31^st Euro Global Summit and Expo on Vaccines & Vaccination June 14-16, 2018 Barcelona, Spain

Lucy Rumbellow is an Immunization Commissioning Manager at NHS England (London Region), England. She has over 10 years’ experience working in public health, health and well-being and is a registered public health practitioner on the UK public health register.

Statement of the Problem: In June 2015, a national publicly funded meningococcal ACWY (MenACWY) immunization programme was introduced in the United Kingdom (UK). This was in response to the rapid rise of invasive meningococcal disease caused by the capsular group W (Men W) particularly amongst adolescents (10-18 years) and young adults (19-25 years). The immunization programme is commissioned by NHS England (NHSE) as part of its Section 7a immunization programmes. It is offered as a routine vaccination to adolescents aged 14 or 15 (UK school years 9 or 10) alongside the teenage booster in the school-based vaccination programme. Uptake is low in London compared to national (76% in Year 9 and 63.1% in Year 10 compared to 84.1% and 77.2% nationally in 2016). It is also lower than the HPV programme given in year 8 (85% in 2016). We set out to explore the factors impacting upon good service delivery in order to improve the commissioning of the services and thereby the uptake. Methodology &Theoretical Orientation: The study design was two-fold. In May 2015, we surveyed our 18 school aged vaccination provider organizations (which cover 32 boroughs and a population of over 1,500,000 school age children) to assess their preparedness for delivery of the MenACWY immunization programme. Five barriers to successful implementation were anticipated: consent forms not being returned; staff capacity; lack of administrative staff; lack of finances and; increasing volume of child flu vaccine delivery. We resurveyed our providers (now reduced to 11 organizations) in July 2017 to see if the same barriers remained and used the survey as a purposive sampling frame for in-depth interviews to explore the facilitators and barriers to MenACWY uptake in schools. Findings: All anticipated barriers remained to good delivery. Six representatives from six organizations agreed to be interviewed. Five main themes emerged from the thematic analysis: people largely accepting but; lack of school support and engagement; poor return of paper consent forms; parents not understanding that MenACWY is different to Men C given to infants and; school delivery impedes meaningful engagement with adolescents. Conclusion & Significance: MenACWY are a well-accepted vaccine yet reported uptake is lower than expected in London. Delivery of the programme is affected by the mechanics of school based delivery including poor return of paper consent forms. Normalizing of school aged vaccination programmes is needed including building relationships with school staff and the wider school community and utilizing digital consent forms and other forms of communication.

Catherine Heffernan is Principal Advisor for Commissioning Immunization and Vaccination Services at NHS England, London Region, England. She is a Consultant in Public Health and has spent the past five years as the London regional lead for immunizations at Public Health England, advising NHS England, London Region on commissioning section 7a immunization programme. She is also an accredited Educational Supervisor for Public Health Registrars and GP trainees and is an Honorary Senior Clinical Lecturer at London School of Hygiene and Tropical Medicine.

Statement of the Problem: Patient invite-reminder systems (also known as call/recall) are consistently cited as being one of the most cost effective ways to improve uptake of vaccination services. It is unknown how applicable this is to routine practice in the UK. The aim of this study is to provide a cross-sectional description of what is currently happening in London GP practices and to provide insights into the facilitators and barriers to embedding good call/recall processes. Methodology & Theoretical Orientation: The study design was two-fold: a survey to provide a cross-sectional description of call/recall systems in London GP practices and qualitative semi-structured interviews to gain further insight into the facilitators and barrier. Between October 2016 and February 2017 we undertook a census of all 1,301 London general practices. The survey was used as a purposive sampling frame for in-depth telephone interviews on experiences and perspectives on operating call/recall system for immunizations. Findings: We had a 60% response rate (684 GP practices) and 25 GP practice managers volunteered to be interviewed. Call/recall processes are variable and decline with age of patient (figure 1) Letters (81%) and telephone calls (80%) are the most popular methods for delivering invite-reminders. No significant difference was found between practices that did call/recall and those who didn’t in terms of deprivation, population demographics and vaccination uptake of 0-5’s national childhood immunization programme. Five main themes emerged from the thematic analysis: (1) no call/recall system was the same; (2) practice preference for letters and phone calls over emails and texts; (3) lack of clarity on what good call/recall should look like; (4) preference to do it themselves rather than automate it and (5) call/recall is time consuming, costly and patients aren’t bothered. Conclusion & Significance: This is the first study to describe how call/recall is utilized in routine practice. Delivery of call/recall is variable, human and paper intensive and not wide-spread. Implementing best practice evidence will require investment and consorted effort.

