The burden of hand, foot, and mouth disease among children under different vaccination scenarios in China: a dynamic modelling study

Background Hand, foot, and mouth disease (HFMD) is a common illness in young children. A monovalent vaccine has been developed in China protecting against enterovirus-71, bivalent vaccines preventing HFMD caused by two viruses are under development. Objective To predict and compare the incidence of HFMD under different vaccination scenarios in China. Methods We developed a compartmental model to capture enterovirus transmission and the natural history of HFMD in children aged 0–5, and calibrated to reported cases in the same age-group from 2015 to 2018. We compared the following vaccination scenarios: different combinations of monovalent and bivalent vaccine; a program of constant vaccination to that of pulse vaccination prior to seasonal outbreaks. Results We estimate 1,982,819, 2,258,846, 1,948,522 and 2,398,566 cases from 2015 to 2018. Increased coverage of monovalent vaccine from 0 to 80% is predicted to decrease the cases by 797,262 (49.1%). Use of bivalent vaccine at an 80% coverage level would decrease the cases by 828,560. Use of a 2.0× pulse vaccination for the bivalent vaccine in addition to 80% coverage would reduce cases by over one million. The estimated R0 for HFMD in 2015–2018 was 1.08, 1.10, 1.35 and 1.17. Conclusions Our results point to the benefit of bivalent vaccine and using a pulse vaccination in specific months over routine vaccination. Other ways to control HFMD include isolation of patients in the early stage of dissemination, more frequent hand-washing and ventilation, and better treatment options for patients.

Anti-SU Antibody Responses in Client-Owned Cats Following Vaccination against Feline Leukaemia Virus with Two Inactivated Whole-Virus Vaccines (Fel-O-Vax® Lv-K and Fel-O-Vax® 5)

A field study undertaken in Australia compared the antibody responses induced in client-owned cats that had been vaccinated using two inactivated whole feline leukaemia virus (FeLV) vaccines, the monovalent vaccine Fel-O-Vax® Lv-K and the polyvalent vaccine Fel-O-Vax® 5. Serum samples from 428 FeLV-uninfected cats (118 FeLV-vaccinated and 310 FeLV-unvaccinated) were tested for anti-FeLV neutralising antibodies (NAb) using a live virus neutralisation assay to identify 378 FeLV-unexposed (NAb-negative) and 50 FeLV-exposed (NAb-positive; abortive infections) cats, following by anti-surface unit (SU) FeLV-A and FeLV-B antibody ELISA testing. An additional 42 FeLV-infected cats (28 presumptively regressively infected, 14 presumptively progressively infected) were also tested for anti-SU antibodies. NAb-positive cats displayed significantly higher anti-SU antibody ELISA responses compared to NAb-negative cats (p < 0.001). FeLV-unexposed cats (NAb-negative) that had been vaccinated less than 18 months after a previous FeLV vaccination using the monovalent vaccine (Fel-O-Vax® Lv-K) displayed higher anti-SU antibody ELISA responses than a comparable group vaccinated with the polyvalent vaccine (Fel-O-Vax® 5) (p < 0.001 for both anti-FeLV-A and FeLV-B SU antibody responses). This difference in anti-SU antibody responses between cats vaccinated with the monovalent or polyvalent vaccine, however, was not observed in cats that had been naturally exposed to FeLV (NAb-positive) (p = 0.33). It was postulated that vaccination with Fel-O-Vax® 5 primed the humoral response prior to FeLV exposure, such that antibody production increased when the animal was challenged, while vaccination with Fel-O-Vax® Lv-K induced an immediate preparatory antibody response that did not quantitatively increase after FeLV exposure. These results raise questions about the comparable vaccine efficacy of the different FeLV vaccine formulations and correlates of protection.

A Universal Dengue Vaccine Elicits Neutralizing Antibodies Against Strains from All Four Dengue Serotypes

Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 to 2006 using computationally-optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macca mulata) that were either immunologically naïve to any DENV serotype or were had pre-existing antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naïve and dengue pre-immune populations. Importance Dengue virus infects millions of people living in the tropical areas of the world. Dengue induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue without induced enhanced disease. A dengue E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for current circulating strains from all four serotypes regardless of immune status. Most Dengue vaccines in development formulate four separate components based on prM-E from a wild type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy

Emergence of Unusual Rotavirus G9p[4] and G8p[8] Strains During Post Vaccination Surveillance in Argentina, 2017-2018

