Search

Limited data exist on the factors affecting feline rabies vaccination outcomes during primary immunization. This study aimed to assess if specific factors (signalment, vaccination count, vaccine brand, and time since last vaccination) correlated with meeting global antibody titer standards and absolute titers in young cats given monovalent inactivated rabies vaccines. Analyzing a dataset from cats tested before their first annual booster using the FAVN test, logistic and linear regression models were applied. Among 379 cats, 94.2 % achieved titers meeting or exceeding the standard threshold (≥0.5 IU/ml). Time since last vaccination proved to be the primary predictor of vaccination success. Cats receiving two vaccinations tended toward higher titers. Age, sex, breed, and vaccine type showed no impact on outcomes. The present study indicates that vaccination failure in young cats is uncommon, and that the time interval from the latest vaccination is the single most important predictor of successful rabies vaccination., Competing Interests: Declaration of Competing Interest All of the authors declare that there is no conflict of interest in this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The costs related to the FAVN tests were covered by the pets’ owners and authors have no competing financial benefit., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Newly synthesized vaccines prepared from formalin-killed bacteria Streptococcus pyogenes were investigated in the current study to evaluate the effectiveness of the newly synthesized vaccine as well as their safety by injected intraperitoneal. The study involved several steps 1st step is the preparation of the vaccine followed by the 2nd step: Evaluate the effectiveness and vaccine safety against pathogenic S. pyogenes through 4 different groups including control (Group I). Group II (Bacterial, infected group), Group III (Vaccine), and the Last group was the challenged group after the vaccination (Vacc + Bac). Different Immunological and biochemical parameters were measured in addition to hematological and histopathological examinations. For example, oxidative/antioxidants, inflammatory biomarkers, fragmentation and cell damage, and finally the histopathological study. The current study showed an increase in all oxidative, inflammatory, and cell damage (DNA fragmentation assays), additionally markedly elevation in histopathological cell damage in the infected group (Group II) compared with the control group. The vaccine and challenged after vaccination group (vaccine + Bacteria), showed great improvement in oxidative biomarkers (LPO) and an increase in antioxidants biomarkers (GSH, SOD, GST, DPPH, ABTS, GR and GPx), Also the inflammation and histopathological examination. The newly synthesized vaccine improved the resistance of Oreochromis niloticus and can be used as a preventive therapy agent for pathogenic bacteria S. pyogenes., (© 2024. The Author(s).)

Introduction: Specific prevention of a number of infectious diseases has been introduced into the vaccination schedule. The production of immunoprophylactic drugs, in order to establish standard properties, including safety and specific effectiveness, requires strict adherence to manufacturing regulations, and the reliability of the results obtained requires monitoring of these parameters. The specific effectiveness of vaccine preparations is standardized according to the indicators of stimulation of specific antibody response formed in the body of vaccinated model biological objects., Objective: Determination of the immune reactivity of white mice to vaccination with the QazVac vaccine to establish the possibility of using them as a biological model in assessing the immunogenicity of the vaccine instead of Syrian hamsters., Materials and Methods: The immune reactivity of model animals was assessed by the seroconversion rate, dynamics of antibody titers to the SARS-CoV-2 virus formed in the body after vaccination with the test vaccine. In the case of seropositivity of animals before administration of vaccine or placebo, the level of immune reactivity was calculated by the difference in antibody titers between control and vaccinated animals or by the difference in antibody titers before and after immunization. Specific antibodies were detected and their titer was determined using a neutralization reaction., Results: The research results showed that the tested biological models had approximately the same immune reactivity to the administration of the QazVac vaccine, confirmed by the level and dynamics of antibody titers. When analyzing the fold increase in antibody titers in comparison to those of control animals, Syrian hamsters were more reactive compared to mice. But SPF white mice were standardized in their lack of the immune reactivity to SARS-CoV-2 virus before the immunization., Conclusion: The data obtained indicate that the immune reactivity of white mice to the administration of the QazVac vaccine in terms of the rate and dynamics of the formation of virus-neutralizing antibodies is approximately equivalent to the immune reactivity of Syrian hamsters. Before immunization with the vaccine, SPF white mice, in contrast to Syrian hamsters, do not have humoral immunity specific to the SARS-CoV-2 virus. The immune reactivity equivalent to that observed of Syrian hamsters and the absence of antibodies to the SARS-CoV-2 virus at a baseline indicate the superiority of the use of white mice in assessing the immunogenicity of vaccines against COVID-19 and/or obtaining specific factors of humoral immunity.

The widespread administration of COVID-19 vaccines has prompted a need to understand their safety profile. This investigation focuses on the safety of inactivated and mRNA-based COVID-19 vaccines, particularly concerning potential cardiovascular and haematological adverse events. A retrospective cohort study was conducted for 1.3 million individuals residing in Abu Dhabi, United Arab Emirates, who received 1.8 million doses of the inactivated BBIBP CorV (by SinoPharm) and mRNA-based BNT162b2 (Pfizer-BioNTech) vaccines between June 1, 2021, and June 30, 2022. The study's primary outcome was to assess the occurrence of selected cardiovascular and haematological events leading to hospitalization or emergency room visits within 21 days post-vaccination. Results showed no significant increase in the incidence rates of these events compared to the subsequent 22 to 42 days following vaccination. Analysis revealed no elevated risk for adverse outcomes following first (IRR 1·03; 95% CI 0·82-1·31), second (IRR 0·92; 95% CI 0·72-1·16) and third (IRR 0·82; 95% CI 0·66-1·00) doses of either vaccine. This study found no substantial link between receiving either mRNA and inactivated COVID-19 vaccines and a higher likelihood of cardiovascular or haematological events within 21 days after vaccination., (© 2024. The Author(s).)

Immersion vaccination, albeit easier to administer than immunization by injection, sometimes has challenges with antigen uptake, resulting in sub-optimal protection. In this research, a new strategy to enhance antigen uptake of a heat-inactivated Vibrio harveyi vaccine in Asian seabass (Lates calcarifer) using oxygen nanobubble-enriched water (ONB) and positively charged chitosan (CS) was explored. Antigen uptake in fish gills was assessed, as was the antibody response and vaccine efficacy of four different combinations of vaccine with ONB and CS, and two control groups. Pre-mixing of ONB and CS before introducing the vaccine, referred to as (ONB + CS) + Vac, resulted in superior antigen uptake and anti-V. harveyi antibody (IgM) production in both serum and mucus compared to other formulas. The integration of an oral booster (4.22 × 10 8  CFU/g, at day 21-25) within a vaccine trial experiment set out to further evaluate how survival rates post exposure to V. harveyi might be improved. Antibody responses were measured over 42 days, and vaccine efficacy was assessed through an experimental challenge with V. harveyi. The expression of immune-related genes IL1β, TNFα, CD4, CD8, IgT and antibody levels were assessed at 1, 3, and 7-day(s) post challenge (dpc). The results revealed that antibody levels in the group (ONB + CS) + Vac were consistently higher than the other groups post immersion immunization and oral booster, along with elevated expression of immune-related genes after challenge with V. harveyi. Ultimately, this group demonstrated a significantly higher relative percent survival (RPS) of 63 % ± 10.5 %, showcasing the potential of the ONB-CS-Vac complex as a promising immersion vaccination strategy for enhancing antigen uptake, stimulating immunological responses, and improving survival of Asian seabass against vibriosis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Influenza viruses can multiply in quails and be transmitted to other animal species. As vaccination reduces virus shedding in chickens, the effect of the killed H9N2 avian influenza virus (AIV) on tissue distribution and virus shedding was evaluated in quails. One hundred 20-day-old quails were divided into six equal groups, kept in separate pens, and fed ad libitum. Before vaccination, blood samples were randomly collected from the wing veins. Four groups were vaccinated with the inactivated H9N2 Razi Institute vaccine at 21 days subcutaneously at the back of neck. Three weeks later, two groups were re-vaccinated. Two weeks later, at the age of 56 days, three groups were challenged with 100 μL of allantoic fluid containing 10 5 EID 50 H9N2 through the oculonasal route. Blood samples were collected from quails at 42, 56, 63, and 70 days from each group to determine AIV antibodies by the hemagglutination inhibition test. Three quails were randomly selected and euthanized from each group on days 1, 3, and 6 post-inoculation (PI). Tissue samples were collected, and the RT-PCR test was performed. No clinical signs or gross lesions existed in any of the groups during the experiment. However, the virus was detected in different tissues on the first, third, and sixth days after the challenge in unvaccinated challenged birds. Virus detection was significantly more frequent in the quails vaccinated once and challenged than in the twice-vaccinated challenged group ( P ≤0.05). On the third day of PI, the virus was detected in some organs of the challenged groups. On the sixth day of PI, the virus was detected only in the lungs of two unvaccinated and once-vaccinated challenged birds. It was concluded that the vaccination of quails against AIV H9 is necessary to protect them from clinical signs, as well as respiratory tract and intestine replication. Two-time vaccination significantly protects the respiratory and intestine tracts, compared to one-time vaccination ( P ≤0.05)., Competing Interests: The authors declare that they have no conflict of interest.

