, Lili Jia, Hongshan Xu, Rui Na, Yonghong Ge, Shaoxiang Liu, Yongxin Yu, Yuhua Li Japanese encephalitis (JE) live attenuated vaccine SA14-14-2 is the most widely used JE vaccine in the world. Large-scale clinical trials have demonstrated satisfactory safety and efficacy profiles. The establishment of genetic and attenuated neurovirulence characteristics and their stabilities of SA14-14-2 virus are important in relation to vaccine safety in humans. Therefore, several researchers have studied and analyzed the full-length gene sequences of the SA14-14-2 virus strain. However, sequencing results have shown a significant difference. Here, we further studied the full-length sequence of three class seed virus banks of the vaccine as well as two vaccine viruses with different passages in primary hamster kidney cells, and compared them with our original stored SA14 parent virus (low passage in mouse brain). The full-length gene sequence determined in this study indicates there were 57 nucleotide and 25 amino acid substitutions of the SA14-14-2 strain compared to its parental SA14 virus strain. The full-length sequences of the three class seed bank viruses and the vaccine virus PHKC8 were completely identical among them, but the working seed virus passaged in primary hamster kidney cells for 17 generations (PHKC17) had a single nucleotide change at the 5′ NCR. Both KM and ICR mice tested by intracerebral (i.c.) or subcutaneous (s.c.) routes with the three class seed viruses and vaccine viruses with ≥5.7 lgpfu/mL remained healthy, but all the mice inoculated with the SA14 parental virus strain died as early as day 5 post-inoculation. The present study provided new information on the full-length gene sequence and attenuated neurovirulence of SA14-14-2. They can be used as a reference sequence for vaccine quality control and surveillance of neurovirulence reversion following vaccination. Moreover, the present results further demonstrated the high genetic and phenotypic stabilities of the SA14-14-2 virus, suggesting the neurovirulence reversion of the vaccine strain will be highly unlikely.

Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Louise Letley, Vanessa Rew, Rehana Ahmed, Katrine Bach Habersaat, Pauline Paterson, Tracey Chantler, Maria Saavedra-Campos, Robb Butler Introduction Due to regular vaccine preventable disease outbreaks and sub-optimal immunisation uptake in the London borough of Hackney, home to the largest Charedi Orthodox Jewish community in Europe, it was decided, in consultation with the community, to implement the WHO Tailoring Immunization Programmes approach (TIP). Design The WHO Tailoring Immunization Programmes (TIP) approach was used. TIP provides a framework based on behavioural insights methodology to identify populations susceptible to vaccine preventable diseases, diagnose supply and demand side barriers and enablers to vaccination and recommend evidence-informed responses to improve vaccination coverage. Results The results of the formative research and behavioural analysis challenged the assumption that a cultural or religious anti-vaccination sentiment existed within the community. Critical issues related to access to and convenience of immunisation services. Service providers in the area have challenges due to having to deliver immunisation services to the large numbers of children without additional resource. Where mothers were choosing to delay or refuse vaccinations their reasons were broadly similar to the wider population. The behavioural analysis identified potential categorisation of subgroups within the community enabling a more tailored approach to addressing concerns and meeting parents’ needs. Conclusion The TIP approach was an effective way of investigating factors linked to sub-optimal immunisation within the Charedi community. The use of behavioural insights enabled the categorisation of subgroups so that more targeted interventions could be developed. The comprehensive stakeholder engagement which is a key pillar of the TIP approach ensured a deeper understanding of the barriers and enablers to vaccination as well as increasing the level of ownership in the community. TIP should be considered as a useful approach to identify main facilitators and barriers to vaccination in communities with suboptimal immunisation uptake.

Description: 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.

Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Amit Saha, Andrew Hayen, Mohammad Ali, Alexander Rosewell, C. Raina MacIntyre, John D. Clemens, Firdausi Qadri Background Evaluations of oral cholera vaccines (OCVs) have demonstrated their effectiveness in diverse settings. However, low vaccine uptake in some settings reduces the opportunity for prevention. This paper identifies the socioeconomic factors associated with vaccine uptake in a mass vaccination program. Methods This was a three-arm (vaccine, vaccine plus behavioral change, and non-intervention) cluster randomized trial conducted in Dhaka, Bangladesh. Socio-demographic and vaccination data were collected from 268,896 participants. A geographical information system (GIS) was used to design and implement the vaccination program. A logistic regression model was used to assess the association between vaccine uptake and socioeconomic characteristics. Results The GIS supported the implementation of the vaccination program by identifying ideal locations of vaccination centres for equitable population access, defining catchment areas of daily activities, and providing daily coverage maps during the campaign. Among 188,206 individuals in the intervention arms, 123,686 (66%) received two complete doses, and 64,520 (34%) received one or no doses of the OCV. The vaccine uptake rate was higher in females than males (aOR: 1.80; 95% CI = 1.75–1.84) and in younger (〈15 years) than older participants (aOR: 2.19; 95% CI = 2.13–3.26). Individuals living in their own house or having a higher monthly family expenditure were more likely to receive the OCV (aOR: 1.60; 95% CI = 1.50–1.70 and aOR: 1.14; 95% CI = 1.10–1.18 respectively). Individuals using treated water for drinking or using own tap as the source of water were more likely to receive the OCV (aOR: 1.23; 95% CI = 1.17–1.29 and aOR: 1.14; 95% CI = 1.02–1.25 respectively) than their counterpart. Vaccine uptake was also significantly higher in participants residing farther away from health facilities (aOR: 95% 1.80; CI = 1.36–2.37). Conclusion The GIS was useful in designing field activities, facilitating vaccine delivery and identifying socioeconomic drivers of vaccine uptake in the urban area of Bangladesh. Addressing these socioeconomic drivers may help improve OCV uptake, thereby effectiveness of the OCV in a community.

Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): M.S. Boukhvalova, A. Mbaye, S. Kovtun, K.C. Yim, T. Konstantinova, T. Getachew, S. Khurana, A.R. Falsey, J.C.G. Blanco Respiratory syncytial virus (RSV) is a significant cause of bronchiolitis and pneumonia. Protection against RSV is associated with neutralizing antibodies against the fusion (F) and attachment (G) glycoproteins. Several RSV vaccine candidates are in development, but their immunogenicity is hard to compare due to the little-understood differences between multiple RSV neutralizing antibody assays used. Existing assays utilize primarily Vero or HEp-2 cells, but their ability to detect G-neutralizing antibodies or antibodies against specific RSV strains is unclear. In this work, we developed an RSV microneutralization assay (MNA) using unmodified RSV and immortalized cell line derived from human airway epithelial cells (A549). Performance of A549-, HEp-2- and Vero-based MNA was compared under the same assay conditions (fixed amount of virus and cells) with regards to detection of neutralizing antibodies against RSV A or B viruses, G-reactive neutralizing antibodies, and effect of complement. Our results indicate that A549 cells yield the highest MNA titers, particularly in the RSV A/A2 MNA, are least susceptible to complement-enhancing effect of neutralizing titer readout and are superior to Vero or HEp-2 MNA at recognizing G-reactive neutralizing antibodies when no complement is used. Vero cells, however, can be more consistent at recognizing neutralizing antibodies against multiple RSV strains. The choice of substrate cells thus affects the outcome of MNA, as some immortalized cells better support detection of broader range of neutralizing antibodies, while others facilitate detection of G-targeting neutralizing antibodies, a long-thought prerogative of primary airway epithelial cells.

Description: 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.

Description: 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.

Description: 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.