Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Al-Mamoon Badahdah, Harunor Rashid, Ameneh Khatami, Robert Booy Background Mass gatherings (MGs) such as the Hajj and Umrah pilgrimages are known to amplify the risk of invasive meningococcal disease (IMD) due to enhanced transmission of the organism between attendees. The burden of IMD at MGs other than Hajj and Umrah has not previously been quantified through a systematic review. Methods A systematic search for relevant articles in PubMed and Embase was conducted using MeSH terms; this was buttressed by hand searching. Following data abstraction, a narrative synthesis was conducted to quantify the burden of IMD at MGs and identify potential risk factors and mitigation measures. Results Thirteen studies reporting occurrence of IMD at MGs or similar crowded settings were identified. Eight studies reported cases or outbreaks in MGs of ≥1000 people; five others reported IMD in other crowded settings; all occurred between 1991 and 2015. All age groups were involved in the identified studies; however the majority of cases (∼80%) were young people aged 15–24 years. The number of affected people ranged from one to 321 cases and the overall crude estimate of incidence was calculated as 66 per 100,000 individuals. Serogroups A, C, B and W were identified, with serogroups A and C being most common. Of 450 cases of IMD reported in non-Hajj/Umrah MGs, 67 (14.9%) had fatal outcomes. Conclusion IMD outbreaks at non-Hajj/Umrah MGs are generally much smaller than Hajj-related outbreaks and affect mainly young people. Health education and vaccination should be considered for attendees of high risk non-Hajj/Umrah MGs, especially those involving adolescents and young adults.

Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Moran Ki, Hwa Young Choi, Minji Han, Jin-Kyoung Oh Background This prevalence-based, cost-of-illness study estimated the health care costs of human papillomavirus (HPV) infection-associated diseases in the era before the introduction of organized HPV vaccination for 12-year-old girls in 2016, South Korea. Methods The claims data provided by the National Health Insurance Service was used to estimate the prevalence of HPV-associated diseases and their direct medical costs, including costs related to hospitalizations, outpatient visits, and medications. Results A total of 1.3 million men and women used medical services for HPV-attributed diseases between 2002 and 2015. Among women, the most common diseases attributable to HPV were cervical dysplasia (64.4%), anogenital warts (12.9%), cervical carcinoma in situ (10.7%) and cervical cancer (2.6%), whereas anogenital warts (80.6%), benign neoplasms of larynx (14.3%), and anal cancers (8.9%) were most common among men. In 2015, the healthcare cost attributable to HPV was 124.9 million US dollars (USD) representing 69.0% of the annual cost of all HPV-associated diseases. At a cost of 75.1 million USD, cervical cancer contributed the largest economic burden in 2015 followed by cervical dysplasia (19.4 million USD) and cervical carcinoma in situ (10.7 million USD). These three conditions represented 58.2% of the total annual cost of all HPV-associated diseases, while 84.2% of the total annual cost was attributable to HPV. Annual health care costs increased from 42.6 million USD in 2002 to 180.9 million USD in 2015. Conclusion The healthcare costs associated with HPV-related diseases in Korea are substantial and increased between 2002 and 2015 mainly caused by increased number of patients. Expanding the target age for HPV vaccination of girls and introducing HPV vaccination for boys are possible ways of reducing the economic burden of HPV-associated disease and should be considered.

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): 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.

Description: Publication date: 25 July 2018 Source: Vaccine, Volume 36, Issue 31 Author(s): Walter H.B. Demczuk, Irene Martin, Shalini Desai, Averil Griffith, Laurence Caron-Poulin, Brigitte Lefebvre, Allison McGeer, Gregory J. Tyrrell, George G. Zhanel, Jonathan Gubbay, Linda Hoang, Paul N. Levett, Paul Van Caeseele, Rita Raafat Gad, David Haldane, George Zahariadis, Gregory German, Jennifer Daley Bernier, Lori Strudwick, Michael R. Mulvey The 13-valent conjugate vaccine (PCV13) was recommended for childhood immunization programs in 2010 in Canada and has decreased the incidence of invasive pneumococcal disease (IPD) in children and changed the epidemiology of IPD in adults. This study investigated the epidemiology of IPD in adults 65 years of age and older in Canada. A total of 7282 invasive S. pneumoniae isolated from adults ≥65 years old were serotyped from 2010 to 2016 and antimicrobial susceptibility was performed on 2527 isolates. Serotyping was performed by Quellung reaction using commercial antisera and antimicrobial susceptibilities were determined by broth microdilution. PCV7 serotypes decreased non-significantly from 2010 to 2016 from 9.1% (n = 96) to 6.7% (n = 72) while the additional six PCV13 serotypes declined significantly from 39.5% (n = 418) to 18.6% (n = 201) (p 〈 0.05). The 23-valent pneumococcal polysaccharide vaccine (PPV23) and non-vaccine (NVT) serotypes increased from 26.3% (n = 278) to 36.2% (n = 393) (p 〈 0.05), and from 25.1% (n = 266) to 38.4% (n = 416) (p 〈 0.05), respectively. There were no significant changes in antimicrobial resistance rates from 2011 to 2016: 24.1% of the IPD from adults ≥65 years were resistant to clarithromycin (n = 609), 10.0% to doxycycline (n = 254), 11.8% to penicillin (n = 299), 5.2% to cefuroxime (n = 131), 6.6% to clindamycin (n = 168), 6.0% to trimethoprim-sulfamethoxazole (n = 152), and 0.5% (n = 12) to ceftriaxone. Although overall incidence of IPD in adults ≥65 years has remained relatively constant from 2010 to 2016, childhood PCV13 vaccination programs have been successful in indirectly reducing IPD caused by PCV13 serotypes in adults through herd immunity effects.

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.

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): 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): 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.