Aim: To compare the seropositivity rate of cancer patients with noncancer controls after inactive SARS-CoV-2 vaccination and evaluate the factors affecting seropositivity. Method: Spike IgG antibodies against SARS-CoV-2 were measured in blood samples of 776 cancer patients and 715 noncancer volunteers. An IgG level ≥50 AU/ml is accepted as seropositive. Results: The seropositivity rate was 85.2% in the patient group and 97.5% in the control group. The seropositivity rate and antibody levels were significantly lower in the patient group (p < 0.001). Age and chemotherapy were associated with lower seropositivity in cancer patients (p < 0.001). Conclusion: This study highlighted the efficacy and safety of the inactivated vaccine in cancer patients. Clinical Trials Registration: NCT04771559 (ClinicalTrials.gov).

Developing new influenza vaccines with improved performance and easier administration routes hinges on defining correlates of protection. Vaccine-elicited cellular correlates of protection for influenza in humans have not yet been demonstrated. A phase-2 double-blind randomized placebo and active (inactivated influenza vaccine) controlled study provides evidence that a human-adenovirus-5-based oral influenza vaccine tablet (VXA-A1.1) can protect from H1N1 virus challenge in humans. Mass cytometry characterization of vaccine-elicited cellular immune responses identified shared and vaccine-type-specific responses across B and T cells. For VXA-A1.1, the abundance of hemagglutinin-specific plasmablasts and plasmablasts positive for integrin α4β7, phosphorylated STAT5, or lacking expression of CD62L at day 8 were significantly correlated with protection from developing viral shedding following virus challenge at day 90 and contributed to an effective machine learning model of protection. These findings reveal the characteristics of vaccine-elicited cellular correlates of protection for an oral influenza vaccine., Competing Interests: Declaration of interests The authors declare the following competing interests: S.N.T., D.L., N.S.K., and C.J.M. are current or former employees of Vaxart Inc. G.P.N. and D.R.M. have received research funding support from Vaxart Inc. M.A., K.K., and B.B. are current or former employees of WCCT Global. D.R.M. is an unpaid advisor for WCCT Global. Z.B. is an employee of CellCarta. CMS is a scientific advisor to and has received research funding from Enable Medicine, Inc., all outside of this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Given that the respiratory mucosa is an important site for the initial replication of Newcastle disease virus (NDV), developing intranasal vaccines for chickens is an effective strategy to protect against this disease. The low immunogenicity of inactivated NDV administered by the mucosal route motivated us to identify a safe and potent adjuvant. Previous studies have shown that bacterium-like particles (BLPs), which serve as mucosal adjuvants, induce effective local and systemic immune responses through TLR2 signaling in both mammals and humans. Here, we report that BLPs could activate the innate immune system of chickens in a manner that was dependent on the combination of chicken TLR2 type 1 (chTLR2t1) and chicken TLR1 type 1 (chTLR1t1). The chicken macrophage-like HD11 cell line was stimulated with BLPs, resulting in the production of nitric oxide and the expression of the proinflammatory cytokines IFN-γ, IL-1β and IL-6. Chickens intranasally immunized with inactivated NDV vaccines mixed with BLP adjuvants exhibited significantly increased levels of local SIgA in their tracheal lavage fluid and as well as hemagglutination-inhibiting antibodies in serum samples. The strong systemic and local immune responses induced by BLP-adjuvanted vaccines provided 100 % protection against intranasal challenge with a lethal dose of virulent NDV without showing any signs of disease. These results indicate that BLPs should be considered for use as a potential mucosal adjuvant for inactivated NDV vaccines and other vaccines for poultry., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Coxiella burnetii causes Q fever in individuals exposed to infected ruminants. Vaccination in 3-4-month-old goats, has been reported to result in significantly greater reduction in C. burnetii shedding compared to goats vaccinated one month before breeding, the most commonly used strategy of controlling Q fever on infected intensively-managed herds. It is possible that an even greater reduction in the number of animals shedding C. burnetii could be achieved if vaccination were administered shortly after protection from colostrum antibodies wanes and animals become susceptible to infection with C. burnetii. This study aimed to evaluate the immunogenicity and safety of a formaldehyde-inactivated phase 1 C. burnetii vaccine in 8-week-old goats. Two injections, four weeks apart, elicited specific IgM and IgG responses in all vaccinated goats (n = 6), while no antibodies were detected in two control groups (n = 12). Swelling at the site of inoculation was observed in all the vaccinated and in 10/11 of the placebo-treated goats but receded after 3 weeks. Weight change and rectal temperatures were also comparable between vaccinated and control goats. The data indicated that this vaccine could be suitable for immunising 8-week-old goats, although further trials to determine level of protection against challenge are required., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Tick-borne encephalitis (TBE) has a substantial impact on human public health in many parts of Europe and Asia. Effective inactivated purified whole-virus vaccines are in widespread use in TBE-endemic countries. Nevertheless, vaccination breakthroughs (VBTs) with manifest clinical disease do occur, and their specific serodiagnosis was shown to be facilitated by the detection of antibodies to a non-structural protein (NS1) that is produced during virus replication. However, recent data have shown that NS1 is also present in the current inactivated vaccines, with the potential of inducing corresponding antibodies and obscuring a proper interpretation of NS1-antibody assays for diagnosing VBTs. In our study, we quantified anti-virion and anti-NS1 antibody responses after vaccination as well as after natural infection in TBE patients, both without and with a history of previous TBE vaccination (VBTs). We did not find significant levels of NS1-specific antibodies in serum samples from 48 vaccinees with a completed vaccination schedule. In contrast, all TBE patients mounted an anti-NS1 antibody response, irrespective of whether they were vaccinated or not. Neither the dynamics nor the extent of NS1-antibody formation differed significantly between the two cohorts, arguing against substantial NS1-specific priming and an anamnestic NS1-antibody response in VBTs.

Although the antibody response induced by primary vaccination with Fel-O-Vax ® FIV (three doses, 2-4 weeks apart) is well described, the antibody response induced by annual vaccination with Fel-O-Vax ® FIV (single dose every 12 months after primary vaccination) and how it compares to the primary antibody response has not been studied. Residual blood samples from a primary FIV vaccination study ( n = 11), and blood samples from cats given an annual FIV vaccination ( n = 10), were utilized. Samples from all 21 cats were tested with a commercially available PCR assay (FIV RealPCR TM ), an anti-p24 microsphere immunoassay (MIA), an anti-FIV transmembrane (TM; gp40) peptide ELISA, and a range of commercially available point-of-care (PoC) FIV antibody kits. PCR testing confirmed all 21 cats to be FIV-uninfected for the duration of this study. Results from MIA and ELISA testing showed that both vaccination regimes induced significant antibody responses against p24 and gp40, and both anti-p24 and anti-gp40 antibodies were variably present 12 months after FIV vaccination. The magnitude of the antibody response against both p24 and gp40 was significantly higher in the primary FIV vaccination group than in the annual FIV vaccination group. The differences in prime versus recall post-vaccinal antibody levels correlated with FIV PoC kit performance. Two FIV PoC kits that detect antibodies against gp40, namely Witness ® and Anigen Rapid ® , showed 100% specificity in cats recently administered an annual FIV vaccination, demonstrating that they can be used to accurately distinguish vaccination and infection in annually vaccinated cats. A third FIV PoC kit, SNAP ® Combo, had 0% specificity in annually FIV-vaccinated cats, and should not be used in any cat with a possible history of FIV vaccination. This study outlines the antibody response to inactivated Fel-O-Vax ® FIV whole-virus vaccine, and demonstrates how best to diagnose FIV infection in jurisdictions where FIV vaccination is practiced.