Background. In 2015, Argentina included RotarixTM monovalent vaccine for universal administration and it showed a sharp decline in all-cause and rotavirus-confirmed cases as well as an immediate predominance of the G2P[4] genotype. The aim of this study was to analyze the impact of rotavirus vaccination on disease burden and genotype distribution in our country following its introduction. Methods. Prevalence and seasonality of laboratory-confirmed rotavirus cases data were assessed. Analyses of circulating genotypes were performed by conventional binary characterization (G and P typing). Phylogenetic study of VP7 gene was performed from emergent unusual strains. Results. During 2017-2018, 1183 rotavirus cases (13.2%) were detected and prevalence was uniform among different age subgroups. Weekly distribution showed a raise of confirmed cases around late July and early August. In 2017 the most frequently detected genotypes were G2P[4] and G3P[8]. However, in 2018 G12P[8] genotype increased and it was detected at a high rate. Noteworthy, the detection of uncommon G9P[4] and G8P[8] strains (bearing DS-1-like genetic backbones) was observed at moderate rates. Conclusions. Following four years of this strategy, the prevalence of rotavirus remained low in children under 5 years of age with a shift of the seasonal peak in early spring. The emergence of uncommon genotypes was due to introduction of new strains rather than to reassortment of local strains. Continuous monitoring of rotavirus burden of disease and genotype distribution provides useful evidence to evaluate existing immunization strategies and to contribute in the development of new vaccines as well.

Molecular Epidemiology of Rotavirus A Strains Pre- and Post-Vaccine (Rotarix®) Introduction in Mozambique, 2012–2019: Emergence of Genotypes G3P[4] and G3P[8]

Group A rotavirus (RVA) remains the most important etiological agent associated with severe acute diarrhea in children. Rotarix® monovalent vaccine was introduced into Mozambique’s Expanded Program on Immunization in September 2015. In the present study, we report the diversity and prevalence of rotavirus genotypes, pre- (2012–2015) and post-vaccine (2016–2019) introduction in Mozambique, among diarrheic children less than five years of age. Genotyping data were analyzed for five sentinel sites for the periods indicated. The primary sentinel site, Mavalane General Hospital (HGM), was analyzed for the period 2012–2019, and for all five sites (country-wide analyses), 2015–2019. During the pre-vaccine period, G9P[8] was the most predominant genotype for both HGM (28.5%) and the country-wide analysis (46.0%). However, in the post-vaccine period, G9P[8] was significantly reduced. Instead, G3P[8] was the most common genotype at HGM, while G1P[8] predominated country-wide. Genotypes G9P[4] and G9P[6] were detected for the first time, and the emergence of G3P[8] and G3P[4] genotypes were observed during the post-vaccine period. The distribution and prevalence of rotavirus genotypes were distinct in pre- and post-vaccination periods, while uncommon genotypes were also detected in the post-vaccine period. These observations support the need for continued country-wide surveillance to monitor changes in strain diversity, due to possible vaccine pressure, and consequently, the effect on vaccine effectiveness.

Enteric Fever in Patients of Lahore: Association of Positive Blood Cultures with the Typhidot Immunoassay Tests and Widal Agglutination

Objective: Laboratory study to assess the correlation of existing Salmonella blood culture isolates with Widal agglutinin titers and EIA-based Typhidot immunoassay antibodies as the gold standard. Materials and Methods: This study was conducted at the department of community medicine KEMU Lahore for six months from June 2017 to November 2018. 2704 blood samples were taken for cultural studies and Widal test in a clinical laboratory among people with symptoms of clinical intestinal fever. Of these, 1497 were isolated from Salmonella; The sera of these patients who did not accompany Typhidot requests were also subjected to spot immunoassay with the informed consent required for bleeding. All sera were stored at 40 ° C until selection. Results: Blood of 802 men (53.6%) and 695 women (46.4%) gave 61.85% S. typhi (n = 926), 31.26% S. Para typhi-A (n = 468) and 6, 88% S. Para typhi. n = 103) insulation. Broad agglutinins were detected in 473 (31.5%) of these people. Without detectable "O" antibodies, 1:80 "H" titers (n = 264: 17.6%) were most commonly observed in children's sera (n = 112; 7.4%). Widal H with agglutinin "O" was recorded in 209 (13.9%) corresponding positive blood cultures, and 104 (6.9%) gave a titre of 1: 320 or more. A total of 1,024 sera (58.4%) did not have detectable Widal antibody. Typhidot immunoglobulin spots (57.1%), negative in 856 sera, were detected in 641 samples (42.8%). IgG-free IgM stains without detectable IgM, IgG stains without IgG were also observed in 22 sera (1.47%) and samples producing S. Para typhi-A isolate (n = 8) and S. Para typhi-B. Conclusion: S. Para typhi-A has often grown in the last decade, suggesting incomplete protective coverage, probably with a monovalent vaccine. Antibodies against Widal and Typhidot agglutinins were detected in the serum of patients with Salmonella growing in blood in 31.5% and 42.8%, respectively. Widal may be misinterpreted because of possible "lower" agglutinins that have not been inoculated, and the EIA immunoassay is particularly limited only to S. typhi. An ICT based Salmonella serotype three indicator is desirable.