Sadao Suzuki has his expertise in Cancer Epidemiology especially primary prevention. He studied Epidemiology and Biostatistics at Harvard School of Public Health and Nagoya University. He has broad experience in epidemiological studies including meta-analysis, randomized clinical trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies. He is also interested in epidemiological methodology. He got an award for Young Investigators from Japan Epidemiological Association in 2005 for the paper in biostatistics entitled: The conditional relative odds ratio provided less biased results for comparing diagnostic test accuracy in meta-analyses.

Nagoya City introduced free HPV vaccination in 2010 and in April 2013 the Ministry of Health, Labour and Welfare included the HPV vaccine in the National Immunization Program. However, in June 2013, the Ministry suspended proactive recommendation of the vaccine after unconfirmed reports of adverse events. To investigate any potential association between the vaccine and reported symptoms, Nagoya City conducted a questionnaire based survey. Participants were 71,177 female residents of Nagoya City born between April 2, 1994 and April 1, 2001. The anonymous postal questionnaire investigated the onset of 24 symptoms (primary outcome), associated hospital visits, frequency, and influence of school attendance. Totally, 29,846 residents responded. No significant increase in occurrence of any of the 24 reported post-HPV vaccination symptoms was found. The vaccine was associated with increased age-adjusted odds of hospital visits for abnormal amount of menstrual bleeding (OR: 1.43, 95% CI: 1.13–1.82), irregular menstruation (OR: 1.29, 95% CI: 1.12–1.49), severe headaches (OR: 1.19, 95% CI: 1.02–1.39), and chronic, persisting abnormal amount of menstrual bleeding (OR 1.41, 95% CI: 1.11–1.79). No symptoms significantly influenced school attendance and no accumulation of symptoms was observed. In this large-scale survey in Nagoya, Japan, we found that the HPV vaccines were not significantly associated with the occurrence of 24 reported symptoms, thus suggesting no causal association between the vaccines and reported symptoms or adverse events.

Andrew Cho is a graduate student of Konkuk University.

Microneedle (MN) vaccination presents many attractive advantages as future vaccine delivery method. MN requires minimal education for administration. Injection in to epidermis and dermis and stimulations of antigen presenting cells such as Langerhans cells and dermal dendritic cells enable robust immune response. Microneedle research results show promising future as alternate delivery method. However, there is more study to be done for the role and effect of adjuvants in microneedle vaccination. In this study, c-di-GMP (cycle-dimeric-guanosine monophosphate), which is an endoplasmic reticulum protein STING (stimulator of interferon genes) ligand, was chosen as potential candidate for microneedle adjuvant. Six week old mice were divided into four groups (fourteen mice in each group) to study protective efficacy of the adjuvant with variation of adjuvant amount. Mice were bled on second and fourth week each for serology tests. Hemagglutination inhibition (HI) and mouse IgG enzyme-linked immunosorbent assay (ELISA) were done with serum collected on week two and four. After the mice were challenged with pH1N1 strain, 4 mice each from the groups were chosen to collect lung and spleen to test for 6 types of cytokine analysis. Remaining mice were watched for fourteen days after the challenge for body weight and mortality. Lung viral titer was determined by plaque assay. Lower titer was observed in lung. All mice in the control group died in five days after the challenge. All adjuvant vaccinated mice survived with lowest body weight loss. One mouse died in the group vaccinated with only virus. Two adjuvant vaccinated groups showed some stimulation of immunity in cellular level. C-di-GMP has proven its capacity as adjuvant in mucosal immunity in previous studies. In this study c-di-GMP showed its capacity as potential candidate for adjuvant in microneedle application.

Jun Beom Kim is a graduate student of Konkuk University. His major is in Veterinary Microbiology and Infectious Disease. He has his expertise in evaluation of poultry vaccines and improving vaccination method.