Avian influenza H9N2 viruses circulate in all types of poultry species, including turkeys, and cause significant losses for the poultry industry in many parts of the word. The aim of this study was to assess the pathogenesis of the Moroccan avian influenza virus (AIV) H9N2 under experimental conditions in turkeys and the protection efficacy of an inactivated commercial vaccine against AIV H9N2. Unvaccinated turkeys showed marked depression sinusitis, respiratory distress characterized by bronchiolar and tracheal rales of moderate severity, and a mortality rate of 50%. Postmortem examinations of dead and euthanatized birds revealed the presence of fibrinous tracheitis and airsacculitis lesions. Vaccination reduced the mortality rate to 20%. Vaccinated birds recovered at day 10 postchallenge, and only 12.5% (1/8) and 37.5% of birds still displayed fibrinous and nonfibrinous airsacculitis lesions, respectively, at day 15 postinoculation. Viral shedding in cloacal and tracheal swabs was lower in vaccinated than in control birds. Although viral RNA was detected in the cloacal swabs of all unvaccinated turkeys at day 3 postinoculation, only 50% of the vaccinated turkeys were positive for virus detection. At day 11 postinoculation, no viral RNA was detected in oropharyngeal swabs of vaccinated turkeys, whereas 40% of the unvaccinated turkeys were still shedding virus.

Coxsackievirus A5 (CV-A5) has recently emerged as a main hand, foot, and mouth disease (HFMD) pathogen. Following a large-scale vaccination campaign against enterovirus 71 (EV-71) in China, the number of HFMD-associated cases with EV-71 was reduced, especially severe and fatal cases. However, the total number of HFMD cases remains high, as HFMD is also caused by other enterovirus serotypes. A multivalent HFMD vaccine containing 4 or 6 antigens of enterovirus serotypes is urgently needed. A formaldehyde-inactivated CV-A5 vaccine derived from Vero cells was used to inoculate newborn Kunming mice on days 3 and 10. The mice were challenged on day 14 with a mouse-adapted CV-A5 strain at a dose that was lethal for 14-day-old suckling mice. Within 14 days postchallenge, groups of mice immunized with three formulations, empty particles (EPs), full particles (FPs), and a mixture of the EP and FP vaccine candidates, all survived, while 100% of the mock-immunized mice died. Neutralizing antibodies (NtAbs) were detected in the sera of immunized mice, and the NtAb levels were correlated with the survival rate of the challenged mice. The virus loads in organs were reduced, and pathological changes and viral protein expression were weak or not observed in the immunized mice compared with those in alum-inoculated control mice. Another interesting finding was the identification of CV-A5 dense particles (DPs), facilitating morphogenesis study. These results demonstrated that the Vero cell-adapted CV-A5 strain is a promising vaccine candidate and could be used as a multivalent HFMD vaccine component in the future. IMPORTANCE The vaccine candidate strain CV-A5 was produced with a high infectivity titer and a high viral particle yield. Three particle forms, empty particles (EPs), full particles (FPs), and dense particles (DPs), were obtained and characterized after purification. The immunogenicities of EP, FP, and the EP and FP mixture were evaluated in mice. Mouse-adapted CV-A5 was generated as a challenge strain to infect 14-day-old mice. An active immunization challenge mouse model was established to evaluate the efficacy of the inactivated vaccine candidate. This animal model mimics vaccination, similar to immune responses of the vaccinated. The animal model also tests protective efficacy in response to the vaccine against the disease. This work is important for the preparation of multivalent vaccines against HFMD caused by different emerging strains., (Copyright © 2021 American Society for Microbiology.)

Porcine Circovirus 2 (PCV2) vaccines are poorly standardized in terms of antigen payload and correlates of protection. Therefore, twenty, 45-day old piglets were divided into four groups of 5 animals each and vaccinated with 800 / 266 / 88 / 0 nanograms, respectively, of an inactivated PCV2b strain formulated in the same oil adjuvant. Twenty-six days later, all the pigs were challenged intranasally with the homologous PCV2b strain. No clinical signs were observed in the pigs under study. Viremia was observed after challenge in all the control pigs, as well as in 3 pigs of the 266 and 88-ng groups (one and two, respectively). No pigs of the 800-ng group developed viremia. On the basis of post challenge viremia, the PCV2b vaccine under study had a titer of 11 Protective Doses (PD) 50 %, and 1 PD 50 amounted to 74 ng of PCV2b Ag. Neutralizing and ELISA Ab titers showed no obvious correlation with protection in the single animals, even though the 800-ng group developed a significantly higher mean Ab response. All the pigs with a PCV2-specific, IFN-gamma response at 3 weeks after vaccination in whole blood samples were protected against viremia. In lymphoid tissues (mainly tonsils and ileum) the presence of sparse reactive histiocytes and multinucleated giant cells was the only PCV2-associated feature and, by immunohistochemistry, only 3 out of 20 subjects showed a low viral load., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Four kinds of avian-derived H5N1 influenza virus, A/Vietnam/1194/2004 (Clade 1), A/Indonesia/5/2005 (Clade 2.1), A/Qinghai/1A/2005 (Clade 2.2), and A/Anhui/1/2005 (Clade 2.3), have been stocked in Japan for use as pre-pandemic vaccines. When a pandemic occurs, these viruses would be used as vaccines in the hope of inducing immunity against the pandemic virus. We analyzed the specificity of antibodies (Abs) produced by B lymphocytes present in the blood after immunization with these vaccines. Eighteen volunteers took part in this project. After libraries of Ab-encoding sequences were constructed using blood from subjects vaccinated with these viruses, a large number of clones that encoded Abs that bound to the virus particles used as vaccines were isolated. These clones were classified into two groups according to the hemagglutination inhibition (HI) activity of the encoded Abs. While two-thirds of the clones were HI positive, the encoded Abs exhibited only restricted strain specificity. On the other hand, half of the HI-negative clones encoded Abs that bound not only to the H5N1 virus but also to the H1N1 virus; with a few exceptions, these Abs appeared to be encoded by memory B cells present before vaccination. The HI-negative clones included those encoding broadly cross-reactive Abs, some of which were encoded by non-V H 1-69 germline genes. However, although this work shows that various kinds of anti-H5N1 Abs are encoded by volunteers vaccinated with pre-pandemic vaccines, broad cross-reactivity was seen only in a minority of clones, raising concern regarding the utility of these H5N1 vaccine viruses for the prevention of H5N1 pandemics.

The mechanisms of trained immunity have been extensively described in vitro and the beneficial effects are starting to be deciphered in in vivo settings. Prototypical compounds inducing trained immunity, such as β-glucans, act through epigenetic reprogramming and metabolic changes of innate immune cells. The recent advances in this field have opened new areas for the development of Trained immunity-based adjuvants (TIbAs). In this study, we assessed in dogs the potential immune training effects of β-glucans as well as their capacity to enhance the adaptive immune response of an inactivated rabies vaccine (Rabisin ® ). Injection of β-glucan from Euglena gracilis was performed 1 month before vaccination with Rabisin ® supplemented or not with the same β-glucan used as adjuvant. Trained innate immunity parameters were assessed during the first month of the trial. The second phase of the study was focused on the ability of β-glucan to enhance adaptive immune responses measured by multiple immunological parameters. B and T-cell specific responses were monitored to evaluate the immunogenicity of the rabies vaccine adjuvanted with β-glucan or not. Our preliminary results support that adjuvantation of Rabisin ® vaccine with β-glucan elicit a higher B-lymphocyte immune response, the prevailing factor of protection against rabies. β-glucan also tend to stimulate the T cell response as shown by the cytokine secretion profile of PBMCs re-stimulated ex vivo. Our data are providing new insights on the impact of trained immunity on the adaptive immune response to vaccines in dogs. The administration of β-glucan, 1 month before or simultaneously to Rabisin ® vaccination give promising results for the generation of new TIbA candidates and their potential to provide increased immunogenicity of specific vaccines., (Copyright © 2020 Paris, Chapat, Martin-Cagnon, Durand, Piney, Cariou, Bergamo, Bonnet, Poulet, Freyburger and De Luca.)

Background: Hand, foot, and mouth disease (HFMD) has posed a serious threat to children's health. Three inactivated monovalent enterovirus 71 (EV71) vaccines are proved to be highly efficacious in phase III clinical trials and are now available in China., Methods: We analyzed the citywide surveillance data on HFMD cases in Chengdu during 2009-2018, and estimated cumulative first-dose EV71 vaccination coverage among children eligible to EV71 vaccination after August 2016 in Chengdu. Time series susceptible-infected-recovered model was developed to analyze basic reproduction number and herd immunity threshold of HFMD. Overall and serotype-specific HFMD incidences and severity risks were compared before and after the EV71 vaccination., Results: Among 3 laboratory-identified serotype categories, i.e. EV71, coxsackievirus A16 (CV-A16), and other enteroviruses, the major serotype attributed to HFMD has been changing across years. The cumulative first-dose EV71 vaccination coverage rate was estimated as 60.8% during the study period in Chengdu. By contrast, herd immunity threshold for EV71-related HFMD was 94.0%. After introduction of EV71 vaccines, the overall incidence of HFMD increased 60.8%, mainly driven by 173.7% and 11.8% increased in HFMD caused by other enteroviruses and CV-A16, respectively, which offset a significant reduction in the incidence of HFMD caused by EV71. The overall case-severity risk decreased from 1.4% to 0.3%, with significantly declined presented in all serotype categories., Conclusions: The incidence and severity of EV71-related HFMD decreased following implementation of EV71 vaccination. Developing multivalent vaccines and strengthening laboratory-based surveillance could further decline burden of HFMD.