Vaccine Preperative Trial for Leptospirosis and their Pathological, Immunological Study by Serum Electrophoresis

Leptospirosis is a fatal infectious disease caused by different serovars of Leptospira spirochetes affecting humans and animals. In the present study, the trials of the whole-cell killed formalin treated monovalent vaccine using Leptospira icterohaemorrhagiae and trivalent vaccine using Leptospira icterohaemorrhagiae, Leptospira louisiana, and Leptospira hebdomadis were studied. The serum electrophoresis studies were done after administration of the vaccine into the experimental albino mice along with the booster dose of the vaccinated serum by densitometric readings. Similarly, the pathological observations were made by dissecting the virulent mice, vaccinated mice, and comparing them with the control mice. The MAT titre was also studied after the booster dose administration of the vaccinated serum. The monovalent and trivalent whole-cell killed formalin treated vaccines shows significant raise in the total proteins, albumin, globulin, α 1 globulin, α 2 globulin, β globulin and γ globulins of the serum as well as increase in significant levels in the antibody levels after the administration of the booster dose at an interval of 14 days. Keywords: Leptospira, Whole-cell killed formalin treated vaccine, Immunological study, Pathological study, Serum electrophoresis.

LB13. Trivalent Hepatitis B (HepB) Vaccine Yields Superior Seroprotection Rates in Adults: Results from the Phase 3 Double-Blind, Randomized Study Comparing Immunogenicity and Safety of a 3-Dose Regimen of Sci-B-Vac™ and Engerix B® (PROTECT)

Background Many adults fail to achieve seroprotection after receiving 3 doses of monovalent HepB vaccines such as Engerix-B® and the response decreases with age and with common co-morbidities. Sci-B-Vac™ is a trivalent HepB vaccine produced in mammalian cells, adjuvanted with aluminum hydroxide, which in addition to small S antigen, contains preS1 and preS2 antigens expressing highly immunogenic T- and B-cell epitopes that may enhance seroprotection rates (SPR) in adults. Methods In a multicentre study, the immunogenicity of 10 µg dose of Sci-B-Vac™ was compared with a 20-µg dose of Engerix-B® given at days 0, 28, and 168 (NCT03393754). Randomization was stratified by study center and age (18–44, 45–64, ≥65 years). Immunogenicity, including SPR (% subjects with anti-HBs levels ≥10 mIU/mL), and safety outcomes were followed to Day 336. The co-primary objectives were (1) non-inferiority in adults ≥18 years and (2) superiority in adults ≥45 years of SPR, 4 weeks after the third dose. Results Of 1,607 randomized subjects, 42.3% were from United States, 41.6% EU, and 16.1% Canada. Males (38.5%) and females (61.5%) were enrolled to 18–44 (18.6%), 45–64 (44.6%), and ≥ 65 year (36.8%) age groups. Both co-primary endpoints were met. In the non-inferiority analysis, SPR in Sci-B-Vac™ recipients aged ≥18 years was 91.4% vs. 76.5% for Engerix-B®; SPR difference: 14.9%; 95% confidence interval (CI) [11.2%, 18.6%]. Superiority analysis showed that SPR in Sci-B-Vac™ recipients aged ≥45 years was 89.4% vs. 73.1% for Engerix-B®—SPR difference: 16.4%; 95% CI [12.2%, 20.7%] (figure). Significantly higher SPR for Sci-B-Vac™ vs. Engerix-B® was noted in subgroups (gender, BMI, diabetes, smoking and particularly age—SPR difference for 45–64 (14.7% [9.8–19.8%]) and ≥ 65 (18.9% [11.6–26.1%]) years. No major safety signals were observed; solicited and unsolicited adverse events were consistent with the known vaccine safety profiles. Conclusion Sci-B-Vac™ met immunogenicity endpoints for non-inferiority in adults aged ≥ 8 years and was superior in adults aged ≥45 years, compared with the monovalent vaccine, Engerix-B®. Sci-B-Vac™ SPR was higher compared with Engerix-B® in key subgroups. No safety signals were observed and safety and tolerability were consistent with the known profile of Sci-B-Vac™. Disclosures Timo Vesikari, MD, VBI (Grant/Research Support, I have received funding from VBI to carry out the reported clinical trial in Finland), Joanne M. Langley, MD, VBI Vaccines (Grant/Research Support), Johanna Spaans, BSc, MSc, VBI Vaccines (Employee), Nathalie Machluf, PhD, SciVac Ltd. (Employee), Dave Anderson, PhD, VBI Vaccines, Inc. (Employee, Shareholder), Vlad Popovic, MD, VBI Vaccines (Employee), Francisco Diaz-Mitoma, MD, VBI Vaccines, Inc. (Consultant, Shareholder, Independent Contractor). Other Authors: No reported disclosures.