Statement of the Problem: Ducks are a natural reservoir for the 16 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes of the influenza A virus. While being highly lethal to chickens, H5N8 HPAI virus can be non-lethal to domestic ducks, which range from asymptomatic infection to severe disease with mortality. In this situation, vaccination is one of the few tools available to control HPAI infection in duck industry. But most oil-adjuvanted vaccines produced for chickens might be inadequate in ducks to provide optimal immunity. In this study, we generated rgH5N9 strain and we assessed the possibility of LAB as a potent adjuvant in inactivated oil-emulsion vaccine. Methodology & Theoretical Orientation: LAB was isolated from Kimchi samples. As one of them, Lactobacillus plantarum was selected based on the in vitro screening assay. We generated rgH5N9 deriving the hemagglutinin gene from HPAI A/Baikal teal/Korea/1449/2014 (H5N8) and neuraminidase gene from the low pathogenic H11N9 that was isolated during the environmental surveillance. The reassortant virus was propagated by inoculating into embryonated chicken eggs. EID50/ml of inactivated antigens supplemented with different dose of LAB was used to formulate a water-in-oil emulsion vaccine. One-week-old Pekin ducks were vaccinated. Hemagglutinin inhibition test (HI test) was conducted using duck serum. Safety of LAB using as adjuvant was demonstrated by rate of gain and histological examination. Findings: The LAB supplement vaccine group showed faster induction of humoral immune response compared to other groups. And rate of gain was not important compared with mock group. Conclusion & Significance: To our knowledge, this is the first study reporting the efficacy of inactivated oil-emulsion vaccine supplemented with LAB in ducks. In this study, the oil-emulsion vaccine combined with the LAB elicited a higher humoral immune response. Although this study did not include responses of immune cells, our results imply that supplementation of LAB to inactivated oil-emulsion vaccine could be an attractive strategy in ducks.

Jei Hyun Jeong is a graduate student who is majoring in Avian Disease at the Veterinary College in Korea. His primary interest in this area is to control and prevent devastating poultry diseases, such as Newcastle disease and Avian Influenza. To accomplish this, he is exploring novel adjuvant system which is effective, safe and economical. In the poultry industry, the cost of the vaccine is still one of the most important determinants, and its significance becomes even greater in developing country, which have been most severely damaged by such infectious diseases. By developing most suitable oil adjuvant, he wants to offer better preventive options to poultry industry in developing country.

Newcastle disease (ND) is one of the most contagious and economically important avian diseases that are characterized by respiratory, nervous and enteric infections. To prevent and control ND in practice, the inactivated NDV vaccine has been widely used. The inactivated vaccines used in poultry industry often require oil adjuvants to elicit a sufficient immune response. SEPPIC Montanide ISA 70 VG (ISA70), which is a ready-to-use oil-based adjuvant, is largely used in the manufacture of oil emulsions for poultry vaccines. Although the inactivated vaccines using ISA70 as an oil adjuvant have still shown great efficacy and safety profile, there has been a need to develop other cheaper oil adjuvants, because of its high cost. In this study, we prepared the inactivated NDV vaccines using ISA70 and Seojin KF-40 (KF40), which is fairly inexpensive mineral oil for veterinary use, as an adjuvant. To compare the protective efficacy of these vaccines, we compared the antibody responses of birds vaccinated with different vaccines and evaluated protection (mortality and virus shed) against challenge with virulent strain of NDV. For the safety study, the birds vaccinated with different vaccines were subjected to evaluate histopathological lesions in injected site. The following tests were conducted: 1) Efficacy test: Each vaccine formulation was evaluated for immunogenicity in 3-week-old specific-pathogen-free chickens. Challenge study with a very virulent NDV was conducted to compare protection against mortality and measure the virus levels in oral and cloacal swabs. 2) Safety test: Body weight gain of each group was evaluated every week and Birds from all of the experimental groups were euthanized. The pectoral muscle tissues were processed and assessed by a pathologist. We found that the efficacy and safety of KF40, as an adjuvant with inactivated NDV vaccine, is comparable to those of ISA 70, which is a standard to other oil adjuvant. In conclusion, KF40 can be used as an effective, safe and inexpensive mineral oil-based adjuvant system.

Dam Hee Park is studying Master’s degree at Konkuk University. He has passion on his work at avian diseases. He is interested in current avian infectious diseases such as infectious bronchitis virus, infectious laryngotracheitis virus and avian influenza. Additionally, he wants to study about variable ways to eradicate or alleviate avian infectious diseases. His final goal as a poultry veterinarian is to take care of Asian poultry farms.