In the last decades, a number of infectious viruses have emerged from wildlife or re-emerged, generating serious threats to the global health and to the economy worldwide. Ebola and Marburg hemorrhagic fevers, Lassa fever, Dengue fever, Yellow fever, West Nile fever, Zika, and Chikungunya vector-borne diseases, Swine flu, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the recent Coronavirus disease 2019 (COVID-19) are examples of zoonoses that have spread throughout the globe with such a significant impact on public health that the scientific community has been called for a rapid intervention in preventing and treating emerging infections. Vaccination is probably the most effective tool in helping the immune system to activate protective responses against pathogens, reducing morbidity and mortality, as proven by historical records. Under health emergency conditions, new and alternative approaches in vaccine design and development are imperative for a rapid and massive vaccination coverage, to manage a disease outbreak and curtail the epidemic spread. This review gives an update on the current vaccination strategies for some of the emerging/re-emerging viruses, and discusses challenges and hurdles to overcome for developing efficacious vaccines against future pathogens., (Copyright © 2020 Trovato, Sartorius, D’Apice, Manco and De Berardinis.)

Despite the benefits of yearly influenza vaccination, accumulating evidence suggests that diminished vaccine efficacy may be related to repeated vaccination. Although studied at the level of B-cell responses, CD4 T-cell responses have not yet been examined. In this study, we analyze CD4 T-cell responses to influenza vaccination in subjects who differ in their vaccine history. We find a striking disparity in their responses, with previously vaccinated subjects exhibiting significantly blunted CD4 T-cell responses and diminished antibody responses. These results suggest that limiting CD4 T-cell help mteaserrlie the diminished or altered antibody responses in repeatedly vaccinated subjects., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Influenza is a highly contagious viral respiratory disease that affects millions of people worldwide each year. Annual vaccination is recommended by the World Health Organization to reduce influenza severity and limit transmission through elicitation of antibodies targeting mainly the hemagglutinin glycoprotein of the influenza virus. Antibodies elicited by current seasonal influenza vaccines are predominantly strain-specific. However, continuous antigenic drift by circulating influenza viruses facilitates escape from pre-existing antibodies requiring frequent reformulation of the seasonal influenza vaccine. Traditionally, immunological responses to influenza vaccination have been largely focused on IgG antibodies, with almost complete disregard of other isotypes. In this report, young adults (18-34 years old) and elderly (65-85 years old) subjects were administered the split inactivated influenza vaccine for 3 consecutive seasons and their serological IgA and IgG responses were profiled. Moreover, correlation analysis showed a positive relationship between vaccine-induced IgA antibody titers and traditional immunological endpoints, exposing vaccine-induced IgA antibodies as an important novel immune correlate during influenza vaccination., (Copyright © 2020 Abreu, Clutter, Attari, Sautto and Ross.)

To understand the role of major histocompatibility complex class I (MHC-I) and MHC-II in vaccine-mediated protection against Coxiella burnetii , we evaluated the protective efficacy of a formalin-inactivated C. burnetii Nine Mile phase I vaccine (PIV) in β 2 -microglobulin-deficient (B2m KO) and MHC-II-deficient (MHC-II KO) mice. Vaccination reduced disease severity in wild-type (WT) and B2m KO mice but failed to reduce bacterial burden in MHC-II KO mice. This suggests that the MHC-II antigen presentation pathway is required for PIV-mediated protection against C. burnetii infection. MHC-I and MHC-II affect antibody isotype switching, since both PIV-vaccinated B2m KO and MHC-II KO mice produced less Coxiella -specific IgG than PIV-vaccinated WT mice. Interestingly, MHC-II and CD4 deficiencies were not equivalent in terms of splenomegaly and bacterial clearance. This demonstrates a partial role for CD4 + T cells while revealing MHC-II-restricted, CD4-independent mechanisms. Adoptive transfer of CD4 + T cells from PIV-vaccinated WT mice to naive CD4-deficient (CD4 KO) mice demonstrated that antigen-experienced CD4 + T cells are sufficient to generate protection. Conversely, transfer of naive CD4 + T cells to PIV-vaccinated CD4 KO mice exacerbates disease. Using Tbet-deficient (Tbet KO) mice, we showed a partial role for Th1 subset CD4 + T cells in vaccine protection. Furthermore, Th1-independent roles for Tbet were suggested by significant differences in disease between PIV-vaccinated Tbet KO and CD4 KO mice. Interferon gamma was shown to contribute to the host inflammatory response but not bacterial clearance. Collectively, these findings suggest that vaccine-induced protective immunity against a murine model of experimental Q fever requires MHC-II-restricted, CD4 + T cell-dependent and -independent mechanisms that can be exploited for a new-generation human Q fever vaccine., (Copyright © 2020 American Society for Microbiology.)

Japanese encephalitis (JE) is a mosquito-borne viral infection which is prevalent in Taiwan. The virus circulates in an enzootic cycle in pigs which serve as amplifying hosts. Outbreaks typically occur during summer. A universal vaccination program using 4-shot mouse brain-derived inactivated vaccine has successfully controlled JE epidemics in Taiwan since 1968. More than 90% of JE cases in recent years were older than 20 years in Taiwan. Because of several drawbacks, mouse brain-derived vaccine has been replaced by newer generation JE vaccines, including inactivated Vero cell-derived vaccine and live chimeric vaccine. The present article describes the recommendations in Taiwan for the use of new JE vaccines and the schedules for shifting between different JE vaccines., Competing Interests: Declaration of Competing Interest Ping-Ing Lee, Yhu-Chering Huang, Kao-Pin Hwang, Ching-Chuan Liu, Cheng-Hsun Chiu, Po-Yen Chen, Chun-Yi Lu, and Nan-Chang Chiu received speech honorarium from Sanofi-Pasteur that produces a live attenuated Japanese encephalitis vaccine. Chun-Yi Lu also received a travel grant from Sanofi-Pasteur. Chih-Jung Chen, Luan-Yin Chang, Hsin Chi, Hsiao-Chuan Lin, Keh-Gong Wu, Yu-Huai Ho, Wu Sun, and Tzou-Yien Lin declare no conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: The quadrivalent influenza vaccine (QIV) contains two influenza B antigens (one of each B lineage), while the trivalent vaccine (TIV) contains solely one. As a result, a mismatch between the circulating B lineage and the lineage in the TIV occurs frequently. We aimed to compare the frequency of clinically significant outcomes in a large cohort of vaccinees receiving either TIV or QIV., Methods: Historical cohort study of all inactivated influenza vaccinees (aged 3 years and older) in a Health Maintenance Organization insuring 1.2 million individuals, over two influenza seasons in which both vaccines were provided non-selectively. Primary outcome was hospital admissions during the influenza season. Multivariate analysis was performed using logistic regression to adjust for relevant covariates., Results: Our cohort included 150 518 and 168 296 vaccinees in the first (S1) and second season (S2), respectively. The two influenza seasons were characterized by high Influenza B activity. Of those vaccinated with QIV, 2074 of 49 726 (4.2%) and 6563 of 121 741 (5.4%) were hospitalized compared with 7378 of 100 792 (7.3%) and 3372 of 46 555 (7.2%) of those vaccinated with TIV (S1 and S2, respectively). After multivariate analysis adjusting for several covariates (gender, age, socioeconomic status, chronic morbidity, timing of vaccination), compared with TIV recipients, QIV vaccinees had lower odds for hospitalization (OR = 0.92, 95% CI 0.87-0.98 and OR = 0.89, 95% CI 0.85-0.93) or emergency department visit (OR = 0.91, 95% CI 0.87-0.95 and OR = 0.84, 95% CI 0.81-0.87) in S1 and S2, respectively (p < 0.001). Lower odds of mortality and influenza-like illness were also observed in S2 (OR = 0.61, 95% CI 0.50-0.75 and OR = 0.92, 95% CI 0.90-0.95, respectively)., Conclusions: In seasons with relatively high influenza B activity, QIV appeared more protective than TIV in Israel., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Influenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses., Methods: We did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050., Findings: Between Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis., Interpretation: The tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The population effects of influenza vaccination in children have not been extensively studied, especially in tropical, developing countries. In rural Senegal, we assessed the total (primary objective) and indirect effectiveness of a trivalent inactivated influenza vaccine (IIV3)., Methods: In this double-blind, cluster-randomized trial, villages were randomly allocated (1:1) for the high-coverage vaccination of children aged 6 months through 10 years with either the 2008-09 northern hemisphere IIV3 or an inactivated polio vaccine (IPV). Vaccinees were monitored for serious adverse events. All village residents, vaccinated and unvaccinated, were monitored for signs and symptoms of influenza illness using weekly home visits and surveillance in designated clinics. The primary outcome was all laboratory-confirmed symptomatic influenza., Results: Between 23 May and 11 July 2009, 20 villages were randomized, and 66.5% of age-eligible children were enrolled (3918 in IIV3 villages and 3848 in IPV villages). Follow-up continued until 28 May 2010. There were 4 unrelated serious adverse events identified. Among vaccinees, the total effectiveness against illness caused by the seasonal influenza virus (presumed to all be drifted A/H3N2, based on antigenic characterization data) circulating at high rates among children was 43.6% (95% confidence interval [CI] 18.6-60.9%). The indirect effectiveness against seasonal A/H3N2 was 15.4% (95% CI -22.0 to 41.3%). The total effectiveness against illness caused by the pandemic influenza virus (A/H1N1pdm09) was -52.1% (95% CI -177.2 to 16.6%)., Conclusions: IIV3 provided statistically significant, moderate protection to children in Senegal against circulating, pre-2010 seasonal influenza strains, but not against A/H1N1pdm09, which was not included in the vaccine. No indirect effects were measured. Further study in low-resource populations is warranted., Clinical Trials Registration: NCT00893906., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Highly contagious Newcastle disease (ND) is associated with devastating outbreaks with highly variable clinical signs among gallinaceous birds. In this study we aimed to verify clinical ND suspicions in poultry holdings in Egypt suffering from respiratory distress and elevated mortality, comparing two groups of ND-vaccinated poultry holdings in three governorates. Besides testing for Newcastle disease virus (NDV), samples were screened for infectious bronchitis virus (IBV) and avian influenza virus (AIV) by RT-qPCR as well as by non-directed cell-culture approach on LMH-cells. Virulent NDV was confirmed only in group A ( n  = 16) comprising small-scale holdings. Phylogenetic analysis of the fusion protein gene of 11 NDV-positive samples obtained from this group assigned all viruses to genotype 2.VIIb and point to four different virus populations that were circulating at the same time in one governorate, indicating independent epidemiological events. In group B, comprising large commercial broiler farms ( n  = 10), virulent NDV was not present, although in six farms NDV vaccine-type virus (genotype 2.II) was detected. Besides, in both groups, co-infections by IBV ( n  = 10), AIV H9 ( n  = 3) and/or avian reovirus (ARV) ( n  = 5) and avian astrovirus (AastVs) ( n  = 1) could be identified. Taken together, the study confirmed clinical ND suspicion in small scale holdings, pointing to inefficient vaccination practices in this group A. However, it also highlighted that, even in an endemic situation like ND in Egypt, in cases of suspected ND vaccine failure, clinical ND suspicion has to be verified by pathotype-specific diagnostic tests. RESEARCH HIGHLIGHTS Velogenic NDV circulates in small-scale poultry holdings in Egypt. Viral transmission occurred among neighbouring farms and over long distances. Co-infections with multiple pathogens were identified. Pathotype specific diagnostic tests are essential to verify ND suspicions.

The goals of our study were to compare the immune response to different killed and modified live vaccines against PRRS virus and to monitor the antibody production and the cell mediated immunity both at the systemic and local level. In the experiment, we immunized four groups of piglets with two commercial inactivated (A1-Progressis, A2-Suivac) and two modified live vaccines (B3-Amervac, B4-Porcilis). Twenty-one days after the final vaccination, all piglets, including the control non-immunized group (C5), were i.n., infected with the Lelystad strain of PRRS virus. The serum antibody response (IgM and IgG) was the strongest in group A1 followed by two MLV (B3 and B4) groups. Locally, we demonstrated the highest level of IgG antibodies in bronchoalveolar lavages (BALF), and saliva in group A1, whereas low IgA antibody responses in BALF and feces were detected in all groups. We have found virus neutralization antibody at DPV 21 (days post vaccination) and higher levels in all groups including the control at DPI 21 (days post infection). Positive antigen specific cell-mediated response in lymphocyte transformation test (LTT) was observed in groups B3 and B4 at DPV 7 and in group B4 at DPV 21 and in all intervals after infection. The IFN-γ producing lymphocytes after antigen stimulation were found in CD4 - CD8 + and CD4 + CD8 + subsets of all immunized groups 7 days after infection. After infection, there were obvious differences in virus excretion. The virus was detected in all groups of piglets in serum, saliva, and occasionally in feces at DPI 3. Significantly lower virus load was found in groups A1 and B3 at DPI 21. Negative samples appeared at DPI 21 in B3 group in saliva. It can be concluded that antibodies after immunization and infection, and the virus after infection can be detected in all the compartments monitored. Immunization with inactivated vaccine A1-Progressis induces high levels of antibodies produced both systemically and locally. Immunization with MLV-vaccines (Amervac and Porcilis) produces sufficient antibody levels and also cell-mediated immunity. After infection virus secretion gradually decreases in group B3, indicating tendency to induce sterile immunity.

ObjectivesTo examine the association between inactivated influenza vaccine (IIV) administration and primary care consultation for joint pain, rheumatoid arthritis (RA) flare, corticosteroid prescription, vasculitis and unexplained fever in people with autoimmune rheumatic diseases (AIRDs)., Methods: We undertook within-person comparisons using self-controlled case-series methodology. AIRD cases who received the IIV and had an outcome of interest in the same influenza cycle were ascertained in Clinical Practice Research Datalink. The influenza cycle was partitioned into exposure periods (1-14 days prevaccination and 0-14, 15-30, 31-60 and 61-90 days postvaccination), with the remaining time-period classified as non-exposed. Incidence rate ratios (IRR) and 95% CI for different outcomes were calculated., Results: Data for 14 928 AIRD cases (69% women, 80% with RA) were included. There was no evidence for association between vaccination and primary care consultation for RA flare, corticosteroid prescription, fever or vasculitis. On the contrary, vaccination associated with reduced primary care consultation for joint pain in the subsequent 90 days (IRR 0.91 (95% CI 0.87 to 0.94))., Conclusion: This study found no evidence for a significant association between vaccination and primary care consultation for most surrogates of increased disease activity or vaccine adverse-effects in people with AIRDs. It adds to the accumulating evidence to support influenza vaccination in AIRDs., Competing Interests: Competing interests: CDM is funded by the National Institute for Health Research (NIHR) Collaborations for Leadership in Applied Health Research and Care West Midlands, the NIHR School for Primary Care Research and an NIHR Research Professorship in General Practice (NIHR-RP-2014-04-026). JSN-V-T acknowledges funding from the NIHR Biomedical Research Centre (acute respiratory infections), MD and AA acknowledge funding from the NIHR Biomedical Research Centre (musculoskeletal theme) Nottingham. Potential conflicts of interest: JSN-V-T is currently on secondment to the Department of Health and Social Care, England (DHSC). The views expressed in this paper are those of the authors and do not necessarily represent those of the National Health Service, NIHR or DHSC. All other authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Several studies have shown that inactivated, whole-cell oral cholera vaccines (OCVs) confer both direct protection on vaccinees and herd protection on populations. Because our earlier cluster-randomized effectiveness trial (CRT) in urban Bangladesh failed to detect OCV herd protection, we reanalysed the trial to assess whether herd effects were masked in our original analysis., Methods: A total of 267 270 persons were randomized to 90 approximately equal-sized clusters. In 60 clusters persons aged 1 year and older were eligible to receive OCV and in 30 clusters persons received no intervention and served as controls. We analysed OCV protection against severely dehydrating cholera for the entire clusters, as in our original analysis, and for subclusters consisting of residents of innermost households. We hypothesized that if OCV herd protection was attenuated by cholera transmission into the clusters from the outside in this densely populated setting, herd protection would be most evident in the innermost households., Results: During 2 years of follow-up of all residents of the clusters, total protection (protection of OCV recipients relative to control residents) was 58% [95% confidence interval (CI): 43%, 70%; P<0.0001], indirect protection (protection of non-OCV recipients in OCV clusters relative to control participants) was 16% (95% CI: -20%, 41%; P=0.35) and overall OCV protection (protection of all residents in the OCV clusters relative to control residents) was 46% (95% CI: 30%, 59%; P<0.0001). Analyses of the inner 75% and 50% households of the clusters showed similar findings. However, total protection was 75% (95% CI: 50%, 87%, P<0.0001), indirect protection 52% (95% CI: -9%, 79%; P=0.08) and overall protection 72% (95% CI: 49%, 84%; P<0.0001) for the innermost 25% households., Conclusion: Consistent with past studies, substantial OCV herd protective effects were identified, but were unmasked only by analysing innermost households of the clusters. Caution is needed in defining clusters for analysis of vaccine herd effects in CRTs of vaccines., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Thirty-six female sheep, previously vaccinated against Bluetongue virus serotype 8 (BTV-8) using inactivated vaccines, were included in this field study. In Germany, vaccination was compulsory in 2008 and 2009, voluntary in 2010 and early 2011, and later, was prohibited in 2011. Due to their age, eighteen sheep had been vaccinated for two or more consecutive years, while a further eighteen animals had only been vaccinated once or not at all. The sheep were blood sampled five ( n = 31) to 7.5 years ( n = 5) after their last vaccination. All serum samples ( n = 36) were tested for BTV group-specific antibodies by an ELISA (IDScreen ® Bluetongue Competition assay, ID Vet). In five of the animals, the BTV-8 serotype-specific antibody titers were measured by serum neutralization (SN). The majority of sheep that were vaccinated annually for two or more years showed a positive ELISA (14/18 sheep) and a SN (two of two sheep) result 5 years after their last vaccination. Most of the sheep vaccinated fewer than twice showed a negative ELISA result 5 to 7.5 years after their last vaccination (13/18 animals). The three animals in this group tested by SN showed one negative and two positive results. This short communication is the first to describe the presence of BTV antibodies in sheep 5 to 7.5 years after vaccination with inactivated BTV-8 vaccines.