Infectious Laryngotracheitis (ILT) virus causes economic losses in poultry due to acute upper respiratory inflammation and reduction in egg production. In order to prevent outbreak of ILT virus, attenuated live vaccines were applied via eye drop or drinking water. Our previous study has developed a novel attenuated vaccine of Infectious Layrngotracheitis virus which possesses thermo-stable characteristic. This feature provides better control of mutation of live vaccine. In our study, group of chickens immunized with TS-V1 vaccine via eye drop, showed protection of the respiratory tract when vaccinated over 102.5 TCID50 dose with positive ELISA titer. Furthermore, positive control group showed decrease in body weight change on 4 and 5 day post challenge. Whereas, vaccinated groups over 102.5 TCID50 dose all showed positive body weight changes. In summary, we have demonstrated the minimum infectious dose for the attenuated Korean isolated strain of infectious laryngotracheitis virus vaccine candidate strain by eye drop administration is 102.5 TCID50. This study will be helpful of developing future vaccination protocols and implementing them properly.

Jun Young Kim is Doctor of Veterinary Medicine and studying Master’s degree at Konkuk University, Seoul, South Korea. His primary research interest is evaluating the pathogenicity, transmissibility and evolution of poultry pathogens such as avian infectious bronchitis virus making live attenuated vaccines for these pathogens. Additionally, he wants to study about variable ways to eradicate or alleviate avian infectious diseases. His final goal as a Poultry Veterinarian is to take care of Asian poultry farms.

Infectious bronchitis virus (IBV) causes an acute and highly contagious viral disease of chickens that is characterized by respiratory signs, nephritis, and reduced egg reproduction. Early infection of chickens leads to permanent damage of the reproductive system, so infected layers do not lay normally at sexual maturity. Recent study shows some infected layers have been found to have ovary cyst which inhibits normal hierarchal ovarian follicle formation. We have previously demonstrated IBV strain K40/09 isolated from a broiler farm in Korea as a novel vaccine candidate. This variant strain belonged to the Korean new cluster 1, which originated from natural recombination between KM91 and QX-IBV and showed a high level of cross-protective efficacy in a previous study. In this study, we evaluated the safety of chicken reproductive organs after heat-adapted attenuated IBV K40/09 CE90 strain vaccination. One-day old SPF chicks were vaccinated by spray administration. We observed clinical sign and cystic oviduct lesion also evaluated by necropsy after 14-week monitoring period post vaccination. As a result, IBV K40/09 CE90 strain vaccination group showed no clinical sign and mortality, and cystic-aplastic oviduct lesion was less than 4.08% in accord with safety requirements of European Pharmacopoeia. The efficacy of IBV K40/09 CE90 also tested. The result revealed that K40/09 CE90 provided protection against virulent K40/09 parental strain and elicited the production of high titers of neutralizing antibody. We conclude that the K40/09 CE90 showed immunogenicity, protective efficacy and safety of reproductive organs required for a live attenuated vaccine. These results indicate that the K40/09 vaccine could be helpful for controlling IBV infection in Korea and have potential to become a novel vaccine candidate not only for broilers, but also for layers and breeders.

Jin-Yong Noh is a PhD candidate at Konkuk University, Seoul, South Korea. His primary research interest is evaluating the pathogenicity, transmissibility, and evolution of poultry pathogens such as avian influenza, Newcastle disease virus, avian reovirus, and making vaccines for these pathogens. He developed virus-like particle (VLP) vaccine against HPAI and ND by using baculovirus system and tested its efficacy in chickens. He also tested pathogenicity and transmissibility of clade 2.3.4.4 HPAI in ferret models to investigate its pandemic potential.

Newcastle disease (ND) is one of the most devastating diseases in poultry with huge losses worldwide. As a causative agent of ND, Newcastle disease virus (NDV) has a wide host range, more than 250 bird species have been reported to be susceptible to the virus. Each NDV isolated from different origins of birds exhibit different host ranges and tissue tropism. For example, NDV isolated from chicken couldn’t transmit through ducks; however, NDV isolated from duck could transmit through chickens. Thus, the origin of NDV strain could be an important factor of vaccine use to specific hosts. In previous study, we found the NDV K148/08 strain from feces of wild mandarin duck and tested for its characteristics. This strain exhibited thermos-stability against heat treatment, enhanced immunogenicity and safety relative to commercially available vaccine strains in chicken. In this study, we utilized the K148/08 strain as a backbone virus to develop a thermostable NDV vaccine vector to broad-range of hosts by using reverse genetics technology. To evaluate the difference between its parental virus and rescued virus, pathogenicity and growth ability was examined by virus titration in eggs, mean death time (MDT), and intracerebral pathogenicity index (ICPI). The rescued virus showed similar features with parental virus as shown in long MDT and low ICPI. Also, it showed similar thermo-stability that can increase the value of vaccine because it does not require a cold chain. NDV vaccine with this strain could increase its utility by future study of adding foreign gene from pathogens that can affect a wide variety of poultry such as highly pathogenic avian influenza (HPAI) because it can be used to broad-range of hosts.