Background: Prior influenza immunity influences the homologous neutralizing antibody responses elicited by inactivated influenza vaccines (IIV), but neutralizing antibody responses to heterologous strains have not been extensively characterized., Methods: We analyzed neutralizing antibody titers in individuals aged 1-88 who received the 2009-2010 season IIV before infection by or vaccination against the 2009 pandemic H1N1 virus. Neutralization titers to homologous and heterologous past, recent, and advanced H1 and H3 strains, as well as H2, H5, and H7 strains, were measured using influenza hemagglutinin pseudoviruses. We performed exploratory analyses based on age, prior-year IIV, and prevaccination titer, without controlling for Type I errors., Results: IIV elicited neutralizing antibodies to past and advanced H1 and H3 strains, as well as to an H2 strain in individuals who were likely infected early in life. The neutralization of avian subtype viruses was rare, and there was no imprinting of neutralization responses to novel avian subtype viruses based on the influenza group. Compared to adults, children had higher seroresponse rates to homologous and heterologous strains, and their sera generated larger antigenic distances among strains. Seroresponse rates to homologous and heterologous strains were lower in subjects vaccinated with prior-year IIV, though postimmunization titers were generally high., Conclusions: IIV elicited neutralizing antibodies to heterologous H1 and H3 strains in all ages groups, but titers and seroresponse rates were usually higher in children. Prior-year vaccination with the same strains tended to blunt IIV neutralization responses to all strains in young and old age groups, yet postimmunization titers were high., (Published by Oxford University Press for the Infectious Diseases Society of America 2018.)

Shiga toxin-producing Escherichia coli O157:H7 (O157) can cause mild to severe gastrointestinal disease in humans. Cattle are the primary reservoir for O157, which colonizes the intestinal tract without inducing any overt clinical symptoms. Parenteral vaccination can reduce O157 shedding in cattle after challenge and limit zoonotic transmission to humans, although the impact of vaccination and vaccine formulation on cellular and mucosal immune responses are undetermined. To better characterize the cattle immune response to O157 vaccination, cattle were vaccinated with either water-in-oil-adjuvanted, formalin-inactivated hha deletion mutant of Shiga toxin 2 negative (stx2 - ) O157 (Adj-Vac); non-adjuvanted (NoAdj-Vac); or non-vaccinated (NoAdj-NoVac) and peripheral T cell and mucosal antibody responses assessed. Cattle in Adj-Vac group had a higher percentage of O157-specific IFNγ producing CD4 + and γδ + T cells in recall assays compared to the NoAdj-Vac group. Furthermore, O157-specific IgA levels detected in feces of the Adj-Vac group were significantly lower in NoAdj-Vac group. Extracts prepared only from Adj-Vac group feces blocked O157 adherence to epithelial cells. Taken together, these data suggest parenteral administration of adjuvanted, inactivated whole-cell vaccines for O157 can induce O157-specific cellular and mucosal immune responses that may be an important consideration for a successful vaccination scheme.

The efficacy of a novel inactivated Lawsonia intracellularis vaccine, Porcilis® Lawsonia, was compared to that of a commercially available live attenuated vaccine in three experimental vaccination-challenge studies in pigs. The efficacy of the new vaccine was further tested under field conditions on a farm with a history of acute ileitis. The novel inactivated vaccine consists of a freeze-dried antigen fraction that is dissolved just prior to use in either the adjuvant or in Porcilis® PCV M Hyo; an existing combination vaccine against porcine circovirus type 2 and Mycoplasma hyopneumoniae. The three experimental vaccination-challenge trials had a similar design and for each trial 75 piglets were used, randomly allotted to three groups of 25 piglets. The pigs were vaccinated at 4 or 5 weeks of age with either Porcilis® Lawsonia in adjuvant or in associated mixed use with Porcilis® PCV M Hyo (group 1), with the live vaccine (group 2), or left as unvaccinated controls (group 3). The pigs were challenged with virulent Lawsonia intracellularis 3, 4 or 17 weeks after vaccination. Post-challenge the pigs were evaluated for clinical signs, average daily weight gain, shedding and macroscopic as well as microscopic immuno-histological ileum lesion scores. In the field study, the mortality and key performance parameters were evaluated over a period of 8 months. The results of all three experimental vaccination-challenge trials showed that Porcilis® Lawsonia induced statistically significant protection against experimental Lawsonia intracellularis infection. This was demonstrated by lower clinical scores, improved weight gain, reduction of Lawsonia intracellularis shedding and reduction of macroscopic as well as microscopic ileum lesion scores when compared to the controls. The protection induced was superior to that of the commercially available live vaccine. In the field study, Porcilis® Lawsonia proved to be highly efficacious; reducing Lawsonia associated mortality to zero and improving key production parameters., (Copyright © 2019 Merck Sharp and Dohm Animal Health. Published by Elsevier Ltd.. All rights reserved.)

In an initial study in specified pathogen free (SPF) chickens, a heterologous virus neutralizing (VN) antibody response to IBV variants Q1, Variant 2 (Var 2), D388/QX (D388), D274 and Arkansas (DPI) was observed using a vaccination programme incorporating two different live-attenuated IBV vaccines, followed by boosting with an inactivated vaccine containing IBV Massachusetts (Mass) antigen. Therefore, a more detailed study was undertaken in SPF layer-type chickens primed with IBV Mass and 793B vaccines. The efficacy of single or repeated vaccination with a multivalent inactivated vaccine containing IBV antigen was determined against challenge with five virulent IBVs: Mass (M41), 793B (4/91), D388, Q1 and Var 2. The parameters assessed were serological response, respiratory signs, egg production, post mortem abnormalities in the reproductive organs and abdomen, and incidence of IBV antigen in kidneys. Increased VN titres were recorded against the five IBV challenge strains, with a significantly higher level of protection against drops in egg production following challenge. The difference between one or two vaccinations with inactivated vaccine was not significant in terms of egg production. However, a significantly increased level of protection was seen in the lower percentage of hens with free yolk in the abdomen and/or peritonitis post challenge with IBV variants, D388, Q1 and Var 2 not included in the vaccination programme. A lower incidence of acute, degenerated ovaries was found in groups given one injection of inactivated vaccine following live priming, and this was significantly lower than in groups given only live priming.

Each year influenza virus infections cause hundreds of thousands of deaths worldwide and a significant level of morbidity with major economic burden. At the present time, vaccination with inactivated virus vaccine produced from embryonated chicken eggs is the most prevalent method to prevent the infections. However, current influenza vaccines are only effective against closely matched circulating strains and must be updated and administered yearly. Therefore, generating a vaccine that can provide broad protection is greatly needed for influenza vaccine development. We have previously shown that vaccination of the major surface glycoprotein hemagglutinin (HA) of influenza virus with a single N -acetylglucosamine at each of the N-glycosylation sites [monoglycosylated HA (HA mg )] can elicit better cross-protection compared with the fully glycosylated HA (HA fg ). In the current study, we produced monoglycosylated inactivated split H1N1 virus vaccine from chicken eggs by the N-glycosylation process inhibitor kifunensine and the endoglycosidase Endo H, and intramuscularly immunized mice to examine its efficacy. Compared with vaccination of the traditional influenza vaccine with complex glycosylations from eggs, the monoglycosylated split virus vaccine provided better cross-strain protection against a lethal dose of virus challenge in mice. The enhanced antibody responses induced by the monoglycosylated vaccine immunization include higher neutralization activity, higher hemagglutination inhibition, and more HA stem selectivity, as well as, interestingly, higher antibody-dependent cellular cytotoxicity. This study provides a simple and practical procedure to enhance the cross-strain protection of influenza vaccine by removing the outer part of glycans from the virus surface through modifications of the current egg-based process., Competing Interests: The authors declare no conflict of interest.

Pathogenic strains of Enterococcus cecorum cause symmetrical paralysis in broilers due to infection of the free thoracic vertebra. The disease caused by pathogenic E. cecorum, known as enterococcal spondylitis or "kinky-back" continues to be responsible for significant losses to the broiler industry worldwide. In outbreaks of pathogenic E. cecorum, gut colonization and sepsis occur in the first three weeks-of-life. Since maternal antibodies are present during this period, we postulated that vaccination of breeders with a polyvalent killed vaccine would protect chicks from challenge. To test this hypothesis, representative isolates from seven genotype groups of pathogenic E. cecorum circulating in the US were chosen to produce adjuvanted killed vaccines (bacterins) and given to broiler-breeder hens. No single strain produced high titres of antibodies to all other strains; however, the combination of serologic reactivity of pathogenic isolates (designated SA3 and SA7) was sufficient to react with all genotypes. Vaccination of commercial broiler-breeder hens with a bacterin composed of SA3 and SA7 did not have any adverse effects. Vaccinated hens developed E. cecorum specific antibodies; however, no significant difference in survival was observed in infected embryos from hens in vaccine or adjuvant only groups. Chicks from vaccinated hens also failed to resist homologous or heterologous challenge during experimental infection. In a macrophage killing assay, pathogenic E. cecorum were found to evade opsinophagocytosis with elicited antibodies. These data suggest that pathogenic strains of E. cecorum possess virulence mechanisms that confound antibody-mediated opsinophagocytosis, complicating vaccine development for this pathogen of broilers.

The bivalent killed whole-cell oral cholera vaccine (BivWC) is being increasingly used to prevent cholera. The presence of O-antigen-specific memory B cells (MBC) has been associated with protective immunity against cholera, yet MBC responses have not been evaluated after BivWC vaccination. To address this knowledge gap, we measured V. cholerae O1-antigen MBC responses following BivWC vaccination. Adults in St. Marc, Haiti, received 2 doses of the BivWC vaccine, Shanchol, two weeks apart. Participants were invited to return at days 7, 21, 44, 90, 180 and 360 after the initial vaccination. Serum antibody and MBC responses were assessed at each time-point before and following vaccination. We observed that vaccination with BivWC resulted in significant O-antigen specific MBC responses to both Ogawa and Inaba serotypes that were detected by day 21 and remained significantly elevated over baseline for up to 12 months following vaccination. The BivWC oral cholera vaccine induces durable MBC responses to the V. cholerae O1-antigen. This suggests that long-term protection observed following vaccination with BivWC could be mediated or maintained by MBC responses., Competing Interests: The authors have declared that no competing interests exist.

Vaccine adverse events and controversial safety issues have occurred in recent decades in Japan: aseptic meningitis following the measles-mumps-rubella combined vaccine (MMR), anaphylaxis after immunization with live virus vaccines and inactivated split influenza vaccine, an increased incidence of febrile illness following the simultaneous administration of inactivated vaccines, and chronic pain with neurological illness after immunization with the human papilloma virus vaccine (HPV). Vaccine adverse events are a matter of concern for the public as well as general practitioners; some are within the range of assumptions that adverse reactions after live attenuated vaccines are related to the nature of their parental wild-type viruses. Vaccines stimulate the innate immunity of host immunological defense mechanisms and induce the development of specific acquired immunity. Some adverse events related to autoimmune responses have been reported, such as idiopathic thrombocytopenic purpura and acute disseminated encephalomyelitis (ADEM). Although a plausible relationship was not demonstrated, the possibility of an association cannot be denied. The pathogenicity of adverse reactions was investigated for anaphylactic reactions, systemic and local reactions following vaccinations. Initial innate immune responses are essential for the development of acquired immunity and are related to adverse events from different viewpoints., (Copyright © 2018. Published by Elsevier Ltd.)

Salmonella Abortusequi causes important clinical diseases in horses possibly leading to abortion. In the present investigation, the protective efficacy of both plain and aluminum hydroxide gel adjuvanted phage lysate was evaluated in guinea pig model. Broad host range bacteriophage P IZ -SAE-2, was characterized and used for generation of lysates. Three different lysate batches, produced through separate cycles and characterized, were pooled together for immunization study. Plain and adjuvanted phage lysate preparations elicited both humoral and cellmediated immunity. The adjuvanted lysate at a dose of 50 μl elicited the highest protective efficacy against direct challenge at 28th DPI. Thus, the present study describes a new method of bacterial inactivation for producing a new class of better & safe immunprophylactic agents. This is the first report of producing an inactivated vaccine candidate using a new approach against equine salmonellosis., (Copyright © 2018 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

Intramuscular (IM) vaccination with formalin-inactivated respiratory syncytial virus (FI-RSV) failed in clinical trials due to vaccine-enhanced respiratory disease. To test the efficacy of skin vaccination against respiratory syncytial virus (RSV), we investigated the immunogenicity, efficacy, and inflammatory disease after microneedle (MN) patch delivery of FI-RSV vaccine (FI-RSV MN) to the mouse skin with or without an adjuvant of monophosphoryl lipid A (MPL). Compared to IM vaccination, MN patch delivery of FI-RSV was more effective in clearing lung viral loads and preventing weight loss, and in diminishing inflammation, infiltrating immune cells, and T helper type 2 (Th2) CD4 T cell responses after RSV challenge. With MPL adjuvant, MN patch delivery of FI-RSV significantly increased the immunogenicity and efficacy as well as preventing RSV disease as evidenced by lung viral clearance and avoiding pulmonary histopathology. Improved efficacy and prevention of disease by FI-RSV MN with MPL were correlated with no sign of airway resistance, lower levels of Th2 cytokines and infiltrating innate inflammatory cells, and higher levels of Th1 T cell responses into the lung. This study suggests that MN patch delivery of RSV vaccines to the skin with MPL adjuvant would be a promising vaccination method., Competing Interests: Mark Prausnitz is an inventor of patents that have been or may be licensed to companies developing microneedle-based products, is a paid advisor to companies developing microneedle-based products and is a founder/shareholder of companies developing microneedle-based products, including Micron Biomedical. These potential conflicts of interest have been disclosed and are being managed by Georgia Tech and/or Emory University. There are no patents or products directly related to the presented manuscript.

Background: Cholera remains an important public health problem in major cities in Bangladesh, especially in slum areas. In response to growing interest among local policymakers to control this disease, this study estimated the impact and cost-effectiveness of preventive cholera vaccination over a ten-year period in a high-risk slum population in Dhaka to inform decisions about the use of oral cholera vaccines as a key tool in reducing cholera risk in such populations., Methodology/principal Findings: Assuming use of a two-dose killed whole-cell oral cholera vaccine to be produced locally, the number of cholera cases and deaths averted was estimated for three target group options (1-4 year olds, 1-14 year olds, and all persons 1+), using cholera incidence data from Dhaka, estimates of vaccination coverage rates from the literature, and a dynamic model of cholera transmission based on data from Matlab, which incorporates herd effects. Local estimates of vaccination costs minus savings in treatment costs, were used to obtain incremental cost-effectiveness ratios for one- and ten-dose vial sizes. Vaccinating 1-14 year olds every three years, combined with annual routine vaccination of children, would be the most cost-effective strategy, reducing incidence in this population by 45% (assuming 10% annual migration), and costing was $823 (2015 USD) for single dose vials and $591 (2015 USD) for ten-dose vials per disability-adjusted life year (DALY) averted. Vaccinating all ages one year and above would reduce incidence by >90%, but would be 50% less cost-effective ($894-1,234/DALY averted). Limiting vaccination to 1-4 year olds would be the least cost-effective strategy (preventing only 7% of cases and costing $1,276-$1,731/DALY averted), due to the limited herd effects of vaccinating this small population and the lower vaccine efficacy in this age group., Conclusions/significance: Providing cholera vaccine to slum populations in Dhaka through periodic vaccination campaigns would significantly reduce cholera incidence and inequities, and be especially cost-effective if all 1-14 year olds are targeted., Competing Interests: The cost analysis under “The impact and cost-effectiveness of controlling cholera through the use of oral cholera vaccines in urban Bangladesh: A disease modeling and economic analysis” was undertaken with Levin and Morgan, a commercial entity. Levin and Morgan contributed to the analysis and writing in the economic analysis component of this paper. AL is also employed by Levin and Morgan.