Wei-Cai Zhang is a Microbiologist, being engaged for long in research on development of antibodies and vaccines against botulinum neurotoxins and biosynthesis of vitamins and coenzymes such as ascorbic acid and pyrroloquinoline quinone.

The botulinum neurotoxins (BoNT) produced by Clostridium botulinum are the most toxic known substances. The serotype A is the most poisonous and common species with extremely potential as a terrorist or biological warfare agent. In this study, recombinant sub-unit vaccines and replicon DNA vaccines against botulinum neurotoxin serotype A are investigated. A completely synthetic gene encoding the Hc domain of BoNT/A was constructed and expressed in E. coli, and full-sized and soluble product was produced. Mice given two vaccinations in 1μg dose of AHc were 100% protected against an intraperitoneal administration of 106 50% lethal doses (LD50) of serotype A toxin. The immunogenicity of a plasmid DNA replicon vaccine encoding the Hc fragment of BoNT/A was investigated. Intramuscular injections of mice with the dendritic cells (DC) -targeted DNA vaccine stimulated more DCs to proliferate and mature than the non-targeted DNA vaccine in the spleen. The DC-targeted DNA vaccine could recruit a large number of DCs and promote their proliferation and maturation at the site of inoculation, while the non-targeted DNA vaccine recruited fewer DCs. In addition, the DC-targeted DNA vaccine induced stronger AHc-specific humoral immune responses, lymphocyte proliferative responses and protective potency against BoNT/A in mice than did pVAX1-SAHc. Moreover, the DC-targeting DNA vaccine provided effective protection after only two inoculations. These results showed that the DC-targeted fusion DNA vaccine could generate strong immunity, indicating that recruiting mature DCs to the site of inoculation is helpful for priming and boosting immune responses. Thus, we propose that the strategy of targeting antigen to DCs in vivo via DEC205 can enhance effectively the potency of DNA vaccines against BoNTs or other pathogens in an animal model. These results showed that recombinant sub-unit vaccines and DNA vaccines could be good candidate vaccines for human use to protect against BoNT/A.

Hyeran Won received his doctoral degree at Department of Biomedical Science from Kyung Hee University, Republic of Korea and worked as a postdoctoral researcher at Cambridge Institute for Medical Research, University of Cambridge, UK in a laboratory of Dr David C Rubinsztein focusing on the role of autophagy in neurodegenerative disease. Currently, he is working as a senior researcher at division of vaccine research, Center for Infectious Diseases Research, Korea National Institute of Health (KNIH), Korea Centers for Disease Control & Prevention, Republic of Korea. His main interests are: to understand the genetic characteristics of Mumps viruses in Korea: to develop the MMR vaccine.

Mumps is a contagious disease caused by the mumps virus and can be preventable with measles, mumps and rubella (MMR) vaccine. MMR vaccine effectiveness has been estimated at 79% for 1 dose and 88% for 2 doses according to the Immunological Basis for Immunization Series Module 16: Mumps, World Health Organization (WHO). Despite the high vaccination coverage, mumps outbreaks still occur globally in vaccinated populations suggesting waning immunity or antigenic differences between vaccine strains and circulating wild-type viruses. In Republic of Korea, after the introduction of the national immunization programs, cases of mumps have become sporadic. In addition, genotype I, H, and F have emerged since its initial isolation. To investigate this concern, we selected genotype I, H and F wild-type mumps virus strains circulated in Republic of Korea from 1998-2017 and analyzed amino acid changes in HN gene which is the major target for neutralizing antibodies. The analysis of HN amino-acid sequence data showed that there are no changes in their glycosylation sites but 4 or 5 differences in neutralizing epitope sites of haemagglutinin-neuramidase(HN) gene between Korean isolates and genotype A vaccine strain. Furthermore, we measured both mumps virus specific IgG titer and a rapid focus reduction neutralization test (FRNT) titres with Korean isolates and sera (n=50) obtained from children aged 1-2 years after receiving 1 dose of (MMR) vaccine. The FRNT titres after receiving 1 dose of MMR vaccine were significantly lower against genotypes I, H and F than against the genotype A vaccine strain [genotype F and H: p<0.001, genotype I: p<0.01]. This finding will possibly contribute to the recurrence of mumps outbreaks in vaccinated populations depending on the degree of conservation or genetic differences of HN gene. Further studies exploring this issue are needed to achieve the elimination of mumps.