Foot-and-mouth disease (FMD) virus is economically one of the world's most important animal pathogens, which can be responsible for losses in livestock trade, as well as frequent and highly disruptive large-scale epidemics. The control of FMD in southern Africa typically includes vaccination of cattle with a trivalent or bivalent vaccine preparation. The objective of this study was to determine the level and duration of the antibody responses conferred by the current FMD vaccination programme in cattle at the western boundary of the Kruger National Park (KNP) in South Africa. Two hundred and eighty-three cattle from four communal dip tanks were longitudinally sampled after vaccination using an inactivated trivalent FMD vaccine (South African Territories (SAT) 1, SAT 2 and SAT 3). Blood samples were collected fortnightly over four months and antibodies were measured using a liquid-phase blocking ELISA. Only 5%, 43%, and 16% of enrolled cattle had evidence of pre-existing antibody responses to the three SAT viruses at the beginning of the study (≥1.6 log 10 titre for SAT 1-3 respectively), which was 7-12 months after the last vaccination campaign. However, 14 days after vaccination this proportion increased to between 66% and 93%, with SAT 2 having the highest proportion. Young animals (<1 year old) tended to have higher predicted baseline antibody levels that peaked by 14 days. Positive serological responses were transient and by 56 days post-vaccination antibody levels begun to decline below the threshold of 1.6 log 10 titre. Predicted peak antibody levels only consistently reached 2.0 log 10 for SAT 2. Serological responses for SAT 2 tended to be longer, but in most cases the duration of antibody levels was short-lived. More research is necessary to determine the reasons for the limited duration of antibody responses, especially among younger cattle, in order to achieve more effective prophylactic vaccination., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The predominant Staphylococcus aureus (S. aureus), an etiological agent of camel mastitis is becoming drug resistant that invites prevention and control strategies. Vaccine production would have a valuable impact on public health. Therefore, in present study, inactivated vaccine with different adjuvants was prepared and evaluated against S. aureus. The vaccinal isolate recovered from camel subclinical mastitis was coagulase positive (PCR based), having expressed pseudocapsule, holding alpha-beta hemolysin characteristics, and multiple drug resistant. Inactivated alum precipitated S. aureus vaccine (APSV) and oil adjuvant S. aureus vaccine (OASV) were prepared after confirming its antigenicity in rabbits. Three groups of rabbits were randomly inoculated with APSV, OASV, and placebo (Unvaccinated, UV). Each group was further divided into two groups based on single and booster dose inoculation. Booster dose of vaccines in rabbits at day 15th of primary inoculation was given. Serum samples were taken on 15, 30, 45 and 60 days of primary inoculation from all rabbits. Analysis of variance was applied to compare geometric mean titer (GMT) of three groups, while t-test was applied to estimate the difference between single and booster dose response. The study found 10 10  CFU/mL S. aureus as standard bacterial load for vaccines with higher and sustained antigenicity. The vaccines were safe from morbidity and mortality, and proved effective and stable for 7 and 4 months at 25 °C and 37 °C, respectively. The OASV produced significantly (p < 0.05) higher immune response followed by APSV throughout trial. The highest GMT by APSV and OASV vaccines with single dose inoculation was 37.92 and 69.92 at day 45th post primary inoculation, respectively. Similarly, 59.20 and 142.40 GMTs were noted with booster dose in case of APSV and OASV, respectively. The booster dose presented significantly (p < 0.05) higher GMT than that of single dose inoculation of vaccines. The study concluded APSV and OASV safe, effective, and stable with significant immunogenic results in experimental rabbits., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Randomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults≥50years of age (NCT02519855)., Methods: Overall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015-2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4., Immunogenicity Endpoints: Varicella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay., Safety Endpoints: Injection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study., Results: The adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed., Conclusion: The concomitant administration of ZV and IIV4 to adults≥50years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The cytotoxic T lymphocyte (CTL) response plays a key role in host recovery from influenza virus infection and in subsequent immunity. Compared to natural infection with influenza virus, however, intranasal vaccination with adjuvant-combined inactivated vaccine elicits only moderate CTL responses. Here we demonstrate that 5 days of consecutive, intranasal vaccination with a combination of inactivated influenza vaccine and poly(I:C) elicits a strong CTL response in the lung. Antigen-captured respiratory DCs did efficiently migrate from the lung to the mediastinal lymph node (mLN) after the 5 day series of inoculations with vaccine and poly(I:C). Importantly, formalin-inactivated whole virus vaccine and poly(I:C) adjuvant have synergic effects on consecutive vaccinations to elicit a strong CTL response in the lung. Although the CTL response was less effective against heterologous influenza virus, we show for the first time that intranasal administration of inactivated influenza virus vaccine and poly(I:C) for 5 consecutive days can elicit high levels of influenza virus-specific CD8 + T cells in the lung., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An inactivated split-virion trivalent influenza vaccine (IIV3; Vaxigrip®, Sanofi Pasteur) has been available globally since 1968. Here, we describe the results of an open-label, post-licensure trial (EudraCT no. 2014-005078-12) to confirm the immunogenicity and safety of the Southern Hemisphere 2015 formulation of IIV3. Adults 18-60 years of age and > 60 years of age (60 per age group) received a single 0.5-ml intramuscular injection of IIV3. Between baseline and day 21 after vaccination, hemagglutination inhibition (HAI) titers for each strain in IIV3 increased, on average, by at least 11-fold for younger adults and at least 5-fold for older adults. After vaccination, 89%-100% of the younger adult participants and 90%-98% of the older adult participants attained seroprotection (HAI titer ≥ 40) for each strain. Also, 66%-81% of younger adults and 45%-63% of older adults seroconverted or had a significant increase in HAI titer for each strain. For both age groups, these post-vaccination immune responses exceeded the criteria of the Committee for Human Medicinal Products former Note for Guidance for influenza vaccines. No serious adverse events were reported, and no new safety signals were detected. In conclusion, this study confirmed that the Southern Hemisphere 2015 formulation of IIV3 was well tolerated, highly immunogenic, and met the criteria for influenza vaccine efficacy and safety.

Purpose: High-dose trivalent inactivated influenza vaccine (HD-IIV3) or recombinant trivalent influenza vaccine (RIV) may increase influenza vaccine effectiveness (VE) in adults with conditions that place them at high risk for influenza complications. This analysis models the public health impact and cost-effectiveness (CE) of these vaccines for 50-64year-olds., Methods: Markov model CE analysis compared 5 strategies in 50-64year-olds: no vaccination; only standard-dose IIV3 offered (SD-IIV3 only), only quadrivalent influenza vaccine offered (SD-IIV4 only); high-risk patients receiving HD-IIV3, others receiving SD-IIV3 (HD-IIV3 & SD-IIV3); and high-risk patients receiving HD-IIV3, others receiving SD-IIV4 (HD-IIV3 & SD-IIV4). In a secondary analysis, RIV replaced HD-IIV3. Parameters were obtained from U.S. databases, the medical literature and extrapolations from VE estimates. Effectiveness was measured as 3%/year discounted quality adjusted life year (QALY) losses avoided., Results: The least expensive strategy was SD-IIV3 only, with total costs of $99.84/person. The SD-IIV4 only strategy cost an additional $0.91/person, or $37,700/QALY gained. The HD-IIV3 & SD-IIV4 strategy cost $1.06 more than SD-IIV4 only, or $71,500/QALY gained. No vaccination and HD-IIV3 & SD-IIV3 strategies were dominated. Results were sensitive to influenza incidence, vaccine cost, standard-dose VE in the entire population and high-dose VE in high-risk patients. The CE of RIV for high-risk patients was dependent on as yet unknown parameter values., Conclusions: Based on available data, using high-dose influenza vaccine or RIV in middle-aged, high-risk patients may be an economically favorable vaccination strategy with public health benefits. Clinical trials of these vaccines in this population may be warranted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)